Testing an Electronic Pre-exposure Prophylaxis (PrEP) Initiation and Maintenance Home Care System to Promote PrEP Among Adolescent Men Who Have Sex With Men (MSM) in Rural and Small Town Areas
Phase: NA
Conditions: Pre-exposure Prophylaxis
Sponsor: Emory University

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ePrEP: Testing an electronic PrEP initiation and maintenance home care system to 
promote PrEP among adolescent MSM  
 
 
 
 
Sponsored by: 
The Eunice Kennedy Shriver 
National Institute of Child Health and Human Development (NICHD) 
 
 
with co-funding from: 
 
The National Institute on Drug Abuse (NIDA) 
 
The National Institute of Mental Health (NIMH) 
 
 
 
 
 
 
 
 
Protocol Chair: 
, PhD 
 
, MD MPH 
 
Protocol Vice-Chair: 
, MD MS 
 
 MD MPH 
 
 PhD 
 
, PhD 
 
  
 
 
 
 
 
 
 
 

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ATN 159 - ePrEP: Testing an electronic PrEP initiation and maintenance home care 
system to promote PrEP among adolescent MSM  
 
 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States 
(US) Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
Investigator of Record: _______________________________________________ 
Print/Type 
 
 
 
 
 
Signed: ___________________________________ Date: ____________________ 
 
 
Title: _____________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ........................................................................................... 2 
TABLE OF CONTENTS……………………………………………………………………………....3 
PROTOCOL TEAM ROSTER ................................................................................................. 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................... 6 
STUDY ABSTRACT ............................................................................................................... 7 
STUDY DESIGN OR SCHEMA .............................................................................................. 8 
1.0 
INTRODUCTION .................................................................................................... 9 
1.1  Background ............................................................................................................ 9 
1.2  Rationale ................................................................................................................ 9 
2.0 
STUDY OBJECTIVES .......................................................................................... 10 
2.1 
Primary Objective: ................................................................................................ 10 
2.2 
Secondary Objective: ............................................................................................ 10 
2.3 
Additional Analyses: ............................................................................................. 10 
2.4 
Study Hypotheses/Research Questions ................................................................ 10 
3.0 
STUDY DESIGN ................................................................................................... 10 
3.1  Study Population ................................................................................................... 11 
3.2 
Sample Size ......................................................................................................... 11 
3.3 
Study Randomization and Stratification ................................................................ 11 
4.0 
SELECTION AND ENROLLMENT OF STUDY PARTICIPANTS .......................... 11 
4.1 
Inclusion Criteria ................................................................................................... 11 
4.2 
Exclusion Criteria .................................................................................................. 12 
4.3 
Recruitment .......................................................................................................... 12 
4.4 
Screening ............................................................................................................. 13 
4.5 
Informed Consent ................................................................................................. 13 
5.0 
STUDY PROCEDURES ....................................................................................... 13 
5.1 
Enrollment Procedures ......................................................................................... 13 
5.2 
Locator/Contact Information  ................................................................................. 14 
5.3 
Randomization Procedures ................................................................................... 15 
5.4 
Intervention ........................................................................................................... 15 
5.5 
Laboratory Procedures ......................................................................................... 17 
6.0 
MEASURES ......................................................................................................... 18 
6.1 
Behavioral Measures ............................................................................................ 18 
6.2 
Clinical and Laboratory Evaluations ...................................................................... 19 

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7.0 
DATA COLLECTION AND SITE MONITORING ................................................... 19 
7.1 
Development of Protocol and Case Report Forms ................................................ 19 
7.2 
Data Records  ....................................................................................................... 19 
7.3  Data Collection ..................................................................................................... 20 
7.4 
Data Submission ................................................................................................... 21 
7.5 
Data Quality Assurance ........................................................................................ 22 
7.6 
Role of Data Management .................................................................................... 22 
7.7 
Study Site Monitoring and Record Availability ....................................................... 22 
8.0 
PARTICIPANT MANAGEMENT ............................................................................ 22 
8.1 
Tracking Participants / Follow-up .......................................................................... 22 
8.2 
Compensation....................................................................................................... 23 
8.3 
Intervening on “Social Harms" ............................................................................... 23 
8.4 
Criteria for Premature Study Discontinuation ........................................................ 23 
9.0 
MONITORING UNTOWARD EFFECTS ASSOCIATED WITH OR RESULTING 
FROM STUDY ...................................................................................................... 24 
10.0 
STATISTICAL/ANALYTIC CONSIDERATIONS .................................................... 25 
10.1 Introduction ........................................................................................................... 25 
10.2 Power Estimates ................................................................................................... 26 
10.3 Statistical Analysis Plan ........................................................................................ 26 
10.4 Cost-effectiveness and Cost-utility Analysis Plan .................................................. 27 
10.5 Missing Data ......................................................................................................... 27 
10.6 Qualitative Data .................................................................................................... 28 
11.0 
HUMAN SUBJECTS ............................................................................................. 28 
11.1 Participants’ Confidentiality ................................................................................... 28 
11.2 Minimizing risk to participants ............................................................................... 29 
11.3 Risks and Benefits ................................................................................................ 29 
11.4 Institutional Review Board (IRB) Review and Informed Consent ........................... 30 
11.5 Prisoner Participation ............................................................................................. 31 
11.6 45 CFR Parts 160 and 164 Standards for Privacy of Individually Identifiable Health 
Information ("Privacy Rule" Pursuant to the Health Insurance Portability and 
Accountability Act - HIPAA)................................................................................... 31 
11.7 Study Discontinuation ........................................................................................... 31 
12.0 
PUBLICATION OF RESEARCH FINDINGS ......................................................... 31 
13.0 
BIOHAZARD CONTAINMENT .............................................................................. 31 
14.0 
REFERENCES ..................................................................................................... 33 

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PROTOCOL TEAM ROSTER 
 
Principal Investigators: 
 (M-PI, Contact PI) 
Associate Professor 
Department of Behavioral Sciences and Health Education 
 
 
 
(M-PI) 
Professor and Chair 
Department of Health Science, Department of Medicine 
 
 
 
 
 Clinical Instructor FellowDivision of Infectious Diseases 
 
 
 
 
 (Co-I) 
Assistant Professor 
Department of Medicine, Division of Infectious Diseases 
 
 
 
 
 (Co-I) 
Assistant Professor 
Department of Epidemiology 
 
 
 
 (Co-I) 
Assistant Professor 
Department of Epidemiology 
 
  
 
 (Site PI) 
Assistant Professor 
Department of Medicine 
 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AC 
 
 
Analytic Core 
ACTG  
 
AIDS Clinical Trials Group 
ACASI  
 
Audio Computer Assisted Self Interview 
AIDS  
 
Acquired Immunodeficiency Syndrome 
API 
 
 
Application Programming Interface 
ATN 
 
 
Adolescent Medicine Trials Network for HIV/AIDS Interventions 
BMSM  
 
Black men who have sex with men 
CASI  
 
Computer assisted self-interview 
CFR 
 
 
Code of Federal Regulations 
CRF 
 
 
Case Report Form 
DBS 
 
 
Dried Blood Spot 
DHHS  
 
U.S. Department of Health and Human Services 
EC 
 
 
Ethics Committee 
EDC 
 
 
Electronic Data Capture system 
ePrEP  
 
Study intervention 
FTC/TAF 
 
Emtricitabine/tenofovir alafenamide 
FTC/TDF 
 
Emtricitabine/tenofovir disoproxil fumarate  
GCP 
 
 
Good Clinical Practices 
HIPAA  
 
Health Insurance Portability and Accountability Act 
HIV 
 
 
Human Immunodeficiency Virus 
HSP 
 
 
Human Subjects Protection 
ICH 
 
 
International Conference on Harmonization 
IRB 
 
 
Institutional Review Board 
MC 
 
 
Management Core 
MSM  
 
Men who have sex with men 
NCHS  
 
National Center for Health Statistics 
NICHD  
 
National Institute of Child Health and Development 
NIDA  
 
National Institute on Drug Abuse  
NIH 
 
 
National Institutes of Health 
OHRP  
 
Office of Human Research Protection 
PI 
 
 
Principal Investigator 
PrEP  
 
Pre-Exposure Prophylaxis 
QNS 
 
 
Query and Notification System 
RDC 
 
 
Remote data capture 
SID 
 
 
Study Identification 
SRV 
 
 
Subject Recruitment Venue 
SSL 
 
 
Secure Socket Layer 
SUS 
 
 
System Usability Scale 
TC 
 
 
Technology Core 
TFV-DP 
 
Tenofovir diphosphate 
YMSM  
 
Young men who have sex with men 

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STUDY ABSTRACT 
 
DESIGN:  
A two-arm randomized controlled trial (RCT) among young 
men who have sex with men (MSM) in Georgia, Mississippi, 
and North Carolina. Participants randomized to the intervention 
will receive the ePrEP home care system for telemedicine 
PrEP care that includes initiation and maintenance in care. The 
ePrEP home care system consists of a smartphone application 
(app) for video-based telemedicine PrEP consultations with a 
clinician, messaging and remote tracking system, and 
behavioral risk surveys that are complemented by home 
specimen collection kits. Home kits allow for remote testing for 
standard laboratory tests for PrEP care. Participants 
randomized to the control condition will be referred to their 
nearest PrEP provider to receive standard of care. Both groups 
will conduct quarterly surveys through an electronic interface 
and home specimen collection of dried blood spots for 
detection of medication at 6 and 12 months after 
randomization. 
 
DURATION: 
Participants will remain in the study for 12 months after 
randomization. 
 
SAMPLE SIZE: 
240 participants (120 intervention, 120 control) 
 
POPULATION:  
Age 18-29, HIV-negative, MSM, from Alabama, Georgia, 
Mississippi, and North Carolina, targeting 50% recruitment of 
highly impacted groups of Black or Latino MSM. 
 
STRATIFICATION:  
1:1 randomization, each site will enroll ~80 participants. 
Participants will be stratified by site. 
 
DATA 
COLLECTION: 
A secure electronic survey platform will be used to collect 
participant data through quarterly surveys. All laboratory tests 
will be conducted in CLIA-certified laboratories, including the 
test for the primary study outcome. App paradata will be 
collected within the study app. Data regarding PrEP care 
interactions between study clinicians and staff will be collected 
through the study app. Case report form data will be collected 
using an electronic data capture system. Interviews will be 
audio-recorded and professionally transcribed. 
 
OBJECTIVES 
1) To assess protective levels of PrEP for those randomized to 
ePrEP system versus those assigned to the standard of care 
(control) condition, as determined by a biomarker for TFV-
DP. 
2) To conduct additional assessments to contextualize trial 
results and facilitate appropriate scale-up. 

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STUDY DESIGN OR SCHEMA 
 
 

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1.0 
INTRODUCTION 
1.1  
Background 
In 2015, MSM continued to account for two-thirds of new HIV cases in the United States.[1] Within 
this elevated risk group, Black MSM and young MSM aged 15-24 bear disproportionate 
burdens,[1] and represent priority populations for intervention. Rural and peri-urban areas across 
the Southeast do not have substantial access to PrEP providers.[2] The National Center for Health 
Statistics (NCHS) classifies counties into six levels of urbanicity: the two smaller levels contain no 
PrEP providers in Georgia, despite these areas containing a substantial MSM population 
(>20,000).[3] Home-based care has the potential to quickly make PrEP services available to the 
large number of MSM in rural and small town areas who currently lack access. 
PrEP scale-up in the US may also be limited by the availability of clinic space and time. A home-
based PrEP support system could address some patient concerns regarding PrEP uptake. One 
limitation of PrEP is the heavy burden of follow-up visits borne by patients, including indirect cost 
(i.e. absence from paid work, need for child-care) and direct cost (i.e. transport, co-payments)[4] 
that could lead to problems with PrEP adherence.[5, 6] The home care system for PrEP is 
comprised of inexpensive, commonly available laboratory supplies such as finger prick devices, 
swabs, and microtubes. Patient self-completion surveys that simulate clinician visit typical 
questions may allow for clinicians to have a higher volume of patients due to time savings. Given 
these inputs, the home care system has the potential to be cost saving, depending in part on the 
level of human resources required to maintain patients in home care. 
Past efforts to address PrEP uptake or adherence for YMSM have been conducted predominately 
in urban areas, and the most successful programs have been approaches tailored for urban 
YMSM. The premise for the study is that a tailored approach for YMSM using telemedicine, 
addressing known barriers of transportation, access to providers, and privacy, is most likely to 
yield high levels of PrEP initiation and persistence in care.  
Using a smartphone application (app), participants assigned to the intervention will receive and 
maintain a PrEP prescription without needing to leave their home (excepting pharmacy pick-up 
or initiation laboratory testing for Hepatitis B in some cases) – achieved through app-based 
surveys/screenings, telemedicine consultations, and home specimen self-collection.  
 
1.2  
Rationale 
1.2.1 Young, Black, and Latino MSM are at high and elevated risk for HIV, and PrEP has been 
demonstrated to prevent HIV transmission. 
In 2015, MSM continue to account for two-thirds of new HIV cases in the United States.[1] Within 
this elevated risk group, Black MSM (10,315/26,645, 39%) and young MSM aged 15-24 
(7,150/26,645, 27%) bear disproportionate burdens.[1] PrEP has high effectiveness: in 
international settings PROUD[7] found 86% reduction in anticipated infections. In domestic 
settings, follow-up of Kaiser Permanente patients in the San Francisco Bay area found no new 
cases of HIV among patients prescribed PrEP.[8]     
 
1.2.2 PrEP provision in rural and small town areas is limited, despite having substantial 
populations of MSM 
A national database of PrEP-prescribing clinics, developed by the authors, indicates a substantial 
lack of PrEP providers in rural areas. Using standard classification of counties in Georgia, the 

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least urban categories (noncore and micropolitan) counties had no PrEP clinics, despite these 
areas containing >20,500 MSM,[3] with the patient population spread across hundreds of miles. 
In practice, this translates to ‘PrEP deserts’ that have no near providers. 
 
1.2.3 HIV prevalence is high among MSM residing in rural areas. 
People residing in areas classified as not being a part of a metropolitan statistical area accounted 
for 18% (7068/40022) of new HIV diagnoses in the US in 2013.[1] HIV prevalence among MSM 
in rural counties is high, with many counties exceeding 15% prevalence.[9] 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective: 
Assess protective levels of PrEP for those randomized to the ePrEP system versus those 
assigned to the standard of care (control) condition, as determined by a biomarker for TFV-DP. 
2.2 
Secondary Objective: 
Conduct additional assessments to contextualize trial results and facilitate appropriate scale-up: 
Aim 2.1 Adjusted analyses of the primary outcome (protective levels of PrEP) that control for 
potential residual confounding, and analyses of secondary outcomes including components of 
PrEP care continuum. 
Aim 2.2 Exploratory analyses of intervention effectiveness across subgroups, and analysis of 
potential mediators of initiation or persistence in PrEP care across both study arms, such as self-
efficacy, urbanicity, or clinical eligibility. 
Aim 2.3 Conduct a series of in-depth interviews with participants regarding their experiences 
along the PrEP care cascade, and with key informants regarding their experiences with ePrEP. 
2.3 
Additional Analyses: 
Conduct cost-effectiveness and cost-utility analyses of the ePrEP intervention. 
2.4 
Study Hypotheses/Research Questions   
Those assigned to the ePrEP intervention will be further along the PrEP care continuum, with 
protective levels of PrEP (the primary outcome) higher among those assigned to ePrEP. 
 
3.0 
STUDY DESIGN 
PrEP-naïve MSM will be recruited into the study, with a focus on Black and Latino MSM, targeted 
to make up half of all participants. A screening will be conducted online and involve a screening 
consent and questions to determine initial eligibility. This will be followed by a full consent (if 
eligible), a baseline survey, and the return of self-collected specimens for testing to determine 
clinical PrEP eligibility. Those eligible for the study will be enrolled into the trial and randomized 
to either intervention (ePrEP) or control (standard of care). Participants assigned to the ePrEP 
intervention (n=120) will have a baseline teleconsultation with a site study clinician who will be 
responsible for prescribing PrEP as indicated.[10] Intervention participants will be offered 
telemedicine consultations at 1, 3, 6, 9 and 12 months, and will complete quarterly home 
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virtual visits consist of surveys, specimen collection, and telemedicine consultation. Those 
assigned to the control condition (n=120) will be referred to a publicly available website that 
geolocates the nearest PrEP provider, www.PrEPLocator.org. Both conditions will have identical 
TFV-DP kit collection for primary outcome assessments (6 and 12 months) and app-based 
surveys for secondary outcomes assessments across all study periods (baseline, 3, 6, 9, and 12 
months). 
 
The three study sites will be staffed by clinicians who will conduct telemedicine consultations and 
supporting staff who will address participant care needs such as referrals for treatment. Study 
recruitment, retention communication, and tracking will be handled by staff at the Emory 
University site. 
 
3.1  
Study Population 
A total of 240 young MSM (aged 18-29) will be enrolled and randomized into the study. All 
participants, at the time of screening, must live in one of the four study site states (AL, GA, MS, 
NC). The study will target enrollment of 50% Black or Latino MSM.   
 
3.2 
Sample Size 
240 total participants, with 120 assigned to intervention and 120 assigned to control. 
 
3.3 
Study Randomization and Stratification 
An electronic data capture system (EDC) will be used to stratify randomization by site to decrease 
the likelihood of Type I error[11] due to the expected association between covariates and study 
outcome. Randomization will be accomplished within the study data management platform; within 
each stratum, the data system will produce a sequential block randomization list. This list will 
automatically populate the appropriate study arm assignment in iDataFax at the time each new 
participant is randomized at any of the three study sites.  
 
4.0 
SELECTION AND ENROLLMENT OF STUDY PARTICIPANTS 
Eligibility assessment includes the inclusion and exclusion criteria listed below. To maintain 
eligibility participants must complete the baseline survey modules within one week of initiating 
them. Inclusion/exclusion criteria that address PrEP eligibility are guided by CDC and WHO 
criteria.[12],[13, 14]  
 
4.1 
Inclusion Criteria 
• 
Assigned male at birth 
• 
Age 18-29 (inclusive) 
• 
Live in a study state (GA, MS, NC, AL) 
• 
Able to provide informed consent and complete survey instruments in English 
• 
Willing to provide complete contact information (including 2 alternate contacts) 
• 
Able and willing to provide ID verification for viewing confirmation only  
• 
Laboratory confirmed HIV negative  
• 
Owns an iOS or Android smartphone capable of running the study app  

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• 
Male sex partners in past 6 months or clinician discretion of epidemiologic context of HIV 
risk[14] 
• 
Behaviorally indicated for PrEP :  
o History of inconsistent or no condom use with more than one partner 
o History of inconsistent or no condom use with one partner who is not mutually 
monogamous 
o Any STI diagnosed in past 6 months 
o Commercial sex work 
o African American MSM reporting anal sex in the past 6 months∗[13] 
o Clinician discretion based on epidemiologic context of HIV risk [14] 
• 
Willing to take FDA-approved daily oral PrEP 
• 
Willing to use study-provided PrEP navigation services 
• 
Willing to self-collect specimens 
 
 
4.2 
Exclusion Criteria 
• 
HIV positive (self-report or laboratory confirmed) 
• 
Chronic Hepatitis B or no verification of hepatitis B vaccination 
• 
Currently enrolled in any HIV prevention trial (biomedical) 
• 
Currently taking oral PrEP based on self-report 
• 
Creatinine clearance <60 ml/min based on the Cockcroft-Gault equation 
• 
Symptoms of acute HIV infection within the prior 30 days 
• 
Contraindications to taking oral PrEP 
• 
Personal diagnosis or family history of hemophilia 
• 
Health insurance with Kaiser Permanente (unable to prescribe PrEP through the study) 
• 
Investigator discretion to exclude anyone whose best interest is not to participate 
• 
Evidence of fraudulent participation, such as duplicate IP address, multiple screening 
attempts, duplicate emails, etc 
 
4.3 
Recruitment  
Participants will be recruited using advertisements on social media platforms and geospatial 
sexual networking apps. Targeted recruitment, based on interest and participant location using 5-
digit ZIP codes for these platforms, will display advertisements to men in geographic areas that 
would indicate potential eligibility for the study. The methods of advertising for the study will 
include banner advertisements and brief electronic messages. Retargeting methods may be used 
send ads to people who clicked initially but did not complete the screener. Additional participants 
may be recruited from referral from other participants, research studies, or research screeners; 
only individuals who have indicated willingness to be contacted regarding future research studies 
will be contacted. Secondary recruitment methods may include flyers at events or places such as 
clinics, organizations, colleges, or local establishments where youth may congregate. We will also 
follow respondent-driven sampling (RDS) methods and use a long-chain referral method to 
supplement recruitment.  
 
 
                                                     
∗ As defined by WHO guidelines of including populations at “substantial risk”.  

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4.4 
Screening 
Potential participants who respond to recruitment procedures will be directed to a webpage that 
includes a brief introduction script and a self-administered online screener. Those who click on 
the electronic ad or who receive an email will be directed to the brief online consent and screener 
to determine eligibility. The online screener will be hosted on a secure electronic survey platform, 
and will include the eligibility script, consent to be screened, and screener questions. A link to a 
PrEP informational video will be included in the screener. Participants may also opt to have 
screening conducted verbally over the phone. For those who meet eligibility criteria for this first 
screening procedure, personal contact information will be requested and recorded, including the 
first name, e-mail, and phone number of the participant.  
 
There will be no identifying information collected from participants determined to be ineligible at 
screening. Therefore, it is possible these individuals could rescreen without the knowledge of 
study staff. We will seek to minimize fraudulent participation through re-screen attempts. 
Participants deemed behaviorally eligible at screening will provide their name and contact 
information. Participant name, email address and phone number will be automatically checked 
for duplicates for the app to be downloaded. Staff will check for duplicates by assessing participant 
photo or other ID through study app and other mechanisms. Results of assessment will be 
recorded on the eligibility checklist. For security, once participant ID is verified, the uploaded 
document will be permanently deleted from the system. Rescreens explicitly allowable by the 
protocol will be noted and considered for eligibility. 
 
4.5 
Informed Consent  
Participants will complete a brief consent for the screening survey.  Then, participants who are 
eligible based on screening will be provided an electronic study consent on a secure electronic 
survey platform, with study staff available by phone to answer any questions during business 
hours. The consent form describes all study procedures, including confidentiality and privacy, 
information about potential risks, discomforts, benefits of participation, and information regarding 
who they can contact with further questions. It also states that participation is voluntary, that 
participants may decide not to take part or to withdraw from the study at any time without penalty 
or loss of any benefit to which they might otherwise be entitled, and that study participation is in 
no way related to being able to access or continue getting care or services at any participating 
study site. Participants can refuse to answer any question, and can withdraw from the study at 
any time. Participants will provide consent using an electronic method to document signature on 
the electronic consent form. Informed consent must be obtained before any study procedures are 
performed. The consent form will only be available in English. Informed consent verification will 
be completed over the phone with study staff prior to baseline visit procedures. Timeline for 
consent is contingent on the timeline of study activities as described in section 5.1.  Participants 
will be asked to sign a new consent if activities are not completed within the specified timeline. 
5.0 
STUDY PROCEDURES 
5.1 
Enrollment Procedures 
There will be two stages of eligibility assessment: screening (including behavioral assessment 
screening) and clinical eligibility screening in which the study clinician determines whether the 
participant is eligible to take PrEP. Each procedure below must be completed prior to moving to 
the next procedure.   

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1. Participants who respond to an electronic ad will complete a brief online consent for 
screening. (Section 4.5)  
2. Participants will complete screening (the first stage of eligibility) and if eligible will 
complete a full study consent (Sections 4.4 and 4.5).  
3. Participants will be called to verify eligibility and consent. 
4. Participants may be scheduled to consult with clinician regarding HIV risk and PrEP 
eligibility. 
5. Participants will be given instructions to download the study app (through GooglePlay or 
Apple Store), and create a personal account for the app on their mobile devices. 
(Section 5.4)  
6. Staff will affirm non-fraudulent participation by assessing participant photo or other ID 
through study app and other mechanisms and record results on the eligibility checklist. 
7. Staff will notify participants to complete the Baseline survey through the app. 
8. Staff will send participants a home test kit to self-collect specimens and return them via 
mailer. (Section 5.5) 
9. Staff will check state immunization records for Hepatitis B or refer participants to testing. 
10. Participants determined to be behaviorally and clinically eligible for the clinical trial will 
be enrolled and randomized. (Section 5.3) 
 
Participants must complete enrollment procedures according to the following schedule. If 
activities are not completed by the specified timeframe, participants will be asked to repeat the 
appropriate previous step. Participants should download the app within 2 weeks of completing 
the Screener. After downloading the app, participants should complete the baseline survey and 
return the home test kit within 4 weeks. Lab results will be returned within 2 weeks after the kits 
are received by the study. The maximum time for enrollment procedures, that does not trigger 
repeat of some study steps, is 8 weeks prior to randomization. 
5.2 
Locator/Contact Information  
Once consented and enrolled, designated site study staff will verify the contact information the 
participant provided in the behavioral eligibility screener. Information to be verified will include the 
already provided working phone number(s) and valid email address(es). Additionally, participants 
will provide valid contact information for two alternate contacts, which may include family 
members and/or friends who can be called in the event the participant cannot be reached by 
phone or email. We will also record whether participants are willing or not willing to receive voice 
and text messages using the contact information provided. Study staff will not leave messages 
unless expressly permitted to do so by the participant. If permission is given to leave messages, 
site staff will assure participants that messages left with a family member or friend will only ask 
the participant to contact study staff and will not include any protected health information or 
information related to study participation. 
 
The contact information will not contain any study data and will be kept secure, separate from 
study records where able, with access limited to designated site research personnel. Site staff 
will maintain contact information collected in the web-based platform retention and scheduling 
database. 
 
For potential participants that provide contact information, but do not download the app, we will 
maintain a database for follow up.  
 

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5.3 
Randomization Procedures  
Upon completion of all eligibility assessments (online behavioral screening, baseline survey and 
clinical), participants will be randomized to either intervention (ePrEP, n=120) or control (standard 
of care, n=120). Participants will be randomized using iDataFax. Randomization will be stratified 
by study site (AL, GA, MS, NC) to decrease the likelihood of Type I error due to the expected 
association between covariates and study outcome.  
 
5.4 
Intervention 
 
5.4.1 ePrEP System 
 
The ePrEP system is a mobile health intervention designed to allow participants to initiate and 
maintain PrEP care from their homes. A unified and secure, web-based platform hosts the study 
app and management portals, allowing for a single database to populate information across these 
study interfaces. Laboratory testing is accomplished through ‘home test kits’ consisting of 
instructions and materials to allow participants to self-collect specimens and return them to a 
central laboratory for appropriate testing. The intervention fully complies with the standard of care 
PrEP provision practices outlined in the CDC/US Public Health Service guidance.[12] 
 
Study App: 
The study app, eP, serves as the primary participant-facing component of the intervention. The 
eP app, which will be downloaded on participants’ phones, includes many features to facilitate 
remote care. Electronic messaging features provide a means for participants to communicate with 
their clinical care team through secure messages, or send documentation needed for PrEP 
navigation through secure photos. Surveys are hosted in the app, and used to populate key forms 
and answer key clinical questions such as medication adherence. Automated notifications of 
progress and appointment reminders are sent, seeking to facilitate engagement in care. A 
timeline-based view shows progress in care, and next steps such as upcoming virtual visits or 
home test kits to be completed. Telemedicine consultations with study clinicians will occur within 
the app through secure video, and scheduling of these consultations will be accomplished through 
a calendaring function. A preferences function will allow participants to alter their profile such as 
changing preferred pharmacy or home shipping address. Some of the app features, particularly 
messaging and survey functionalities, will also be used to incorporate components of interaction 
that are specific to research study participation. The app is hosted in a secure environment, 
compliant with all relevant security protocols, and will use password protected entry to enhance 
privacy. (Section 7.3.4) 
 
The eP app has two versions: one for the intervention group and one for the control group.  When 
participants first download the app, they will only be able to see the initial parts of the app needed 
for study initiation: baseline survey modules and home test kit tracking. Once the participant is 
randomized, their version of the app will open up to show them the timeline of the study visits 
information based on the group they are assigned.  The intervention group will be able to see and 
use all components of the eP app. The control group will only be able to see the parts of the app 
that are applicable to research: surveys, tracking home test specimens (the mail-in DBS card for 
TFV-DP), and  messaging functionality for communication with study staff.  
 

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Management portals: 
 
Administrator portal: Study staff will manage participant interactions through a web-based 
interface that exchanges data directly with the eP app. Study staff will use the participant 
management system to securely exchange messages with participants using the eP app. 
The participant management system will have a dashboard to manage and track participant 
completion of study-related activities, such as survey completion or scheduling of 
telemedicine consultations. 
 
Clinician portal: Clinicians will view clinically-relevant participant information in a web-based 
interface that exchanges data with the administrator interface and the eP app. Participant 
information viewable to clinicians will include lab results and participant self-reports of sexual 
behavior, PrEP adherence, and PrEP side effects. A calendaring function will be used by 
clinicians to make time slots available for telemedicine consultations so that participants can 
schedule through the eP app. Telemedicine consultation data, including clinician notes, will 
be collected in the clinician interface for each telemedicine consultation.  
 
Home Test Kit:  
ePrEP will use a mail-based specimen self-collection system that has previously been pilot-
tested.[16] Participants will receive a plain box via standard mail that includes instructions and 
materials for each specimen to be collected. Participants will be provided with video and written 
instructions as well as a call-in help line for the home collection system (during business hours). 
After specimen collection, participants will enclose them in a prepaid mailer to be sent directly to 
the lab. Testing of all specimens will be performed at CLIA-certified laboratories using FDA-
approved tests. (Section 5.5)  
 
Telemedicine: 
The eP app includes a secure video component that will allow for study telemedicine consultations 
between study clinicians and participants. This will allow study clinicians to evaluate participants 
at standard, quarterly prescribing intervals for PrEP. Participants may also ask questions of their 
study clinician using the eP secure messaging system.  
 
5.4.2 PrEP Initiation/Continuation 
If laboratory, clinical and behavioral survey results do not show contraindications to PrEP 
initiation/continuation, the study clinician will initiate or renew the PrEP prescription. Eligible 
participants will be initiated with a 3-month prescription for FTC/TDF or FTC/TAF by the site study 
clinician. Standard PrEP financial navigation services will be delivered by study staff trained in 
order to ensure uniformity of intervention provision. The navigation will use Gilead medication 
assistance and co-pay access programs, in addition to state-specific programs, to facilitate 
access to PrEP at low or no cost to participants. We will seek to make home delivery of PrEP 
prescriptions from pharmacies available. If a participant’s insurance does not allow for the home 
delivery, participants will pick up PrEP from their preferred local pharmacy. Enrolled participants 
not on PrEP, due to discontinuation or never having initiated, will continue participation in the 
scheduled research assessments. With clinician guidance, such participants can choose to 
uptake PrEP at any point during the study. 
 
5.4.3  PrEP Discontinuation / Restart 
Regular study interactions include telemedicine consultation, surveys, and messaging with staff.  
If through any of these interactions a participant reports a gap of not taking PrEP for ≥10 days, 
this will be defined as a PrEP discontinuation. Participants who have discontinued PrEP will be 

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allowed to re-initiate during the study with clinical re-evaluation and repeat HIV testing. An 
additional creatinine test will not be needed as long as previous results were within acceptable 
range in the past 6 months. Reasons for discontinuing or restarting will be captured. 
 
5.4.4 Research Staff Training  
Study staff and clinicians will complete HSP and GCP training. Staff will be trained on using the 
ePrEP web-based portal for participant management, and on eP app functionality. Study clinicians 
will discuss case scenarios for PrEP patients for more standardized approaches to specific 
scenarios seen by PrEP clinicians.   
 
5.4.5 Intervention Monitoring/Quality Control 
The principal investigator will monitor data collection throughout the study, will ensure that 
protocols and procedures are followed, all adverse event reports are reviewed (if any), 
confidentiality procedures are implemented, and the UNC IRB is alerted if unexpected concerns 
arise. The study may also be subject to a quality assurance audit by the sponsor or its designees, 
as well as inspection by appropriate regulatory authorities.  
 
5.5 
Laboratory Procedures 
All study lab tests will be conducted at CLIA-certified laboratories using FDA-approved tests. 
Participants will self-collect whole blood in microtubes from finger prick for creatinine and syphilis 
(using antibody test with reflexive RPR) tests. Whole blood collected on dried blood spot (DBS) 
cards will be used for HIV testing. Pharyngeal swabs, rectal swabs and a urine sample will be 
collected for gonorrhea and chlamydia testing. Hepatitis B surface antigen will be tested either 
through Quest/LabCorp, local health department, or self-collect. Participants may be referred to 
local testing services, if needed. The Alabama Department of Public Health, Georgia Department 
of Public Health, Mississippi State Department of Health, and the North Carolina Department of 
Health and Human Services will be notified of confirmed positive results in accordance with state 
public health reporting laws, a procedure that will be explained to participants at consent. 
 
Baseline testing: All participants will be tested for HIV, syphilis, creatinine, gonorrhea, chlamydia, 
and Hepatitis B. 
 
Follow-up testing: Intervention participants will be tested for HIV, syphilis, gonorrhea, and 
chlamydia quarterly. Creatinine will be tested at months 3 and 9. All participants are scheduled to 
return DBS cards for TFV-DP testing at months 6 and 12. 
 
5.5.1 HIV Testing 
HIV testing may be conducted on either whole blood or DBS. 4th generation HIV tests will be 
conducted using DBS cards that participants self-collect through finger prick. Standard of care 3rd 
generation tests may be run if unable to conduct 4th gen test on DBS sample. Specimens with a 
reactive result on the antibody-based test will undergo confirmatory testing per established 
protocols on DBS specimens. If confirmed, results will be returned to participants by study staff 
experienced in HIV care linkage. 
 
 
5.5.2 STI Testing 

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All participants will be tested for syphilis and pharyngeal, urethral, and rectal gonorrhea and 
chlamydia at Baseline. Intervention participants will be tested for syphilis gonorrhea, and 
chlamydia (pharyngeal, urethral and rectal) at quarterly follow-up virtual visits. Reflexive RPR titer 
will be conducted if the syphilis antibody test is reactive. Hepatitis B surface antigen will be tested 
to determine chronic hepatitis B status at Baseline. 
 
5.5.3 Safety Labs 
Creatinine will be checked at Baseline, in order to calculate creatinine clearance for eligibility 
determination. Creatinine testing will be repeated at months 3 and 9 in accordance with CDC 
guidance. Creatinine will be tested from participant self-collected whole blood specimens using a 
point-of-care machine. Creatinine clearance will be calculated using the Cockcroft-Gault equation, 
with participant’s self-reported weight at baseline. If creatinine clearance <60 ml/min on follow-up 
testing, the prescribing physician will make an assessment and recommendation regarding 
whether the participant will need repeat testing and/or temporary or permanent discontinuation of 
PrEP.  
 
5.5.4 Dried Blood Spots 
Participants will be informed of expectations regarding specimen collection at baseline. DBS 
cards will be sent to both intervention and control participants for primary outcome assessment 
at 6 months and 12 months. Spots will be collected on a filter paper card and dried for ≥4 hours 
prior to mailing. Once returned to the lab, the primary outcome assessment DBS specimens will 
be stored in a laboratory freezer at -20˚C until they are batch tested for TFV-DP levels at the UNC 
Kashuba Lab. The Kashuba Laboratory will also measure emtricitabine-triphosphate (FTC-TP) 
from the DBS cards for secondary analyses.  
 
 
5.5.5  Referrals 
In the case of an initial (4th gen) positive HIV test done through the study, participants will be 
instructed to discontinue PrEP dosing. Participants testing positive will be referred for study-
provided HIV confirmatory testing. Upon receipt of positive HIV confirmatory test results, the 
linkage to care process will be initiated within two business days. For changes in creatinine 
clearance, study clinicians will consider discontinuing PrEP for any participants with calculated 
creatinine clearance below 60 ml/min. As needed, the linkage to care process for low creatinine 
results will be initiated within two business days. For positive STI tests, participants will have PrEP 
prescriptions initiated or renewed, and be referred to STI treatment at a local agency. Site study 
staff will follow-up with participants testing positive for STI to encourage participants to seek 
appropriate care. Laboratory test results will be provided to participant providers if requested and 
authorized to release. 
 
6.0 
MEASURES  
6.1 
Behavioral Measures 
 Pre-entry or screening measures 
• 
Screener for Behavioral Eligibility: The screener asks basic demographic questions and 
behavioral eligibility questions.  
 

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6.1.2 Pre-intervention (baseline) measures 
• 
Baseline Survey: The baseline survey will include questions in the domains of 
demographics, sexual history, potential correlates of initiating and maintaining in PrEP 
care, mental health, and stigma. To continue to be eligible for randomization, all survey 
modules must be completed within a week of starting the first module. After completing 
the baseline survey (and if clinically eligible) participant will be randomized into control or 
intervention arm.  
 
6.1.3 On-Study measures 
• 
1-Month CRF: Intervention participants will have a telemedicine consultation with study 
staff or clinician to assess experiences one month after initiating PrEP. CRF will record 
adherence and side effects. 
• 
Surveys for participants in both arms at months 3, 6, 9 and 12: categories include sexual 
behavior, PrEP cascade, and the validated system usability scale (SUS).  
 
6.1.4 Premature Discontinuation/Off-Study measures 
Participants will be asked to answer several brief questions, to be recorded on a CRF, 
documenting reasons for study withdrawal.  
 
6.2 
Clinical and Laboratory Evaluations  
6.2.1 Baseline measures 
• 
Home Test Kit: HIV, and Creatinine tests will determine clinical eligibility for the study.  
 
6.2.2 On-Study measures  
• 
HIV: 4th generation HIV tests will be conducted using whole blood specimen. HIV testing 
will be conducted quarterly. 
• 
DBS: TFV-DP levels will be assessed at months 6 and 12 to gain an understanding of 
participant adherence to their PrEP regime. These research outcome results will not be 
returned to the participants or clinicians.  
 
 
7.0 
DATA COLLECTION AND SITE MONITORING 
 
7.1 
Development of Protocol and Case Report Forms 
The Protocol Team, in collaboration with the Management Core (MC) and Analytic Core (AC), is 
responsible for the development of this protocol and the Case Report Forms (CRFs) needed to 
collect the information required to implement this protocol.  
 
7.2 
Data Records  
Participant-related study information will be identified through a study ID number (SID) and 
participant code (participant first initial and two-digit day of birth) on all participant CRFs and 
survey data. SID will be used wherever possible in place of personally-identifying information. 

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Source documents, such as laboratory results, the clinician dashboard, and CRFs, will be 
accessible only to the study staff and study clinicians on a role-based standard.  
SIDs will not be entered into the mobile app and instead a unique app ID will be assigned to each 
participant and used when logging into the app. These unique App IDs will be provided by the 
developer. Participant locator/contact information will be stored securely in the web-based 
interface (Section 7.3.4). 
 
7.3  
Data Collection  
7.3.1 CRFs 
Study monitoring data, including information about eligibility and monitoring untoward effects, will 
be collected on CRFs. CRFs will be completed electronically through iDataFax. All CRFs will be 
distributed to study staff through iDataFax. 
 
7.3.2 Electronic Surveys 
Self-administered surveys at Baseline, 3, 6, 9 and 12 month virtual visits will be completed by 
participants on personal devices via surveys hosted on a secure electronic platform. Data 
collected using electronic surveys will remain confidential and be stored on a secure electronic 
platform, accessed by an application programming interface (API) to populate the eP app and 
administrative portals. The platform API is linked to the eP app allowing participants to take 
survey’s on their personal devices. SID will be used in order to link the interview responses to the 
participant’s CRF data.   
The survey will be an embedded webpage, hosted on the study’s electronic survey platform, 
which appears to participants to be a seamless component of the eP app. The survey will be split 
into multiple modules to ease participant burden imposed by long surveys. 
 
7.3.4 Data Security 
Electronic Survey Data Security 
Utilizing a role-based standard, authorized users will be granted unique login names and 
passwords to access survey data on the survey platform servers. To ensure data privacy, as soon 
as data is entered (in real-time), it will be encrypted during transmission to the Adolescent 
Medicine Trials Network for HIV/AIDS Interventions (ATN) Analytic Core (AC) using Secure 
Socket Layer (SSL) technology. When downloaded, the data is stored in a secure database on 
an AC server within the AC data center. SSL encryption will be used for transfers of information 
online and data will be stored in the secure, HIPAA-compliant servers of SurveyGizmo. The 
Emory AC team maintains a business partner HIPAA agreement with SurveyGizmo.  
 
Participant management system data security 
The ePrEP participant management system has two components: a back-end “office” that is an 
interface for administrators and clinicians to manage participants and store data, and a 
participant-facing mobile app called eP. Emory University holds Business Associate Agreements 
(BAA) with all components interacting with the app and hosting servers including Microsoft Azure, 
Zoom, and SurveyGizmo to ensure HIPAA compliance. 

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The back-end office participant management system, hosted in the cloud, interacts with a custom, 
secure API developed to communicate data to and from the server. It also interacts with a HIPAA-
compliant video conferencing service, Zoom. Both connections are over a secure connection. The 
cryptographic algorithm the ePrEP participant management system uses is the AES 256 
algorithm, with the key hardcoded on the server side. The system uses SSL to communicate with 
the API. The key size is 128 bits. The system only includes API authentication; there is no other 
hard-coded information that exists within the system.  
Users and devices will be authenticated through the eP app using form authentication through a 
unique user ID and password, or through login authentication that uses ID and password settings 
from Facebook or Google. The app will provide no data to Facebook/Google, and vice versa; 
instead the app will simply use the Facebook/Google system to authenticate the appropriate user 
to allow for log-in to the eP app. Once an authentication system is established, the eP app will 
allow users to log in with TouchID if it is enabled on their phone. 
All relevant compliance requirements are met by the eP app, including HIPAA compliance, and 
security measures for personal health information including auto log out feature. All API’s for the 
eP application are HIPAA compliant. Sensitive data including participant’s demographic 
information (name, phone number, and email address) will be accessible in the application. The 
participant management system stores lab results as an encrypted database within the central 
Structured Queried Language (SQL) server that is secure and accessed only via authenticated 
administrators and clinicians. SQL is a programming language that manages data contained in 
relational database management systems. The lab results will not be stored in the participant 
mobile facing application.  
 
7.3.5 Zoom Platform Description  
For the telemedicine consultations conducted through the eP application, the study will rely on 
the Zoom platform. Zoom will be embedded into the eP app. Participants will use it to 
communicate with their ATN site study clinician in face-to-face video chat, and text based 
conversation. Our implementation of Zoom is HIPAA-compliant, and Emory University has 
entered a Business Associate Agreement (BAA) with Zoom. Zoom includes the following 
functions to protect users: End-to-End encryption, connects automatically using udp and tcp port 
8801, 8802, and 8804 or HTTPS (port 443/TLS), encryption with the Advance Encryption 
Standard (AES) 256-bit algorithm. Session keys are generated with device unique hardware ID 
to avoid data being read from other devices.  This ensures that the consultation cannot be 
eavesdropped or tampered with.  
7.4 
Data Submission 
7.4.1 CRFs 
Electronic CRFs in iDataFax will be used to collect key study data (e.g. randomization 
assignment) and to record study milestones such as study discontinuation, PrEP discontinuation 
and restarting, clinician decisions regarding PrEP, referrals, and adverse events (AE). AC staff 
will work with study investigators and the Management Core (MC) to develop CRFs.  
7.4.3 Survey Data Transmission 

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Only authorized users, based on correct login, will be able to access and open the study surveys. 
To ensure data privacy, as soon as data is entered (in real-time), it will be encrypted during 
transmission to the AC using Secure Socket Layer technology.  The data will then be immediately 
stored in a secure database on an AC server within the AC data center. 
 
7.4.4 Retention Data 
Study staff will track participant scheduling and retention through the administrator portal of the 
ePrEP system. All retention data will be stored in the cloud through HIPAA compliant Microsoft 
Azure. Access to this database requires user permissions and secure log in. Incremental backups 
of the entire database are performed regularly to create database redundancy.  
 
7.5 
Data Quality Assurance 
Investigators receiving federal funding must adhere to the Code of Federal Regulations (CFR) to 
protect research participants and produce reliable study information. Sites participating in 
research sponsored by the NICHD need to have an internal quality assurance (QA) plan that will 
identify problems and correct errors in research study records.  
 
7.6 
Role of Data Management 
The AC will provide instructions concerning the recording of study data on the CRFs, and entry 
of the data into iDataFax. Electronic survey results will be linked to the ePrEP participant 
management system back-end office used by study staff. Lab results will be entered into the 
participant management system back-end office. Only trained study staff will have access to the 
web portal dashboard and will be allowed to conduct data entry or exports. 
  
7.7 
Study Site Monitoring and Record Availability 
Site monitors from the MC and AC may visit participating study sites to review a selected portion 
of the individual participant records, including consent forms, CRFs and supporting source 
documentation to ensure the protection of study subjects, compliance with the protocol, and 
accuracy and completeness of records. Regulatory files, as required, will also be inspected to 
ensure that regulatory requirements are being followed. 
 
The site investigator will make study documents (e.g., consent forms, case report forms) and 
pertinent hospital or clinic records readily available for inspection by the local IRB, the site 
monitors, the NICHD, the Office of Human Research Protection (OHRP), or the sponsor’s 
designee for confirmation of the study data. 
 
8.0 
PARTICIPANT MANAGEMENT 
8.1 
Tracking Participants / Follow-up 
All participants will be followed prospectively for 12 months after assignment to the intervention 
or control conditions. Research assessments, completed at the participant’s home, will be 
identical for intervention and control participants: surveys at 3, 6, 9, and 12 months, and DBS 
specimen collection and mailing at 6 and 12 months. All participants will be reminded of their 
upcoming assessments through the study app. All participants will be followed up for study 
retention regardless of whether they are actively taking PrEP and/or engaged in PrEP care. 

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Intervention participants will have a 1-month telemedicine consult with the ePrEP site study staff 
or clinician, providing an open forum to answer questions/concerns, assess side effects, 
adherence, behavioral risk, symptoms of acute HIV infection or STD, and provide appropriate 
clinical management. The intervention arm will have home test lab assessments and telemedicine 
consultations at 3, 6, 9 and 12 months with their ePrEP site study clinician. Participants assigned 
to the intervention will receive automatic reminders for scheduled ePrEP site study clinician 
telemedicine consultations.    
 
Control participants will complete surveys at 3, 6, 9, and 12 months, and home DBS specimen 
collection and mailing at 6 and 12 months. Control participants will be sent electronic reminders 
to complete their research assessments. Follow-up calls may also be used for participants who 
need further reminding and additional follow-up. 
 
All study virtual visits have a set window period for the participant to complete. If a participant 
misses a virtual visit or scheduled follow-up assessment, they will be allowed to continue in the 
study for the following virtual visits. They will remain on a 12-month study timeline.  
 
8.2 
Compensation 
The study will compensate all participants who complete baseline procedures with $100. 
Participants will receive $50 for completing the baseline survey and eligibility verification steps, 
and $50 for sending back the home test kit. Follow-up compensation will be $40 for electronic-
survey completion and $40 for DBS collection. Individuals who complete the eligibility screener 
may also receive up to $10. Participants who refer individuals for the study can receive $10 
incentive for up to 5 referrals for a maximum of $50. 
 
8.3 
Intervening on “Social Harms"  
All sites have specific policies governing the treatment of human subjects. These policies specify 
that medical and psychological assistance will be available in the event a participant should 
require further evaluation or treatment. Participants will be referred to a local clinic that is able to 
assist the participant further. 
While participants will be informed that they may refuse to answer any question at any time, 
responses or reactions to certain questions may indicate distress on the part of the participants.  
If at any time during the study, a participant divulges that he or she is at risk for harm, including 
but not limited to being abused or experiencing violence, if harm is suspected or likely, or if the 
participant states he or she is suicidal/homicidal, measures will be taken to ensure his or her 
safety. Reporting will be done as appropriate to the situation and the legal statutes, and referrals 
will be provided to appropriate support, counseling or treatment resources. 
 
8.4 
Criteria for Premature Study Discontinuation 
Participants may voluntarily withdraw from the study for any reason at any time. No further data 
collection will occur from the date the decision is made to permanently discontinue the subject 
from the study. The study investigators also may withdraw participants from the study in order to 
protect participant or staff safety. Study staff will record the reasons for all withdrawals. Early 
study discontinuation may occur for the following reasons: 
• 
Participant has a confirmed HIV-positive test 

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• 
If the study is terminated prior to its planned end date 
• 
If the study clinician or the PI determines it is in the participant’s best interest to discontinue 
participation in the study 
• 
If a participant threatens study staff 
Any unexpected adverse events that meet the new safety information reporting criteria will be 
immediately reported to the UNC-CH IRB and the respective sites’ IRBs if applicable. Study staff 
will complete a Study Stop form for participants who are discontinued. This form will include the 
date, last virtual visit completed, and reason for study discontinuation.  
9.0 
MONITORING UNTOWARD EFFECTS ASSOCIATED WITH OR RESULTING 
FROM STUDY 
 
The study will have study clinicians prescribing FDA-approved oral PrEP, in accordance with 
Gilead’s label indications for tenofovir disoproxil fumarate/ emtricitabine (Truvada) or 
emtricitabine/ tenofovir alafenamide (Descovy). The prescription of PrEP in the study will also 
follow guidance from the US Public Health Service and US Centers for Disease Control and 
Prevention. The study will not be providing study drug. Individuals will be getting prescribed 
medications from a local pharmacy. Side effects due to the medication will be monitored but not 
considered study-related adverse events.  
The frequency and severity of side effects from Truvada and Descovy are listed as follows (items 
in bold are from the package insert): 
 
• 
Very Common (approximate incidence > 50%): none 
• 
Common (approximate incidence > 25 - 50%): none  
• 
Likely (approximate incidence of > 10 - 25%) and Mild to Moderate (no disruption to 
temporary interference with daily activities; may include prescription intervention): 
nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, 
and rash.   
• 
Infrequent (approximate incidence of > 1 - 10%) and Mild to Moderate (temporary 
interference with daily activities; may include prescription intervention) : diarrhea, 
abdominal pain, decrease in weight, generalized weakness, shortness of breath, 
increased cough, runny nose, allergic reaction, skin darkening of the palms of hands 
and/or soles of feet, muscle pain and weakness.   
• 
Rare (approximate incidence < 1%) and Severe to Life threatening: bone pain and 
bone changes, worsening or new kidney damage or failure, liver problems, increases in 
pancreatic enzyme, increased triglycerides, increased creatine phosphokinase (CPK) 
which could mean muscle damage, lactic acidosis and severe hepatomegaly with 
steatosis that may result in liver failure  
 
Site staff must first follow their own IRB’s procedure for reporting and managing untoward effects.  
 
There are two types of untoward effects to be identified: (1) those related to the participant and 
(2) those related to the study staff. 
 

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First, the study will catalogue any untoward effect related to the participant. All adverse events 
(AE) reported will be assessed by the PI for the study site in which the participant was enrolled 
for the severity, expectedness and relatedness. Reporting is required for occurrences including 
social harms, psychological distress and serious life-threatening events such as suicide attempts. 
These may be immediately apparent to the study staff, such as the participant’s emotional upset 
requiring referral for counseling; or they may be delayed and reported later to study staff, such as 
physical harm to an individual for having participated in the study. Study staff will notify the team 
of these untoward effects using the iTech Query and Notification System (QNS) accessible 
through the iTech website (https://itechnetwork.org). 
 
Serious adverse events (SAE) will be adverse events that result in death, are life threatening, 
requires or prolongs hospitalization, causes disability, or poses other significant hazards. Severity 
of AEs will be classified as follows: mild, moderate, and severe. Mild AEs will be events that do 
not require medical attention and are easily tolerated. Moderate AEs will be events that require 
simple and routine medical treatment and may cause some interruption to daily life. SAEs will be 
defined as above. AEs will also be categorized as definitely, possibly, or not related to the study. 
AEs that are definitely related will follow a logical causal sequence from a study activity. Possibly 
related events will follow a logical causal sequence from a study activity but may also be due to 
non-study activities. Not related events will be events that do not follow a logical causal sequence 
from any study activity. All adverse events require reporting to the ATN via the iTech Query 
system within 24 hours of becoming aware of the adverse event. Study staff will be briefed during 
the training on the scope of possible untoward effects and instructed to report events. 
 
Second, study staff may encounter untoward events during virtual visits that personally affect 
them. Training and guidance will seek to minimize this risk. The protocol chairs should be notified 
of these events so that they may be immediately addressed, evaluated, and guidance modified 
or expanded to minimize similar risk to other staff. 
 
A Safety Monitoring Committee (SMC) will receive standard data reports on a quarterly basis. The 
chair of the SMC will lead biannual calls to discuss study progress, and convene additional SMC 
meetings as needed based on interim reporting. The SMC will be tasked with stopping the study 
if the intervention proves to be significantly outperforming the standard of care, or if the inverse 
occurs. We will conduct one interim analysis comparing the efficacy of the intervention in the 
active arm to the control arm, with efficacy based on differences in trial success versus failure 
using the primary outcome definition (detectable Tenofovir at 12 months). We will use the O’Brien-
Flemming spending function on the Z test statistic assuming a final alpha of 0.05 such that the 
interim Z statistic bounds are -2.96 and 2.96. If the intervention efficacy is outside those bounds, 
the trial will be stopped. If the intervention is significantly outperforming the standard of care, the 
study will seek to adjust study design and supplements to open the intervention arm. The SMC 
will monitor several other factors, including HIV seroconversion, changes in kidney function, 
behavioral disinhibition, medication adherence, persistence in PrEP care, and differential loss to 
follow-up. 
 
10.0 
STATISTICAL/ANALYTIC CONSIDERATIONS 
 
10.1 
Introduction 

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10.1.1 A total of 240 participants will be enrolled at baseline to account for a 20% expected loss 
to follow-up during 12-months of study follow-up.  
10.1.2 Primary Outcome: The primary outcome will be detectable TFV-DP drug levels at the 
month 12 study virtual visit based on an intention to treat analysis. Using standard 
pharmacological models,[17] TFV-DP level can be used to infer the mean number of days per 
week PrEP is ingested over a time period of approximately 1-month preceding specimen 
collection. The cut point used for the primary outcome measure will be TFV-DP levels considered 
to be a surrogate for substantial HIV protection: >700 fmol/punch, a level indicating ≥ 4 doses per 
week. The intervention efficacy measure will be quantified as the difference in proportions of the 
intervention arm with this outcome compared to the control arm. For the power calculations, we 
will therefore use a two-sample comparison of proportions.  
10.1.3 Secondary Outcomes: Secondary outcome measures will be harmonized, to the extent 
possible, with ATN measures. Safety/tolerance outcomes will include: acute HIV symptoms, 
medication tolerance assessed based on side effects; adherence with number of pills taken in the 
past week; demographic, socio-economic, and sexual behavioral risk measures derived from the 
National HIV Behavioral Surveillance (NHBS) instrument and our previous research 
instruments;[10, 18] PrEP perceptions and PrEP use adapted from the NHBS instrument as well 
as other sources;[10, 19] commonly used measures for depression;[20] illicit and non-prescription 
drug use,[21] sexual stigma,[22] HIV severity and risk perceptions,[23] HIV knowledge,[21] 
medication adherence self-efficacy,[24] the systems usability scale,[25, 26] healthcare 
coverage,[27] and use of social and geosocial networking sites.[27] We will also seek to 
understand rationales for those who fail to persist in PrEP, assessing perceptions of PrEP barriers 
and concerns.[28, 29] The Kashuba Laboratory may also measure emtricitabine-triphosphate 
(FTC-TP), which will allow for additional study analyses regarding recency of PrEP dosing.[30] 
 
10.2 
Power Estimates  
10.2.1 All analyses will assume 80% power to detect a difference at a two-sided 5% significance 
level. We will also assume a 20% attrition rate in both arms, with independent censoring. 
Assuming that 5% of participants in the control arm are above cut-point levels of the outcome 
measure (Section 10.1.2), we will have sufficient power to detect a minimum detectable effect 
size of 13% absolute difference in the outcome measure (e.g. ≥18% of participants in the 
intervention arm have outcome measures above the cut-point threshold). A sensitivity analysis 
determined that to allow for detection of a scenario where intervention outcome level = 
control+20% absolute increase, our study would remain sufficiently powered with any control 
participant uptake level ≤15%.  
 
10.3 
Statistical Analysis Plan 
10.3.1 Aim 1: Analyses of primary outcome that control for potential residual confounding, and 
analyses of secondary outcomes including initiation of and retention in PrEP care. 
Logistic regression and log-linear models will be used to estimate the association between 
intervention arm and the primary study outcome, TFV-DP level. If prognostic factors associated 
with the outcome remain insufficiently balanced through stratified randomization, we may adjust 
for these factors in our models. Potential confounding factors that may be included are medication 
self-efficacy and motivation to take PrEP. Per protocol assessments that account for potential 

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changes in intervention as delivered will be conducted. For instance, this would account for 
participants assigned to the intervention condition opting to instead receive standard of care PrEP 
from a non-study clinician. A number of secondary analyses will be conducted using regression 
models. Intervention impact on the secondary outcomes of PrEP initiation and PrEP persistence 
will be determined using analogous regression models. Another secondary analysis will be to 
model log10 (TFV-DP levels) as the outcome variable. An additional secondary analysis will 
account for changes in PrEP eligibility over time, per CDC guidelines. This has the potential to 
detect significant smaller “sub-clinical” differences in adherence between the intervention and 
control study arms. Similarly, an analysis with FTC-TP will allow for a more sensitive and sub-
clinical assessment of PrEP use. Other specific and aggregate measures of safety including: 
renal function, HIV incidence, and incident bacterial STI will be assessed. 
 
10.3.2 Aim 2: Exploratory analyses of intervention effectiveness across subgroups, and analysis 
of potential mediators of initiation or persistence in PrEP care across both study arms, such as 
self-efficacy and urbanicity.  
Heterogeneity of the intervention effects across subgroups will be explored, including that of 
stratification (race), and socioeconomic indicators. Understanding variables associated with 
success or failure in home care for PrEP will inform future research, and potentially guide clinician 
recommendations or policy regarding bringing PrEP to scale. For participants who seroconvert 
during the study, levels of TFV-DP, PrEP persistence, and other clinically-relevant study data will 
be analyzed. 
10.4 
Cost-effectiveness and Cost-utility Analysis Plan 
We will employ standard methods of cost analyses, as recommended by the U.S. Panel on Cost-
effectiveness Health and Medicine [31] and as adapted to HIV/AIDS programs.[32] This will be 
accomplished by conducting an economic analysis from the payer perspective (the cost to the 
party implementing the program) and societal perspective (the payer costs plus the cost to the 
participant for participating in the program) to estimate the cost, cost-effectiveness, and cost-utility 
of the intervention relative to standard of care. Comprehensive cost analysis will be conducted to 
assess the cost of developing and implementing the ePrEP intervention, using a micro-costing 
approach to estimate net costs. Cost-effectiveness analyses will include calculating the 
incremental cost-effectiveness ratio (ICER) for the cost per HIV infection averted compared to 
standard of care as: [(CostIntervention – CostStandardofCare)] / [(Infections AvertedIntervention – Infections 
AvertedStandardofCare)]. The health effect will be defined as the projected reduction in HIV infections 
over time associated with adopting the intervention relative to standard of care. The base, 
standard of care, model will estimate the number of infections expected in the absence of the 
intervention, and may vary under different assumptions of baseline and clinic-based PrEP 
coverage outside of the intervention.[33] In the cost-utility analysis, we will calculate the cost per 
quality-adjusted life year (QALY) saved. QALYs saved by averting an HIV infection will be up-to-
date estimates from the literature. Sensitivity analyses (varying levels of access, coverage, and 
adherence and exploring the impact of generic drug pricing, one of the major determinants of 
PrEP cost-effectiveness.[34]) may be tested as unique intervention scenarios for the cost-
effectiveness and cost-utility analyses. 
 
10.5 
Missing Data 
Several procedures will be used to conduct data analysis when data for either outcomes or 
covariates are missing. The first step will be to assess the extent and pattern of missing data. If 

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data are missing for only a few cases, then data analysis will be conducted only on study 
participants with complete data. However, when such a strategy would result in loss of data from 
a substantial proportion of participants, or if this approach would lead to biased or inaccurate 
results, then some form of imputation may be performed for secondary analyses. The form of 
imputation used will depend on the nature of the data that are missing. 
  
10.6 
Qualitative Data  
In-depth interviews (IDI): In-depth interviews will be conducted after completion of 12-month 
assessments with key participants to explore the experience of eP app users and standard of 
care participants over time. Participants asked to participate in IDI will have to sign a separate 
informed consent form and will be compensated $50 for their time.  Interviews will use a timeline, 
activity-based approach that uses data such as history of PrEP use to prompt participant 
memories and create an interactive discussion between moderator and participant regarding 
PrEP care and care seeking experiences. Topics will include: (1) barriers and facilitators to PrEP 
care, (2) problems with and benefits of the ePrEP system or standard of care, (3) ways to address 
problems and amplify success of ePrEP or standard of care, and (4) factors that influence 
successful persistence in or fall-off from PrEP care. IDI’s will be conducted until data saturation 
has been reached. Purposive sampling of study participants will include up to 15 IDI with 
participants maintained in PrEP care as determined by self-report of PrEP prescription (10 
intervention, 5 control) and up to 15 IDI with participants not maintained in PrEP care (10 
intervention, 5 control).  
 
 
Analysis of IDI: Transcriptions and interviewer notes will be entered into a qualitative software to 
facilitate data management and analysis. Coding will be in line with the constant comparison 
analysis method, leveraging real-time identification of main themes, and exploring them in further 
depth among subsequent participants. Final analysis will compare data within and across codes 
and themes to answer study questions regarding ePrEP adaptation, scale-up considerations, and 
future research directions.  
  
11.0 
HUMAN SUBJECTS 
This study will be conducted in compliance with the protocol, ICH Good Clinical Practice 
guidelines, and 45 CFR Part 46. 
 
11.1 
Participants’ Confidentiality 
All laboratory specimens, questionnaires, surveys, and reports will be identified by a coded 
identification number and participant code in order to maintain participant confidentiality. 
Participants will provide their names, mailing address and preferred contact information (email 
or cell phone number for SMS) into the app which will be used when ordering CareKits. Study 
staff will confirm shipping address with the participant before the kit is shipped. This personal 
information will be used only for the purposes of fulfilling the order, confirming participation in 
the study and returning lab testing results, and will be kept in a database with secure login 
requirements.  All records with personally-identifying information will be kept separate from 
study data when practicable. In some instances, such as interactions with study clinicians, 
participant identifying data will be available along with study data as needed. Access to these 
data will be limited and role-based. Participant information will not be connected to identifying 

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information where possible. Clinical information will not be released without written permission 
of the participant, except as necessary for monitoring by authorities specified in Section (7.7). 
To maximize privacy, the app’s mobile phone icon is listed as “eP”. The app stores require a 
description of the app, and we only provide vague information that will not reveal the purpose or 
topic of the study. The eP app is a shell for the secure, cloud-based hosting servers, and will not 
store any data on the mobile device. All devices must be authenticated after completing the 
eligibility screener and before the participant can log into the app. The app requires secure log 
in each time it is accessed.  
 
Analytic Core Role in Confidentiality 
Every effort will be made to ensure that study participants are protected from risks. The main risk 
specific to the role of the Analytic Core is breach of confidentiality.  
Breach of Confidentiality: A potential risk to participants is violation of confidentiality. We will take 
the utmost caution to protect the confidentiality of all responses. We will minimize this risk by 
maintaining confidentiality and discretion throughout all research procedures and data 
management and analysis. All Analytic Core research staff members are required to complete 
ethical clearance certification regarding protection of human subjects through UNC-CH or Emory 
University. We also have a strong data and safety monitoring plan in place to protect participants. 
Adverse events will be reported to the UNC-CH and Emory IRB, individual research PI institutional 
IRBs and SRV site-specific IRBs using Adverse Event Reporting Forms created by the Analytic 
Core. Reports of serious adverse events will be sent within 24 hours of notification by the PIs. 
Annual updates on enrollment and retention will also be sent to the IRBs.  
Participants may be concerned about the security of their data, particularly since it is collected 
and stored electronically. The Analytic Core has significant experience developing security 
protocols for Internet-based studies, and will take a variety of steps to ensure participant security, 
including using a dedicated server behind a firewall, encryption of data, separation of identifiers 
from responses when possible, and password-protected access to data. Therefore, we believe 
that this risk will be low. 
11.2 
Minimizing risk to participants 
Every available step will be taken to minimize the risk of identifying/linking data being 
subpoenaed, stolen, or inadvertently released. Certificates of Confidentiality are automatically 
issued by the NIH, and will cover this study. All research staff members will be required to 
complete CITI ethical training regarding protection of human subjects through their relevant IRBs. 
All studies will have documented procedures to safeguard against the risk of the linking 
information being stolen by keeping such information in secure spaces to which only essential 
study personnel who have completed CITI certification for human subjects research ethics training 
(http://citiprogram.org) will have access.  
11.3 
Risks and Benefits 
11.3.1 Risks 
Risks to participants in this research study may include:   
The measurements that are involved in this study require finger prick to collect blood samples. 
This procedure may cause local discomfort, bleeding, or bruising; rarely small clot or infection can 

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occur at the blood draw site. This measurement should not be considered greater than minimal 
risk in and of itself given its routine use in general health care delivery.  
 
To minimize the risk of participants feeling uncomfortable about answering personal questions, 
we will use Computer Assisted Self Interview (CASI) methods for the study's surveys. In CASI, 
participants read survey questions on a mobile phone and use a combination of keyboard and 
touchscreen entry to input the answers themselves. In-depth interviews will be conducted through 
telephone or the eP app. 
To minimize risks to confidentiality, we will secure study data with all appropriate physical, 
electronic and operational protections. Data will be stored in a physically secure environment. All 
data files will have encryption and strong password protection. Any identifiable data will either be 
stored on Emory University's secure servers or will be on fully encrypted laptops. Electronic 
surveys and online eligibility screening will take place on an encrypted commercial survey 
website, SurveyGizmo (http://www.surveygizmo.com/survey-software- features/secure-link/). 
This site has been used by the investigators for thousands of online surveys with MSM with no 
data security breaches. 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, and will sign a 
confidentiality agreement before receiving access to any participant data.  
Procedures will be developed to minimize indirect disclosure that a participant is participating in 
an HIV- related research study, or a study that enrolls MSM. Participants will be asked preferred 
method(s) of contact. No study-related messages will ever mention HIV prevention or the nature 
of the research 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.  
We use SSL encryption for transfers of information online, and SurveyGizmo has a business 
partner HIPAA agreement with Emory. SurveyGizmo’s servers are HIPAA compliant. Qualitative 
data analysis will be conducted on a secure software program (e.g. MaxQDA, Dedoose, Atlas.ti). 
All study personnel names on this application have completed training and received certification 
in Human Subjects Research Protection (CITI Program) and HIPAA regulations. They will 
continue to renew this training in compliance with institutional policies.  
11.3.2 Benefits   
Possible individual benefits of participation include access to HIV and STI testing at study initiation 
for all participants, and remote access to pre-exposure prophylaxis for HIV prevention for 
participants assigned to the intervention arm.   
 
11.4 
Institutional Review Board (IRB) Review and Informed Consent 
This protocol, the informed consent documents and any subsequent modifications will be 
reviewed and approved by the IRB responsible for the oversight of the study. The informed 
consent will describe the purpose of the study, the procedures to be followed, and the risks and 
benefits of participation. Written informed consent will be obtained from the participant through 
an electronic procedure. The consent form will be kept on file on secure servers, and a copy of 
the consent form will be available for download by the participant.  

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11.5 Prisoner Participation 
NICHD has concluded that this protocol does NOT meet Federal requirements governing prisoner 
participation in human subject research and should NOT be considered by local IRBs for the 
recruitment of prisoners. Subjects enrolled who subsequently become incarcerated or are placed 
in detention will be study stopped. If incarceration is less than 3 months, they may be able to 
restart study activities. Study visits cannot be conducted during the period of incarceration or 
detention.  
 
11.6 
45 CFR Parts 160 and 164 Standards for Privacy of Individually Identifiable Health 
Information ("Privacy Rule" Pursuant to the Health Insurance Portability and Accountability Act - 
HIPAA) 
Each site is responsible for adherence to their individual institution’s HIPAA policies and 
procedures. 
 
11.7 
Study Discontinuation 
This study may be discontinued at any time by the NICHD.  
 
12.0 
PUBLICATION OF RESEARCH FINDINGS 
Any presentation, abstract or manuscript will be made available for review by the study 
sponsors prior to submission.   
 
13.0 
BIOHAZARD CONTAINMENT  
After home collection of specimen(s) for testing, participants will place the specimen collected in 
the provided packaging, which meets all federal regulations for shipment of Biological 
Substances, Category B (UN3373). Staff trained in biohazard handling will store specimens or 
ship them to the appropriate laboratory. Handling of specimens will be conducted in compliance 
with guidance from CDC, and with Federal and local laws, with OSHA blood-borne pathogens 
standards. This policy includes the samples being transported by ground to the local laboratory. 
Compliance will be achieved by education of personnel involved with packaging and transporting 
specimens.  
 
All infectious specimens must be shipped as Diagnostic Specimens according to current IATA 
Shipping Guidelines for Infectious Substances Class/Div. 6.2. Refer to individual carrier guidelines 
(e.g. FedEx, Airborne Express) for specific instructions. 
 
13.1 Future Storage  
Participants will be asked during the consenting process if they give permission to have 
samples stored for future research. DBS specimens collected from participants who agree to 
have samples stored for future use will be stored at Emory University or contracted laboratory. 
Only study staff will have access to the samples. Personal identifying information will not be 
kept with the samples. These samples could assist with other research, such as DBS validation 

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measures. Participants who do not agree to have specimens stored will have specimens 
discarded after study lab tests are conducted.  
 
 

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