DOT Diary (D2): Developing a Mobile App With Combined Automated DOT and Daily Sexual Diary for Monitoring and Improving PrEP Adherence: DOT Diary Optimization Pilot
Phase: PHASE4
Conditions: Adherence, Medication, Risk Behavior, Pre-Exposure Prophylaxis, HIV Prevention
Sponsor: Public Health Foundation Enterprises, Inc.

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DOT Diary Optimization Pilot Protocol 
 
Version 2.0 January 11, 2018 
 
Full title: 
DOT Diary Optimization Pilot Protocol 
 
Investigator’s Names: 
Susan P. Buchbinder, MD 
Gordon Kessler 
Nicole Laborde, PhD, MPH 
Albert Y. Liu, MD, MPH 
Hyman Scott, MD, MPH 
Laura Shafner 
Aaron J. Siegler, PhD 
Ariane van der Straten, PhD, MPH 
Eric Vittinghoff, PhD 
 
 
 
Sponsor’s Name:  
National Institutes of Health, National Institute of Mental Health 
 
Date: 
January 11, 2018 
 
Version: 
2.0 
 
 

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1.0 Background 
 
In July 2012, the FDA approved pre-exposure prophylaxis (PrEP) with daily tenofovir disoproxil 
fumarate co-formulated with emtricitabine (TDF/FTC) for reduction of sexually acquired HIV 
infection. However, adherence to daily oral PrEP has been so low in a number of studies as to 
preclude assessment of efficacy in some populations,1,2 and to under-estimate efficacy in 
others.3 To date, the only real-time adherence methodology used in PrEP trials has been 
electronic medication containers such as MEMSCap and WisePill.4,5 However, these devices do 
not directly confirm pill ingestion, can easily be defeated by extra openings without ingestion, 
and data have been lost by faulty transmission or loss of devices.6-9 Pill counts are even more 
easily defeated, by pill-dumping. Although drug levels in blood have become the standard for 
estimating adherence, between-person variability in pharmacokinetics (PK) as well as practical 
and financial limits on the frequency of blood sampling prevent this approach from providing 
accurate day-to-day information on adherence. To accurately estimate biological efficacy in 
clinical trials, new methods are needed to confirm and track pill ingestion accurately over time. 
Software-based methods that leverage existing smartphones, do not require changes to the 
medication itself, and can be optimized based on participant behavior will facilitate real-time 
monitoring and feedback at the patient, site, and study levels. Together, these will ensure 
maximal adherence during trial conduct, and enable unbiased estimation of biological PrEP 
efficacy. Finally, an accurate and scalable adherence measurement tool that is used 
successfully in clinical trials has the potential to increase PrEP uptake and adherence in diverse 
clinical settings with high-risk populations. 
 
In 2014, men who have sex with men (MSM) accounted for 70% of new HIV diagnoses in the 
United States, and MSM are the only US population in which new HIV infections are 
rising.10 Black and Latino men are at particularly high risk, with HIV infection rates estimated to 
be 6.6 and 2.9 fold higher than among White men. Disparities in HIV prevalence increased in 
2008-2011, and grew fastest in the youngest age groups.11 Young MSM (YMSM) accounted for 
nearly 20% of the estimated HIV diagnoses nationwide and over 80% of new HIV infections 
among youth in 2014. Furthermore, Black and Latino YMSM accounting for 55% and 33% of 
HIV infections among YMSM, respectively.10 Despite the promise of PrEP in preventing HIV 
acquisition among YMSM, PrEP uptake has been low in this vulnerable population. According to 
national prescription data, youth under 24 are the least likely to initiate PrEP, with only 9% of 
PrEP initiations in 2015 occurring in this age group.12  In a recent national survey, only half of 
YMSM aged 15-24 had heard of PrEP, and 1.7% had ever used PrEP.13 Demonstration projects 
also highlight challenges with PrEP uptake and adherence. In the US Demo Project of 550 
MSM, only 20% were age 25 or under, and PrEP uptake was lower among younger, non-white, 
and less educated persons.14 In multivariate analysis, the only independent predictors of 
adherence as measured by tenofovir diphosphate levels in dried blood spots were Black race 
(adjusted odds ratio, aOR 0.28, 95% CI 0.12-0.64) and enrollment in Miami (aOR 0.32, 95% CI 
0.17-0.60).15 Self-reported adherence, pill counts, and medication possession ratios did not 
completely explain the disparities in TFV-DP levels. Similar findings were seen in the ATN 110 
study of YMSM aged 18-22, where PrEP uptake was only 16%, and PrEP adherence was lower 
among Black YMSM and declined overall during follow-up, particularly with less frequent visits.16 
Clearly, future PrEP studies must include sizeable numbers of African American, Latino, and 
young MSM, who are at high risk for HIV and may require timely adherence support, triggered 
by an accurate measure of adherence. 
 
Because of its ability to ensure treatment adherence, directly observed therapy (DOT) has been 
used for decades both to measure and maximize adherence for treatment of tuberculosis 
infection,17 and more recently has been used to ensure protocol-defined dosing in PrEP PK 

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studies.18 A number of studies have found DOT to be successful in improving adherence to 
antiretroviral therapy,19-21 including in African American and Latino populations.22,23 However, 
the cost and logistical complexity of DOT in large clinical trials can be prohibitive. Automated 
DOT (aDOT), using artificial intelligence with advanced features to detect diversion, combines 
the accuracy of in-person DOT with the convenience of real-time centralized data collection and 
monitoring. AiCure has developed a HIPAA-compliant smartphone app which uses artificial 
intelligence software to automate DOT. The system works through a webcam to automatically 
confirm that the right patient is taking the right medication at the right time, using security 
features to identify evidence for cheating; biometrics used to confirm patient identity also protect 
against duplicate enrollment and multiple registration of users with same or similar names. 
Medication adherence data are automatically transferred to a centralized cloud-based 
dashboard for real-time analysis. The AiCure platform has been pilot tested in a variety of 
clinical settings and populations, including patients with schizophrenia, attention deficit 
hyperactivity disorder (ADHD), and stroke.24 
 
In the DOT Diary research project (PI: Buchbinder, R01MH109320-01), the AiCure aDOT 
smartphone app has been adapted for use in monitoring and supporting Truvada® PrEP use 
among YMSM through formative work (UCSF IRB Study 15-17436) and initially piloted in the 
DOT Diary Cheating Protocol (IRB Study 16-18933). As part of this development work, a sexual 
diary has been integrated into the aDOT app to assist YMSM in understanding whether they are 
receiving protection from PrEP for individual sexual episodes, and when it is particularly 
important to take PrEP (e.g. after a sexual episode). Specifically, the sexual diary allows 
participants to track sexual encounters, sexual behaviors that occurred in each encounter, and 
rating characteristics of partners. Partner-specific information (e.g. ratings) entered by 
participants is not transmitted to the study team and remains on the phone in the password-
protected app. The app provides a calendar displaying all days in which PrEP medication was 
taken, and all days in which sexual activity occurred, allowing participants to see coverage of 
sexual encounters with PrEP.  Based on pharmacokinetic and pharmacodynamic data from 
prior PrEP trials, the app will also indicate the estimated level of protection achieved from PrEP 
(e.g. low, medium, high), and also provide personalized messages on the additional numbers of 
doses needed to maximize protection.  
 
In the next stage of app development, we will conduct the DOT Diary Optimization Pilot to 
identify areas of the app that require refinement to maximize the acceptability and ease of use 
of the DOT adherence monitoring app. We will assess overall acceptability and ease of use of 
the integrated DOT Diary (D2) app over an 8 week period, elicit feedback on the dashboards 
used by staff to track PrEP adherence, and assess participant preferences for feedback on non-
use or frequent self-reported dosing on the app. The goal of this pilot study will be to refine and 
optimize the app for further testing in a larger and longer pilot study among YMSM at risk for 
HIV acquisition. We will conduct this pilot protocol among YMSM in Atlanta and San Francisco 
Bay Area, two metropolitan regions heavily impacted by HIV,25 yet differing in 
sociodemographics, as well as in the availability and uptake of HIV prevention services, 
including PrEP. These diverse research locations will allow collection of data to inform app 
development among a broad group of YMSM. 
 
2.0 Optimization Pilot Study Objectives 
 
2.1 Primary Objectives 

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1. 
To assess key attributes including acceptability and ease of use of DOT Diary over 8 
weeks by MSM on PrEP and identify potential improvements to the app to 
maximize acceptability 
2. 
To evaluate the quality of execution and persistence of use of the DOT and sexual 
diary components of DOT Diary by young MSM on PrEP over an 8-week period 
and identify potential improvements to the app to maximize quality of execution 
and persistence 
2.2 Secondary Objectives 
1. 
To assess participant preferences for feedback on non-use or self-reported dosing 
that over-rides the DOT Diary app   
2. 
To assess situations and reasons for sub-optimal use of the app, for the purpose of 
app optimization 
3. 
To get a preliminary assessment of overall PrEP adherence by tenofovir diphosphate 
levels in DBS among young MSM using the DOT Diary app  
 
3.0 Research Locations 
The pilot study research activities will be implemented at two study sites, 1 in the Atlanta area 
and 1 in the San Francisco Bay area, in accordance with local approvals. These sites are the 
following: 
 
 
Bridge HIV, San Francisco Department of Public Health, San Francisco, California 
 
Emory University, Atlanta, GA 
 
4.0 Study Population 
This study is designed to enroll a diverse population of YMSM in Atlanta and the San Francisco 
Bay Area. Although no restrictions are put on the racial/ethnic make-up of the study participants, 
sites will strive to enroll at least 70% African American or Latino YMSM into this study. 
4.1 Inclusion criteria 
 Self-identifies as a man 
 Age 18-35 at enrollment 
 Reports having anal sex with a man or trans woman in the past 12 months and one or 
more of the following criteria in the past 12 months: 
 
Any condomless anal sex (not in a mutually monogamous relationship with 
an HIV-negative partner) 
 
Two or more anal sex partners 
 
Self-reported STI (gonorrhea, chlamydia, syphilis) 
Having a known HIV-positive sexual partner 
 HIV-negative as determined by a negative 4th generation HIV test at screening and 
negative rapid 4th generation test at enrollment 
 Currently taking PrEP or interested in initiating PrEP 
 Eligible to take PrEP 
 Creatinine clearance ≥60 ml/min as estimated by Cockcroft-Gault equation at screening 
 Hepatitis B surface antigen (HBsAg) negative 

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 Willing and able to provide written informed consent 
 Able to read and speak English 
 Smartphone ownership compatible with DOT Diary 
 Meets local locator requirements 
 Lives, works or plays in Atlanta Metropolitan Area, San Francisco, Alameda, Marin, 
Contra Costa, Santa Clara, or San Mateo Counties 
  
 
4.2 Exclusion criteria 
 Any reactive HIV test at screening or enrollment 
 Signs or symptoms of acute HIV infection at screening or enrollment 
 History of pathological bone fracture not related to trauma 
 Taking nephrotoxic medications 
 History of participation in the active arm of an HIV vaccine trial 
 In a mutually monogamous sexual relationship with an HIV-negative partner for the past 
12 months 
 Unable to commit to study participation for 8 weeks 
 Any medical, psychiatric, or social condition or other responsibilities that, in the 
judgment of the investigator, would make participation in the study unsafe, complicate 
interpretation of study outcome data, or otherwise interfere with achieving the study 
objectives.  
We will enroll approximately half of the participants who are already on PrEP (n=10) 
and half who are de novo PrEP users (n=10). 
4.3 Recruitment 
 
 
Participants will be recruited through a variety of strategies, including online and social 
 
media strategies (e.g. craigslist, Grindr and Facebook ads); distributing posters, flyers, 
 
and palm cards about the study; and direct outreach at local venues frequented by 
 
YMSM, including community based organizations, schools, churches, and community 
 
events. Those that express interest through advertisements will be followed-up with by 
 
study staff over the phone and/or email, if preferred. In addition, former participants who 
 
have previously given consent to be contacted for future research may also be directly 
 
contacted for recruitment. This will include participants from prior PrEP studies. 
 
4.4 Co-enrollment Guidelines 
 
 
Participants in this study will not be allowed to take part in other concurrent 
 
interventional research studies during their participation in this study; co-enrollment in 
 
observational studies may be allowable with approval of the protocol team. This is due, 
 
in part, to concerns about participant study burden, American Red Cross-mandated 
 
limitations on per-unit-time phlebotomized blood volumes, and confounding in the 
 
interpretation of the study data. 
 
4.5 Participant Retention 
 

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Once a participant enrolls in the DOT Diary Optimization Pilot, the study site will make 
every effort to retain him for the entire follow-up period in order to minimize possible bias 
associated with loss-to-follow-up. Study site staff are responsible for developing and 
implementing standard operating procedures (SOPs) that reflect retention strategies 
necessary to achieve the required retention goal of 90% at the final study 
assessment/visit. Components of such procedures may include: 
 
 
Thorough explanation of the study visit schedule and procedural requirements during 
the informed consent process and re-emphasis at each study visit. 
 
Collection of detailed locator information at the study Screening Visit, and active 
review and updating of this information at each subsequent visit.  
 
Use of appropriate and timely visit-reminder mechanisms.  
 
Immediate and multifaceted follow-up for missed visits.  
 
4.6 Participant Withdrawal 
 
Regardless of the participant retention methods used, participants may voluntarily 
withdraw from the study for any reason at any time. The site investigator also may 
withdraw participants from the study to protect their safety and/or if they are unwilling or 
unable to comply with required study procedures after consultation with the Protocol 
Team. Participants also may be withdrawn if the study sponsor, government or 
regulatory authorities, or site IRBs/ECs terminate the study prior to its planned end date. 
Study staff will record the reason(s) for all withdrawals from the study in participants’ 
study records.  
 
5.0 Study Design 
 
5.1 Overview 
 
This is an optimization pilot study to evaluate and optimize the acceptability, ease of use,  
quality of execution and persistence of use of DOT Diary among young MSM on PrEP 
over an 8-week period, and to refine the app to maximize acceptability for longer periods 
of use (6 months or more) in future studies. We will enroll up to 20 total participants 
(approximately 10 per city) who are either taking PrEP or willing to initiate PrEP at the 
enrollment visit. All participants will be provided the DOT Diary app which will be 
downloaded on to their own personal smartphone and asked to use it over the 8-week 
study period. Participants will return for follow-up visits at 4 and 8 weeks for study drug 
provision (week 4 only) and quantitative and qualitative acceptability assessments. 
 
5.2 DOT Diary app 
 
DOT Diary is a smartphone app designed to track participant adherence to oral PrEP 
 
use and sexual behaviors on a day-by-day basis. DOT Diary is built upon AiCure's 
 
HIPAA-compliant platform which uses artificial intelligence software to automate directly 
 
observed therapy (aDOT).  The system works through a webcam to automatically 
 
confirm that the right patient is taking the right medication at the right time, using security 
 
features to identify evidence for cheating, as well as biometrics to confirm patient identity 
 
and protect against duplicate enrollment and multiple registration of users with same or 
 
similar names. Medication adherence data are automatically transferred to a centralized 
 
cloud-based dashboard for real-time analysis. These data are encrypted and 

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stored, creating a real-time audit trail of every dosing; all protected health information  
 
 
(PHI) is encrypted and withheld from  view on the dashboard.  
 
To facilitate participant tracking of sexual encounters, a sexual diary has been integrated 
with the AiCure aDOT system to create the DOT Diary app. The sexual diary allows 
participants to track sexual encounters, sexual behaviors that occurred in each 
encounter, and rating  characteristics of partners. Partner-specific information (e.g. 
ratings) entered by participants is not transmitted to the study team and remains on the 
phone in the password-protected app. The app will provide a calendar displaying all 
days in which PrEP medication was taken, and all days in which sexual activity occurred, 
allowing participants to see coverage of sexual encounters with PrEP.  Based on 
pharmacokinetic and pharmacodynamic data from prior PrEP trials, the app will also 
indicate the estimated level of protection achieved from PrEP (e.g. none, low, medium 
high), and dosing needed to maximize protection. Participants will be provided 
information that these are estimates of protective levels, and that protection from PrEP is 
not 100%.  
 
 
5.3 Provision of PrEP 
 
Enrolled participants will be provided with PrEP in the form of daily oral FTC/TDF, 
dispensed in 30-pill bottles. Participants who are on PrEP will be asked to use the study 
supply, as this will eliminate issues with gaps in availability of medication. Participants 
will be instructed to take one pill orally once daily with or without food. The drug will be 
provided for 8 weeks (2 bottles total). Two bottles may be dispensed at the enrollment 
visit to the participant to ensure adequate supply between study visits. If participants 
experience difficulties in accessing PrEP after study participation due to insurance 
issues or lack of a health care provider willing to prescribe PrEP, PrEP medication may 
be provided to participants for an additional 3 months (3 bottles) after study completion 
to ensure continued access to PrEP. Beginning at the enrollment visit, study staff will 
assist participants in securing ongoing access to PrEP, including providing linkages to 
local PrEP-prescribing providers/clinics and assisting participants with benefits and PrEP 
navigation.  
 
5.4 Study Product Formulation, Content, and Storage  
 
FTC/TDF is a fixed dose combination tablet containing 200 mg of emtricitabine (FTC) 
and 300 mg of tenofovir disoproxil fumarate (TDF) in each tablet. FTC/TDF study tablets 
must be stored at 25°C, with excursions permitted to 15°C-30°C (59°F-86°F) (see USP 
Controlled Room Temperature). FTC/TDF tablets must be stored in the original 
container while at the site or site pharmacy. Each container is packaged with a child-
resistant screw cap and contains a silica gel to protect the product from humidity. 
 
FTC/TDF 200mg/300mg is available as Truvada®, a medication approved by the U.S. 
Food and Drug Administration (FDA) for treatment of HIV-1 infection and for PrEP to 
reduce the risk of sexually acquired HIV-1 in adults at high risk. Further information on 
Truvada® is available in the current package insert, which is located at http://rsc.tech-
res.com/safetyandpharmacovigilance. 
 
5.5 Study Product Supply and Accountability  

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Truvada® is manufactured and provided by Gilead Sciences, Inc. Truvada® will be 
shipped directly to the site per the Site-Specific Protocol (SSP). Sites will dispense study 
medication, either directly or through a site pharmacist, as described in their SSP. 
Procedures for storage and destruction of unused study products are described in the 
SSP. 
 
5.6 Study procedures 
 
An overview of the study visit and procedures schedule is presented in Table 1. 
Presented below is additional information on visit-specific study procedures.  At all visits, 
locator information will be confirmed, and participants will be provided risk reduction 
counseling, condoms, and lubricant, and a $50 stipend. At all visits, study staff will work 
with all participants to establish continued access to PrEP after completion of the 8-week 
study. Study staff will assist with PrEP navigation services, including referrals to local 
PrEP providers/clinics and linkage to PrEP navigators who can help evaluate insurance 
eligibility, facilitate coverage for PrEP medication and services, and assist with Truvada®  
medication and co-pay assistance programs. 
 
Table 1: Study visits and procedures
 
SCR 
ENR Weeks 
4 
Week 
8 
Obtain informed consent 
√ 
 
 
 
Obtain demographic, risk data, cell phone compatibility for 
assessment of eligibility 
√ 
 
 
 
Locator information 
√ 
√ 
√ 
√ 
Risk reduction counseling, provide condoms and lube 
√ 
√ 
√ 
√ 
Blood tests (HIV 4th gen, creatinine, RPR) 
√ 
√ 
 
√ 
Blood test: HbSAg 
√
 
Rapid 4th gen HIV test (fingerstick) 
 
√ 
 
 
Oral, rectal swabs for GC, CT 
 
√ 
 
√ 
Urine for GC, CT 
 
√ 
 
√ 
Medical history, limited physical examination† 
 
√ 
* 
* 
Confirm eligibility criteria met 
 
√ 
 
 
Download app, provide instructions 
 
√ 
 
 
Dispense TDF/FTC: 1 month of pills (additional month can 
be administered at enrollment) 
 
√ 
√ 
 
Observe first dose using DOT (clinic staff) and DOT Diary 
(app) 
 
√ 
 
 
Provide PrEP Basics, adherence counseling 
 
√ 
 
 
Assist with PrEP and benefits navigation  
√
√ 
√
CASI: sexual behavior (baseline, week 4 and 8), DOT Diary 
use and acceptability (weeks 4 and 8) 
 
√ 
√ 
√ 
DBS collection 
 
 
√ 
√ 
DOT Diary acceptability qualitative interview 
 
 
√ 
√ 
Provide stipend 
√ 
√ 
√ 
√ 
†Medical history and physical exam may be performed at screening and updated at 
enrollment per site preference 
 
*if indicated 
 
 

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5.6.1 Screening Visit 
 
Participants who express interest in participating in the study will be pre-screened by 
telephone, according to what is allowed at each site, to avoid unnecessary screening 
visits. The study is briefly described by telephone, and those participants who remain 
interested are scheduled for a screening visit. 
Study staff will verify that participants meet the eligibility criteria outlined above. All 
screening procedures will take place in a private room. Staff will review the informed 
consent form, including study purpose and design, to ensure that the potential volunteer 
understands the study and wants to participate. Participants will then be asked to undergo 
a test of understanding to ensure that they understand the goals of the study, and 
understand the app and privacy safeguards. Participants who are eligible and demonstrate 
good understanding of the study may then be screened for the study, after signing the 
consent form. If the participant answers multiple questions on the test of understanding 
incorrectly, and is not able to explain the correct answers after additional counseling, the 
staff may elect to either decline to proceed with screening the participant, or ask the 
participant to return for an additional screening visit. If upon re-taking the test of 
understanding at the follow-up visit, the participant still has multiple incorrectly answered 
questions, the participant will not be allowed to enroll. 
After signing the informed consent, staff will ask the participant to complete a form 
collecting comprehensive locator information. The participant's blood will be drawn for HIV 
testing, creatinine, RPR, and hepatitis B surface antigen (HBsAg) testing. Participants will 
also be provided risk reduction counseling, condoms, and lubricant. The participant will be 
provided a $50 for completion of screening procedures. 
 
5.6.2 Enrollment visit 
 
Participants who are eligible after screening will return to the clinic for an enrollment visit. 
An HIV 4th generation rapid test will be performed, and urine and rectal/pharyngeal swabs 
will be collected for STI testing. Participants will complete an online questionnaire via 
computer-assisted self-interview (CASI) that gathers data on baseline demographics, drug 
use and sexual behaviors, knowledge and use of PrEP, and experience using technology. 
Participants will also be provided risk reduction counseling, condoms, and lubricant. A 
study clinician will then perform a medical history and limited physical exam (this may be 
done at screening and updated at enrollment, based on site preference).  Study staff will 
confirm participant eligibility and enroll the participant into the study. Participants will be 
dispensed 1 bottle of TDF/FTC (30 pills). A second bottle may be dispensed to ensure the 
participant will have enough pills prior to his next visit. Participants will also be provided 
the PrEP Basics handout and adherence counseling regarding importance of daily 
adherence to PrEP for maximal protection and strategies to integrate pill-taking into one's 
routine. Participants will also be provided instructions to download the app on to their 
smartphone. Study staff will demonstrate how to use the DOT Diary app, and participants 
will complete the tutorial in the app and demonstrate taking their first dose of TDF/FTC 
using the app. Participants will also select a daily dosing time, and the app will be 
programmed to send the participant a daily text message or app notification at this time to 
take their pill and use the app. Participants will also set preferences regarding the sexual 
diary, including preferences regarding partner rating items. The participant will be provided 
a $50 stipend for completion of the enrollment visit.  One week after enrollment, study staff 

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will check-in with participants by phone to see if they are having any issues with using the 
app or experiencing any problems with taking PrEP. 
 
5.6.3 Week 4  
 
At the week 4 visit, participants will be dispensed 1 bottle of TDF/FTC pills (if not 
dispensed at enrollment) and complete a CASI assessing sexual and drug use behavior, 
use of the various components of DOT Diary, and acceptability of the app. Participants will 
have a medical history and limited physical exam based on symptoms, and their blood 
collected for DBS.  Participants will also complete a qualitative interview to provide 
additional feedback on the acceptability of various components of the app and how they 
could be improved. Study staff will review the context and reasons for overriding the DOT 
component of the app, situations in which the app was particularly easy or difficult to use, 
and other contextual information to probe how the app might be improved for both 
acceptability and persistence of use. Participants will also be asked about their use of the 
diary component, including facilitators and barriers of diary use, communication about 
protection level, the interface of sexual practices and pill taking, and other contextual 
information to probe how the app might be further improved.  
 
All qualitative interviews will be audio-taped; portions or whole interviews may be 
transcribed if they are particularly informative. Between follow-up visits, study staff will 
reach out to participants by phone or text message in the event of prolonged non-use or 
multiple overrides of the device. During the qualitative interview, participants will be asked 
to provide feedback about these contact attempts made by study staff to optimize 
communication.  Based on this feedback and at the direction of the protocol team, the 
algorithm for follow-up with participants may be adapted during the trial, with the goal of 
optimizing these escalation algorithms by the completion of the pilot. 
 
5.6.4 Week 8 visit 
 
In addition to the procedures described at the week 4 visit, participants will have blood 
tests for HIV (4th generation assay), creatinine, and RPR, as well as urine and oral and 
rectal swabs for GC/CT at the week 8 visit. They will also complete a CASI assessing 
sexual and drug use behavior, use of the various components of DOT Diary, and 
acceptability of the app. Participants will also complete a qualitative interview to obtain 
feedback on the app after 8 weeks of use. In addition to the topics discussed at week 4, 
participants will be asked about the acceptability and ease of use of the app overall and of 
different components of the app, whether they thought data in the app accurately 
represents their pill-taking and sexual behaviors, as well as willingness to use the app in 
future studies of PrEP. As this is the final visit, the participant will be thanked for his 
participation, and a notation will be made on whether he is interested in contact for future 
studies. If the participant has not yet established outside access to PrEP, study staff may 
dispense an additional 3 bottles of TDF/FTC to minimize gaps in PrEP coverage while 
they assist the participant in securing ongoing access to PrEP. 
 
After the week 8 visit is complete, staff will also be asked to comment on how well the 
staff-facing interface worked with each participant, including suggestions for improving the 
app. 
 
5.6.5 Toxicity Management  

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The site investigator has the discretion to hold TDF/FTC at any time if s/he feels that 
continued medication use would be harmful to the participant or would interfere with 
treatment deemed clinically necessary according to the judgment of the investigator. 
Clinical or laboratory abnormalities that require follow-up will be documented and the 
clinical provider will contact the participant to schedule an interim visit for follow-up and/or 
repeat laboratory testing. All participants reporting an adverse event will be followed 
clinically until the occurrence resolves (returns to baseline grade, defined as grade at 
enrollment) or stabilizes, or until an effective referral to local health care providers is 
accomplished. 
 
5.6.6 Procedures for participants with suspected or confirmed HIV infection 
 
The Protocol Team must be notified of any reactive HIV test result identified at any time 
after study enrollment. Individuals who have one or more reactive or positive HIV tests at 
Screening are not eligible to participate in this study. Furthermore, at Screening and 
Enrollment, individuals with any signs or symptoms consistent with acute (pre-
seroconversion) HIV infection will not be enrolled. Participants who have any reactive or 
positive HIV test result after enrollment will stop TDF/FTC PrEP and will be referred 
immediately for HIV primary care and treatment per local clinic guidelines.  
 
5.6.7 Interim contacts and visits 
 
Interim contacts and visits (those between regularly scheduled follow up visits) may be 
performed at participant request or as deemed necessary by the investigator or designee 
at any time during the study. All interim contacts and visits will be documented in 
participants’ study records and/or applicable Clinical Research Forms (CRFs).  
 
Some interim visits may occur for administrative reasons. For example, the participant 
may have questions for study staff or wish to provide new contact information. Interim 
visits at which no data are collected are not documented on CRFs. Other interim contacts 
and visits may occur in response to Adverse Effects (AEs) experienced by study 
participants, or loss of study medication. When interim contacts or visits are completed in 
response to participant reports of AEs, study staff will assess the reported event clinically  
and provide or refer the participant to appropriate medical care.  In the event of loss of 
study medication, additional TDF/FTC medication may be dispensed to the participant per 
the discretion of the site investigator, and the protocol team will be notified of this 
occurrence. 
 
5.6.8 Early termination of study participation 
 
Participants may voluntarily withdraw from the study for any reason at any time. The site 
investigator may, with the approval of the Protocol Team, withdraw participants before 
their scheduled termination visit to protect their safety or staff safety, and/or if participants 
are unable or unwilling to comply with study procedures. Participants also may be 
withdrawn if the study sponsors, government or regulatory authorities (including the OHRP 
and US FDA), or site IRB terminate the study prior to its planned end date. Study staff will 
record the reason(s) for all withdrawals in participants’ study records. The week 8 visit 
procedures should be followed when possible, in the event that a participant chooses to 
withdraw early from the study. 
 

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5.6.9 Risks to participation 
 
Phlebotomy  
Venipuncture is sometimes associated with discomfort. Phlebotomy may lead to 
discomfort, dizziness, bruising, swelling, and rarely, an infection at the venipuncture site. 
 
HIV and STI Testing  
Examination and swabbing of the pharynx and rectum can be associated with discomfort. 
Participants may become embarrassed, worried, or anxious when completing their HIV 
risk assessment and/or receiving HIV counseling. They also may become worried or 
anxious while waiting for their HIV and STI test results. Individuals who learn that they 
have an STI or HIV infection may experience anxiety or depression related to their test 
results. Trained clinic staff will be available to help participants deal with these feelings. 
 
Sensitive Questions  
Participants will be asked questions about their sexual behavior that may make them feel 
uneasy. Participants do not have to answer any question that they do not want to and can 
stop answering the questions at any time. Participants may also become embarrassed, 
worried, or anxious when being counseled about PrEP.  
 
 
Confidentiality  
Although study sites will make every effort to protect participant privacy and confidentiality, 
it is possible that participants' involvement in the study could become known to others, and 
that social harms may result (e.g., because participants could become known as at "high 
risk" for HIV infection or be thought to be HIV-positive). For example, participants could be 
treated unfairly or discriminated against, or could have problems being accepted by their 
families and communities. In addition, we are evaluating a mobile app that captures 
information about the participant’s dosing of PrEP and sexual encounters with partners. 
Multiple measures have been taken in the app to protect participant confidentiality, 
including password protection of the app, and blurring and encryption of images prior to 
electronic transmission. However there is the possibility that this information could become 
known to others. Study data will be stored using password protected databases and 
double-locked cabinets will be used to store contact and consent forms, which will have 
participant identifying information.  
 
HIV Resistance  
It is possible that a participant who is taking PrEP and becomes infected with HIV during 
this study may develop viral resistance mutations to TDF/FTC. Multiple steps will be taken 
to minimize the risk of drug resistance. HIV testing will be performed at Screening and 
Enrollment, and then at the week 8 visit. Persons with acute viral syndromes that may 
reflect acute HIV infection will not be eligible for enrollment. If acute HIV infection is 
suspected after enrollment, the participant will undergo evaluation using tests described in 
the SSP Manual. These steps should minimize the risk of drug resistance occurrence by 
identifying HIV infection in its early stages and stopping TDF/FTC. If any participant 
becomes HIV- infected during the study and develops TDF or FTC resistance, an 
alternative treatment regimen could be used that is not impacted by resistance to these 
drugs. 
 
TDF/FTC Side Effects.  

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TDF/FTC is a FDA-approved drug licensed for the indication of PrEP for HIV prevention. 
Risks and side effects related to TDF/FTC include the following:  
 
Gastrointestinal intolerance (such as nausea, abdominal pain, diarrhea, or vomiting) 
 
Flatulence 
 
Headache 
 
Sleep disturbance 
 
Rash 
 
Redistribution/accumulation of body fat. This has been observed in HIV-infected patients 
receiving combination antiretroviral therapy. The mechanism and long-term 
consequences of these events are currently unknown. A causal relationship has not 
been established. These effects are not expected in this study involving a brief exposure 
to antiretroviral drug. 
 
Rare, but serious side effects include: 
 
Lactic acidosis/severe hepatomegaly with steatosis 
 
Renal impairment, including cases of acute renal failure and Fanconi’s syndrome (renal 
tubular injury with severe hypophosphatemia) 
 
Increase in bone metabolism leading to osteopenia or osteomalacia 
 
Hypersensitivity reaction 
 
5.6.10 Benefits to the subject or future benefits 
 
Individuals may not experience any direct benefits by participating in the research. As part 
of study participation, participants will be provided up to 5 months of free TDF/FTC PrEP 
and assistance with PrEP navigation to establish ongoing PrEP access. There may be 
benefits for future PrEP trials or PrEP use, if information gained results in an improved 
aDOT app. 
 
6.0  Data management and analysis 
 
6.1 Data management 
CASI data will be collected online using Qualtrics and stored in password-protected 
databases. The aDOT app will require a unique log-in and password and secure 
connections will be utilized as a way to protect confidentiality. Participants will be assured 
that the information they provide will be managed with the highest standards of 
confidentiality. All study staff will be trained in Good Clinical Practice (GCP) and will have 
received additional training about maintaining confidentiality. 
 
The AiCure smartphone app makes a real-time determination of whether the participant 
has properly administered their medication, providing reminders and encouraging following 
proper procedures to ensure medication ingestion as prescribed.   Study participants will 
receive a medication reminder at a time within a predefined window. This notification 
reminds patients to take their medication dose while using the AiCure smartphone app.  
Participants will follow a series of prescribed steps in front of the front-facing webcam to 
visually confirm their ingestion of the medication. The application on the smartphone will 
make an automated determination of whether the patient has properly taken their 
medication at the prescribed time. There is no need for a healthcare provider to review the 
administration, nor would a healthcare provider need to be available at the time the patient 

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takes their medication. The amount of guidance that the device provides to the patient is 
automatically reduced as the patient becomes more proficient at using the application. 
After the device confirms proper medication ingestion, video recordings will be encrypted 
and transmitted to a secure centralized location for further analysis.  Once received at the 
centralized location, the data is then removed from the provisioned device (store and 
forward). The captured data and video is reviewable through a roles and rules restricted 
system ensuring privacy of the information allowing access to the data by study team 
members at the research sites. Video data from the AiCure smartphone app will only be 
available to researchers and will be analyzed for proper medication administration.  
Individuals outside the clinical sites will not know the identity of the study participants and 
will not have access to any medical or health records of the patients. Video data will be 
destroyed on or before January 1, 2020. The system is compliant with the Health 
Insurance Portability and Accountability Act (HIPAA), which protects the privacy and 
security of healthcare information. 
Phone numbers of the patients may also be collected and stored in an encrypted manner. 
Storing the phone numbers will allow for direct communication with patients, including 
automated messaging from the Platform device and contact by healthcare providers or 
other monitoring personnel.  At no time is the phone number visible to healthcare 
providers or monitoring personnel.  Individuals outside the clinical sites will not be provided 
with patient names, nor will they be given access to patient medical records. 
Audio-recorded qualitative interviews during study visits will be recorded onto digital media 
using a portable recorder that records directly into computer readable format and can be 
transferred from the recorder and stored in an encrypted volume that is then stored on a 
secure computer or burned on a DVD which will be stored in a locked cabinet. The data 
will be transferred via USB cable to a password-protected, encrypted volume created on a 
laptop computer. Only study personnel will have access to the password. A copy of the 
encrypted volume would be stored on secured servers at one of the research institutions 
for study team members at different research sites to access. The encrypted volume will 
be opened (mounted) only when it is being used for analysis purposes.  At all other times, 
the encrypted volumes containing the data will remain closed (dismounted) and thereby 
encrypted. Because the data are stored in an encrypted format, the risk of unauthorized 
access is very low.  
 
6.2 Statistical Analysis 
 
6.2.1 Primary Objectives 
The primary objectives of the study are: 
 
1. 
To assess key attributes including acceptability and ease of use over 8 weeks of use 
of DOT Diary by MSM on PrEP and identify potential improvements to the app to 
maximize acceptability 
Using CASI, we will assess acceptability and ease of use of the app overall and of 
different components of the app using the Client Satisfaction Questionnaire (CSQ-8), 
a validated assessment tool assessing various domains of the app with 
demonstrated high internal consistency across a number of studies,48 and the 
System Usability Scale, a validated 10-measure scale that assesses subjective 
usability of a system, as well as other measures of acceptability and ease of use of 

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the app. Average values of our measures of acceptability and ease of use will be 
estimated with 95% confidence intervals.  Margins of sampling error (MSEs).   The 
proposed sample of 20 participants will allow us to estimate means within margins of 
sampling error (i.e., half widths of 95% confidence intervals) of 0.47 standard 
deviations (SDs). Areas of refinement of the app will be elicited through qualitative in-
depth interviews and analyzed as described below. 
 
2. 
To evaluate the quality of execution and persistence of use of the DOT and sexual 
diary components of DOT Diary by young MSM on PrEP over an 8-week period 
and identify potential improvements to the app to maximize quality of execution 
and persistence 
We will estimate the average use of DOT and the diary, as proportions of days and 
weeks on study, respectively. Frequency of use and time spent on different app 
components will be calculated.  MSEs.  Population proportions will be estimated 
within MSEs of 13-22 percentage points, depending on the sample proportions. 
 
 
6.2.2 Secondary Objectives 
 
The secondary objectives of the protocol are: 
 
1. 
To assess participant preferences for feedback on non-use or  self-reported dosing 
that over-rides the device   
2. 
To assess participant perception of concordance between a review of app data and 
their actual pill-taking and sexual practices; including reasons for discrepancies 
3. 
To get a preliminary assessment of overall PrEP adherence by tenofovir diphosphate 
levels in DBS among young MSM using the DOT Diary app 
 
6.2.3 Qualitative Data analysis 
Recordings of the in-depth interviews (IDIs) will be analyzed using MAXQDA software for 
qualitative analysis. The analysis team will include members at both San Francisco and 
Atlanta study site, as well as a representative from AiCure. Interviewers will complete a 
debrief report promptly following each interview to capture results relevant to the study 
objectives.  Debrief reports will also include an assessment of whether the interview merits 
additional in-depth analysis. Debriefing reports have been shown to be of sufficiently high 
quality to use as a primary source. 26 Debrief reports and selected transcripts  will be 
reviewed to for emergent themes and results relevant to the study objectives.  Team 
members will create summary reports based on this analysis for use in providing feedback 
and suggestions in achieving study goals. Debrief reports will be reviewed promptly in order 
to provide feedback and suggestions for subsequent interviews. The first two audio 
recorded interviews and resulting debrief report at each site will be reviewed by a member 
of the team at the other site in order to assure uniformity in interview approaches and 
information included in debrief reports.  
 
7.0 Safety Monitoring and Adverse Event Reporting 
 

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7.1 Safety Monitoring and Clinical Data Review  
A multi-tiered safety review process will be followed for the duration of this study. Close 
cooperation between the Protocol Chair, study site investigators, study coordinator, 
statistician, and other study team members will be necessary to monitor participant safety 
and to respond to occurrences of toxicity in a timely manner. The research team will have 
regularly scheduled meetings during the period of study implementation, and additional ad 
hoc calls will be convened if required. 
The study site is responsible for continuous close monitoring and management of AEs. The 
study site investigators are responsible for the initial evaluation and reporting of safety 
information at the participant level, and for alerting the Protocol Team if unexpected 
concerns arise. The site will have SOPs describing methods for AE reporting and toxicity 
management to ensure that AEs are reported and managed in accordance with the protocol 
and for alerting the Protocol Team if unexpected concerns arise. 
7.2 Adverse Event Definition and Reporting  
An AE is defined as any untoward medical occurrence in a clinical research participant 
administered a study product and which does not necessarily have a causal relationship 
with it. As such, an AE can be an unfavorable or unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporally associated with the use of a 
study product, whether or not considered related to the product.  
As daily oral FTC/TDF for PrEP is a licensed medication, we will focus assessment of AEs 
on the known toxicity profile of the medication, including creatinine elevations / decreases in 
creatinine clearance, bone fractures / toxicity, and symptoms associated with a start-up 
syndrome (e.g. diarrhea, nausea, headache, abdominal gas). A targeted symptom review 
will be performed at each visit using a symptom checklist focused on symptoms associated 
with FTC/TDF. The severity of these symptoms will be graded according to the following 
scale in order to aid clinical management of symptoms. 
 
 
Abnormal creatinine values will be graded according to the following scale: 
 
 

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Study participants will be provided a telephone number and contact information for an on-
call clinician and will be instructed to contact the clinician to report any AEs as-needed. For 
life-threatening events, participants will also be instructed to seek immediate emergency 
care. At the time a laboratory AE requiring retesting or follow-up is identified, participants will 
be called back to the clinic if possible, and will be followed as deemed clinically appropriate. 
All participants reporting any AE assessed as related to FTC/TDF administration (see 
Section 7.3) will be followed clinically, until the AE resolves (returns to baseline) or 
stabilizes.  
 
7.3 Assignment of Relationship to FTC/TDF  
Relatedness is an assessment made by a study clinician of whether or not the event is 
related to the TDF/FTC administration. The relationship of all clinically relevant AEs to the 
FTC/TDF will be assessed per the clinical judgment of the investigator based on the 
package insert. 
 
7.4 Reporting Requirements for this Study  
The site investigator will report an adverse event to the local IRB if study staff determines it 
may qualify as a Serious or Unexpected Adverse Event that is assessed to be related to 
study product. An adverse event is defined as being unexpected if the event exceeds the 
nature, severity or frequency described in the current IRB Application including the protocol, 
consent form and prescribing information.  
A serious adverse event (SAE) includes any AE that meets any of the following criteria: 
o Result in death  
o Are life-threatening AEs 
o Require inpatient hospitalization or prolongation of existing hospitalization 
o Result in persistent or significant disability/incapacity;  
An unexpected AE also includes any AE that meets any of the following criteria: 
 
Results in subject withdrawal from study participation, 
 
Due to an overdose of study medication, or 
 
Due to a deviation from the IRB approved study protocol 
 
In addition, all SAEs will be reported to the Protocol Team within 72 hours of recognition by 
study staff. 
 
7.5 Social Impact Reporting 
 
Although the study site will make every effort to protect participant privacy and 
confidentiality, it is possible that participants' involvement in the study could become known 
to others, and that a negative social impact may result (e.g. participants could be perceived 
as being HIV-infected or at "high risk" for HIV infection). For example, participants could be 
treated unfairly, or could have problems being accepted by their families and/or 
communities. Negative social impacts from use of the app will also be monitored, such as 
unintended loss of privacy or confidentiality. Negative social impacts will be collected during 
regular visits. In the event that a participant reports a negative social impact, every effort will 
be made by study staff to provide appropriate care and counseling to the participant as 
necessary, and/or referral to appropriate resources for the safety of the participant. Each 

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site will provide such care and counseling in accordance with standardized guidance.  While 
maintaining participant confidentiality, the study site may engage its Community Advisory 
Board (CAB) in exploring the social context surrounding instances of social impacts, to 
minimize the potential occurrence of such an impact. 
 
8.0 Laboratory Specimens and Biohazard Containment 
 
8.1 Local Laboratory Specimens  
Specimens will be collected for testing at the local laboratory. All testing will be done as part 
of standard of care except DBS. Local laboratory evaluations/procedures will include: 
 
HIV testing  
 
Serum creatinine for creatinine clearance  
 
HBV testing (HBsAg)  
 
Syphilis testing  
 
Urine GC/CT testing  
 
Rectal GC/CT testing  
 
US local laboratories must be certified under the Clinical Laboratory Improvement 
Amendments (CLIA-certified).  Rapid HIV testing may be performed under a CLIA-waiver at 
the research clinic site. 
The study site will adhere to standards of Good Clinical Laboratory Practice (GCLP), and 
local standard operating procedures for specimen management including proper collection, 
processing, labeling, transport, and temporary storage of specimens.  
 
8.2 Dried Blood Spots (DBS)  
Dried blood spot (DBS) specimens will be collected at the week 4 and 8 visits. Specimens 
will be frozen and batch shipped to the University of Colorado Pharmacology Laboratory for 
testing of TDF-DP and FTC-TP drug concentrations.  
 
8.3 Biohazard Containment 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the United States 
Centers for Disease Control and Prevention (CDC). All infectious specimens will be 
transported in accordance with United States Code of Federal Regulations (42 CFR 72). 
 
9.0 Administrative Procedures 
 
9.1 Training 
Recruiters and staff who collect data will complete CITI, GCP, and Human Subjects training, 
and also a minimum of one hour of training on recruitment procedures, use of the aDOT 
app, and all study instruments. Trained qualitative interviewers will conduct the in-depth 
interviews and code the responses. 
 

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9.2 Confidentiality  
All staff are required to sign an oath of confidentiality and receive annual training on 
maintaining confidentiality, privacy, and handling questions about study participants from 
friends, employees, and insurance companies. Study staff will discuss any privacy concerns 
the participant may have regarding the need to contact them, via phone or e-mail, and 
contact methods will be tailored accordingly. A participant’s involvement in this study will not 
be divulged without the subject’s written permission, except as necessary for monitoring by 
the sponsor and/or its contractors; other government and regulatory authorities, and/or the 
local IRBs. 
Information collected from subjects will be handled in the most confidential manner possible. 
All data will be coded by a subject number. Personal identifier records will be kept in a 
password protected computer files and double-locked cabinet at the study site, and any 
forms with identifying information will be stored separately from other study data. Digital 
audio and video recordings will be encrypted and stored on password protected computers 
until destroyed. A Business Associates Agreement for HIPAA has been established with 
AiCure to ensure confidentiality and security of data stored by AiCure. In case of hard drive 
failure, backup copies of video data will be stored for safekeeping as encrypted volumes. 
Transcripts of the recordings will be transcribed in such a way as to not have any identifying 
information present. Participation in study visits will take place in a private office. 
Questionnaires and surveys will not include any personal identifiers. 
Each patient will assign and maintain their own password for access to the app and any 
data therein. Any patient-related data stored in the local device, including sexual history 
data, will be stored in an encrypted state at all times, and will be unencrypted only when 
access is requested after password confirmation by the user. 
 
9.3 Informed Consent 
The informed consent process will conform to local IRB consent standards. Informed 
consent will be written and obtained at the study site in a private room, before any study 
procedures are initiated. Potential participants will be given a copy of the informed consent 
form and the Experimental Subject’s Bill of Rights, and a study staff member will offer to 
review the form with the participant, and answer any questions the participant may have. 
The informed consent will be witnessed by a member of the study staff.  A copy of the 
signed form will be given to the participant and the original will be kept in a separate, locked 
file. 
 
10.0 
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Haberer JE, Baeten JM, Campbell J, et al. Adherence to antiretroviral prophylaxis for 
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Bekker LG, Hughes J, Amico KR, et al. HPTN 067/ADAPT Cape Town: A Comparison of 
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Sullivan P, Sineath C, Kahle E, Sanchez T. Awareness, willingness and use of oral pre-
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Cohen SE, Vittinghoff E, Bacon O, et al. High Interest in Preexposure Prophylaxis 
Among Men Who Have Sex With Men at Risk for HIV Infection: Baseline Data From the 
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15. 
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Integrated With Municipal- and Community-Based Sexual Health Services. JAMA Intern 
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Hosek S, Rudy B, Landovitz R, et al. An HIV pre-exposure prophylaxis (PrEP) 
demonstration project and safety study for young men who have sex with men in the 
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17. 
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Liu AY, Yang Q, Huang Y, et al. Strong relationship between oral dose and tenofovir hair 
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Chaiyachati KH, Ogbuoji O, Price M, Suthar AB, Negussie EK, Barnighausen T. 
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22. 
Hu D, Juarez DT, Yeboah M, Castillo TP. Interventions to increase medication 
adherence in African-American and Latino populations: a literature review. Hawai'i 
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23. 
Ma M, Brown BR, Coleman M, Kibler JL, Loewenthal H, Mitty JA. The feasibility of 
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25. 
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States and Dependent Areas, 2013. HIV Surveillance Report, Vol 25. 2015. Accessed 
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26. 
Simoni JM, Beima-Sofie K, Amico KR, Hosek S, Johnson MO, Mensch B. Can “Debrief” 
Reports Expedite Qualitative Studies?  A Post-Hoc Analysis of VOICE-D Trial Data. 
Adherence 2017; June 4-6, 2017; Miami, FL.