Conditions: HIV/AIDS Substance Use Disorders Adherence, Medication
Keywords: PrEP Substance Use Disorder Digital Pills Medication Adherence
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 16
Healthy volunteers: no

Brief summary:
This study deploys a novel digital pill with Emtricitabine/Tenofovir (TDF/FTC) among MSM with substance use to monitor PrEP adherence. The investigators will enroll N=15 HIV uninfected MSM with self reported substance use who are on PrEP or initiating PrEP to use digital pills over encapsulating TDF/FTC for 3 months. The investigators will assess the feasibility of using digital pills in this study population as well as understand the acceptability of digital pills for adherence measurement using semi-structured individual interviews. Additionally, the investigators will measure adherence over time, as well as episodes of suboptimal PrEP adherence.

Detailed description:
Eligible study participants will be screened and enrolled at Fenway Health (Boston, MA). Participants will complete a quantitative assessment on their history fo substance use, sexual risk and PrEP adherence, and be trained to use the digital pill for 90 days and instructed to take PrEP daily during the course of the study. Participants will return each month for a study visit to assess their use of the technology. At study visit 1 and 3, we will obtain dried blood spots (DBS) to measure drug levels and to confirm adherence detected by the digital pill. The investigators will also obtain drugs of abuse screens from DBS. At the final study visit (3 months), participants will undergo a semi-structured qualitative interview to understand the user response to digital pills.

Arms:
arm 1: Digital Pills containing Truvada ingested once daily as PrEP

Interventions: intervention 1: Digital pill intervention 2: Truvada
Intervention descriptions: intervention 1: Digital pills over encapsulating Truvada intervention 2: Truvada prescribed with digital pills for PrEP

Protocol document:
Prot_000.pdf: 
 
Version 11.1 
 
 
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DigiPrEP Detailed Protocol 
 
Official title:  Feasibility and Acceptability of Digital Pills to Monitor PrEP Adherence in MSM With 
Substance Use  
 
NCT number:  NCT03842436  
 
Document date:  November 05, 2019 
 
 


 
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Detailed Protocol for Feasibility and Acceptability of Digital Pills to Monitor PrEP Adherence in MSM with 
Substance Use Disorder (DigiPrEP) 
IRB Protocol: 1087733 
Version 11.1, November 5, 2019 
Principal Investigator: Peter R Chai MD MMS 
 
I. Background and Significance 
Digital pills provide real-time verification of medication ingestion events and can be used to monitor medication 
adherence; previous studies have demonstrated their acceptability in real-world patient populations.1-3 Digital 
pills comprise a radiofrequency emitter combined with a standard gelatin capsule that is compounded with a 
study medication.4 Upon ingestion of the digital pill, the chloride ion gradient in the stomach energizes the 
radiofrequency emitter, transmitting a unique signal of medication ingestion that is captured by a wearable 
Reader. The Reader acts as a relay, storing and transmitting ingestion data to a smartphone and cloud based 
server. Ingestion data is then available for real time interpretation by clinicians. Digital pill technology has been 
previously applied to opioid ingestion, diabetes management, and as a surrogate for directly observe therapy in 
schizophrenics.1-3  
 
Direct measures of medication adherence are an important advance in the study of medication adherence, 
especially among patients with poor adherence linked to substance use disorder. Although recent studies have 
demonstrated pre-exposure prophylaxis (PrEP) with once daily Truvada is efficacious in preventing HIV 
infection, protection is highly dependent on adherence. There is a clear dose response relationship between PrEP 
adherence and prevention of HIV transmission.2 Post-hoc analyses of the iPrEX data (corroborated by the PROUD 
and iPERGAY studies) found that individuals whose drug levels were consistent with taking 4 or more doses of 
TDF/FTC a week had a greater than 90% level of protection from HIV; but only 50% of MSM in iPrEX achieved 
consistent adherence.2,4-6 Substance use among MSM occurs syndemically in the context of other mental health 
vulnerabilities (most notably depression, sexual trauma, and intimate partner violence7 that increase their risk for 
condomless anal sex and HIV infection). Similarly, among HIV-infected MSM, the impact of substance use on ART 
adherence and HIV treatment outcomes is also well established18, 20 and recent studies have already identified 
substance use as a significant barrier to optimal PrEP adherence among MSM.19, 21 
 
II. Specific Aims 
 
Aim 1: Technology Optimization. To optimize the acceptability of DigiPrEP among MSM or transgender individuals 
with self-reported substance use through individual interviews (N=30); 
Aim 2: Technology Deployment. To deploy DigiPrEP in MSM with self-reported substance use who are on PrEP 
(N=15) in a 90-day open label, proof-of-concept trial; and  
Aim 3: Technology Evaluation. To evaluate the user response and primary care physician response to using 
DigiPrEP in the real-world through qualitative interviews. 
 
III. Subject Selection 
 
Aim 1 Inclusion Criteria: 
1. MSM (cisgender male)  
2. Self-reported use of non-alcohol 
substances of abuse in past 6 months 
3. On PrEP or qualifies for PrEP 
4. Age 18 or older 
Aim 1 Exclusion Criteria: 
1. Does not speak English 
2. HIV positive 
 


 
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Aim 2 Inclusion Criteria: 
1. MSM (cisgender male)  
2. Self-reported use of non-alcohol 
substances of abuse in past 6 months 
3. Currently taking PrEP 
4. Has qualifying laboratory tests (Cr, hepatitis 
B immunization, STI testing and syphilis) 
5. Age 18 or older 
Aim 2 Exclusion Criteria: 
1. Does not speak English 
2. HIV positive 
3. Identifies as transgender 
4. Estimated creatinine clearance <60ml/min 
5. Active hepatitis B treatment 
6. Does not own a smartphone 
7. Taking proton pump inhibitors 
8. History of Crohn’s disease or ulcerative colitis 
9. History of bowel surgery, gastric bypass, bowel 
stricture 
10. History of GI malignancy or radiation to abdomen 
11. Unable/unwilling to ingest digital pill 
Aim 3 Inclusion Criteria: 
1. Participants in Aim 2 will be enrolled in 
Aim 3. 
Aim 3 Exclusion Criteria: 
1. Did not participate in Aim 2. 
 
 
Due to the exploratory nature of this proposal, we will enroll only MSM individuals (cisgender male) in this 
study with the intent of generating preliminary data on feasibility of the digital pill in order to conduct future 
studies with transgender men and women. 
 
IV. Subject Enrollment 
 
For all aims of this study, we will publicize the study at Fenway Health primary care provider (PCP) meetings.  
 
Recruitment of Fenway Patients 
Aim 1:  We will advertise the study through monthly research meetings at The Fenway Institute, and we will 
ask Fenway Health primary care physicians and other Fenway Health clinicians to refer patients to us. 
Potential participants will also be screened during clinical appointments at Fenway Health by study staff. New 
patients at Fenway Health are given a Notice of Privacy Practices which informs them that their protected 
health information may be utilized for research when the research proposal is IRB-approved and conducted in 
accordance with HIPAA privacy and confidentiality rules. Further, under HIPAA, as employees of the covered 
entity (Fenway Health), the study staff may utilize medical records to identify potential participants. Potentially 
eligible patients will be identified using crystal reports. A study staff member will then work with medical 
assistants and/or providers before approaching patients to assess interest. After entering the room and prior to 
screening, the study staff member will explain the study before asking permission to complete the screening 
questionnaire. Those who appear to be eligible will be invited to participate in the study after their appointment, 
or set up an appointment in the future. We will also post flyers and cards advertising the study at Fenway 
Health and throughout the greater Boston area, as well as via social media platforms (Grindr, Scruff, Growler, 
and Facebook). Participants who are interested in the study will call the RA and undergo a phone screen to 
ensure they meet enrollment criteria prior to being scheduled for a study visit.  
 
Aim 2/3:  We will utilize chart review, as well as screening during clinical appointments at Fenway Health (as 
described above) to identify HIV negative MSM with a history of substance use disorder who have qualifying 
laboratory evidence and are prescribed PrEP at Fenway Health. We will also identify potential participants 
through posted flyers in the greater Boston area, email blasts from the Fenway Health recruitment team, and 
social media advertisements. Email blasts from the Fenway Health recruitment team are received by patients 
and general public who sign up to receive general emails from Fenway Health regarding its daily operations, 
events and research studies. If applicable, we will inform their treating clinicians that their patient might be 
eligible for the study. The clinician will tell the patient about the study and acquire permission from the patient 
for study staff to speak with them at their next regularly scheduled clinic appointment or provide them with 
contact information for the study team. We otherwise will utilize crystal reports using our HIPAA Waiver to 


 
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screen potential Fenway Health participants, and approach them on the medical floors after consultation with 
the medical team. If potential participants are interested in the study after a discussion with their primary care 
physician, we will arrange a time to contact the participant and discuss the study in further detail. We will 
schedule an appointment with the study staff to discuss DigiPrEP. If participants enroll in the study, we will 
have them sign a medical release of information form to notify their treating clinician at Fenway Health about 
their participation. Additionally, we will ask participants in Aim 1 if they would be willing to participate in Aims 
2/3. Participants who are interested in the study can respond to posted flyers, recruitment emails, or social 
media advertisements will call the RA and undergo a phone screen to ensure they meet enrollment criteria 
prior to being scheduled for a study visit. 
 
Passive Recruitment 
We will also post flyers and cards advertising the study at Fenway Health and throughout the greater Boston 
area, and engage in recruitment via social media platforms (Grindr, Scruff, Growler, and Facebook) in order to 
extend our reach to as many potentially eligible individuals as possible. Participants who are interested in the 
study will call or email the RA and undergo a preliminary phone screen to ensure they meet basic enrollment 
criteria prior to being scheduled for a study visit. 
 
Shared Cross-study Recruitment 
As potential participants are screened for DigiPrEP, they may additionally be eligible for a parallel study that is 
testing the use of the digital pill for PrEP adherence linked to a smartphone behavioral intervention in MSM 
with moderate to severe stimulant use disorder (PrEPSteps- IRB 1162312). While screening participants, if 
their schedules do not allow them to participate in DigiPrEP, but they indicate willingness to participate in other 
Fenway Studies, we will discuss the PrEPSteps study with them as described in our cross study screener. 
Participants who would benefit from learning about their PrEP adherence would likely also benefit from 
interventions that boost adherence as studied in PrEPSteps. We therefore will share screener data between 
the two studies in the case that participants also qualify for PrEPSteps and would like to participate. Both 
studies are conducted by the same PI and study coordinators.  
 
V. Study Procedures 
 
Aim 1:  In this aim, we will conduct individual interviews (see uploaded document Aim 1 Interview) of MSM with 
self-reported substance use currently on or qualifying for PrEP. Study participants will sign informed consent 
prior to the qualitative interview. An audio-recorded individual interview will be conducted by the RA or study 
investigator. We will explore the digital pill, acceptance of the technology, willingness to use technology for 
PrEP adherence and willingness to interact with the technology to reinforce adherence and address influencers 
of adherence. Interviews will be audio recorded, transcribed, and analyzed by the study team (see section VI), 
after that audio recordings will be destroyed. Participants will also complete a brief self-report questionnaire 
(see uploaded document (DigiPrEP_selfreport_questionnaire). At the end of the visit, the participant will be 
remunerated via a $40 gift card. 
 
Aim 2/3:  In Aims 2 and 3, we will deploy DigiPrEP in MSM who are already prescribed PrEP. This portion of 
the study will involve 5 study visits over the course of 3-4 months where participant ingest DigiPrEP daily. 
Participants will be prescreened via phone to assess initial eligibility for participation; if eligible, they will be 
scheduled for an in-person Screening Visit, where they will sign informed consent and full eligibility will be 
determined via rapid HIV test and review/conduct of necessary blood work. If determined to be eligible at the 
Screening Visit, participants will be scheduled for Study Visit 1; in the interim, a 90-day supply of digital pills will 
be ordered for shipment to the Fenway Pharmacy. At Study Visit 1, participants will be trained in the use of the 
digital pill and complete a self-report questionnaire (same questionnaire as in Aim 1). At Study Visit 2, we will 
dispense an additional 30-day supply of the digital pill, review adherence data with the participant, conduct a 
pill count of remaining pills, and conduct a blood draw for adherence. At Study Visit 3, we will dispense a final 
30-day supply of the digital pill, review participant adherence data, and conduct a pill count of remaining pills. 
Following both Study Visits 2 and 3, we will also forward adherence data from the study visits to the 
participant’s Fenway Health PCP, if applicable. At Study Visit 4, the final visit, we will review adherence data, 


 
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conduct a pill count of remaining pills, and conduct a blood draw for adherence. Additionally, as part of Aim 3, 
we will conduct a 20-minute semi-structured exit interview to assess participants’ experiences in the study.  
 
Aim 2 – Prescreening:  Study participants prescreened on the phone who do not have a PCP at Fenway 
Health will be asked to bring their most recent copies of laboratory data to the in-person Screening Visit 
(chemistry or creatinine, evidence of hepatitis immunization status (within the past 6 months), sexually 
transmitted infection screening (STI) and syphilis screening (within the past 3 months)). If participants do not 
have qualifying laboratory tests, we will notify the participant that we will conduct any needed laboratory testing 
at the Screening Visit. We will send participants an email with a list of labs they should bring as part of the 
reminder for the Screening Visit. 
 
Aim 2 – Screening Visit:  This is the first study visit. During this visit, the participant will meet the RAs and 
study team. We will explain the course of the study, obtain written informed consent, and obtain a signed 
medical release of information form and completed locator form from participants. During the informed consent 
process, we will ask if participants want us to relay adherence data from the digital pill to their PCP; if they opt 
in, we will send monthly adherence information to their PCP. After obtaining consent, we will conduct a rapid 
HIV test to ensure that participants are HIV negative. We will also review laboratory data with participants; if 
they did not bring lab results with them (or grant us access to lab results via an online patient portal, following 
signing of medical release form), we will call their PCP and confirm their eligibility for PrEP (see 
DigiPrEP_PCP_communication_script). If participants are missing any required labs, they will receive those 
tests at this visit. If individuals screen positive for active hepatitis infection, or have creatinine clearance 
<60ml/min, they will be ineligible for the study and referred back to their PCP for continued medical care. 
Individuals who test positive for STIs will be referred to their PCP for treatment. If they do not have a PCP, they 
will be referred to HIV care or STI care at Fenway Health or Brigham and Women’s Hospital. Once we have 
reviewed all required laboratory work, and confirmed HIV status as negative, we will schedule participants for 
Study Visit 1. Additionally, following this visit, and prior to Study Visit 1, we will order a 90-day supply of digital 
PrEP for eligible participants (process detailed below following description of study visit procedures). 
 
Aim 2 – Study Visit 1:  During Study Visit 1, participants will complete a baseline self-report questionnaire, 
and the study team will conduct a short training around operation of the digital pill system (i.e., digital pills, 
Reader device, and mobile application) and instruct participants on basic troubleshooting of the technology. 
We will also help participants to download the mobile application where their adherence data will be recorded 
and accessible, train them on how to use the app, and register them on the collaborator interfaces (iAssist and 
Nomi). Participants will be provided with a 30-day supply of digital PrEP (Truvada); participants will then ingest 
their first digital PrEP dose during the visit to demonstrate their understanding of how to operate the digital pill 
system and to ensure the technology is functioning properly. Participants will receive a brief reference guide 
(see refguide) with key contact information and basic information regarding the digital pill and Reader. 
Participants will be scheduled for Study Visit 2, which will occur a maximum of 30 days (i.e., 23-30 days) after 
Study Visit 1, in order to ensure that participants do not run out of digital pills prior to receiving a refill. We will 
contact study participants via text message on days 1, 2, 5, and 7 to ensure technology is functioning. 
Additionally, beginning one week after Study Visit 1, participants will receive brief weekly surveys through the 
Nomi interface asking them to self-report substance use and sexual activity (see DigiPrEP Study 
Messages_Participant Only). At the end of Study Visit 1, participants will be remunerated via a $25 check.   
 
Aim 2 – Study Visit 2:  We will contact participants on days 23, 25, and 29 to remind participants of their 
Study Visit 2 appointment. During this study visit, participants will have blood drawn via phlebotomy and placed 
on a blood spot card in order to assess PrEP adherence. De-identified specimens will be banked for future use 
in drug abuse screening. We will review digital pill adherence data with participants in Nomi and conduct a pill 
count to validate adherence data from the digital pill and Reader. We will review discordant counts, periods of 
Reader activity that suggest no use of the Reader device, and digital pill use with the participant. We will 
additionally review any potential nonadherent events detected by the digital pill with participants using timeline 
followback to gauge potential reasons for nonadherence. We will view the adherence interface with study 
participants and discuss events surrounding potential nonadherence events. We will record user responses to 


 
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each of these timeline followback events. We will also dispense an additional 30-day supply of digital pills to 
participants. We will schedule participants for Study Visit 3 prior to discharge, which will occur a maximum of 
30 days (i.e., 23-30 days) after Study Visit 2. Participants will be reminded that we will pass their adherence 
data along to their PCP; participants will have the option of opting out of this mechanism at each study visit. At 
the end of Study Visit 2, the participant will be remunerated via a $25 check. 
 
Aim 2 – Study Visit 3:  We will contact participants on days 53, 55, and 59 to remind them of their Study Visit 
3 appointment. During this visit, we will review adherence data from the digital pill in Nomi, conduct pill counts 
with participants, address discordant counts and review reader activity with the participants and address any 
nonadherence events potentially linked to sexual activity or substance use. The participant will receive a final 
30 day refill of digital pills and will be remunerated via a $50 check. 
 
Aims 2/3 – Study Visit 4:  This is the final study visit. We will contact participants on days 83, 85 and 89 to 
remind participants of Study Visit 4, including a reminder to bring all DigiPrEP equipment to this visit to return 
to the study team. Participants will have blood drawn for adherence, and we will review adherence data from 
the digital pill in Nomi and conduct pill counts. Additionally, we will conduct a 20-minute semi-structured 
interview (see Aim 3 Exit Interview) to assess participants’ experience working with DigiPrEP and participating 
in the study. Participants will be encouraged to return to their PCP for continued PrEP prescribing. If they do 
not have a provider who can continue to prescribe PrEP following the end of the study, we will refer them to a 
provider at Fenway Health or the Brigham and Women’s Hospital infectious disease clinic. Participants will be 
remunerated a total of $150 at the end of this visit (i.e., the planned $75, as well as an additional $75 for 
assistance finding and troubleshooting bugs in the mobile app, and for completion of all study procedures). 
 
Participant contact:  We will contact participants via text message at described times after study visits (see 
DigiPrEP Study Messages_Participant Only). Additionally, if participants do not respond to text messages 
(e.g., technology check-ins at days 1, 2, 5, 7), or to study appointment reminders, we will contact them via 
phone, text, and/or email. If we do not detect digital pill ingestions for 48 hours (2 doses) or if there are more 
than 2 missed doses in a week, we will contact participants via phone, text, and/or email to understand if there 
are issues with operating the digital pill or if missed doses represent true medication nonadherence. If we are 
unable to reach participants, we will leave phone or text messages, and call participants back the next 
business day. We will also communicate information about the study, including required lab work 
documentation for the Screening Visit, to participants via email. 
 
Drug procurement:  Digital pills are procured from Curant Pharmacy (our collaborating pharmacy). Once 
participants sign informed consent during the Screening Visit, and we have confirmed qualifying laboratory 
work and eligibility, we will securely email a Drug Order Form to Curant. This order form will contain the 
following information, as required by Curant: (1) participant’s name; (2) participant’s date of birth; (3) participant 
study ID number; (4) participant’s anticipated start date; (5) target drug delivery date; and (6) delivery 
information for pharmacist at Fenway Pharmacy. Following receipt of the Drug Order Form, Curant will FedEx 
90 digital pills (three 30-day supplies) to the Fenway Pharmacy. Confirmation of shipment receipt will be 
documented in the DigiPrEP Pharmacy SOP binder. At Study Visits 1, 2, and 3, we will complete a Prescription 
Card that study staff will bring to the Fenway Pharmacy, who will sign out drug to us. If participants no-show 
during their study visit, we will return and sign back in drug to the Fenway Pharmacy. In the event that a 
participant drops out of the study and we have remaining drug assigned to them in the Fenway Pharmacy, we 
will securely email a Cancel Order Form to Curant, along with a new Drug Order Form, requesting the required 
number of replacement bottles of drug, and/or new participant labels (as applicable). Curant will mail new 
participant labels to place on existing bottles of drug, as well as any additional bottles of drug, as needed. 
 
Study visit scheduling:  We will schedule study visits as close to 30 days apart as possible. Recognizing that 
participants may have scheduling conflicts, we will seek to schedule participants for study visits 2, 3 and 4 
within 7 days prior to the 30-day mark in order to prevent participants from running out of digital PrEP pills. 
 


 
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Participant messaging:  Participants will receive standard SMS text messages, as well as notifications from the 
mobile application which receives their adherence data from the digital pill. Upon enrollment in Nomi and 
iAssist interfaces at Study Visit 1, participants will receive a welcome message, including a contact number for 
the DigiPrEP study team. Participants will receive three technology check-in messages during the first week 
using the digital pill (on days 2, 5, and 7); these messages will prompt participants to respond with “0” for “I 
need help with something,” or “1” for “Everything’s OK!” If participants text back “0,” the study team will contact 
the participant to assist them further. Beginning one week after Study Visit 1, participant will also receive an 
anonymous REDCap link to a brief weekly survey, asking them to self-report substance use and sexual activity 
for the past week. Participants will also receive text messages reminding them of upcoming study visits. 
Depending on messaging settings in the Nomi interface, participants may also receive app notifications for 
ingestion confirmations, as well as messages related to Reader battery life and confirmations of manually 
recorded ingestions (see DigiPrEP Study Messages_Participant Only for detailed content and timing of all 
participant messaging).  
 


 
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Potential participant directly contacted study RA, 
referred by Fenway Health primary care physician, or 
identified via medical record review and screened 
during clinical appointment at Fenway Health
Screening Visit:  Consent & Eligibility
- Meet RA and study team
- Explain study and sign informed consent
- Sign medical release of information form 
- Conduct rapid HIV test 
- Review and/or obtain lab work to confirm eligibility
Study Visit 1:  DigiPrEP Setup
- Self-report questionnaire 
- Technology training
- Dispense 30 days of PrEP (Truvada digital pill)
Study Visit 2:  Day 30  (-7 days)
- Review DigiPrEP data
- Blood draw for adherence
- Refill 30 days of PrEP (Truvada digital pill)
Study Visit 3:  Day 60  (-7 days)
- Review DigiPrEP data, pill counts
- Refill 30 days of PrEP (Truvada digital pill)
Study Visit 4:  Day 90  (-7 days)
- Review DigiPrEP data, pill counts, return equipment
- Blood draw for adherence
- DigiPrEP interface text messages 
on days 1, 2, 5, 7 to ensure DigiPrEP 
is working  
- DigiPrEP interface text messages 
on days 23, 25, 29 to remind 
participants of Study Visit 2 
- DigiPrEP interface text messages on 
days 53, 55, 59 to remind 
participants of Study Visit 3 
- DigiPrEP interface text messages on 
days 83, 85, 89 to remind 
participants of Study Visit 4 
If eligible: 
- Order 90-day supply of digital PrEP  
 
If ineligible: 
 - Refer back to PCP for treatment / 
continued medical care 


 
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VI. Biostatistical Analysis 
 
Aim 1: We will conduct qualitative analysis on individual interviews in aim 1 to elucidate themes of technology 
acceptance, design, and optimal timing and delivery of messaging.  
 
Aim 2: We will calculate descriptive statistics regarding the degree of adherence collected from the digital pill. 
We will also calculate the accuracy of the digital pill in comparison to pill counts and validate ingestion data 
compared to dried blood spot data. Because this is a pilot, proof-of-concept study, we will not be powered to 
determine the degree of adherence the use of a digital pill alone confers upon study participants. 
 
VII. Risks and Discomforts 
 
We anticipate the major risks due to DigiPrEP are the potential for exposure to metal components in the digital 
pill, and retention of the radiofrequency emitter portion of the digital pill. Major psychological discomforts could 
occur during study interviews when participants are asked about their adherence patterns. 
Exposure to Metal Components in Digital Pill: The Digital Pill is manufactured from the same basic 
components as other ingestible medical devices. The radiofrequency tags contain minimal amounts of silver, 
zinc and magnesium that are significantly less than the recommended daily intake of these metals. In order 
to prevent absorption of these metals, the radiofrequency tag is coated with an epoxy and ethyl cellulose 
coating in a technique that is used for other ingestible medical devices.8,9 Extensive experience in the use of 
ingestible small bowel endoscopy cameras has not reported adverse events related to the exposure of 
electronic components.10,11  
 
Digital Pill Radiofrequency Emitter Retention: Study participants may experience retention of the 
radiofrequency emitting portion of the digital pill. A study assessing the efficacy of the capsule portion of 
DigiPrEP among healthy volunteers documented 560 successful ingestion events without any adverse effects. 
Dr. Chai has completed a pilot study that recorded 96 ingestions with the digital pill containing oxycodone 
without any adverse events.2 Additional pilot data from Novartis of over 100 participants who ingested 
radiofrequency tagged gelatin capsules revealed no reports of sensor retention (Personal communication 
from Joris VanDam, Novartis). An additional investigation to determine the safety of digital pills demonstrated 
no retention of any of the components of the digital pill by abdominal imaging.9 The best comparison to the 
digital pill are capsule endoscopy pills which are over twice the size of digital pills. Over a decade of experience 
of capsule endoscopy has revealed a capsule retention rate of less than 2%.10,12 In the case of a retained 
endoscopy pill, patients were mostly asymptomatic, and treatment consisted only of oral fluid administration. 
Patients who elected to have the capsule removed successfully underwent elective partial small bowel 
resection with pathologic findings including mild bowel stricture or intimal ulceration from capsule retention.13 
Complication rates among patients with Crohn’s disease, bowel neoplasm, radiation enteritis, or stricture were 
higher.14,15 In high-risk patients, standard therapy for retained endoscopy pills included aggressive oral 
hydration with successful removal of the retained pill.16 We believe that the risk of retention of a DigiPrEP 
capsule will be less than that of a capsule endoscopy pill given the smaller dimensions of the digital pill. Unlike 
a capsule endoscopy pill, DigiPrEP is dissolvable with only the radiofrequency emitting portion of the capsule 
passing through the gastrointestinal tract. In order to minimize the risk of DigiPrEP capsule retention, we plan 
to exclude patients with underlying bowel disease or surgical intervention to the bowel.  
 
Psychological discomfort of disclosing adherence patterns: Participants may experience psychological 
discomfort in disclosing and learning of their adherence data during study visits. As their Fenway Health PCP 
may be given participant’s adherence data, participants may also experience the psychological discomfort 
knowing that their PCP knows about their adherence to PrEP during the study period. 
 
VIII. Potential Benefits 
 


 
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Participants may indirectly benefit from participation in the study by improving their adherence to PrEP. 
Interacting and using DigiPrEP may confer some increased adherence among study participants.  
 
IX. Data Monitoring and Quality Assurance 
 
We will review and monitor data from DigiPrEP for each study participant. At each study visit, participants will 
undergo pill counts to correlate adherence data from DigiPrEP, and calculate the accuracy of the digital pill to 
measure PrEP adherence. Any discrepancies between the digital pill and pill counts will be addressed in real 
time at each study visit with the participant. For each participant, we will also review signaling from the digital 
pill to the Reader with our industry collaborator (eTectRx) to ensure there are no errors in data transmission 
contribution to missed adherence events. If errors occur as a result of data transmission, we will annotate this 
on the ingestion data. 
 
The study investigators will conduct QA to review data after half of the patients (N=7) of Aim 2/3 are enrolled to 
ensure that data is accurate and no errors have been made. 
 
The principal investigator (Dr. Chai) will be responsible for monitoring adverse events during the study, but 
Drs. Mayer and O’Cleirigh will assume this responsibility in the event that Dr. Chai is unavailable.  The role of 
the responsible person is 1) to identify the concern, 2) develop and appropriate response that involves 
consultation whenever possible to alleviate or minimize any adverse event, and 3) to ensure that the adverse 
event is reported in a timely manner to the responsible authority. 
 
Participants will be monitored for occurrence of events defined as any undesirable experience or unanticipated 
benefit. Events may occur during recruitment, technology deployment, and qualitative interviewing. For 
example, a participant may become distressed when asked questions about substance abuse and its impact 
on PrEP adherence. Based upon previous research couched in technology among hidden populations, we 
anticipate that these effects will be minimal. The principal investigator will assess whether an undesirable 
experience occurred (adverse event) and will record details of all adverse events (death, life threatening illness, 
new serious or permanent disability) that occur. Should such an event occur, the principal investigator will 
report the event within 24 hours to the Fenway Institute IRB. 
 
The adverse event case report form will include a description of all undesirable experiences, required 
interventions, and an assessment of the subject after the event if possible.  An estimate of the extent of injury, 
and prevention strategies will be reported. The principal investigator will classify the relationship of the study 
protocol to the event as follows: 
• 
Not related: The event is clearly related to factors such as the subject’s clinical state, not with the study 
protocol. 
• 
Remote: The event was most likely related to factors such as the subject’s clinical state, not with the 
study protocol. 
• 
Possible: The event follows a reasonable temporal sequence associated with participating in the study 
and/or is consistent with events related to responding to queries about stress/drug craving but is 
possibly related to factors such as the subject’s clinical state. 
• 
Probable: The event follows a reasonable temporal sequence associated with participating in the study 
and/or is consistent with events related to responding to DigiPrEP or digital pills and cannot be 
reasonably explained by factors such as the subject’s clinical state. 
The severity of an adverse event in both groups is defined as a qualitative assessment of the degree 
or intensity of an adverse event as determined by the principal investigator as follows: 
• 
Mild: No impact (in anyway) on the subjects. 
• 
Moderate: Impacts on the subject but is not life-threatening or incapacitating. 
• 
Severe: Fatal, life threatening, permanently disabling; severely incapacitating; requires/prolongs 
inpatient hospitalization. 


 
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All adverse events will simultaneously be reported to the NIH project officer.  The report will summarize the 
facts of the case, including the date and a description of the subject; whether the event is related to the study’s 
protocols; the steps that have been taken to address the issue; whether the event provides emerging 
knowledge about the risks of the study that should be conveyed to respondents; and whether the consent 
form should be revised. 
 
Data Safety Monitoring Board 
Dr. Chai, will select three external investigators with expertise in PrEP, substance use disorder, technology 
security and behavioral interventions to participate on a data safety monitoring board (DSMB) for aim 2 (pilot 
randomized controlled trial) of the research plan. The DSMB will convene annually during aim 2 of the 
research plan. Additionally, the DSMB will meet when N=10 study participants are enrolled in aim 2. They will 
review the data, and any potential study related adverse events prior to approving the continuation of 
recruitment. The responsibilities of the DSMB will include: 
• 
Reviewing the research protocol, consent form, and plans for DSMB. 
• 
Evaluating the progress of the pilot randomized controlled trial: recruitment, retention, data quality, site 
performance, adverse events. 
• 
Protection of participant safety 
• 
Making recommendations to Dr. Chai and the Fenway Institute IRB regarding continuation, termination 
or modification of the study depending on benefits or adverse events. 
• 
Ensuring the confidentiality of study data. 
• 
Reviewing adverse events. 
• 
Providing annual written reports to Dr. Chai, and Gilead Sciences (study sponsor) required regarding 
safety concerns, continuation or modification of the research plan. 
 
Data Safety. The protection of data for this study includes the following: 1) Data are collected through a HIPAA 
compliant web server hosted by eTectRx, then securely relayed to a cloud-based program (NOMI) that drives 
smart interventions in DigiPrEP. The cloud-based database is hosted behind the secure firewall through 
eTectRx, and accessed through Fenway Health computers. 2) Study participants are identified by a unique 
numeric identification; their protected health information (PHI) is never linked to ingestion data captured by 
eTectRx, or the cloud-based program. 3) Study participant PHI is collected and stored on a secure Microsoft 
Excel worksheet which will be created on a secure, password protected desktop computer located at TFI where 
only Dr. Chai, his study mentors and a trained research assistant (RA) will have access. 4) All data (ingestion 
data on the cloud-based database and PHI) is stripped of all identifying information by Dr. Chai prior to 
transmission to collaborators at BWH, MGH, BIDMC and Children’s hospital. We will also share deidentified 
data with our sponsor, Gilead Sciences. 5) Deidentified ingestion data as well as demographic data will be 
securely stored on the TFI server; we will access this data for later investigations under a separate IRB protocol. 
6) At study completion, the link between the identifying information and their data is destroyed, as is contact 
information. Two sets of the cleaned data set will be maintained—one working copy at Brigham and Women’s 
Hospital, and one at the Fenway Institute. This approach ensures that the data survives a failure of one storage 
location. 6) Finally, all study staff have completed the CITI Course in the Protection of Human Subjects online 
training in research ethics and good clinical practice to ensure that all staff are compliant with confidentiality 
training. 
Data Tracking: Data will be automatically logged into the web interface hosted by eTectRx with a date/time 
stamp to ensure accurate record keeping of all data and linking to the results. All data will be securely accessed 
at Fenway Health. 
Data Entry Process: Protected health information, including study participant demographics, substance use 
disorder  history, and HIV risk factors will be collected by Dr. Chai and the research assistant and entered into 
REDCap, a secure web application being used for data storage and management. A separate spreadsheet of 


 
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study participant contact information and a technology log including participant mobile phone number, 
electronic mail (email) address, identifiers of the Receiver, study smartphone and a log of dispensed digital 
pills will also be maintained by Dr. Chai and the RA. All logs will be stored behind TFI firewall and password 
protected. Dr. Chai will also maintain a second copy of the logs as a backup in his secure office behind the 
BWH firewall Data loaded onto the interface cannot be edited. Each variable with missing data (such as an 
interruption between smartphone and sensor) will be identified and a placeholder (“<<-99>>”) is entered to 
connote a missing value. Data from the digital pill is recorded on the eTectRx interface and automatically 
transferred via a HIPAA-compliant secure link to the adherence interface (NOMI). Ingestion data may 
potentially require editing if there are transmission failures, errors from the reader device, or manually recorded 
data from study participants. All of these potential edits will be identified by eTectRx in collaboration with the 
study team. Edits to data will be agreed upon by both parties and approved by the PI. An audit trail of all 
potential edits will be maintained, one copy at eTectRx and one copy at TFI. We will additionally comply with 
Fenway regulations regarding reporting of adverse events and ensuring data quality. Landmark Associates Inc, 
an external company, will be contracted to transcribed audio-taped interviews. 
 
Data storage: Raw ingestion data, transcripts from this study and self-report questionnaires will not be made 
publicly available. Deidentified data may be shared with Gilead Sciences who is funding the study, as well as 
industry collaborators eTectRx and NOMI. For future investigations that use deidentified participant data, we 
will submit IRB protocols detailing the use of this data. Partners Health Dropbox is being used for file storage in 
the study. 
 
 
X. References 
 
1. 
Browne SH, Behzadi Y, Littlewort G. Let Visuals Tell the Story: Medication Adherence in Patients with 
Type II Diabetes Captured by a Novel Ingestion Sensor Platform. JMIR mHealth uHealth 
2015;3(4):e108–19.  
2. 
Chai PR, Carreiro S, Innes BJ, et al. Digital Pills to Measure Opioid Ingestion Patterns in Emergency 
Department Patients With Acute Fracture Pain: A Pilot Study. Journal of medical Internet research 2017; 
3. 
Kane JM, Perlis RH, DiCarlo LA, Au-Yeung K, Duong J, Petrides G. First experience with a wireless 
system incorporating physiologic assessments and direct confirmation of digital tablet ingestions in 
ambulatory patients with schizophrenia or bipolar disorder. The Journal of clinical psychiatry 
2013;74(6):e533–40.  
4. 
Chai PR, Castillo-Mancilla J, Buffkin E, et al. Utilizing an Ingestible Biosensor to Assess Real-Time 
Medication Adherence. J Med Toxicol 2015;:1–6.  
5. 
Chai P, Rosen RK, Boyer EW. Ingestible Biosensors for Real-Time Medication Adherence Monitoring: 
MyTMed. Hawaii: IEEE & Computer Society Press; 2016.  
6. 
Chai PR, Carreiro S, Rosen RK, Boyer EW. Patient Acceptance of Ingestible Biosensor Systems. 
Washington DC: 2016.  
7. 
Chai PR, Ranney ML, Rosen RK, Lewis DM, Boyer EW. Crowd-Sourced Focus Groups on Twitter: 
140 Characters of Research Insight. Proceedings of the th Hawaii International Conference on 
System Sciences 2017;:3746–53.  
8. 
Euliano N. ID-Cap GI Sensor Toxicology Report.  
9. 
Flores GP, Peace B, Carnes TC, et al. Performance, Reliability, Usability, and Safety of the ID-Cap 


 
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System for Ingestion Event Monitoring in Healthy Volunteers: A Pilot Study. Innovations in Clinical 
Neuroscience 2016;13(10):1–8.  
10. 
Li F, Leighton JA, Sharma VK. Capsule endoscopy: a comprehensive review. Minerva 
gastroenterologica e dietologica 2007;53(3):257–72.  
11. 
Nakamura T, Terano A. Capsule endoscopy: past, present, and future. Journal of gastroenterology 
2008;43(2):93–9.  
12. 
Trifan A, Stanciu C. Capsule endoscopy--a new frontier. Revista medico-chirurgicala a Societatii de 
Medici si Naturalisti din Iasi 2004;108(4):739–46.  
13. 
Li F, Gurudu SR, De Petris G, et al. Retention of the capsule endoscope: a single-center experience of 
1000 capsule endoscopy procedures. Gastrointestinal endoscopy 2008;68(1):174–80.  
14. 
Vanfleteren L, van der Schaar P, Goedhard J. Ileus related to wireless capsule retention in suspected 
Crohn's disease: emergency surgery obviated by early pharmacological treatment. Endoscopy 2009;41 
Suppl 2:E134–5.  
15. 
Cave D, Legnani P, de Franchis R, Lewis BS. ICCE Consensus for Capsule Retention. Endoscopy 
2005;37(10):1065–7.  
16. 
Li F, Gurudu SR, De Petris G, et al. Retention of the capsule endoscope: a single-center experience of 
1000 capsule endoscopy procedures. Gastrointestinal endoscopy 2008;68(1):174–80.  
 

SAP_001.pdf: 
 
1 
DigiPrEP Statistical Analysis Plan 
 
Official title:  Feasibility and Acceptability of Digital Pills to Monitor PrEP Adherence in MSM With 
Substance Use  
 
NCT number:  NCT03842436  
 
Document date:  September 03, 2021 
 
 


 
2 
DigiPrEP Statistical Analysis Plan 
 
 
Sociodemographics.  
Descriptive statistics were calculated for selected variables.  
 
Digital pill system (DPS) performance and engagement metrics.  
To analyze the performance of the DPS, the ground truth of PrEP ingestion events were defined 
as the pill counts obtained each month (i.e., the number of unused pills returned, subtracted from the 
number of pills previously dispensed). The number of DPS-recorded ingestions – which included the 
number of both Reader-detected and manually-reported ingestions – was compared with the aggregate 
pill count at each monthly timepoint; this was defined as the overall performance metric for the DPS. 
The Reader-detected ingestions count was used to reflect the number of times the DPS was operated 
correctly. Successful DPS operation was defined as ingestion of a digital pill, proper use of the 
wearable Reader, and confirmation of the ingestion on both the Reader and the app.  
Reader-detected ingestions and manually-reported ingestions that co-occurred within 30 
minutes were identified and reconciled; these events likely represented episodes in which a digital pill 
was ingested, and the ingestion was detected by the Reader, but the participant elected to manually 
record the ingestion in-app because the Reader was not correctly paired to the smartphone or was 
delayed in detecting the ingestion. Additionally, several ingestions were manually reported due to a 
known programming error in the app early in the study. As such, two participants were instructed to 
manually log all ingestions until an app update was made available; ingestion data for these two 
individuals were downloaded from their Readers at the end of the study period, and all Reader-detected 
ingestions were reconciled with manually-reported ingestions.  


 
3 
Participant engagement with the DPS was measured by calculating the total number of DPS-
recorded ingestions and comparing the number of monthly DPS-recorded ingestions across each month 
of the study period.  
 
TFV-DP in DBS.  
We also compared drug concentrations of TFV-DP as measured in DBS at months one and 
three to DPS-recorded PrEP adherence. First, we identified all DBS samples that, as a result of 
scheduling challenges, were obtained more than five days after the conclusion of DPS-recorded 
ingestions, and excluded these DBS samples from analysis, as they resulted in incomplete data to 
compare with DPS-recorded ingestions. All other DBS samples were paired, based on their collection 
dates, with the corresponding average of DPS-detected ingestions during the three-week period prior to 
DBS collection. We dichotomized TFV-DP levels using a cutoff of ≥700 fmol/punch to indicate at 
least four doses of PrEP ingested per week.1,2 Using TFV-DP in DBS <700 vs ≥700 fmol/punch as a 
dichotomous variable, and considering the granular continuous adherence data from the digital pill, we 
then calculated a point biserial correlation between TFV-DP in DBS and digital pill adherence. Finally, 
we analyzed the paired TFV-DP concentrations and DPS-recorded adherence data at months one and 
three, and calculated Pearson’s correlation coefficients for each independent timepoint. Analyses were 
completed using SAS (version 9.4).3  
 
Qualitative analyses.  
Qualitative user experience interviews were transcribed and coded using applied thematic 
analysis.4,5 A codebook was generated. All interviews will then double-coded by two study team 
members; coding was paused and evaluated every five transcripts to ensure consistency and to resolve 
and document any discrepancies. A kappa statistic was calculated, utilizing a cutoff of > 0.8 to ensure 
interrater reliability between coders. Coders reviewed aggregate coding to identify and discuss final 


 
4 
themes surrounding user experiences, which were reviewed by the study team as a whole. Qualitative 
analyses were facilitated by NVivo software.6 
 
 
 


 
5 
References 
 1.  Anderson PL, Liu AY, Castillo-Mancilla JR, et al. Intracellular tenofovir-diphosphate and 
emtricitabine-triphosphate in dried blood spots following directly observed therapy. Antimicrob 
Agents Chemother. 2017;62(1):e01710-17. doi:10.1128/AAC.01710-17 
2.  
Grant RM, Anderson PL, McMahan V, et al. Uptake of pre-exposure prophylaxis, sexual 
practices, and HIV incidence in men and transgender women who have sex with men: a cohort 
study. The Lancet Infectious Diseases. 2014;14(9):820-829. doi:10.1016/S1473-3099(14)70847-3 
3.  
SAS Institute Inc. SAS.; 2013. 
4.  
Guest G, MacQueen K, Namey E. Applied Thematic Analysis. SAGE Publications, Inc.; 2011. 
5.  
Braun V, Clarke V. Using thematic analysis in psychology. Qualitative Research in Psychology. 
2006;3(2):77-101. doi:10.1191/1478088706qp063oa 
6.  
QSR International. NVivo Software.; 2018. 
 
 
 
 


 
6 
Figure Captions 
 
 
Figure 1. Overview of digital pill system (DPS)  
 
The DPS includes an ingestible sensor within a gelatin capsule that over-encapsulates a medication. 
When ingested, it is activated by gastric fluid, broadcasting a radiofrequency signal that is acquired by 
a wearable Reader device and relayed to a smartphone which can display and transmit real-time 
adherence metrics. Image courtesy of etectRx. 
 
Figure 2. Engagement with DPS over the 90-day study period 
 
Engagement with the DPS was consistent over the 90-day study period. While the number of DPS-
recorded ingestions decreased from month 2 to 3, this was paralleled by a decrease in PrEP adherence 
from month 2 to 3 (A). Individual-level engagement with the DPS was high with most participants (B). 
The participant who was temporarily lost to follow-up was excluded from the above graph; therefore, 
only 14 participants are included. 
 
Figure 3. DPS-recorded adherence and nonadherence from sample participants   
 
DPS adherence graphs from selected participants illustrating context around patterns of adherence and 
nonadherence. Identification of weekend substance use leading to nonadherence (A), but a return to 
PrEP adherence during the week (B); entering a new relationship with a partner who was not accepting 
of PrEP, resulting in long-term nonadherence (C); temporal changes, from ingesting PrEP with 
breakfast during the week (D), to liberalized ingestion patterns on weekends (E); and routine changes 
leading to nonadherence, including visiting a partner’s home on weekends (F). Red X = no recorded 
ingestion during dosing window. Blue circle = DPS-recorded ingestion. 
 
 
 
 
 


 
7 
List of Supplemental Digital Content 
 
Supplemental Figure 1. Study enrollment schema 
 
Supplemental Table 1. DPS-recorded ingestion events versus pill counts, by month over study period 
 
Supplemental Figure 2. Schematic of reconciliation surrounding manually-reported digital pill system 
ingestion events