Measuring and Monitoring Adherence to ART With Pill Ingestible Sensor System
Phase: NA
Conditions: HIV/AIDS, Medication Adherence
Sponsor: University of California, Los Angeles

  
Measuring and Monitoring Adherence to ART  
With Pill Ingestible Sensor System 
 
 
NCT02797262 
 
 
Rev. December 26, 2018  
 
 
 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 1 of 28 
Investigator: Eric Daar, MD, Honghu Liu, Ph.D. 
 
1) Title  
Measuring and Monitoring to ART with Pill Ingestible Sensor System 
 
2) HSC Review History 
Version 1.0 - 12/31/15 
Amendment # 1 – 1/26/16 
Continuing Review – 12/13/16 
Amendment # 2 – 12/30/16 
Amendment # 3 – 6/7/17 
Amendment # 4 – 10/1/18 
Amendment # 5 – 12/5/18 
 
3) Objectives 
The first goals of this study are to confirm the bioavailability of over-encapsulated antiretrovirals 
(ARVs) and to pilot the use of the PROTEUS DISCOVER® [(Proteus Digital Health Feedback) 
(Proteus Discover ®)] system to determine approaches that maximize patient acceptability and 
optimize the system to be utilized. The team will build a real-time data collection hub and establish 
an automated feedback system to send a text message when no ingestion has been detected 
within a pre-specified time after a scheduled dose.  
 
Bioavailability of over encapsulated ARVs will be conducted on at least nine (modified per Letter of 
Amendment # 1 dated 1/29/16) commonly used ARV formulations with six patients for each 
medication. We will then pilot the PROTEUS DISCOVER® system in 15 patients in an iterative 
process in which approaches to real time data handling, over encapsulation, patch and medication 
delivery and text messaging are tested and patient feedback and suggestions are elicited and 
incorporated into the system. The second goals are to evaluate the feasibility, acceptability and 
sustainability of the system, and assess the system's accuracy in describing adherence and 
efficacy in fostering adherence. Accuracy will be described as the association between adherence 
measured by the PROTEUS DISCOVER® system and adherence measured by other methods 
including plasma drug level concentration and self-report of prescribed medications taken. Efficacy 
is described as the impact of the system on leveraging adherence to ART and improving selected 
outcomes (exploratory).  
 
4) Background 
Introduction of antiretroviral therapy (ART) is lifesaving, but adherence to ART is critical to optimize 
outcomes. The limitations of current adherence measures constrain our ability to develop 
interventions to facilitate dose-taking and most methods do not actually measure real-time 
ingestion of medications or allow for immediate provision of feedback in the event of missed doses. 
The PROTEUS DISCOVER® system addresses these limitations, but has yet to be tested in 
people being treated for HIV infection. The PROTEUS DISCOVER® system involves use of an 
ingestible sensor, an edible material that can be over-encapsulated with a readily available and 
standardized product (Capsugel, Greenwood, SC, USA) so it is co-ingested with prescribed 
medication. The ingestible sensor is activated by stomach liquid, and is sensed by a monitor-patch 
that is worn by the patient and contains a microchip and a tiny battery. The monitor sends a 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 2 of 28 
Bluetooth signal to the patient’s mobile device (e.g., cell phone), which in turn sends an encrypted 
message to a central server, thus allowing for a real-time signal that signifies a dose has been 
taken. As part of this proposal, we will create a real time data receiving hub and add a system that 
provides real-time automated text message feedback to the patient when a dose is missed. The 
ingestible marker and the personal monitor are FDA-approved for safety and have the CE mark 
(Conformité Européenne, meaning "European Conformity") of approval, indicating they also meet 
European Union safety requirements. 
 
Recent Information 
Analysis of the pharmacokinetic data around a single dose of over-encapsulated tenofovir 
disoproxil fumarate/emtricitabine (Truvada) were completed. The assays for plasma tenofovir 
levels reported relatively low Cmax (maximum serum concentration) and Tmax (time at which 
cmax is observed) when compared to historical data for this medication when not over-
encapsulated.  Although the team does not believe these differences in drug levels are clinically 
significant, for scientific rigor and patient safety we propose to repeat the assays using a modified 
study design. For this study for each of 6 individuals to be studied we will collect pharmacokinetic 
data after ingestion of non over-encapsulated dose and then this will be repeated in the same 
patient with the over-encapsulated pill. This strategy will allow us to compare levels between the 
pill with and without over-encapsulation in the same individual.  We will attempt to study the same 
6 individuals included in the original study; however, if a subject is no longer taking truvada or 
otherwise unavailable, he/she will be replaced with another subject who is currently taking this 
medication.  
 
Recent Information 
Analysis of the pharmacokinetic data around a single dose of over-encapsulated tenofovir 
alefanamide/emtricitabine/bictegravir (Biktarvy) were completed. The assays for plasma bictegravir 
levels reported relatively low when compared to historical data for this medication when not over-
encapsulated.  For scientific rigor and patient safety we propose to repeat the assays using a 
modified study design. For this study for each of 6 individuals to be studied we will collect 
pharmacokinetic data after ingestion of non over-encapsulated dose and then this will be repeated 
in the same patient with the over-encapsulated pill. This strategy will allow us to compare levels 
between the pill with and without over-encapsulation in the same individual.  We will attempt to 
study the same 6 individuals included in the original study; however, if a subject is no longer taking 
biktarvy or otherwise unavailable, he/she will be replaced with another subject who is currently 
taking this medication. 
 
5) Setting of the Human Research 
Recruitment of study subjects will take place at the CDCRC building and at Harbor-UCLA Medical 
Center – Building N-24.  
 
The study will be conducted by the LA Biomed at Harbor-UCLA HIV Medicine Group located in 
CDCRC Building. Recruitment will take place at the Harbor-UCLA HIV Clinic.  
 
Los Angeles BioMedical Research Institute at HUMC 
Dr. Daar will serve as one of the multiple PD/PI on this project. He will oversee the efforts 
conducted by his group in the development of protocol and implementation of various stages of the 
proposed study. This will include getting IRB approval, recruiting, enrolling and retaining study 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 3 of 28 
subjects and assuring appropriate acquisition of data. He will then be involved in data clean up, 
analysis and then reporting of research findings. 
University of Nebraska Medical Center 
Dr. Fletcher will contribute to the design of a sampling scheme for when to obtain blood samples 
for quantitation of antiretroviral drug concentrations. Antiretroviral drug concentrations in the blood 
samples will be quantified in Dr. Fletcher’s laboratory, the Antiviral Pharmacology Laboratory using 
UPLC/MS/MS methods. Dr. Fletcher will contribute to the pharmacokinetic analysis and 
interpretation of the data generated. 
Yale University 
Dr. Rosen will serve as the Subaward Principal Investigator and will be responsible for supervision 
and day-to-day management of all aspects of the study in New Haven. Dr. Rosen will be 
responsible for assisting with the development of the Proteus system, and will store and analyze 
the qualitative data collected describing patients’ experience with the system. He will provide 
content area and clinical expertise to Dr. Liu, with whom he will speak weekly. 
 
6) Resources Available to Conduct the Human Research 
The study sample will be recruited through HIV clinics at Harbor-UCLA Medical Center and its 
satellite clinic in Long Beach, California. The clinics care for approximately 1,250 underserved 
patients, including 50% Hispanic and 25% African American and 20%women. The study subjects 
are expected to reflect the diversity of the clinic patient population with good representation of 
women, Hispanics and African Americans. 
Drs. Daar (mPI) and Corado (Co-I) care for patients in these clinics and have substantial 
experience in studies of HIV treatment and prevention, including measurement and intervention of 
adherence to ART and wireless monitoring of adherence to ART. 
 
Enrollment:  
Pilot phase (Bioavailability and Feasibility):  
54 subjects were enrolled and completed participation in the bioavailability phase of the study.  
In an effort to increase the number of possible candidates for the Trial Phase of the study, the 
team would like to enroll 12 more subjects to evaluate the bioavalability of 2 newly approved anti-
HIV medications:   
Bicktarvy® (bictegravir, emtricitabine and tenofovir alafenamide) – 6 subjects 
Symtuza™(darunavir, cobicistat, emtricitabine and tenofovir alafenamide) – 6 subjects 
 
The pilot phase of the study has already been completed 15 subjects were enrolled.   
 
Modified per LOA # 1 dated 1/29/16 
 
Trial Phase: 120 subjects will be enrolled; about 150 subjects will need to be screened to meet 
our goal. To date 30 subjects have been approached and 10 have enrolled to the study. 
 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 4 of 28 
7) Prior Approvals 
Version 1.0 - 12/31/15 
Amendment # 1 – 4/5/16 
Continuing Review – 12/22/16 
Amendment # 2 – 2/1/17 
Amendment # 3 – 6/7/17 
Amendment # 4 – 10/1/18 
Amendment # 5 – 12/5/18 
 
 
8) Study Design 
a) Recruitment Methods 
 
 
Recruitment of study subjects for all Stages of this study will take place at the HIV clinic at the 
LABioMed CDCRC building and the Harbor -UCLA Medical Center – Building N-24. A satellite HIV 
clinic in Long Beach - Tom Kay Clinic - will also serve as a referral site for the study. 
 
 
Primary care providers will be informed about the study and requirements for participation. They 
will talk to potential subjects and refer them to the study staff if interested. 
 
The Harbor-UCLA HIV Clinic is the second largest public HIV clinic in Los Angeles County, 
with approximately 1,000 HIV-infected persons followed at this facility and approximately 
250 followed at a satellite clinic in Long Beach. These patients are ethnically diverse with 
approximately 50% being Hispanic, 25% African-American and nearly 25% female. 
See below – “Recruitment” 
 
 
Recruitment: Both active and passive recruitment approaches will be used to recruit participants: 
a.  Clinic-wide information sessions will be conducted by the research team on a regular basis. 
b.  IRB approved posters, flyers, and brochures will be posted and readily available in each 
clinic; 
c.  Potentially eligible patients will be identified by conversation with the primary care providers. 
The primary care providers will ask potential participants if they are interested to participate 
in the study. If they agree, a research assistant will they interview the subjects to evaluate 
their interest. If they express interest a consent form will be provided; if they agree to 
participate, they will be asked to sign the consent form. .  
 
Recruitment will also occur by direct recruitment of patients, fliers, and advertisements. 
Direct recruitment will be done by direct invitation by clinic staff. Patients who are appearing 
for their regularly scheduled visit will be asked by a member of the clinic staff if they are 
interested in learning more about the study from a member of the research staff. If a patient 
expresses interest in learning more about the study, the patient will be contacted by a 
member of the research staff. 
 
Interested patients will be interviewed by a member of the research staff to determine 
eligibility for participation and to be enrolled. The staff member will explain the study, and if 
the patient is interested in participating, will read the informed consent. The patient will be 
given a copy of the informed consent. 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 5 of 28 
 
 
Subject Compensation.   
Subjects in the bioavailability portion of the study will receive $80 for the study. Subjects 
participating in the pilot phase of the study will receive $50/visit.  
Subjects participating in the Trial phase study will receive $50 (cash) for screening and follow up 
visits and $150 (check) at baseline (for completing the PK evaluations – Modified per Amendment 
dated 11/19/18 
 
b) 
Inclusion and Exclusion Criteria for all Stages of study 
Primary care providers will be informed about the study and requirements for participation. They 
will talk to potential subjects and refer them to the study staff if interested. 
 
Inclusion criteria:  
1- HIV-infected individuals in HIV care 
2- Receiving ART with sub-optimal adherence estimated by either  
patient (self-reports < 90% adherence over last 28 days) or treating clinician (e.g., based on gaps 
 
in treatment (e.g. missed appointments) or viral load elevations within last 6 months that the 
treating clinician attributes to possible nonadherence) [This will not be an inclusion criteria for 
bioavailability portion of the study]; 
3- Demonstrate ability to take over-encapsulated antiretroviral medications at the time of screening 
4- Able to provide informed consent. 
 
Exclusion criteria:  
1- Inability to follow the study procedures manifested during the intake, as evidenced by mental  
confusion, disorganization, intoxication, withdrawal, risky or threatening behavior  
2- Pregnancy  (Evaluated during the screening visit through a pregnancy test. 
 
c) 
Local Number of Subjects 
Pilot phase (Bioavailability and Feasibility): 54 subjects were enrolled and completed participation 
in the bioavailability phase of the study.  
In an effort to increase the number of possible candidates for the Trial Phase of the study, the 
team would like to enroll 12 more subjects to evaluate the bioavalability of 2 newly approved anti-
HIV medications:   
Bicktarvy® (bictegravir, emtricitabine and tenofovir alafenamide) – 6 subjects 
Symtuza™(darunavir, cobicistat, emtricitabine and tenofovir alafenamide) – 6 subjects 
 
 
Trial Phase: 120 subjects will be enrolled; about 150 subjects will need to be screened to meet our 
goal. 
 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 6 of 28 
 
d) 
 Study Endpoints 
1. Pilot Stage 
a. Bioavailability of over-encapsulated ARVs: Blood level of each drug will be tested on 
blood sample drawn before the dose (time 0) and at 1, 2, 4, and 6 hours post a witnessed 
dose to establish maximum concentration (Cmax). Blood levels of Bictegravir will be 
evaluated as per protocol amendment dated 12/26/18 
 
b. Pilot to test procedures, process, operations and patients’ reactions to the PROTEUS 
DISCOVER® system.  Qualitative survey data collected over phone at day 3 and 14 of 
study and then face-to-face at weeks 4, 8, 12 and 16. Interviewers will collect feedback on 
what is and is not working with the system, including everything from taking the over-
encapsulated pills, being monitored, wearing the patch, receiving text messages and 
collecting recommendations for changes to the system. 
 
2. Trial Stage 
Outcome Measures 
The primary outcomes: 
 Adherence to ART measured by PROTEUS DISCOVER® system for 16 weeks, including 
both percent of prescribed medication taken and dose-timing error (DTE). 
 Drug level concentrations from blood draw. Drug level concentration will used to define 
adherence. We will measure drug level concentration 3 times at baseline to make sure that 
we can detect it (the 1st one to detect previous adherence, the 2nd and 3rd to detect current 
adherence), and weeks 4, 8, 12, 16, 20, 24, and 28. Drug level concentration adherence will 
be quantified with a novel pharmacokinetic-based approach as published. Brundage et al. 
described the pharmacokinetic-based method of estimating adherence based on 
intrapatient variability. Fletcher et al. described a sparse sampling method of measured drug 
concentrations translated into a single metric of exposure (e.g. amount of drug in the body) 
as a measure of adherence. Self-Reported Medication Adherence will be determined with a 
widely-used measure of self-reported adherence for percent of prescribed dose taken 
during the preceding seven days. This tool is easy to use and has been significantly 
associated with virological and immunological outcomes. Self-reported adherence will be 
measured at baseline, and week 4, 8, 12, 16, 20, 24, and 28. Due to its potential bias, self-
reported adherence will be calibrated by drug level concentration to leverage its accuracy 
and used in analysis when calibrated self-report adherence is appropriate to be used. 
 
The secondary outcomes: 
 Viral Load and CD4 will be measured at baseline, week 4, 8, 12, 16, 20, 24, and 28. 
 
Process Measures: Patient perceptions and acceptability of the PROTEUS DISCOVER® 
system will be measured at baseline, and week 4, 8, 16, and 28. These will be evaluated by 
quantitative (first) and then qualitative interviews. The items in the quantitative interview will 
be rated on five-item Likert scales ranging from very strongly disagree to very strongly 
agree. Domains to be assessed will include overall satisfaction (would recommend to friend, 
would use outside of study setting, satisfied with system), utility, and specific items such as 
helpfulness and convenience. In addition, we will ask participants to rate specific items 
specific to the PROTEUS DISCOVER® system (comfort of patch, comfort receiving text 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 7 of 28 
messages) and issues that were identified during the qualitative interviews during the pilot 
stage. 
Analytical approaches for Each of the Aims: 
Specific aim 1: Evaluate the feasibility, acceptability and sustainability with the PROTEUS 
DISCOVER® system for measuring and monitoring adherence to ART among HIV-infected 
patients. 
 
Hypothesis 1a. Greater than 70% of the patients assigned to the PROTEUS DISCOVER® system 
will rate that the system fits with their routine activities and daily living (feasibility). To test this 
hypothesis, we will perform analyses in two levels: (1) Obtain point estimates of ratings about the 
PROTEUS DISCOVER® system and conduct one group binomial test of the proportion with 
answers that indicates a fit (or better fit). This will be done at each of the time point of baseline, 
and weeks 4, 8, 16 and 28; (2) Repeated measures analyses to examine change over time. 
Generalized linear mixed models (GLMM) will be used to model the changes of ratings over time 
controlling patient characteristics (e.g., demographics, regimen type (single/multiple pill), and viral 
load (detectable or undetectable)). GLMM can model not only global fixed effects (e.g., the 
regimen type), but also random effects (e.g., change over time within a person). Patients’ rating of 
automated text feedback system will also be evaluated and analyzed. 
 
Hypothesis 1b. Fewer than 15% of patients assigned to the PROTEUS DISCOVER® system will 
discontinue use of the system during the course of the study (acceptability). To test this, we will 
use similar approaches of one group binomial and GLMM as described in H1a to test acceptability 
through rate of discontinuing use of the PROTEUS DISCOVER® system. We will document the 
number of participants who complete the study, and how much technical assistance they need and 
receive. We will use non-inferiority tests for one proportion to compare acceptability with prefixed 
proportion at 15%. 
 
Hypotehesis 1c. The rate of discontinuing use of the PROTEUS DISCOVER® system will not 
increase over the course of the 16-week monitoring period (sustainability). To test this, we will use 
GLMM to model dropping off from using the PROTEUS DISCOVER® system and evaluate if there 
is a significant increase over time through parameter estimate of time (fix effect part) in the model. 
We will also document the number of participants who complete the study; and how much 
technical assistance they need and receive to assist the analysis. 
 
Specific aim 2: Evaluate the accuracy of the PROTEUS DISCOVER® system in measuring 
adherence. 
 
Hypothesis 2a. Adherence determined by the Proteus pill ingestible sensor system will be highly 
correlated with adherence determined by blood drug level of ARVs within the PROTEUS 
DISCOVER® group. Drug level concentrations from blood draw will be obtained for patients in both 
of the PROTEUS DISCOVER® and Usual Care (UC) groups to serve as an objective norm. We 
will use the pharmacokinetic-based method of assessing adherence based on intrapatient 
variability, or use the sparse sampling of measured concentrations translated into a single metric of 
exposure (e.g. amount of drug in the body) as a measure of adherence. Full parametric 
correlations (e.g., Pearson correlation (r)) between adherence measured by sensor and by drug 
level will be calculated and tested.  
 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 8 of 28 
Hypothesis 2b. the correlations between adherence measured by the Proteus pill ingestible sensor 
system and adherence measured by drug level concentration of ART will be significantly higher 
than the correlation between self-reported adherence and drug level concentration of ART in the 
UC group. The strength of association between adherence measured by the Proteus pill ingestible 
sensor system versus adherence measured by drug level concentration of ART will be determined 
by calculating the Pearson correlation (r). Statistical significance tests between two correlation 
coefficients will be conducted. 
 
Hypothesis 2c. Both the sensitivity and specificity of the automated text messages received by 
patients for detecting a missed dose will be higher than 95%. A two-way table of estimated number 
of missed and non-missed doses by patients (row) and the corresponding number of issued and 
non-issued test messages by the automated feedback system (column) will be created to 
summarize the data about text message feedback. Sensitivity, specificity, positive and negative 
predicted values will be calculated, and tested with binomial test approaches. 
 
Specific aim 3: Evaluate the efficacy of the PROTEUS DISCOVER® system for monitoring and 
facilitating adherence to ART. To leverage its accuracy, self-reported adherence will be calibrated 
by adherence measured through drug level concentration by a calibration model fitted with data 
from both PROTEUS DISCOVER® and UC groups. The calibrated self-report of adherence will be 
used in analysis of Hypothesis 3a. The level of adherence to ART of the PROTEUS DISCOVER® 
group will be modeled by generalized additive mixed model (GAMM) to evaluate the adherence 
trend change over time for 28 weeks. The adherence change trend before and after 16 weeks will 
be compared. 
 
Hypothesis 3a. Adherence as measured by drug level concentration and calibrated self-report will 
be higher in the PROTEUS DISCOVER® group than in the UC group. GLMM will be used for 
modeling adherence to ARV across the contact periods. A group (PROTEUS DISCOVER® or UC) 
dummy variable will be included in the model to test if the level of adherence is different between 
the two groups. If the distributions are substantially skewed, we will evaluate categorized clinical 
cut-off values using generalized estimating equation (GEE) analysis.  For possible non-linear 
relationships between outcomes and time, we will use GAMM. In addition, we will evaluate 
possible group differences in demographics (e.g., gender, race) and control for these variables in 
modeling outcomes. 
 
Hypothesis 3b. use of the PROTEUS DISCOVER® system will be associated with lower levels of 
particular patterns of non-adherence than the UC group over time. We will make full use of 
machine learning and data mining methods to identify statistically significant patterns in the data. 
The machine learning and data mining methods we will use include tree models [e.g., classification 
and regression trees (CART) random forests, Generalized Additive Models]; we will use GLMM 
and GAMM to model adherence between PROTEUS DISCOVER® and UC group over time to 
determine if it differs between groups. The GAMM modeling will graphically show the change trend 
over time.  We will also evaluate the distribution of DTEs and its changes over time in the 
PROTEUS DISCOVER® group. 
 
Hypothesis 3c. use of the PROTEUS DISCOVER® system will be associated with lower viral loads 
and higher CD4 counts than the UC group. GLMM and GAMM will be used to model viral load and 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 9 of 28 
CD4 of patients in the PROTEUS DISCOVER® group and the UC group across the contact 
periods (baseline and follow-ups) to evaluate a group x time interaction. 
 
Hypothesis 3d. differences in adherence and virologic and clinical outcomes between the 
PROTEUS DISCOVER® and UC groups will be sustained during the 12 week follow-up after 
discontinuation of the PROTEUS DISCOVER® system. GLMM/GEE and GAMM will be used to 
model the adherence and virologic and clinical outcomes including parameterization that can 
distinguish the 16-week trial and the 12-week follow-up periods. 
 
g) Procedures Involved in the Human Research 
 
Study Design. 
The study team propose to develop a data receiving hub and add to these components an 
automated text message that is sent to the patient when a dose is missed. The ingestible sensor 
and patch monitor system is already FDA-approved as safe, but has yet to be tested in HIVinfected 
patients in clinical setting. The first goals of this study are to confirm the bioavailability of 
overencapsulated antiretrovirals (ARVs) and to pilot-test the use of the PROTEUS DISCOVER® 
system in 15 participants prescribed ARVs to test and identify approaches that optimize the use of 
this measuring and monitoring system. The next goals are to determine the system's feasibility, 
acceptability, sustainability, accuracy and efficacy in fostering ART adherence. Feasibility, 
acceptability and sustainability will be assessed by patients’ rating of the system and the rate of 
dropping off from using the system. Accuracy will be evaluated by the associations between 
adherence to ART measured by the PROTEUS DISCOVER® system and other adherence 
measures such as plasma drug level concentrations of ARVs and self-report. Efficacy will be 
assessed by comparing adherence of participants assigned to the PROTEUS DISCOVER® 
system and participants assigned to usual care (UC) over time, with exploratory outcomes of viral 
load and CD4. We will recruit 120 of HIV-infected patients 18 years or older with sub-optimal 
adherence. Participants will be randomized to receive the PROTEUS DISCOVER® system or UC 
for 16 weeks with monthly assessments. The durability of effects of the PROTEUS DISCOVER® 
system after stopping the use of the system will be determined during a 12-week follow-up stage. 
In summary, we will evaluate the feasibility, acceptability and sustainability of using the PROTEUS 
DISCOVER® system; assess the accuracy of the PROTEUS DISCOVER® system in measuring 
adherence to ART; and evaluate the efficacy of the PROTEUS DISCOVER® system for monitoring 
and leveraging adherence to ART. 
 
The study goals will be achieved through three operational stages: 
(1) Stage I—Preparation Stage will build the foundation and set up the needed systems and 
procedures. This first stage will involve setting up the real time data collection system, developing 
the system to deliver real time patient feedback via text messages, and setting-up over-
encapsulation procedures and logistics through the Los Angeles Biomedical Research Institute at 
Harbor-UCLA Medical Center Investigational Pharmacy. 
 
(2) Stage II—Pilot Stage will confirm bioavailability of over-encapsulated ARVs and pilot-test and 
optimize the procedures and systems developed in Stage I to ensure smooth operations in the trial 
stage of the study. At least five different ARVS will be tested among six patients each for a total of 
30 patients. Second, we will pilot-test and optimize the procedures and systems developed in 
Stage I with 15 patients. During this pilot, we will assign patients to use the PROTEUS 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 10 of 28 
DISCOVER® system for 16 weeks. Some of the specific aspects of the system we will be 
evaluating, and possibly modifying are: (a) the real-time data collection process through mobile 
device, (b) the real time automated patient feedback texting system, (c) methods for over-
encapsulating tablets, and (d) patients’ acceptability with the PROTEUS DISCOVER® system, 
including automated text feedback message. 
 
(3) Stage III—Trial Stage is shown in Figure 1. In the first 16 weeks, we will test overall utility 
(including feasibility, acceptability and sustainability) of the PROTEUS DISCOVER® system, its 
accuracy for measuring adherence and its impact on enhancing patients’ level of adherence and 
selected outcomes. Durability of any observed effects will be examined during a 12-week post-
Proteus system follow-up period. 
 
 
Justification of Trial Stage Study Durations: 
Duration of testing PROTEUS DISCOVER® system: The sixteen weeks was chosen because it is 
long enough to test feasibility and acceptability and to detect an effect of many effective 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 11 of 28 
adherence-promoting systems. It is also long enough to detect problems with sustained use of the 
system (e.g. fatigue with using the patches, use of an on-line pager system to increase adherence 
to antiretroviral medications, etc.) The system is likely to become easier to use in future years with 
longer-lasting patches and lower costs but studies like this one are necessary to establish proof of 
concept and the PROTEUS DISCOVER® system's feasibility, acceptability, accuracy and efficacy 
in a clinical population. 
Duration of follow-up for retention of effects: A twelve week follow-up is long enough to detect rapid 
dissipation of any effects of using the PROTEUS DISCOVER® system. The PROTEUS 
DISCOVER® system is being tested in this early stage study as a standalone system, without 
other efforts to effect long-term adherence improvement (e.g. with a behavioral intervention.) 
Although ideally we would conduct longer-term testing of the system in order to address questions 
about long-term use, we decided against such a design because of the cost such testing would 
entail and the need to first establish feasibility, acceptability, accuracy and short-term effects. 
Pilot Stage 
a. Bioavailability of over-encapsulated ARVs: Eligible patients will be identified that are 
already on stable regimens with one of the drugs of interest including TDF/FTC, ABC/3TC, 
TDF/FTC/EFV, ABC/3TC/DTG, TDF/FTC/EVG/COBI, TAF/FTC/EVG/COBI and when 
approved TAF/FTC and TAF/FTC/RPV (Modified per LOA 1 dated 1/29/16) . The study will 
evaluate 6 patients on each of the drugs of interest. All participants will be counseled to 
ensure compliance with their HIV medications. Participants will be queried as to the number 
of doses of HIV medications not taken in the previous 3 days, and this number will be 
recorded. The time and date of all doses of HIV medications taken the day prior to the PK 
study day will be recorded on a case (study) record form (CRF). The PK study will not be 
performed if a participant reports missing any doses of HIV medication on the day prior to 
the PK study. If this situation occurs, the participant will be counseled about medication 
adherence, and a repeat PK study may be performed ≥ 5 days later. On the day of the PK 
study, the participant will come in, have a pre-dose (time 0) blood sample obtained, take an 
observed dose and have blood drawn at 1, 2, 4, and 6 hours post dose.  The time of doses 
of HIV medications given on the day of the PK study, and the exact time that blood samples 
are obtained, will be recorded on a CRF. Drug concentrations will be determined in Antiviral 
Pharmacology Laboratory at University of Nebraska Medical Center. We will compare 
observed Cmax values with those from published literature. The finding that Cmax values 
are within the expected range will confirm the lack of any adverse effect of over-
encapsulation on absorption.  If this is not the case we will exclude the drug in question from 
the Pilot and main study. 
Subjects taking a Tenofovir/Emtricitabine (FTC/TDF, Truvada) will be asked to complete two 
6-hr evaluations. One without over-encapsulation and one other in which the medication will 
be over-encapsulated as described above.  
Subjects taking a Tenofovir alefanamide/Emtricitabine/Bictegravir (FTC/TAF/BIC, Biktarvy) 
will be asked to complete two 6-hr evaluations. One without over-encapsulation and one 
other in which the medication will be over-encapsulated as described above.  
 
 
9-17-18 – The bioavailability of Tenofovir/Emtricitabine has already been completed. Only 
subjects taking this combination of medications required two 6-hrs evaluations.  
 
As of August 2018, 2 new drug combinations have been approved for the treatment of HIV:  

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 12 of 28 
 Bictegravir, Emtricitabine & Tenofovir alafenamide (Biktarvy®) 
 Darunavir/Cobicistat/Emtricitabine/Tenofovir alafenamide (Symutza™) 
 
The study will evaluate six (6) subjects on each of these drugs for a total of 12 additional 
subjects. The total number of subjects to be enrolled to the bioavailability phase of the study 
will be 66 (54 already enrolled and complete) . The process of evaluating the bioavailability 
of these two new drugs will be similar to what was done for the other drug combinations as 
described above. 
 
12/26/18 - The bioavailability tests of Tenofovir alefanamide/Emtricitabine/Bictegravir were 
completed on 12/6/18. Only subjects taking this combination of medications required two 6-
hrs evaluations.  
 
 
b. Pilot to test procedures, process, operations and patients’ reactions to the PROTEUS 
DISCOVER® system.  Fifteen patients including at least 6 women and 4 Hispanics who 
meet inclusion criteria will be provided the Proteus system and a mobile phone that is 
programmed for study-related communication, data upload, and data review. These 
individuals will pilot the use of the PDHS system to identify approaches that optimize the 
procedures and operation process. This phase of the study will be for 16 weeks.  At initial 
orientation they will have the Proteus app installed on their smart phones, and if they don’t 
have one we will provide. The system will be explained with pictures and graphics, and a 
handout summarizing the information will be provided.  An initial debriefing will occur three 
days after beginning to use the system and again at week 2, both by phone and then at 
week 4, 8, 12 and 16.  In face-to-face data collection visit.  During the visits interviewers will 
be trained in principles of qualitative interviewing with semi-structure format seeking 
feedback on what is and is not working with the system, including everything from taking the 
over-encapsulated pills, being monitored, wearing the patch, receiving text messages and 
collecting recommendations for changes to the system. 
 
9/18/18 - The Pilot phase of the study has already been completed. 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 13 of 28 
 
Trial Stage 
Overview. The schedule of assessment administration is summarized in table 3 below. 
Table 3. Schedule of Assessment Administration 
 
Measure (From survey and lab test) 
Screening 
Baseline 
Weeks 
Screening and Baseline Measures 
 
 
 
 
 
 
 
 
 
 
-30 
0 
4 
8 
12 
16 
20 
24 
28 
  Baseline Characteristics Questionnaire 
X 
 
 
 
 
 
 
 
 
  HIV History 
X 
 
 
 
 
 
 
 
 
  Tolerability of Ingesting encapsulated pill 
X 
 
 
 
 
 
 
 
 
Outcome Measures 
 
 
 
 
 
 
 
 
 
  Adherence measured by sensor 
 
X 
X 
X 
X 
X 
 
 
 
  Self-reported medication adherence for both groups 
X 
 
X 
X 
X 
X 
X 
X 
X 
  Drug level concentration from blood draw for both groups 
 
X 
X 
X 
X 
X 
X 
X 
X 
  Viral load/CD4 
X 
 
X 
X 
X 
X 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
Process Measures 
 
 
 
 
 
 
 
 
 
  Patient perceptions and acceptability of the PROTEUS 
DISCOVER® system 
 
 
X 
X 
 
X 
 
 
X 
 
1Continuous measure on daily basis from baseline through week 16. 
 
A research assistant will complete the baseline assessments within 30 days of screening using 
computer-based and paper-based assessments. Responses will be directly entered into a 
computer database by the research assistant. Once entered, all responses will be anonymous and 
no personal identifying information will be recorded. The research assistant performing the follow-
up assessments will do the best to remain blinded to the randomization allocation. In the event of 
missed visits, at least six attempts will be made to contact patients by telephone and letter. Even if 
a contact was not successful at any follow-up visit, further attempts will be made at each 
subsequent scheduled study visit. Table 3 summarizes the assessment schedule. Patients will 
be compensated for completing the baseline assessment ($40) and for each follow-up assessment 
($40). 
 
Screening and Baseline Assessments: Patients will be screened with research assistants to 
complete Eligibility Form, informed consent, and consent to contact with providers to determine 
current medication regimen, determining if the patient meets suboptimal adherence criteria and 
tolerability of over-encapsulated pill. Patient interview will be audio taped. 
 Baseline Characteristics Questionnaire Socio-demographics, including, age, gender, 
race/ethnicity, language, educational level, marital status, source of income and residential 
status, will be collected. 
 HIV History. A brief HIV clinical history will assess years since HIV diagnosis, years on HIV 
treatment, current HIV regimen, overall pill burden, and disease co morbidity. 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 14 of 28 
 
Trial Stage 
This will include randomization to PROTEUS DISCOVER® group or UC group for 16 weeks 
(Figure 1). During these 16-weeks, adherence of the PROTEUS DISCOVER® group will be 
measured by pill ingestible sensor, plasma drug level and self-report, and adherence of the UC 
group will be measured only by plasma drug level and self-report. After 16 weeks there will be a 
post PROTEUS DISCOVER® follow-up period where all subjects will be followed for an additional 
12 weeks during which adherence of both groups will be measured by plasma drug level and self-
report as outlined in Table 3. 
 
The objective adherence measure of drug level concentration will be obtained to serve as norm for 
patients in both groups throughout the 28 weeks with blood draw schedules of three samples at 
baseline [(to establish patient specific response bases) at times 0 (before taking anti-HIV 
medicines) and 2 and 6 hours after taking the medications)] and one sample each at weeks 4, 8, 
12,16, 20, 24 and 28. With three blood draws scheduled around the time of an administered dose 
to establish patient-specific pharmacokinetics. The schedule of blood draws relative to drug 
administration and other conditions will be specified for each drug by Dr. Fletcher. During the trial 
phase, the date and time of all doses of HIV medications taken the day prior and the day that blood 
concentrations are obtained will be recorded on a case (study) record form (CRF).  
Plasma HIV RNA and CD4 cell count will be obtained with the same time schedule as drug level 
blood draw. This same blood draw schedule of plasma HIV RNA and CD4 cell count outcomes 
with the drug level concentrations will enable us to blind patients for drug level concentration test to 
reduce “white coat” effect on adherence as assessed by drug levels. Patient surveys of 
demographics and baseline information will be done at baseline. Perceptions of wearing the patch, 
use the PROTEUS DISCOVER® system, automated texting feedback system and others will be 
done at weeks 4, 8, 16, and 28. 
 
 
 
(1) Proteus Ingestible Sensor and Monitor 
The system consists of an ingestible sensor and an externally worn adhesive monitor, the patch-
monitor. Together, the ingestible sensor and patch-monitor can be used to directly confirm 
whether, when, or how many doses of prescribed medication are actually taken. 
 
(2) Proteus Digital Health Feedback System with Real Time Data Collection 
Building on the available Proteus devices, we will design and create a PROTEUS DISCOVER® 
system (Fig. 2) to transmit the adherence data using mobile technology to allow treatment 
monitoring that is, direct confirmation of the type, dose, date and time of oral pharmaceutical 
ingestion using wirelessly observed therapy (WOT). We will set up a database system (e.g., using 
ACCESS or MySQL) on a UCLA-based server using a dynamic programming language (e.g., PHP 
or Perl). We will use WinSSHD for secure remote access and file transfer. WinSSHD supports 
public key authentication, SCP, SFTP. When the patch-monitor comes into proximity of the 
patient’s mobile phone, the monitor’s stored data are encrypted and transmitted via Bluetooth to 
the patient’s phone. The phone sends the data using industry standard encryption (the same 
encryption utilized by banks) to a secured, centralized data center for storage and processing at 
UCLA. Processed data can then be relayed for display to the patient and/or medical professionals, 
as designated by the patient. The WOT system directly confirms adherence to oral medication 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 15 of 28 
electronically and wirelessly, eliminates the need for direct observation by a health worker and 
allows anytime, anywhere, objective confirmation of dosing. 
 
(3) Automated Text Feedback System 
We will use a secure and confidential web-based interface to send a short message service (SMS) 
text when a dose has not been ingested within a pre-determined time, informing the participant that 
a dose was missed. We will build on our experience in the CARE study and that of other groups to 
do the following: 
a)  Customize with patients the schedule of messages (what window qualifies as a missed 
dose, and how soon after a dose is missed a text message is sent) 
b)  Customize the content of the text messages. Options offered to patients will include use of a 
code for medication-taking to disguise the message if seen by someone else (e.g. message 
to “eat your veggies”), exhortations (“remember your health, take the dose” or “remember 
your mom, take your meds”), or more HIVspecific messages (e.g. “efavirenz was due at 
8PM”). 
 
(4) Over-Encapsulation Procedures 
Ingestible Sensors will be assembled in conjunction with device carriers. Proteus will directly 
provide sensors inside a placebo of a tablet dose form (about 3mm in diameter and 1mm in 
thickness). We will use over encapsulation with capsules provided by Capsugel (Greenwood, SC, 
USA) which has been used in other Proteus studies. This will provide a vehicle to combine any 
solid-dosage drug product inside a capsule with an Ingestible Sensor tablet dose form. ARVs of 
various form factors (e.g., a tablet or a capsule) can be placed inside the capsule along with the 
Ingestible Sensor tablet dose form. With the over-encapsulation method, the Ingestible Sensor, the 
drug product, and the standard excipient materials are completely contained within the capsule. 
Over-encapsulation provides an Ingestible Sensor-enabled dosage form with a familiar 
appearance to patients. Over encapsulation will be performed and handled by the Investigational 
Pharmacy at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and 
will be done to one of the pills to be taken at a given time to an individual. If taking multi-pill 
regimen the verification that the other medications were taken will be accomplished by self-report 
and plasma drug level monitoring. 
 
e) 
Data and Specimen Banking 
 
No banking of specimens will be done in this study. 
 
Data sharing plan: This project will adhere to the spirit and letter of the NIH guidelines on data 
sharing as published online at: NIH Data Sharing Policy, 
http://grants1.nih.gov/grants/policy/data_sharing/ and to University Intellectual Property policy. We 
will create final merged and de-identified analytic files (no any PHI) that include behavioral and 
adherence measures and make them as widely and freely available as possible for educational, 
research, and nonprofit purposes while safeguarding the privacy of subjects and protecting 
confidential and proprietary data. We will be sensitive to situations in which even de-identified data 
could lead to “deductive disclosure” of participants’ identities. Our approach to data sharing will 
include (1) Sharing data via website, particularly the summarized and aggregated results. (2) 
Sharing data through an electronic copy of the data sets. (3) Sharing data through a hard copy of 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 16 of 28 
summarized information. (4) Sharing data and findings through national academic meetings and 
conferences. 
 
f) 
Data Management  
Sample Size Calculation and Power Analysis 
Sample size calculation and power analysis was conducted based on the primary outcome of 
adherence to ART. Using repeated measures analysis with intra-subject correlation of 0.1, a type I 
error of 0.05, a type II error of 0.2, and average number of available data points six, 60 subjects in 
each of the PROTEUS DISCOVER® and UC groups will enable us to detect an effect size as 
small as 0.23 between the two groups, which is statistically and clinically meaningful. Thus, we will 
have sufficient statistical power to carry out the analyses for aims 2 and 3 (analyses for plasma 
HIV RNA and CD4 count are exploratory). For analyses of aim 1, 60 subjects in the PROTEUS 
DISCOVER® group will enable us to obtain stable point estimates. Thus, we have sufficient power 
for the study. 
 
Stage I—Preparation Stage 
PROTEUS DISCOVER® system with Real Time Data Collection 
Building on the available Proteus devices, we will design and create a PROTEUS DISCOVER® 
system (Fig. 2) to transmit the adherence data using mobile technology to allow treatment 
monitoring that is, direct confirmation of the type, dose, date and time of oral pharmaceutical 
ingestion using wirelessly observed therapy (WOT). 
 
We will set up a database system (e.g., using ACCESS or MySQL) on a UCLA-based server using 
a dynamic programming language (e.g., PHP or Perl). We will use WinSSHD for secure remote 
access and file transfer. WinSSHD supports public key authentication, SCP, SFTP. When the 
patch-monitor comes into proximity of the patient’s mobile phone, the monitor’s stored data are 
encrypted and transmitted via Bluetooth to the patient’s phone. The phone sends the data using 
industry standard encryption (the same encryption utilized by banks) to a secured, centralized data 
center for storage and processing at UCLA. Processed data can then be relayed for display to the 
patient and/or medical professionals, as designated by the patient. The WOT system directly 
confirms adherence to oral medication electronically and wirelessly, eliminates the need for direct 
observation by a health worker and allows anytime, anywhere, objective confirmation of dosing. 
 
Automated Text Feedback System 
We will use a secure and confidential web-based interface to send a short message service (SMS) 
text when a dose has not been ingested within a pre-determined time, informing the participant that 
a dose was missed. We will build on our experience in the CARE study and that of other groups to 
do the following 
---customize with patients the schedule of messages (what window qualifies as a missed dose, and 
how soon after a dose is missed a text message is sent) 
---customize the content of the text messages. Options offered to patients will include use of a 
code for medication-taking to disguise the message if seen by someone else (e.g. message to “eat 
your veggies”), exhortations (“remember your health, take the dose” or “remember your mom, take 
your meds”), or more HIV-specific messages (e.g. “efavirenz was due at 8PM”). 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 17 of 28 
 
Stage III—Trial Stage 
The third stage will test overall utility (including feasibility, acceptability and sustainability) of the 
PROTEUS DISCOVER® system, its accuracy for measuring adherence and its impact on 
enhancing patients’ level of adherence and the effect on virologic and clinical outcomes 
(exploratory), the retention of its impact on keeping up with adherence and improvement of plasma 
HIV RNA and CD4 cell count after the 16-week usage of the PROTEUS DISCOVER® system. For 
this stage, we will recruit 120 HIV/AIDS patients with sub-optimal adherence to ART. Patients will 
be observed and followed up for a total of 28 weeks, with the initial 16-week trial period including 
the PROTEUS DISCOVER® versus UC, and a subsequent 12-week post trial follow-up period 
where both groups receive UC alone. 
 
Research participants will be interviewed by specially trained research assistants, using 
standardized assessment instruments. Subjects will also complete self-report rating forms. All 
assessments will be recorded directly into a computer database and monitoring system. 
Participants’ names will appear only on the consent form, the HIPAA authorization form, medical 
records, and a “key” form kept by the Project Director. With the exception of the “key” form linking 
subject ID numbers and names, research records will contain only the subject’s study ID number 
(and no patient identifiers), and medical records will contain only subject names (and no subject ID 
numbers). Research staff will have access to patient names only during active participation. 
 
Clinical Site Monitoring and Record Availability 
UCLA will review the individual subject records, including consent forms, CRFs, supporting data, 
and medical records to ensure protection of study subjects, compliance with the protocol, and 
accuracy and completeness of records.  
 
g) 
Confidentiality 
.  
All evaluation forms, reports, and other records that leave the site will be identified by coded 
number only to maintain subject confidentiality. All computer entry and networking programs 
will be done with coded numbers only. Clinical information will not be released without 
written permission of the subject, except as necessary for monitoring by UCLA, NIH or other 
government agencies as part of their duties to ensure that research subjects are protected. 
 
All research information is considered confidential. Our data collection and management 
procedures are fully compliant with HIPAA. Access will be limited to personnel intimately involved 
in the study. Right to privacy for participation in this research will be protected through anonymous 
coding of research data and proper storage of research records. 
 
a. Limits to confidentiality: These limits include disclosure of acute suicidality, homicidality, or 
abuse of a minor, as is standard in clinical practice. Research data will be identified by code 
number and will not include names, although enrollment records must also be kept and these 
records will include names. 
 
b. Data Collected: The study forms have been designed to avoid collecting identifiable information; 
no Protected Health Information (PHI) will be collected on study forms. We generally collect only 
protocol session dates. These dates are changed to ‘number of sessions completed’ when data 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 18 of 28 
sets are anonymized and released to other investigators. All computers used by research staff are 
password protected. 
 
c. Enrollment Records Containing PHI: Clinical enrollment records are kept separate from research 
data, and are not available without a client’s written consent. Participants’ names will appear only 
on the consent form and the HIPAA authorization form, kept by Dr. Daar. Both P.I.s (Drs. Liu and 
Daar) will keep a “key” form that links the study IDs to their names; this form will be stored on a 
secure server separate from the study data. Research data will also be collected from the treating 
clinicians such as initial eligibility information. To allow clinicians to provide information candidly, 
data collected from clinicians will be kept confidential from both third parties and the patients being 
enrolled. Only researchers officially appointed to work on this project will have routine access to 
protected health information. The sponsor, and agencies or departments with responsibility for 
research compliance will have access to protected information if necessary for oversight of study 
conduct (e.g. review that consent forms are completed properly). These other agencies include: 
Institutional Review Boards, Office of Research Compliance, government representatives, when 
required by law, UCLA Harbor Medial Center Clinic representatives, the Department of Health and 
Human Services, and the Food and Drug Administration. At the conclusion of the study, all locator 
data will be destroyed. Source data will be sent to a secure location (Iron Mountain) and will be 
destroyed 7 years after publication of the study results. 
 
d. Preparation of Reports: The research records will be used to prepare reports that do not include 
client identification. 
 
e. Staff training: All project staff will receive this training as provided by the UCLA, Harbor-UCLA, 
Yale and Nebraska Medical Center Office of Compliance and Office of Privacy and Information 
Security, Data collection and management procedures at UCLA, Harbor-UCLA, Yale and Nebraska 
Medical Center are fully compliant with HIPAA. 
 
f. Certificate of Confidentiality: The study team has applied for a Certificate of Confidentiality to 
minimize the risk of forced disclosure in a legal or other proceeding. The Certificate, and the study 
consent form, will indicate the exceptions to confidentiality in which information may be disclosed 
without a patient’s consent including danger of imminent harm to self or others, abuse or neglect of 
a child, and abuse or neglect of an elderly person.  
 
g. Patient Behavior: Administrative termination will be considered if the patient’s behavior is 
incompatible with safe completion of the research protocol. 
 
h. Release of study information at Conclusion of Study: Patients who are enrolled in the study will 
have a debriefing session at the conclusion of their study participation at which they will review 
their adherence data (including ARV blood level data) with the research assistant. Patients will also 
be offered the study data to present to their providers if the patient chooses to do so 
 
i. Difficulties providing informed consent: As noted earlier, participants will be asked questions at 
the time of enrollment to determine whether or not they understand key aspects of the study 
procedures. In addition to the usual consent procedures, the researcher obtaining consent will 
document the discussion of the study, including questions raised by the participant. 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 19 of 28 
All records will be kept locked. All computer entry and networking programs will be done with 
coded numbers only. Clinical information will not be released without written permission of the 
subject, except as necessary for monitoring by the NIH, study monitors, OHRP, or other 
government agencies as part of their duties to ensure that research subjects are protected. 
 
No laboratory specimens will be stored at this site. All test required for the study will be performed 
in real time.  
 
 
Data will be stored locally until 2 years after the completion of the study 
Only study personnel associated with the study will have access to the data 
The study coordinator will be responsible for receipt and transmission of data to the 
collaborating institutions 
Data and specimens will be handled by the local study personnel 
 
Audio-recordings: To make sure that the subject's confidentiality and privacy are protected, the 
following steps will be taken: 
 We will ask subjects to provide informed consent for taping some of the sessions.  
However, they have the right to refuse taping. If they agree to taping, they have the right 
to stop taping at any time during the session. 
 Audio recordings will be treated as confidential research records.  The tapes will be 
stored in a locked cabinet and labeled with the subject’s unique identifier code number 
and the date of the session.  The audio-taped files will be encrypted with password 
protection. Access to audiotapes will be limited to members of the research team. 
 Secure email system and secure FTP site will be used to transfer the research data 
(including audio recordings) between the data collection site at LABiomMed, UCLA 
research team and the Yale research team.  
 
 
h) 
Provisions to Monitor the Data to Ensure the Safety of Subjects 
Data and Safety Monitoring Plan 
We are planning to use a reliable and secure system for data collection, monitoring and reporting 
that we have used in our clinical trial for the past 10 years. It consists of a database hosted on a 
network of secure servers that will be used to collect and store data on server-based applications. 
New assessments are easily programmed and added to specific studies. All connections to the 
systems are secured and encrypted using 128-bit strong encryption protocols and only authorized 
users are able to access the system. All data is stored in encrypted files, and multiple backups of 
the system and all data are maintained. The system monitors participant progression through the 
study and reports are generated for the project director and Principal Investigator (PIs) when 
assessments are not completed. Additional reports can be provided on study logistics to monitor 
study progress and protocol compliance. At the completion of the study, or at any point during the 
study, all data collected can be transferred to the PIs or DSMB in the form of electronic data files 
using the format predetermined for reviewing. At the request of the PIs, all data from its systems 
including the backups can be erased. 
 
Data monitoring procedures involve an organizational structure of clearly defined tasks assigned to 
all research personnel involved in the conduct of this study. The organizational structure used to 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 20 of 28 
ensure quality of data in this project include: 1) extensive training and close supervision of 
research assistants in data collection; 2) direct entry of most data at time of collection; and 3) 
utilization of on-line error-checking procedures. The PIs will supervise data procedures. All error 
corrections will be fully documented in the research records of the study. All research personnel 
will be required to participate in and document training in protection of human subjects and the 
responsible conduct of scientific research. 
 
Data entry and review in this study will be conducted using a web-based data collection and 
monitoring system. The Web based data system, provided by LinkZero, is designed to fulfill strict 
requirements of a clinical trial regarding data collection, monitoring, and reporting from the 
recruitment of participants to the delivery of data sets suitable for statistical analyses at the end of 
the trial. Briefly, the user of this system, after connecting to the server using a secure connection 
protocol, is presented with on-screen forms that allow information to be entered. Data is entered 
directly into web-based assessment forms or is transferred from other records when they are 
available (e.g. urine screens, HIV markers). The system monitors the subject progression along 
his/her schedule and this information is used for reporting. For example, if results of particular 
weekly or monthly assessments are not in the system within a specified window of time (e.g., 2 
days), reports are generated and sent automatically via email to designated recipients (such as the 
PI or other investigators). The end user of the system, a research assistant or data manager, can 
also be informed about protocol violations, such as missing assessments or schedule lapses via 
on-screen messages. Therefore, corrective actions can be undertaken expeditiously without 
substantial loss of data or research protocol violations. 
 
Another set of automatic email reports, sent on a weekly or less frequent basis, provides a set of 
designated recipients (e.g., the PI or Project Director) with information about study logistics, such 
as number of subjects enrolled, number of subjects active in the protocol, gender composition of 
the sample, percentage of missing data by each assessment instrument, or any other information 
necessary to monitor the progress of the project and the compliance with the protocol. A fully 
computerized system allows this type of monitoring without furnishing investigators with data that 
could influence the outcome of the study. The system meets the highest security and reliability 
standards. All connections to the systems are secured and encrypted using 128- bit strong 
encryption protocols and only authorized users are able to access the system. All data is stored in 
encrypted files; the system has multiple backups maintained by the staff of LinkZero. At the 
completion of the study, or at any point during the study, all data collected can be transferred to the 
PI, or other designated person, such as the study statistician in the form of electronic data files 
using the format predetermined by the PI and the investigators. LinkZero at the request of the PI 
will erase all data from its systems including the backups. 
 
The research team will meet weekly to review the overall progress of the study, and discuss 
progress of each subject in the study. All members of the research team will be familiar with 
procedures for identifying and reporting possible adverse reactions. All adverse events are 
reported using the Institutional Review Board (IRB) standard template for reporting adverse 
events. The PI at the site of the adverse event will review all adverse events, classify the attribution 
of adverse events (e.g., definitely, probably, possibly related; unlikely or unrelated) and grade the 
severity of the event, utilizing the FDA’s definition of serious adverse events, on a 6-point scale 
(0=no adverse event or within normal limit; 1=mild; 2=moderate; 3=severe; 4=life-threatening; 
5=fatal). Serious unanticipated or anticipated adverse events will be reported immediately to the 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 21 of 28 
IRB and to NIH. Adverse events will be reported in summary form at least annually to the IRB. The 
summary will include the number of subjects enrolled and a summary of graded adverse events to 
date, using the chart format included in the UCLA University Data Safety and Monitoring Plan 
template. The PI will evaluate all adverse events and determine whether the event affects the 
Risk/Benefit ratio of the study and whether modifications to the protocol (e.g., Risks to Subjects) or 
consent form (e.g., Risks and Inconveniences) are required. 
 
The PI is responsible for monitoring the data and conducting performance and safety reviews, at 
the specified frequency. Either the PI or the IRB have the authority to stop or modify the study. The 
monitoring by the IRB will occur annually at the time of re-approval. The PI will conduct data and 
safety review at least quarterly and at any time a serious adverse event occurs. During the review 
process, the PI will evaluate whether the study should continue unchanged, requires modification 
or amendment to continue, or should discontinue enrollment. 
 
Safety monitoring plan: In this study we will use the FDA definition of SAEs. The P.I. at the site the 
SAE was detected will be responsible for reporting it. 
 
Any SAEs will be immediately reported to the P.I. Reports will include a description of the event, 
relevant progress notes and records, and a summary of recent contacts with the patient. This 
summary will include any warning signs of the adverse event, the patient’s general state and any 
information suggesting a causal link between study participation and the event. These will be 
reported to the UCLA and LaBiomed at UCLA-Harbor IRBs and to the NIH Grants Project Officer 
within 3 working days. 
 
Patients with HIV have an extremely high frequency of medical and psychiatric difficulties. 
Therefore, changes in physical or psychiatric condition, medication regimen or the presence of 
medication side effects are not untoward and do not constitute adverse events. It is extremely 
unlikely that the study procedures would exacerbate any of these. Anticipated adverse events 
include complaints about the study procedures, and any occurrence in which the patient attributes 
discomfort, harm or disability to the study procedures. 
 
In this study, assessment for adverse events will be a routine part of every study and visit and 
phone call. SAEs and AEs will be screened for in the timeline follow-back. Operationalized, any 
report that a patient required overnight treatment in any facility (emergency room, detoxification, 
hospitalization) will constitute an SAE, as will any report of death, serious disability or 
hospitalization or death of another individual due to direct action of patient. 
 
Every year, Drs. Daar and Liu (Co-PI at UCLA) will review study enrollment-to-date, SAEs and 
AEs, urine toxicology test results, side effect reports and other data as it deems necessary. A 
written summary including this information will be provided to the two IRBs with the protocol 
renewal and to NIH with the grant renewal. 
 
i) 
Withdrawal of Subjects 
The study doctor may stop subjects from taking part in the study at any time without their consent if 
the study is cancelled, subjects are not able to attend visits as required, or their doctor thinks is not 
in their best interest. 
 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 22 of 28 
 
 
9. 
Risks to Subjects 
Blood Drawing: Participants will have ten blood draws (three at baseline and at months 1-7) as a 
result of their participation in the study. Blood drawing can cause some pain and result in a 
hematoma. Plasma HIV RNA and CD4 cell count will be obtained with the same time schedule as 
drug level blood draw. This same blood draw schedule of plasma HIV RNA and CD4 cell count 
outcomes with the drug level concentrations will enable us to blind patients for drug level 
concentration test to reduce “white coat” effect on adherence as assessed by drug levels. We will 
ask patients to get permission to withhold information from them about the purpose of the blood 
draw. 
 
Rating Scales and Assessments: These are all noninvasive and should not add risk. The major 
inconvenience is the time it takes to complete the assessments and that they may be somewhat 
tedious to complete. 
 
Monitoring System-Related Risk: Refer to current version of Investigator Brochure for the study 
device. 
The ingestible marker and the personal monitor of the monitoring system are FDA-approved for 
safety and have the CE mark (Conformité Européenne, meaning "European Conformity") of 
approval, indicating they also meet European Union safety requirements. The potential risks 
include: 
1- Nausea 
2- Vomiting 
3- Constipation 
4- Difficulty swallowing the pills 
5- Bitter taste 
6- Abdominal cramping (very rare) 
7- Stomach pain (very rare) 
8- Asthma attacks 
9- Non-cardiac chest pains 
10- Risk that participants could find the co-encapsulation pill (which includes the sensor) is larger 
and thus less comfortable to swallow than the antiretroviral (ARV) medication alone: 
11- Risk that participants could find wearing patch uncomfortable: 
12- Possible skin irritation/itchy/allergic, although very rare in prior trials. 
13- Risk that Proteus system inaccurate 
 Risk that message sent even though the medication was taken, and patient takes a second 
dose of the medication because he/she mistakenly thinks the dose was missed when it was 
not;  
 Risk that reminder not sent when med missed; 
 Risk that Proteus system associated with worse adherence than existing method of taking 
medication. 
14- Risk that over-encapsulation alters pharmacokinetics. 
 
Risk from resistant strains of HIV: Risk that patients may not take medications due to over-
encapsulation or other study-related issues and that this could be associated with emergent drug 
resistance. 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 23 of 28 
 
Loss of Confidentiality. There is the possibility that confidential information obtained during the 
study will be disclosed, given the social and legal sanctions associated with HIV status, and 
psychiatric symptoms. Patient names and other identifying information will not appear on research 
records. Text message reminders will be messages patients choose to receive, with as much or as 
little HIV-related information as they choose. 
 
Audiotaping of Interviews: 
During the study we would like to audio record some of the sessions with the study staff.  The 
purpose of this is for the study team to hear your opinion about the system and how we can make 
it better. .   
 Recordings will be reviewed by members of the research team who are trained to review 
recordings. 
 Recordings will be identified by number only.  Names will not be noted by the study staff or 
reviewer on any recordings. 
 Subjects may choose to stop being recorded at any time and can still be in the study.  This 
decision will not change their care in any way. 
 All study recordings will be kept in locked file cabinets and/or password protected 
computers.  Only study staff will have access to them.  Study records (including audio 
recordings) will be stored until the completion of the study 
 Information from the recordings may be published or shared in study reports in aggregate to 
help describe the sessions and how they were conducted, but names or other data that 
might reveal personal information will not be revealed in any reports or writings that may 
result from this study. 
 
If applicable, indicate which procedures may have risks to an embryo or fetus should the subject be 
or become pregnant. 
Subjects cannot take part in this study if they are pregnant or planning to become pregnant. The 
risks of the PROTEUS DISCOVER® system to a pregnant woman and her fetus (unborn baby) are 
not known. Women who are having sex that could lead to pregnancy must agree not to become 
pregnant while taking part in this study.  
 
Monitoring System-related risk: 
 Risk that participants could find the over-encapsulated pill (which includes the sensor) is 
larger and thus less comfortable to swallow than the ARV medication alone: 
o Screening will include taking the over encapsulated product prior to enrollment and 
we will monitor and offer regular pills to anyone who reports this is impacting them. 
 Risks hat participants could find wearing patch uncomfortable (e.g., Skin 
irritation/itchy/allergic) 
o we will warn participants of this possibility, and ask them to stop using the patch if it is 
consistently discomforting. 
 Risk that Proteus system inaccurate 
o Risk that message says med not taken when actually was 
 
 
– this is very rare 
 
 
– will warn participants of this possibility 
o Risk that reminder not sent when med missed 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 24 of 28 
– was not an issue in Centralized Off-site Adherence Enhancement (CARE) 
automated system but will monitor this 
 Risk that Proteus system associated with worse adherence 
o will have Data Safety and Monitoring Board (DSMB) with semi-annual unblended 
review of study data 
 
Blood Drawing: Participants will have ten  blood draws (three at baseline and at months 1-7) as a 
result of their participation in the study. Blood drawing can cause some pain and result in a 
hematoma. 
 
Plasma HIV RNA and CD4 cell count will be obtained with the same time schedule as drug level 
blood draw. This same schedule of plasma HIV RNA and CD4 cell count outcomes with the drug 
level concentrations will enable us to reduce “white coat” effect on adherence assessed by drug 
levels. We will ask patients to get permission to withhold information from them about the purpose 
of the blood draw. 
 
Risk that over-encapsulation alters pharmacokinetics. To address this there will be a lead in 
study to assure approximate bioequivalence of commonly used ARVs when taken with, compared 
to without over encapsulation. 
 
Risk that patients on study may take drugs less frequently, such as if they are bothered by 
over encapsulation of medications and that this could result in emergence of resistant strains of 
HIV Because periods without ARV medication may allow resistant strains of HIV to emerge, we will 
institute procedures to insure that interruptions in effective ARV associated with using the Proteus 
system are promptly remedied. These safety procedures include: 
a.  Reminding participants of their right to switch to their usual medication-taking system at any 
time. We will make clear to participants that one aim of the study is to learn if the Proteus 
system is acceptable to patients, not to insist they use it whether they like it or not. Note that 
the study analyses involve intent-to-treat, so we will follow patients assigned to the Proteus 
condition, whether they continue to use the Proteus system or not. Thus, there is no 
financial incentive for patients to use the Proteus system in order to continue to receive 
payments for study participation. We will make this clear to participants upon enrollment. 
 
b.  We will ask people who “strongly disagree” with a statement about the Proteus system 
being “convenient” (or similar concept such as “usable”) if they feel it is in any way making it 
less likely, compared to the way they usually take their medication, that they will take their 
medication as prescribed. Participants who feel the Proteus system is making adherence 
less likely will be encouraged to discontinue use of the Proteus system and use another way 
to take medications. We will, however, allow participants who want to continue using the 
Proteus system to do so. These patients may be judging that overall, the Proteus system is 
likely to help them take their medication as prescribed, despite some inconvenience, 
because it has offsetting advantages (knowing one is monitored, reminder system). 
 
10. 
Potential Benefits to Subjects 
Benefits to Participants: Patients enrolled in this study may have enhanced adherence which 
could improve their medical condition. Payment for participation during the Pilot and trial Study: 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 25 of 28 
Patients will be paid for completing data collection assessments with a research assistant 
according NIH standards. 
 
Benefits to Others: If the PROTEUS DISCOVER® system is effective, it might be adopted by 
other treatment facilities. This project may demonstrate the benefit of a system to help patients 
improve their adherence to ART. Given the enormous health, economic and societal costs of 
progression of HIV, the risk-benefit ratio is favorable. 
 
The Benefit/Risk ratio: The potential benefits realized of the device system are substantial, and 
the risks posed by the device system are small. The benefits of study participation outweigh the 
risks. 
 
Importance of knowledge to be gained 
Overall, the study risks are reasonable in relation to the importance of the potential benefits for 
both the participants and science that reasonably can be expected to result. The risks associated 
with participating in this study can be categorized as minimal. 
 
11. 
Provisions to Protect the Privacy Interests of Subjects 
The study doctors and staff will do everything they can to protect their privacy.  In addition to the 
efforts of the study staff to help keep their personal information private, the study team has applied 
for a Certificate of Confidentiality from the Department of Health Services.  This certificate means 
that researchers cannot be forced to tell people who are not connected with this study, such as the 
court system, about their participation.  
 
Measures to protect privacy  
 Use a private setting for completing sensitive surveys or interviews  
 Collect only the minimal amount of information necessary  
 Avoid and limit the collection of identifiable information, and/or signatures  
 Use discrete recruitment methods to eliminate identification of participants based on a 
stigmatizing or sensitive condition  
 Confirm the participant’s identity at the first encounter  
 Never discuss the participant’s case with anyone without the participant's permission 
(including family and friends during off-duty hours)  
 Never leave hard copies of forms or records where unauthorized persons may access them  
When on-site: 
 
Conduct interviews in a private room.  
 
Never discuss cases or use participant names in a public area such as hallways or elevators 
 
If a staff member or health care worker requests participant information, establish his or her 
authority to do so before disclosing anything  
 
Keep records that contain participant names and other identifying information in closed, 
locked files  
 
Carefully protect computer passwords or keys; never give them to unauthorized persons  
 Don't leave sensitive or confidential information on an answering machine that other people 
can access  
 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 26 of 28 
At the end of the study the study team will create final files (no any PHI) that include behavioral 
and adherence measures and make them as widely and freely available as possible for 
educational, research, and nonprofit purposes while safeguarding your privacy and protecting 
confidential and proprietary data. We will be sensitive to situations in which even de-identified data 
could lead to “deductive disclosure” of their identity Our approach to data sharing will include (1) 
Sharing data via website, particularly the summarized and aggregated results. (2) Sharing data 
through an electronic copy of the data sets. (3) Sharing data through a hard copy of summarized 
information. (4) Sharing data and findings through national academic meetings and conferences. 
 
12. 
Compensation for Research-Related Injury 
If subjects are injured because of this research, emergency medical care will be available. The 
care will not necessarily be free of charge. Financial compensation for any injury from this research 
is not available. If they are injured because of this research, they should first try to contact the 
principal investigator. If they cannot reach the investigator, they may call the hospital emergency 
department. They can also call the Los Angeles Biomedical Research Institute at Harbor-UCLA 
Medical Center, Compliance Office, for further information on the availability of medical treatment 
or compensation. 
 
13. 
Economic Burden to Subjects. 
None 
 
14. 
Consent Process 
 
This site will follow the HRP-090 SOP regarding the consenting process. 
 
Consent forms for the human subjects are obtained face-to-face, by the designee in a private office 
or exam room, and the consent forms are explained to them fully. The subjects are then asked if 
they have any questions and if everything is understood, they are asked to sign the consent form 
in front of a witness. 
 
Plenty of time will be provided to the subject to make decisions about study participation. They will 
be allowed to take the consent form home and when they are ready to begin they can return to the 
study site to sign the consent form. 
 
Non-English Speaking Subjects 
 Indicate what language(s) other than English are understood by prospective subjects or 
representatives.  
 If subjects who do not speak English will be enrolled, describe the process to ensure that the 
oral and written information provided to those subjects will be in that language. 
Spanish speaking individuals will be invited to participate. Study documents will be translated to 
Spanish. Bilingual study personnel will be available during the consenting process 
 
15. 
Process to Document Consent in Writing 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 27 of 28 
Describe whether you will be following “SOP: Written Documentation of Consent (HRP-091).” If 
not, describe whether and how consent of the subject will be documented in writing. 
 
Written Documentation of Consent SOPs (HRP-091) will be followed. 
Consent: Voluntary informed consent will be obtained from all patients prior to participation. 
Consent will be obtained by a member of the research team after the research procedures and 
risks associated with participation have been explained to the candidate. Participants will be 
informed that they are free to decline participation and withdraw from the study at any time and 
that neither action will adversely affect their relationship with study personnel or their clinic staff. A 
signed copy of the consent form will be provided to all potential patients. 
 
Consent to Obtain Baseline Information from Clinicians: Patients will provide written informed 
consent at the time of screening for the research staff to interview their treating clinicians to confirm 
the patients’ regimen so that patients are counseled to take the correct regimen 
 
16. 
Vulnerable Populations 
HIV-infected individuals who with problems to maintain adherence to antiretroviral medications will 
be included in the study. 
 
All above populations will be excluded. 
 
17. 
Drugs or Devices 
Ingestible Sensors will be assembled in conjunction with device carriers. Proteus will directly 
providesensors inside a placebo of a tablet dose form (about 3mm in diameter and 1mm in 
thickness). We will use over encapsulation with capsules provided by Capsugel (Greenwood, SC, 
USA) which has been used in other Proteus studies. This will provide a vehicle to combine any 
solid-dosage drug product inside a capsule with an Ingestible Sensor tablet dose form. ARVs of 
various form factors (e.g., a tablet or a capsule) can be placed inside the capsule along with the 
Ingestible Sensor tablet dose form. With the over-encapsulation method, the Ingestible Sensor, the 
drug product, and the standard excipient materials are completely contained within the capsule. 
Over-encapsulation provides an Ingestible Sensor-enabled dosage form with a familiar 
appearance to patients. Over encapsulation will be performed and handled by the Investigational 
Pharmacy at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and 
will be done to one of the pills to be taken at a given time to an individual. If taking multipill regimen 
the verification that the other medications were taken will be accomplished by self-report and 
plasma drug level monitoring. 
The patches and smart phones will be handled by the study staff under the supervision of the 
authorized investigators. 
 
18. 
Multi-Site Human Research 
This study is a collaboration with investigators at Los Angeles Biomedical Research Institute at 
Harbor-UCLA Medical Center (Daar), UCLA (Liu), University of Nebraska (Fletcher) and Yale 
(Rosen).  All patient enrollment and follow-up will be exclusively conducted at Los Angeles 
Biomedical Research Institute at Harbor-UCLA Medical Center. 

Measuring and Monitoring Adherence to ART with Pill Ingestible Sensor System 
 
Rev. December 26, 2018 
 
Page 28 of 28 
The research team will meet weekly via teleconference to review the overall progress of the study, 
and discuss progress of each subject in the study. All members of the research team will be 
familiar with procedures for identifying and reporting possible adverse reactions.  
 
19. 
Community-Based Participatory Research 
The LABioMed/Harbor-UCLA HIV Clinical Trials Unit has a local Community Advisory Board 
(CAB). The CAB meets monthly.  Meetings are publicized through emails to our community 
partners.  The CAB is an open group and currently consists of 10-15 community members from a 
variety of racial/ethnic/gender populations.  Further, it represents many community organizations, 
as well as people living with HIV/AIDS, many of whom have participated in clinical trials at each of 
the sites.  The meetings consist of educational and scientific discussions regarding HIV-related 
treatments and care.  These have included new drugs for treatment naïve patients, diagnosing and 
managing cognitive impairment, therapeutic vaccines, and updates from national and international 
conferences.  The remainder of each meeting is spent in review of currently enrolling trials, 
reviewing and commenting on CAB drafts of future studies, and other CAB business. 
 
20. 
Sharing of Results with Subjects 
Results of laboratory tests will be provided as soon as they are received. Final results of the study 
will be disseminated through direct mail to study participants and presentations at group forums.