Keep it SIMPLE: Improving Anti-Coagulation Medication Adherence for Patients With Non-valvular Atrial Fibrillation
Phase: NA
Conditions: Atrial Fibrillation, Medication Adherence
Sponsor: Tammy Toscos

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Keep it SIMPLE: Improving Anti-Coagulation Medication Adherence 
for Patients with non-valvular atrial fibrillation  
 
NCT02690649 
November 30, 2017 
 
 

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Keep it SIMPLE: Improving Anti-Coagulation Medication Adherence 
for Patients with non-valvular atrial fibrillation  
 
Protocol version 7.0 
Protocol version date: November 30, 2017 
 
Protocol ID: PRC15-0709 JNJ 
 
Co-Sponsor-Investigators: 
 
Michael J Mirro, MD 
Tammy Toscos, PhD 
Parkview Research Center 
3602 New Vision Drive 
Fort Wayne, IN 46845 
(260) 266-5938 
(260) 266-5586 
Michael.Mirro@parkview.com 
Tammy.Toscos@parkview.com 
 
Supported by: 
Janssen Scientific Affairs, LLC, a Johnson & Johnson Company (JNJ) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
PROTOCOL SYNOPSIS .................................................................................................................3 
STUDY BACKGROUND .................................................................................................................4 
RATIONALE AND OBJECTIVES ...................................................................................................5 
RESEARCH DESIGN AND METHODS..........................................................................................8 
1.) PHASE 1: INTERVENTION DESIGN AND BUILD ............................................................................ 8 
2.) PHASE 2: INTERVENTION TRIAL ............................................................................................... 19 
ETHICAL CONCERNS..................................................................................................................29 
CONSENT PROCESS AND DOCUMENTATION .................................................................................. 29 
CONFIDENTIALITY PROTECTION .................................................................................................... 29 
SUBJECT WITHDRAWAL ................................................................................................................ 29 
DATA SAFETY AND MONITORING BOARD ...................................................................................... 29 
ALTERNATIVES.............................................................................................................................. 29 
RISK ANALYSIS.............................................................................................................................. 29 
BENEFIT ANALYSIS ........................................................................................................................ 30 
COST TO PATIENTS ....................................................................................................................... 31 
PATIENT COMPENSATION ............................................................................................................. 31 
SHARING OF RESULTS ................................................................................................................... 31 
FINANCIAL SOURCES..................................................................................................................... 31 
CONFLICT OF INTEREST ................................................................................................................. 31 
SIGNATURE LINE.........................................................................................................................32 
REFERENCES...............................................................................................................................32 
APPENDIX .....................................................................................................................................36 
 
 

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PROTOCOL SYNOPSIS 
Protocol Title  
 
 
Protocol ID 
 
Study Site 
 
Study Design 
 
Patient Participation 
 
Study Duration 
 
Purpose 
 
 
 
 
 
 
 
Keep it SIMPLE: Improving Anti-Coagulation Medication Adherence for Patients 
with non-valvular atrial fibrillation  
 
PRC15-0709 
 
Parkview Research Center 
 
Interventional; Longitudinal 
 
Approximately six months 
 
Approximately twenty-four months 
 
This study is designed to develop patient focused strategies that improve 
adherence to anticoagulant medication in patients with non-valvular atrial 
fibrillation (AF). There are two phases to the study: Intervention Development and 
Intervention Trial. The intervention to be developed during Phase 1 includes 
tailored health education messaging delivered through a personal health record, 
MyChart. During the development of the intervention in Phase 1 we will use a 
patient-centered, iterative design process that includes interviews, prototype 
development and testing. One trigger for health education messaging will be 
failure to take, fill, or refill anticoagulant medication prescription – information 
obtained from an e-prescribing data feed to the electronic medical record 
(Surescripts) and use of a smart pill bottle (AdhereTech – HIPAA compliant, FDA-
registered Class I medical device) that sends notification in real time when 
participants open or fail to open their pill bottle. The intervention trial in Phase 2 
will be comprised of two groups, control and experimental. Both the control and 
experimental group will receive standard care, which includes access to MyChart. 
In addition to standard care, both groups will receive training on the use of 
MyChart and the AdhereTech smart pill bottle, and medication adherence for both 
groups will be monitored with Surescripts e-prescribing software and AdhereTech 
smart pill bottle use. The experimental group will receive the intervention: tailored 
health messaging delivered via MyChart pertinent to AF and oral anticoagulant 
use. Outcomes of this work include a novel intervention, as well as information 
regarding patient preferences for tailored education. 
 
Specific Aims: Aim 1: Determine AF patient preference for content, timing, and 
delivery mode of tailored educational information about AF and anticoagulant 
therapy; Aim 2: Determine the impact of tailored messaging via personal health 
record on adherence to anti-thrombotic therapy and health outcomes in people 
living with AF; Aim 3: Determine the feasibility of measuring medication adherence 
with queries to electronic prescribing software and use of ‘smart’ pill bottles.  
 

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STUDY BACKGROUND  
The proposed—Keep it SIMPLE, Study—will focus on promoting safe and prescribed 
use of anticoagulant medication in patients living with non-valvular atrial fibrillation (AF). 
The risk of thromboembolism (primarily stroke) is a key factor resulting in emergency 
room visits, re-hospitalization and death in AF patients. The non-adherence to oral 
anticoagulation therapy is a frequent causative factor.1 There are many factors that 
contribute to the complexity of medication non-adherence among the AF patient 
population, including patient knowledge about AF and related therapies, the patient’s 
health beliefs and concerns, patient-provider communication, and the particular 
reminder systems and habits that patients develop to help them consistently and 
correctly take medication. Therefore, education aimed at changing behavior related to 
medication adherence must be tailored to the patient’s specific needs. Typically, 
physicians provide brief advice to patients and their families during their outpatient 
visits. However, the impact of this advice on lifestyle changes and medication 
compliance has been limited.2 The evolution of electronic health tools (e.g. patient 
portals to personal health records, web-based tools, and mobile applications) has 
created an opportunity to provide additional tailored education and coaching to patients, 
which may result in increased patient engagement and improved health outcomes.  
 
According to a report issued by the U.S. Department of Health and Human Services 
(HHS) Office of the National Coordinator (2014), there is potential for health information 
technology (IT) to improve medication adherence by supporting consumer decision-
making and coordination between patients and health care providers.3 The goal of this 
research study is to evaluate the effectiveness of electronic health tools on engagement 
and health literacy of patients with AF and to evaluate the resultant effect on medication 
adherence and health outcomes. The proposed project combines new innovations and 
applications to Parkview’s previous work evaluating the impact of personal health 
records (PHRs) on patient engagement, which has yielded promising results.4,5,6,7,8  
 
Parkview Research Center, under the direction of Dr. Michael J Mirro, recently 
completed a two-arm randomized, prospective 6-month pilot study to explore the impact 
of a PHR on medication adherence and patient engagement in patients with AF who 
were taking the novel oral anticoagulant medication, dabigatran. Patients in that study 
were provided access to a PHR, Epic’s MyChart. The intervention group (N=44) 
received one-on-one training on MyChart use and received educational newsletters 
about dabigatran at 4, 6 and 10 weeks via MyChart. The control group (N=41) received 
the standard care and PHR access without any training or health education. A survey, 
comprising 54 questions pertaining to technology acceptance, medication knowledge, 
medication adherence, and patient activation measure (PAM), was sent to both groups 
at the baseline and the end of study. Medication dispensing data collected from the 

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pharmacy where patients filled their prescriptions were used for calculating the 
medication possession ratio (MPR).  
 
Results from that study revealed that knowledge of dabigatran and MPRs increased 
significantly in the intervention group, but not in the control group. Self-reported 
medication adherence also increased by 10% in the intervention group, compared to 
4% in the control group. In the proposed project, we plan to develop a more robust 
approach to impact medication adherence with ALL types of oral anticoagulants- vitamin 
K antagonists (VKAs) and novel oral anticoagulants (NOACs) - that includes tailored 
messaging to patients via MyChart during key transitions in care such as new AF 
diagnosis or changes in medication. The proposed study provides an opportunity to 
further explore the utilization of health information technology tools in relation to self-
management of AF and adherence to anticoagulation therapy.  
 
Study Hypothesis: 
 
Our hypothesis is that tailored messaging delivered via a personal health record will 
enhance patient engagement and health literacy related to atrial fibrillation and 
anticoagulant therapy, which in turn will improve medication compliance and health 
outcomes.  
 
Specific Aims: 
Aim 1: Determine AF patient preference for content, timing, and delivery mode of 
tailored educational information about AF and anticoagulant therapy. 
Aim 2: Determine the impact of tailored messaging via personal health record on 
adherence to anti-thrombotic therapy and health outcomes in people living with AF. 
Aim 3: Determine the feasibility of measuring medication adherence with queries to 
electronic prescribing software and use of ‘smart’ pill bottles. 
 
RATIONALE AND OBJECTIVES  
 
Medication safety and adherence, especially at transitions across the continuum of 
care, is a primary concern for healthcare providers, the U.S. Food and Drug 
Administration, as well as the Centers for Medicare & Medicaid Services. A key target 
for improvement in adherence regimens related to medication is the AF population 
receiving anticoagulation therapy due to the prevalence of the disease and the 
devastating impact of non-adherence. Estimates of the prevalence of AF in the United 
States ranged from ~2.7 million to 6.1 million in 2010, and AF prevalence is expected to 
rise to between ~5.6 and 12 million in 20509. The risk of AF increases with age, with 
over 70% of cases occurring in adults over the age of 65. People with AF are twice as 

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likely to die and almost 5 times more likely to have a stroke than those without AF.10 AF 
also contributes a substantial economic burden. In the US, the direct cost of treating 
patients with AF is reported to be about $6 billion11 and the direct cost of AF-related 
stroke is approximately $8 billion each year.12  
 
The American College of Cardiology, Heart Rhythm Society and the American Heart 
Association guidelines for managing patients with AF recommended oral 
anticoagulation (OAC) therapy to prevent thromboembolism for the majority of patients. 
Historically, warfarin (Coumadin) has been the gold standard for managing 
thromboembolic risk in AF. The use of Coumadin requires intensive follow-up of INR 
(international normalized ratio) blood values at the “Coumadin Clinic,” careful dosage 
calibration and the intense education of patients regarding dietary restrictions and 
dangerous drug interactions. The INR monitoring program thus becomes a surrogate 
marker of medication compliance. Novel oral anticoagulants such as rivaroxaban 
(Xarelto), apixaban (Eliquis), dabigatran (Pradaxa) and edoxaban (Savaysa) have 
recently emerged as important therapeutic alternatives. These medications do not have 
to be followed as carefully as Coumadin and have fewer side effects, drug interactions 
and no dietary restrictions. The transition from Coumadin to a novel anticoagulant 
eliminates the need for patients to go to the Coumadin clinic regularly for blood work 
that confirms compliance (INR test). Thus, the decreased need for close clinical follow-
up and education with novel anticoagulants introduces the possibility of further 
diminished medication adherence. During the preparation of this proposal, Parkview 
Research conducted a meeting with 10 individuals living with AF and using 
anticoagulants to obtain their insight and input into the research plan. During this 
meeting, our patient partners emphasized the importance of getting information at key 
junctures in treatment, for example when first starting or changing anticoagulant 
medication.  
 
Figure 1 presents a summary of questions generated by our patient partners. The 
proposed intervention will attempt to answer these questions and offer support to 
patients when they need it most, during transitions in therapy. The outcome may be 
enhanced medication safety/adherence and reduced stroke risk.  
 
 
 
 
 
 
 
 

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Topic 
Patient Questions 
Staying in therapeutic 
range 
How do I manage INR levels? How do I balance diet and alcohol 
intake? How often do I need INR blood draws? 
Home INR monitoring 
What is home INR monitoring? When can I use home monitoring vs. 
going to clinic for monitoring? Who is best suited for home INR 
monitoring? Is this a good option for me? 
Anticoagulant 
medication choice 
What is the difference between Coumadin (warfarin) and new Novel 
agents? When will I get to talk about my medication choices with the 
doctor because my office visit is too short? How can I make an 
educated decision about switching from Coumadin to a Novel agent 
when I don’t know about lab testing, reversal agents, or how much it 
will cost me? If I don’t go in to the “Coumadin clinic” for testing 
anymore because I switch to a Novel agent, when will I see my health 
care team to ask questions between office visits? Why does ATU clinic 
only test Coumadin patients, can’t they provide education on Novel 
agents in addition? 
AF disease process 
How does AF affect my other body systems in the long run? What 
changes can I make in my lifestyle to lessen AF burden on my body, 
mind and spirit? 
Communication with 
healthcare provider 
How can I get more time to talk with my providers about AF? How can I 
get quick answers to my questions? 
Information and data 
feedback 
How do I know my medicine is working? How can I track changes in 
my heart rhythm? Will I get too much information about how I am doing 
with my AF and will it make me more stressed? 
Figure 1- Challenges of oral anticoagulant therapy 
 
Patient engagement is an important goal for this project because it may lead to greater 
patient satisfaction with their care and better health outcomes in general, not only stroke 
prevention. Helping patients become aware of their health issues and giving them the 
knowledge to make the best decisions may lead to better outcomes – key for AF 
patients is adherence to anticoagulant therapy regimen. Medication adherence is known 
to be a complex and widespread problem in the US, often called “the other drug 
problem.” Atreja, et al (2005) grouped adherence-promoting interventions into six 
categories that form the mnemonic SIMPLE: S-simplify the regimen; I-impart 
knowledge; M-modify patient beliefs and human behavior; P-provide communication 
and trust; L-leave the bias; E-evaluate adherence.13 We are grounding our project on 
this model and therefore coining the name “Keep it SIMPLE.”  
 
 

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RESEARCH DESIGN AND METHODS 
 
There will be two phases in this study. In the first phase, we will use a patient-centered 
approach to design and build a PHR based educational intervention based on patient 
preferences for content, timing and delivery mechanism. In the second phase, we will 
test the intervention in a six-month randomized controlled trial.  
 
Table 1 – High-level timeline for 24-month study 
 
Specific Aims 
Methods 
Timeline* 
Phase 1 – 
Intervention 
Design and 
Build 
Aim 1: Determine AF patient 
preference for content, timing, and 
delivery mode of tailored educational 
information about AF and 
anticoagulant therapy 
Intervention design: focus 
groups; wireframe modeling of 
interaction  
~0-6 
months 
Intervention build: build trigger 
from Surescripts data feed and 
AdhereTech smart pill bottle; 
implement educational 
messaging in PHR  
~3-10 
months 
Phase 2 – 
Intervention 
Trial 
Aim 2: Determine the impact of 
tailored messaging via personal 
health record on adherence to anti-
thrombotic therapy and health 
outcomes in people living with AF. 
2-arm, 6-month trial of PHR 
intervention (N= ~160) 
~10-22 
months 
Aim 3: Determine the feasibility of 
measuring medication adherence with 
queries to electronic prescribing 
software and use of ‘smart’ pill bottles 
Dissemination 
Data analysis and manuscript 
preparation 
Target both cardiology and 
health informatics venues 
~22-24 
months 
*Timeline is based on approximate (~) dates 
 
1.) PHASE 1: INTERVENTION DESIGN AND BUILD 
 
Specific Aim 1: Determine AF patient preference for content, timing, and delivery mode 
of tailored educational information about AF and anticoagulant therapy. 
 
During the first 10 months of the study, we will recruit a diverse group of AF patients to 
determine preferences for information about AF and anticoagulant therapy. We will use 
a user-centered design approach and best practices in human-computer interactions 
(HCI) to determine the desired content, timing, and delivery of tailored education in the 
PHR. We will build out wireframe models (low fidelity messaging prototypes) based on 
focus group findings to perform usability testing and further refine the intervention (PHR 
tailored messaging) design. The intervention component will assess the impact of 
pushing tailored health education messages to patients through their PHR. The tailored 
health education will be specifically aimed at improving patient compliance with 

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anticoagulant therapy. The tailoring algorithm will be developed through a patient-
centered, iterative design process that includes: focus groups, wireframe modeling, 
prototype development and testing.  
 
a.) Focus Groups 
There will be four focus groups (two for patients newly diagnosed for atrial 
fibrillation and two for patients switching to a novel oral-anticoagulant 
medication), including separate discussion rooms for partners and caregivers.  
Each session will last approximately two hours, and each session will have 
approximately 4-10 patients, along with their partners, caregivers and support 
persons.  Research staff will facilitate discussions. 
 
This data will act to help the research team design the technology intervention 
best suited for patients’ needs who are taking anticoagulant medication for atrial 
fibrillation.  Through a guided presentation and discussion, patients will have the 
opportunity to share their experiences with atrial fibrillation and anticoagulant 
use.  The focus groups will foster discussion related to patient perceptions of the 
usability of the PHR as a means to encourage medication adherence.  
 
i. Patient Selection 
 
a) Study Population: The study population for this focus group is 
comprised of all adult, ambulatory PPG-Cardiology patients with non-
valvular atrial fibrillation who are taking an oral anti-coagulant 
medication. Patients’ caregiver, partner, and/or support persons will 
also be invited to participate in the focus group sessions. When 
patients are contacted, the following populations will be eligible to 
enroll: 
1. Both the patient and their caregiver, partner, and/or support 
persons 
2. The patient only 
3. The patient’s caregiver, partner, and/or support persons only 
 
b) Sample Size: Focus Groups: 4 groups; 20≤N≤120  
 
c) Inclusion/Exclusion Criteria: 
 
                            Inclusion Criteria 
1. Diagnosis of Atrial Fibrillation (Paroxysmal, Persistent, Permanent) 
– focus groups 1 & 2: patients diagnosed ≤ 6 months  
– focus groups 3 & 4: patients diagnosed ≥ 6 months 

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2. Receiving Oral Anticoagulation (VKA or NOAC) for non-valvular AF 
– focus groups 1 & 2: on VKA or NOAC  
– focus groups 3 & 4: changed VKA to NOAC within last 6 months 
3. *Physically and Mentally capable of providing Informed Consent 
4. *Age 18 years or older 
5. *Ability to read and understand English 
6. Current Patient of PPG-Cardiology 
*3, 4, and 5 must apply to caregivers, partners, and/or support persons 
 
                            Exclusion Criteria 
1. Absence of History of Atrial Fibrillation (AF) 
2. *Does not meet Inclusion Criteria 
3. Anticoagulation with VKA or NOAC for reasons other than non-
valvular AF 
4. *Designated as part of a vulnerable subject population that the 
investigator or designee identifies to have compromised autonomy 
related to potential study participation 
5. Currently participating in another Parkview study that involves PHR 
use 
*Only 2 and 4 apply to caregivers, partners, and/or support persons 
 
d) Enrollment:  
A list of adult patients who meet inclusion criteria will be provided by the 
Anticoagulation Therapy Unit (ATU) Clinic and Parkview Physicians 
Group-Cardiology. If needed, an additional list of adult patients who meet 
inclusion criteria will be obtained from patient records at Parkview 
Physicians Group-Cardiology using Epic reporting tools. Research staff 
will review these patient charts to identify if they meet inclusion criteria, or 
if factors in the exclusion criteria are identified. This study will not affect 
patient standard of care. Before contacting patients, the principal 
investigator will leave a series of periodic voicemails for all clinical staff at 
Parkview Physicians Group-Cardiology to inform them of the study and 
ask that physicians contact the research team if they do not want any of 
their patients to be recruited for the study.  Research staff will contact 
patients by telephone. Patients who are interested in participation will be 
mailed a copy of the informed consent to review prior to their scheduled 
focus group. Patients, and their participating caregiver, partner, and/or 
support persons as applicable, will undergo the informed consent process 
immediately preceding the focus group session.  
 
 

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ii. Study Design 
 
a) Quantitative Data Collection and Analysis:  
 
Besides age, gender, and basic demographics, we will perform detailed 
testing using five instruments to quantify participant characteristics; 1) the 
Medication Adherence Survey (MAS)15, an eight question survey that is 
well validated to predict medication compliance, 2) the Patient Activation 
Measure (PAM), a 13 question survey well-validated to measure patient 
engagement16, 3) the Atrial Fibrillation Knowledge Scale, an 11 item 
survey designed to assess AF understanding17, 4) Newest Vital Sign a six-
question health literacy survey18 , and 5) Altarum Consumer Engagement 
(ACE) Measure19, a 12 question survey validated to measure patient 
engagement. These five survey instruments will be incorporated into a 
focus group patient and participant (caregiver/partner/support persons) 
survey to be built out in Survey Monkey®, an on-line tool to design, collect 
and analyze surveys and responses. Survey Monkey enables covered 
entities to collect protected health information (PHI) in online surveys in a 
way that permits compliance with the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA). SSL (Secure Sockets Layer), a 
protocol developed for transmitted private documents or information via 
the internet, creates a secure connection between a client and a server, 
encrypting sensitive information being transmitted through the web page. 
After consenting participants, we will ask them to complete demographic 
information and survey (Table 2). 
 
All data will be aggregated by Parkview Research Center (PRC) and 
statistical analysis will be performed by PRC and the Indiana University 
School of Medicine, Department of Biostatistics. Additional consultants, 
partners, or business associates will be utilized as necessary. 
 
b) Qualitative Data Collection and Analysis:  
 
Focus groups are used to bring together a collection of individuals and ask 
them their perceptions, opinions, beliefs, and attitudes towards a product, 
service, concept, or idea. In this project, researchers will lead group 
discussion by prompting participants with questions in an interactive group 
setting where participants are free to engage in conversation. The 
questions will be focused on understanding the preferred content, timing, 
and delivery mechanism of tailored health education aimed at 
understanding AF and related anticoagulant therapy. 

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All focus group sessions will be video recorded, with participant 
permission and researchers will take field notes. Investigators will review 
the transcribed digital recordings and field notes and perform thematic 
analysis to develop a codebook. All documents will be imported into 
NVivo, and identified by session date and time. The investigators will 
independently review each session's recording to identify patterns within 
the participants’ responses, annotating the recording with relevant 
concepts through NVivo. Using the method of grounded theory and 
constant comparison20,21, the investigators will meet in a series of three or 
more review sessions to compare concepts, resolve discrepancies in 
interpretation, explore the various meanings of words, discuss emergent 
themes, and resolve ambiguities, until consensus is achieved and 
potential biases in interpretation are reconciled22. Important user themes 
will be built using this iterative process of reviewing and grouping concepts 
during the review sessions. The relevance and importance of themes will 
be assessed using a rating schema of frequency, convergence and 
intensity. Frequency represents the number of times that the topic appears 
in the users’ discussion, and is documented using NVivo’s frequency 
reporting feature. Convergence, the relative occurrence of the topic, will 
be assessed as high, medium, or low. Intensity is defined as the emotion 
and importance of the topic to the user, and will be assessed using a scale 
of high, medium or low based on a subjective analysis of the digital 
recording for vocal tone, pace and volume. According to grounded theory, 
we will continue an iterative process of review and data collection until no 
new concepts are discovered and content saturation is reached21. A 
summary of relevant themes will be compiled and used to develop low 
fidelity prototypes (wireframes) of the PHR intervention.  
 

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Table 2 – Validated Survey Instrument Descriptions* 
Validated Survey 
Instrument 
Description 
System Usability 
Survey (SUS) 
 
SUS is a computer self-efficacy measures questionnaire that has long been used to assess 
a user’s belief that they have the capability to successfully interact with a computer 
system.  Based on social psychology, self-efficacy has been found to influence the user’s 
behavior related to use of the system23.  Within the domain of healthcare, patients must 
see themselves as capable of successfully using the PHR24,25.  The ten question survey asks 
the patient to indicate whether they are able to complete a task under a variety of 
conditions, such as step by step instructions, on-call user help, or initial training in getting 
started26. 
Medication 
Adherence Survey 
(MAS) 
 
The MAS is an eight question patient survey that provides reliable predictions of patient 
medication compliance15. The MAS has a strong correlation with clinical outcomes in 
patients with hypertension and other conditions27.  Patients with greater knowledge, 
attitude, satisfaction and coping skills were more likely to have high medication 
adherence, those stressed or requiring a complex medication scheme were less likely to 
be adherent28. 
Patient Activation 
Measure (PAM) 
 
The patient activation measure (PAM) is a 13 question survey using a 4-point Likert scale. 
It is a robust and well-validated assessment tool developed by Hibbard and colleagues16 to 
measure the level of patient engagement in their health.  The PAM is a scale that reflects 
a developmental model of activation. Activation appears to involve four stages: (1) 
believing the patient role is important, (2) having the confidence and knowledge 
necessary to take action, (3) actually taking action to maintain and improve one’s health, 
and (4) staying the course even under stress. PAM scores are independent of traditional 
socio-economic and demographic such as race, income or education and instead 
emphasize what the patient can do to help themselves. Hibbard et al. demonstrated that 
coaching improves PAM scores, medication adherence and reduces re-hospitalization 
rates29,27. 
Atrial Fibrillation 
Knowledge Scale 
 
The AF Knowledge Scale is a validated tool that consists of 11 items concerning AF in 
general, symptom recognition. This tool was developed due to a need for a specific 
instrument to detect gaps in the knowledge of AF patients. The AF Knowledge Scale can 
be successfully used in an outpatient care setting as an important tool in the tailoring of 
patient education17. 
Newest Vital Sign  
(NVS) 
 
The NVS is a validated instrument that screens for health literacy in approximately three 
minutes18.  Participants are given a nutrition label, and then asked six questions about it. A 
score of 0-1 suggests a high likelihood of limited literacy; a score of 2-3 indicates the 
possibility of limited literacy; a score of 4-6 indicates adequate literacy30. The NVS has 
been found to provide results comparable to more extensive health literacy tests31, but it 
is considered to be the most practical tool because it also assesses numeracy, an element 
of health literacy that is often not represented in other tools32. 

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Altarum Consumer 
Engagement (ACE) 
Measure 
The Altarum Consumer Engagement (ACE) measure is a 12 question survey validated to 
assess a patient’s level of engagement in their health using the three domains of 
commitment, informed choice, and navigation. The ACE measure expands upon other 
validated survey instruments and broadens the measurement of engagement by including 
questions related to modern sources of information, such as online health resources and 
provider ratings. The survey serves as a reliable predictor of health status, health 
behaviors, medication adherence, and health resource utilization19. 
Ten-Item 
Personality 
Inventory (TIPI) 
The Ten-Item Personality Inventory (TIPI) measure is a 10-item measure of the Five-Factor 
Model. The psychometrics for the TIPI are known and reasonable. This measure provides 
for an assessment to be completed in less than one minute, far less than other personality 
measures.  
* The items from each of these survey instruments, along with demographics, will be incorporated into 
participant surveys to be administered during the focus groups and technology trial.  
 
b.) Design Survey  
The secure online program, Survey Monkey will be used to administer the 
survey. After prospective participants have been identified, and it is confirmed 
that they meet the inclusion criteria, the research team will contact individuals to 
participate in the survey. Potential participants will be contacted through up to 
three methods as applicable per patient: MyChart message, email, or letter. If 
individuals wish to participate, they will be instructed through MyChart, email, or 
letter to access the informed consent and subsequent survey through the 
provided secure link to Survey Monkey. Individuals who have read and agree to 
the informed consent online, will then be able to access the online survey. 
Subjects may opt out of taking the survey at any time. Recruitment and survey 
materials are additionally being submitted for IRB review.  
 
Survey Monkey enables covered entities to collect protected health information 
(PHI) in online surveys in a way that permits compliance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). SSL (Secure 
Sockets Layer), a protocol developed for transmitted private documents or 
information via the internet, creates a secure connection between a client and a 
server, encrypting sensitive information being transmitted through the web page. 
SSL encryption is automatically turned on for all Survey Monkey surveys in this 
study. IP (Internet Protocol) address may be tracked to prevent the survey from 
being taken twice, but this information will not be collected by the research team. 
However, we will collect participant name and email address in order to send 
their eGiftcard compensation. 
 
The surveys will be received by research staff and analyzed. The information will 
be used to develop content for an intervention aimed at enhancing medication 
adherence.  

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i. Patient Selection 
 
a) Study Population: The study population for the survey is comprised of 
all adult, ambulatory PPG-Cardiology patients with non-valvular atrial 
fibrillation who are taking an oral anti-coagulant medication.  
 
b) Sample Size: 5≤N≤150 
 
c) Inclusion/Exclusion Criteria: 
 
                            Inclusion Criteria 
1. Diagnosis of Atrial Fibrillation (Paroxysmal, Persistent, Permanent)  
2. Receiving Oral Anticoagulation (VKA or NOAC) for non-valvular 
AF 
3. Physically and Mentally capable of providing Informed Consent 
4. Age 18 years or older 
5. Ability to read and understand English 
6. Current Patient of PPG-Cardiology 
 
                            Exclusion Criteria 
1. Absence of History of Atrial Fibrillation (AF) 
2. Does not meet Inclusion Criteria 
3. Anticoagulation with VKA or NOAC for reasons other than non-
valvular AF 
 
d) Enrollment:  
A list of adult patients who meet inclusion criteria will be provided by the 
Anticoagulation Therapy Unit (ATU) Clinic and Parkview Physicians 
Group-Cardiology. If needed, an additional list of adult patients who meet 
inclusion criteria will be obtained from patient records at Parkview 
Physicians Group-Cardiology using Epic reporting tools. Research staff 
will review these patient charts to identify if they meet inclusion criteria, or 
if factors in the exclusion criteria are identified. This study will not affect 
patient standard of care. Before contacting patients, approval will be 
obtained in Epic from each patient’s primary cardiologist, as well as the 
principal investigator. Focus Group patients who indicated they would like 
to be contacted for future phases of the study will also be contacted. 

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Research staff will contact patients by MyChart message, email, or letter. 
Patients will be sent up to two reminders to participate in the survey if they 
wish. Patients who are interested in participation will be able to access the 
survey through the secure link provided in the MyChart message, email, or 
letter. Patients will be presented to informed consent in Survey Monkey 
immediately preceding the survey questions.  
 
ii. Survey Questions 
 
 
A copy of the survey questions, as they will appear in Survey Monkey, is 
included in the submission packet for IRB review. 
 
c.) Wireframe Prototyping and Testing (Design Session) 
During the study design sessions, we will use value-based software engineering 
and agile development methods to link the diverse group of patients with experts 
in human-computer interaction (HCI) to create models of desired PHR workflow. 
 
i. Patient Selection 
 
a) Study Population: The study population for the individual design 
sessions is comprised of all adult, ambulatory PPG-Cardiology patients 
with non-valvular atrial fibrillation who are taking an oral anti-coagulant 
medication. 
 
b) Sample Size: 5≤N≤20   
 
c) Inclusion/Exclusion Criteria: 
 
Inclusion Criteria 
1. Diagnosis of Atrial Fibrillation (Paroxysmal, Persistent, Permanent)  
2. Receiving Oral Anticoagulation (VKA or NOAC) for non-valvular 
AF 
3. Physically and Mentally capable of providing Informed Consent 
4. Age 18 years or older 
5. Ability to read and understand English 
6. Current Patient of PPG-Cardiology 
 
                            Exclusion Criteria 
1. Absence of History of Atrial Fibrillation (AF) 
2. Does not meet Inclusion Criteria 

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3. Anticoagulation with VKA or NOAC for reasons other than non-
valvular AF 
 
 
 
d) Enrollment:  
A list of adult patients who meet inclusion criteria will be provided by the 
Anticoagulation Therapy Unit (ATU) Clinic and Parkview Physicians 
Group-Cardiology. If needed, an additional list of adult patients who meet 
inclusion criteria will be obtained from patient records at Parkview 
Physicians Group-Cardiology using Epic reporting tools. Research staff 
will review these patient charts to identify if they meet inclusion criteria, or 
if factors in the exclusion criteria are identified. This study will not affect 
patient standard of care. Before contacting patients, approval will be 
obtained in Epic from each patient’s primary cardiologist, as well as the 
principal investigator. Patients who participated in the focus groups and/or 
the survey who indicated they would like to be contacted for future phases 
of the study will also be contacted. Research staff will contact patients by 
telephone. Patients who are interested in participation will be mailed a 
copy of the informed consent to review prior to their scheduled individual 
design session. Each patient will undergo the informed consent process 
immediately preceding their designated design session. 
 
ii. Study Design 
 
 
We will incorporate the use of modeling tools called “wireframes” as part 
of our user interface design process to generate a prototype. Wireframes 
are said to be a best practice when designing user interfaces and are 
especially helpful for interactive projects that are complex and require 
quick iterative changes. It allows users to see changes instantly. Using the 
wireframe modeling tool we can start with gray box wireframes and evolve 
them from low-fidelity to high-fidelity user interface design with ease. Low-
fidelity modeling may be as simple as a rough sketch. The creation of 
PHR models using wireframes will allow us to alter the user interface, 
often in a matter of minutes so that users can see their suggestions 
immediately. 
 
Many wireframe tools allow the incorporation of interactivity including flash 
animation, and front-end web technologies such as, HTML, CSS, and 
JavaScript.  Other features of wireframe tools include:  the ability for the 

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designer to easily drag and drop components, a presentation mode to test 
wireframe interactions, a revision history for tracking design iterations, 
access to large libraries of wireframe components, real-time collaboration 
with all team members through a chat option, and access to a whiteboard 
for drawing doodles on wireframes. 
 
These “wireframes” help a project team collaborate more effectively since 
they are more abstract, using rectangles and labeling to represent content. 
High-fidelity “wireframes” can easily be passed along to developers for 
implementation because they incorporate a level of detail that matches the 
design of the fully functional user interface. 
 
The wireframes, after being produced by the research staff, will be 
evaluated through one-on-one design sessions. This session involves 
priming a participant with a fictitious scenario and observing their 
interaction with the system to find relevant content. The objective of this 
exercise is to identify how successfully the proposed design meets their 
education and information requirements. In addition, each design session 
will involve completion of the survey administered in the previous phase 
(Design Survey) and participation in closing discussion questions. Patients 
who previously participated in the design survey will not need to retake the 
survey. The survey, closing discussion questions, and scenarios for 
patient use are included in the submission packet for IRB review.  
 
Each of these individual sessions will last one to two hours and will be 
video recorded, with participant permission. Qualitative data from the 
recorded interviews may be used to iteratively adjust the wireframe 
models with each design session. The final wireframes will help the project 
team validate the planned design.  
 
 
d.) Intervention Build 
We will apply what we learned in the iterative design process described in parts 
a) and b) above to build a working prototype in a PHR, Epic’s MyChart. One 
trigger for health education messaging used in the intervention will be failure to 
take, fill, or refill anticoagulant medication prescription – information obtained 
from an e-prescribing data feed to the electronic medical record (Surescripts) and 
use of the AdhereTech smart pill bottle (HIPAA compliant, FDA-registered Class I 
medical device) that sends notification in real time when participants open or fail 
to open their pill bottle. Thus, we will build in the necessary elements in the 
technology to create triggers for push messaging of health information through 

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the PHR. We will perform robust testing of the intervention and make 
adjustments as needed.  
 
 
 
2.) PHASE 2: INTERVENTION TRIAL 
 
Aim 2: Determine the impact of tailored messaging via personal health record on 
adherence to anti-thrombotic therapy and health outcomes in people living with AF. 
 
Aim 3: Determine the feasibility of measuring medication adherence with queries to 
electronic prescribing software and use of ‘smart’ pill bottles. 
 
During the last 12 months of our study, we will conduct a 6-month trial of the 
intervention designed and built in Phase 1 of the study to examine the impact on patient 
engagement and medication adherence. Patients who meet inclusion criteria and agree 
to participate will be randomly assigned to one of two groups – Experimental or Control. 
The research team will alternate random assignment to experimental or control group in 
order to achieve equal numbers of patients receiving VKA and NOAC medication across 
both groups. Please see Figure 2 below, outlining the study group assignment process. 
 
 
Figure 2: Tech Trial Study Group Assignment Process 
 
i. Patient Selection 
 
a) Study Population: The study population is comprised of all adult, 
ambulatory PPG-Cardiology patients with non-valvular atrial fibrillation 
who are taking an oral anti-coagulant medication 
 
a. Sample Size: Approximately 160 patients (80 Control/80 Experimental 
Groups; randomized/un-blinded) 
AF patients 
(N=160)
Assigned to 
Experimental 
Group (N=80)
AF patients 
receiving VKA 
(N=40)
AF patients 
receiving 
DOAC (N=40)
Assigned to 
Control Group 
(N=80)
AF patients 
receiving VKA 
(N=40)
AF patients 
receiving 
DOAC (N=40)

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*Based on prior data, the within-group standard deviation of the 
medication possession ratio (MPR) is estimated to be 10%.4,5,6,7,8 MPR is 
considered a continuous variable and sample size calculations are based 
on comparing the difference in two mean MPR values. With a final sample 
size of 64 subjects per group completing the study, the study will have 
80% power to detect a 5% difference in MPR between groups, assuming 
two-sided tests each conducted at a 5% significance level. To account for 
a 20% dropout rate, 80 subjects will be enrolled per group. 
 
b) Inclusion/Exclusion Criteria: 
 
                            Inclusion Criteria 
1. Diagnosis of Atrial Fibrillation (Paroxysmal, Persistent, Permanent)  
2. Receiving Oral Anticoagulation (VKA or NOAC) for non-valvular AF 
3. Physically and Mentally capable of providing Informed Consent 
4. Age 18 years or older 
5. Access to Computer and Internet  
6. Ability to read and understand English 
7. Current Patient of PPG-Cardiology 
8. Willing to have a MyChart account 
 
                            Exclusion Criteria 
1. Absence of History of Atrial Fibrillation (AF) 
2. Does not meet Inclusion Criteria 
3. Anticoagulation with VKA or NOAC for reasons other than non-
valvular AF 
4. Prescribed the anticoagulation medication Dabigatran, as this 
specific NOAC cannot be transferred from its original pill bottle to 
the study smart pill bottle 
5. Unable to physically or cognitively carry out the tasks necessary for 
utilizing a PHR such as; blindness, loss of function of arms, 
cognitive impairments (per chart review) that would interfere in 
learning a new task 
6. Designated as part of a vulnerable subject population that the 
investigator or designee identifies to have compromised autonomy 
related to potential study participation 
7. Currently participating in another Parkview study that involves PHR 
use 
8. Not willing to have a MyChart account 

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9. Previously participated in the study focus groups 
10. Previously participated in the study design sessions 
 
 
 
c) Enrollment:  
A list of adult patients who meet inclusion criteria will be provided by the 
Anticoagulation Therapy Unit (ATU) Clinic and Parkview Physicians Group-
Cardiology. An additional list of adult patients who meet inclusion criteria will 
be obtained from patient records at Parkview Physicians Group-Cardiology 
using Epic reporting tools. Research staff will also recruit participants during 
education sessions held by the Parkview Heart Institute, which have been 
funded by Boston Scientific. The research staff will be introduced by the 
Parkview Heart Institute coordinator, but will not present at any time during 
the education session. Attendees of the education sessions will be given an 
information folder already provided by the Parkview Heart Institute. The 
research team has permission to include a flyer (see attached flyer), that can 
be included in the folder, which provides a short summary about the study. 
The research team will also distribute recruitment flyers to individuals who 
may be interested in participating in the study that are in attendance at the 
education session. Those attendees who express an interest in participating 
will have their contact information recorded by the research team or will 
contact the Informatics Research Nurse coordinator as listed on the flyer. As 
with all possible participants, research staff will review patient charts to 
identify if they meet inclusion criteria, or if factors in the exclusion criteria are 
identified. This study will not affect patient standard of care. Before contacting 
patients, the study nurse coordinator will contact Parkview Physicians Group-
Cardiology physicians to inform them of the study and receive permission to 
recruit their patients for the study. Eligible patients will be contacted by 
research staff during scheduled ambulatory care visits or contacted by 
telephone. Eligible patients may also be notified of the study through 
MyChart, email, or letter and directed to contact research staff by phone if 
interested in participating. Patients may decide to proceed with the informed 
consent process at the time of the office visit or schedule another 
appointment for the study. If the communication is by telephone, 
appointments will be made at a time convenient for the patient to undergo the 
informed consent process and patients will be mailed a copy of the informed 
consent to review prior to their scheduled appointment. Patients will undergo 
the informed consent process during their appointment and those who meet 

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inclusion/exclusion criteria, agree to participate in the study and sign the 
informed consent will be enrolled in the study.  
 
ii. Study Design 
 
 
a) Experimental Group: 
Upon enrollment in the study, patients in the experimental group will be   
requested to do the following for their participation in the study: 
• Follow standard of care, which includes access to MyChart 
Separate from standard of care: 
• Receive an AdhereTech smart pill bottle to use for dispensing their 
anticoagulation medication at home. 
• Receive training on the use of the AdhereTech smart pill bottle and 
commit to using in their daily routine for their anticoagulant 
medication 
• Receive one-on-one training aimed at use of the MyChart PHR 
• Use the PHR intervention: patients in this group will have the 
MyChart intervention designed and built in Phase 1 of this study – 
tailored health messaging delivered via MyChart pertinent to non-
valvular atrial fibrillation and oral anticoagulation and stroke. 
o In addition to the tailored health messaging, patients will 
also receive periodic messages asking them to evaluate the 
health information they have received. 
• Participate in an initial study visit, which includes the enrollment 
and training process above, as well as one follow up study visit 
and exit interview at approximately 6 months. 
• Complete a patient survey at the initial study visit and follow up 
visit at approximately 6 months 
• Submit information about their prescription history related to their 
anticoagulant medication for the study period 
o Patients may obtain this information from their pharmacy or 
print it out from their online pharmacy account. Patients will 
receive a letter from the Principal Investigators and a 
Medication dispensing record form to provide to their 
Pharmacist requesting anticoagulant dispensing information 
required for the study. The printout will be collected by the 
patient or a study representative with permission from the 
patient. 
 
b) Control Group: 

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                      Upon enrollment in the study, patients in the control group will be     
                      requested to do the following for their participation in the study: 
• Receive a smart pill bottle to use for dispensing their 
anticoagulation medication at home. 
• Receive training on the use of the smart pill bottle and commit to 
using in their daily routine for their anticoagulant medication 
• Follow standard of care, which includes access to MyChart 
• Receive one-on-one training aimed at use of the MyChart PHR 
• Participate in an initial study visit, which includes the enrollment 
and training process above, as well as one follow up study visit 
and exit interview at approximately 6 months. 
• Complete a patient survey at the initial study visit and follow up 
visit at approximately 6 months 
• Submit information about their prescription history related to their 
anticoagulant medication for the study period 
o Patients may obtain this information from their pharmacy or 
print it out from their online pharmacy account. Patients will 
receive a letter from the Principal Investigators and a 
Medication dispensing record form to provide to their 
Pharmacist requesting anticoagulant dispensing information 
required for the study. The printout will be collected by the 
patient or a study representative with permission from the 
patient. 
• At the conclusion of the study, participants in the control group will 
be sent a link to access the tailored health messaging sent to the 
experimental group, delivered via MyChart. 
 
 
c) Quantitative Data Collection and Analysis:  
 
Besides age, gender, and basic demographics, we will perform detailed 
testing using six instruments to quantify patient characteristics; 1) the 
System Usability Survey (SUS), a commonly used ten question evaluation 
tool with Likert-scale responses to identify comfort with technology14, 2) 
the Medication Adherence Survey (MAS)15, an eight question survey that 
is well validated to predict medication compliance, 3) the Patient Activation 
Measure (PAM), a 13 question survey well-validated to measure patient 
engagement16, 4) the Atrial Fibrillation Knowledge Scale, an 11 item 
survey designed to assess AF understanding17, 5) Newest Vital Sign a six-
question health literacy survey18 ,  6) Altarum Consumer Engagement 

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(ACE) Measure19, a 12 question survey validated to measure patient 
engagement, and 7) Ten-Item Personality Inventory (TIPI), a ten question 
survey used to assess patient personality. The first six survey instruments 
will be incorporated into a baseline and follow-up patient survey to be built 
out in Survey Monkey®, an on-line tool to design, collect and analyze 
surveys and responses. The TIPI survey will be used only at the 6-month 
study follow-up visit. Survey Monkey enables covered entities to collect 
protected health information (PHI) in online surveys in a way that permits 
compliance with the Health Insurance Portability and Accountability Act of 
1996 (HIPAA). SSL (Secure Sockets Layer), a protocol developed for 
transmitted private documents or information via the internet, creates a 
secure connection between a client and a server, encrypting sensitive 
information being transmitted through the web page. After consenting 
participants, we will ask them to complete demographic information and 
survey (Table 2). 
 
Patient surveys will be comprised of questions aimed at assessing patient 
engagement, health literacy, and medication adherence. Patient 
engagement will be assessed using the validated survey instruments, the 
Patient Activation Measure (PAM) and the Altarum Consumer 
Engagement (ACE) Measure, number of logins to MyChart and secure 
messaging activity with provider/health coach. We will also evaluate health 
literacy using questions aimed at patient understanding of anticoagulant 
use in AF. Medication adherence will be measured using the MAS 
validated survey instrument developed by Morisky and patient pharmacy 
refill records. In an attempt to make the medication adherence data more 
robust, we will extract refill record data from electronic prescribing 
software (Surescripts) on study patients. In addition, all patients will use 
smart pill bottles to dispense their anticoagulation medication. These 
bottles will track medication adherence by the opening of the bottle cap, 
and will record data accordingly. The bottles will not be set up to alert 
patients or deliver any intervention for medication adherence. 
 
In order to determine the exact tailored health messaging patients will 
receive, study staff will identify the following information in patients’ 
electronic health records: 
1. Duration of time since AF diagnosis (Approximate days, months, 
and/or years) 
2. Current oral anticoagulant prescribed 

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3. Duration of time since beginning to take the above anticoagulant 
(Answer in approximate days, months, and/or years) 
4. History of switched anticoagulant 
5. If yes to above, type of anticoagulant taken before current one 
 
Concurrent with the educational messages sent to patients through 
MyChart, patients will periodically be sent a short survey asking them to 
evaluate the health information they just received. 
 
In addition, to measure the impact of the intervention we will collect 
specific health outcomes related data, PHR login frequency, and 
frequency of calls to the clinic. Quantitative measures of both study 
groups, control and experimental will be collected on both study groups, 6 
months prior to beginning of study to baseline and baseline to end of 6-
month trial.  
 
1) Major Adverse Events: Death, Stroke, Any Embolic Event, Major 
Bleeding (transfusion) 
2) Health Care Utilization: Hospitalization. ER visits, Office Visits, 
Calls to Office  
 
See Table 3 for all quantitative measures, purpose and timing of 
collection. 
 
All data will be aggregated by Parkview Research Center (PRC) and 
statistical analysis will be performed by PRC and the Indiana University 
School of Medicine, Department of Biostatistics. Additional consultants, 
partners, or business associates will be utilized as necessary. 
 
Table 3 – Quantitative Data Collected and Timing* 
Data Item 
Type 
Source 
Purpose 
6-mo prior 
to trial 
Baseline 
End of 6 
month trial 
Age 
Numeric 
EHR & 
Survey 
Demographic characterization; 
Risk for Bleeding: HAS-BLED  
 
√ 
 
Gender 
Numeric 
code 
EHR & 
Survey 
Demographic characterization 
 
√ 
 
Race/Ethnicity 
Numeric 
code 
EHR & 
Survey 
Demographic characterization 
 
√ 
 
Insurance status 
Numeric 
code 
EHR 
Demographic characterization 
 
√ 
 
Zip Code 
Numeric 
code 
Survey 
Demographic characterization 
 
√ 
 

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Employment status 
Numeric 
code 
Survey 
Demographic characterization 
 
√ 
 
Yearly income 
Numeric 
code 
Survey 
Demographic characterization 
 
√ 
 
Education level 
Numeric 
code 
Survey 
Demographic characterization 
 
√ 
 
Household occupants 
Numeric 
code 
Survey 
Demographic characterization 
 
√ 
 
Self-reported ability to 
use a computer 
Numeric 
code 
Survey 
Demographic characterization 
 
√ 
√ 
Self-reported ability to 
use the internet 
Numeric 
code 
Survey 
Demographic characterization 
 
√ 
√ 
Current proxy MyChart 
access 
Numeric 
code 
Survey 
Demographic characterization 
 
√ 
√ 
Potential future 
MyChart proxy access 
Numeric 
code 
Survey 
Demographic characterization 
 
√ 
√ 
Self-reported MyChart 
usage 
Numeric 
code 
Survey 
Demographic characterization 
 
√ 
√ 
Current 
anticoagulation 
medication 
Numeric 
code 
EHR & 
Survey 
Demographic characterization 
 
√ 
√ 
Marital status 
Numeric 
code 
EHR 
Demographic characterization 
 
√ 
 
Height 
Numeric 
EHR 
Demographic characterization 
 
√ 
 
Weight 
Numeric 
EHR 
Demographic characterization 
 
√ 
 
BMI 
Numeric 
EHR 
Demographic characterization 
 
√ 
 
Date of AF diagnosis 
Numeric 
EHR 
Demographic characterization 
 
√ 
 
Type of AF 
Numeric 
code 
EHR 
Demographic characterization 
 
√ 
 
eGFR or Creatinine 
Clearance  
Numeric 
EHR 
Risk for Bleeding: HAS-BLED  
 
√ 
 
History of Diabetes 
Y/N 
EHR 
Risk of Stroke: CHA2DS2_VASc 
 
√ 
 
History of Coronary 
Artery Disease 
Y/N 
EHR 
Risk of Stroke: CHA2DS2_VASc 
 
√ 
 
History of Congestive 
Heart Failure 
Y/N 
EHR 
Risk of Stroke: CHA2DS2_VASc 
 
√ 
 
History of 
Hypertension 
Y/N 
EHR 
Risk for Bleeding: HAS-BLED  
Risk of Stroke: CHA2DS2_VASc 
 
√ 
 
History of stroke/ 
TIA/thromboembolism 
Y/N 
EHR 
Risk for Bleeding: HAS-BLED  
Risk of Stroke: CHA2DS2_VASc 
 
√ 
 
History of MI/ 
PAD/aortic plaque 
Y/N 
EHR 
Risk of Stroke: CHA2DS2_VASc 
 
√ 
 
Bleeding History 
Y/N 
EHR 
Risk for Bleeding: HAS-BLED  
 
√ 
 
Specific Medication 
Y/N 
EHR 
Risk for Bleeding: HAS-BLED  
 
√ 
 
Alcohol Use 
Y/N 
EHR 
Risk for Bleeding: HAS-BLED  
 
√ 
 
Arterial embolus 
Y/N 
EHR 
Health outcome 
6 mo. – 
Baseline 
 
Baseline – 6 
mo. 

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Hemorrhage 
Y/N 
EHR 
Health outcome 
6 mo. – 
Baseline 
 
Baseline – 6 
mo. 
Hospitalizations 
Y/N 
EHR 
Health outcome 
6 mo. – 
Baseline 
 
Baseline – 6 
mo. 
Stroke 
Y/N 
EHR 
Health outcome 
6 mo. – 
Baseline 
 
Baseline – 6 
mo. 
Death 
Y/N 
EHR 
Health outcome 
n/a 
 
Baseline – 6 
mo. 
Calls to 
Anticoagulation 
Treatment Unit (ATU) 
Numeric 
ATU 
Burden/ Patient Engagement 
6 mo. – 
Baseline 
 
Baseline – 6 
mo. 
Prescription Refill 
Frequency 
Numeric 
EHR 
Assess medication adherence 
6 mo. – 
Baseline 
 
Baseline – 6 
mo. 
Smart Pill Bottle Use 
Numeric 
Report 
Daily report of pill bottle 
opening, date/time stamped 
 
√ 
√ 
MAS 
Numeric 
Survey 
Assess medication adherence 
 
√ 
√ 
PAM 
Numeric 
Survey 
Assess patient engagement 
 
√ 
√ 
SUS 
Numeric 
Survey 
Computer use self-efficacy 
 
√ 
√ 
AF Knowledge Scale 
Numeric 
Survey 
Assesses knowledge of AF 
disease  
 
√ 
√ 
New Vital Sign 
Numeric 
Survey 
Assesses health literacy 
 
√ 
√ 
ACE 
Numeric 
Survey 
Assess patient engagement 
 
√ 
√ 
TIPI 
Numeric  
Survey 
Assess patient personality  
 
 
√ 
PHR Login Frequency 
Numeric 
EHR 
Assess engagement 
6 mo. – 
Baseline 
 
Baseline – 6 
mo. 
PHR webpage and 
video view frequency 
Numeric 
EHR 
Assess engagement 
 
 
Baseline – 6 
mo. 
PHR messages/phone 
calls to study staff 
Numeric/ 
Qualitative 
EHR 
Burden/ Patient Engagement 
 
 
Baseline – 6 
mo. 
Appointments 
scheduled 
Numeric 
EHR 
Assess engagement 
 
 
Baseline – 6 
mo. 
*See Appendix for scoring of HAS-BLED risk for bleeding and CHA2DS2_VASc risk of stroke 
 
 
d) Qualitative Data Collection and Analysis:  
We will conduct semi-structured interviews at the conclusion of the 6-
month study period with all participants in both the control and 
experimental groups. This data will act to fill the gaps that remain in 
survey data, as it allows for a deeper examination of particular issues with 
people living with AF. Participants will be asked questions in order to flesh 
out more detail around the usage patterns of the tested technologies, 
patient engagement, technology acceptance and experience with patient-
provider communication. 
 
All interviews will be audio recorded, with participant permission and 
researchers will take field notes. Investigators will review the transcribed 
digital recordings and field notes and perform thematic analysis to develop 

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a codebook. All documents will be imported into NVivo, and identified by 
session date and time. The investigators will independently review each 
session's recording to identify patterns within the participants’ responses, 
annotating the recording with relevant concepts through NVivo. Using the 
method of grounded theory and constant comparison20,21, the investigators 
will meet in a series of three or more review sessions to compare 
concepts, resolve discrepancies in interpretation, explore the various 
meanings of words, discuss emergent themes, and resolve ambiguities, 
until consensus is achieved and potential biases in interpretation are 
reconciled22. Important user themes will be built using this iterative 
process of reviewing and grouping concepts during the review sessions. 
The relevance and importance of themes will be assessed using a rating 
schema of frequency, convergence and intensity. Frequency represents 
the number of times that the topic appears in the users’ discussion, and is 
documented using NVivo’s frequency reporting feature. Convergence, the 
relative occurrence of the topic, will be assessed as high, medium, or low. 
Intensity is defined as the emotion and importance of the topic to the user, 
and will be assessed using a scale of high, medium or low based on a 
subjective analysis of the digital recording for vocal tone, pace and 
volume. According to grounded theory, we will continue an iterative 
process of review and data collection until no new concepts are 
discovered and content saturation is reached21. A summary of relevant 
themes will be compiled and used to further describe the impact of the 
intervention. 
 
 
 
Table 4 – Qualitative Data Collected and Purpose 
Data Item 
Type 
Source 
Purpose 
Lifestyle challenges with AF 
Narrative 
Patient 
Interviews 
Define needs for intervention 
Cover gaps in quantitative survey 
data related to health literacy 
Barriers to medication adherence 
Narrative 
Patient 
Interviews 
Define needs for intervention 
Cover gaps in quantitative survey 
data related to medication adherence 
Concerns with anticoagulant use 
Narrative 
Patient 
Interviews 
Define needs for intervention 
Cover gaps in quantitative survey 
data related to health literacy 
Educational needs for AF 
Narrative 
Patient 
Interviews 
Define needs for intervention 
Cover gaps in quantitative survey 
data related to health literacy 
Experience with tested 
technologies 
Narrative 
Patient 
Interviews 
Cover gaps in quantitative survey 
data related to Technology 
Acceptance 

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Barriers to use of tested 
technologies 
Narrative 
Patient 
Interviews 
Cover gaps in quantitative survey 
data related to Technology 
Acceptance 
Suggestions for change in tested 
technologies 
Narrative 
Patient 
Interviews 
Cover gaps in quantitative survey 
data related to medication adherence 
Usage patterns of patient portal 
Narrative 
Patient 
Interviews 
Cover gaps in quantitative survey 
data - patient engagement 
Experience with patient-provider 
communication 
Narrative 
Patient 
Interviews 
Define needs for intervention Cover 
gaps in quantitative survey data - 
patient engagement 
 
e) Intervention: 
 
The study intervention was developed based upon findings from the first 
phase of the study. The intervention entails sending tailored health 
educational messaging through MyChart. In order to tailor the health 
education per patient, an algorithm was developed from the phase 1 
findings to determine what messages each patient will receive based on 
their specific needs. The algorithm was created based on patients’ length 
of AF diagnosis, length of time on current anticoagulant medication, type 
of anticoagulant medication, and history of past anticoagulant medication. 
 
During enrollment, patients will be instructed to contact study staff if their 
anticoagulant medication is changed or permanently discontinued at any 
point during the study. If their anticoagulant medication is permanently 
discontinued, patients will be instructed to stay in the study even while 
they are not taking their anticoagulant. Sometimes patients’ 
anticoagulation therapy is temporarily discontinued for surgery or other 
health reasons. In order to maximize patient safety when these temporary 
holds on medications occur, tailored messages related to medication 
administration and compliance will include a disclaimer that if their 
medication has been stopped then this information is supplementary and 
they should follow their doctor’s instructions first and foremost. 
 
Concurrent with the educational messages sent to patients through 
MyChart, patients will periodically be sent a short survey asking them to 
evaluate the health information they just received. These questions will 
enable patients to evaluate the content, timing and delivery format of the 
interventional messaging. The survey will be administered through Survey 
Monkey, and the MyChart message will contain a secure link to access 
the survey. 
 
ETHICAL CONCERNS 

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CONSENT PROCESS AND DOCUMENTATION 
Informed consent will be obtained from patients before any study activities commence. 
 
CONFIDENTIALITY PROTECTION 
Data collected through chart review will be coded with the key kept in a separate 
location.  Any data stored electronically will be password protected, encrypted, stored 
on a secure server and will be kept in an office with limited access.  Any paper files will 
be kept in an office with limited access. 
 
SUBJECT WITHDRAWAL 
Patients may withdraw from the study at any time.  If funding for this study should be 
stopped early patients will be notified by telephone.  If a patient elects to withdraw, only 
data collected from enrollment to withdrawal date will be utilized. 
 
DATA SAFETY AND MONITORING BOARD 
There will be no Data Safety Monitoring Board (DSMB) for this minimal risk and small 
sample size study.  
 
ALTERNATIVES 
Patients may elect not to participate in the study.  
 
RISK ANALYSIS 
Potential risks (adverse effects) to subjects: 
• Patients may feel uncomfortable answering questions on the survey(s) or 
interview(s). 
• Possible risk of breach of confidentiality of personal and/or health information. 
• Patients may feel anxious or stressed upon receiving push messaging through 
their PHR if they have difficulty understanding it. 
 
Precautions taken to minimize risk: 
Patients will be informed that they can decline to answer any questions at any time.  All 
data will be stored in a password protected electronic format. Collection of Protected 
Health Information (PHI) will be limited to the amount necessary to achieve study aims. 
Data will be accessible to the study supporter (Janssen Scientific Affairs), Parkview 
Research Center study personnel as well as PRC’s consultants, partners, and/or 
business associates who are directly involved in this study.  Analog data will be stored in 

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designated areas with limited access. Computers/electronic files will be password 
protected. All data will be encrypted during electronic transmission.  
 
Patients will be advised to contact the study doctor or the study coordinator to have their 
questions and concerns addressed regarding the condition-specific information provided 
through their PHR. 
 
Management of Safety Data: 
This study has been designated as an interventional study.  Janssen requirements for 
Investigator-Initiated Study (IIS) interventional studies are all adverse events regardless 
of causality and special situations excluding those from subjects not exposed to a 
Janssen Medicinal Product and product quality complaints with or without an adverse 
event will be reported, once the subject’s signed and dated Informed Consent Form is 
obtained until the subject has completed participation in the study and for 30 days after 
the last dose of study drug. Though this study is not classified as a clinical drug trial, 
adverse events will be reported to Janssen, the supporter of this study, as some study 
patients may be taking a medication developed by Janssen Pharmaceuticals, Xarelto 
(rivaroxaban). Please see appendix for a full description of adverse events and 
reporting to Janssen Scientific Affairs. 
 
BENEFIT ANALYSIS 
While this project may not be of direct benefit to patients, the information that they 
provide may improve assistive measures of medication adherence and will contribute to 
increasing the collective understanding of medication adherence and the use of 
information technology to improve patient engagement and health literacy. 
 
COST TO PATIENTS 
There will be no cost to patients. 
 
PATIENT COMPENSATION 
To reimburse patients for their time, effort, and travel expenses they will receive $50 
upon completion of the baseline visit and $50 upon completion of the follow up visit.  If 
patients are requested to and agree to participate in the focus groups, the patient and 
their partner or caregiver will each receive an additional $40.  If patients are requested 
to and agree to participate in the design phase session for prototype testing, they will 
receive an additional $40. All patients and participants will receive payment on a 
ClinCard, a secure reloadable debit card specifically used for compensation in research 
studies. For the design survey only, patients who are requested to and agree to 
participate in the design survey will receive a $20 amazon eGiftcard sent to their email. 

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For the design survey only, patients who are requested to and agree to participate in the 
design survey will receive a $20 amazon eGiftcard sent to their email. If patients do not 
have a valid email address, they will be compensated with a $20 ClinCard or prepaid 
credit card.  
 
SHARING OF RESULTS 
No individual results will be shared with patients/providers. Results from this study are 
planned to be submitted to scholarly/scientific journals for publication and shared at 
scientific conferences. No patients/providers will be identified in these forums. 
 
Results may be shared with consultants, partners, or business associates who are directly 
involved in this study. 
 
Survey information and patient usage patterns from this study will be aggregated and 
analyzed and reported in written reports (including publications) and presentations. 
 
FINANCIAL SOURCES 
This study is being made possible through a grant from Janssen Scientific Affairs, LLC. 
 
CONFLICT OF INTEREST 
There are no known conflicts of interest. All financial and other relationships will be 
reported to the PH IRB per the IRB policy. 
 
 
 
 
 
SIGNATURE LINE 
 
My name typed below shall have the same force and effect and is as legally binding 
as my written signature. 
 
Michael Mirro, MD  
 
 
 
 
 
     11/30/2017 
Co-Sponsor-Investigator 
 
 
 
 
 
 
Date 
 
 
Tammy Toscos, PhD 
 
 
 
 
 
     11/30/2017 
Co-Sponsor-Investigator 
 
 
 
 
 
 
Date 
 
 

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REFERENCES 
 
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emergency department visit rates and subsequent hospital admissions for atrial fibrillation 
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2. Brown, T. M., Siu, K., Walker, D., Pladevall-Vila, M., Sander, S., & Mordin, M. (2012). 
Development of a conceptual model of adherence to oral anticoagulants to reduce risk of 
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5. Daley, C.N., Doshi, R.P., Heral L.D., Mirro M.J. (2013) Applying Health Information 
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Healthcare Research and Quality; June 2013. http://www.effectivehealthcare.ahrq.gov  
 
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SIMPLE: Improving Anti-Coagulation Medication Adherence for Patients with non-valvular 
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000349; 10.1136/amiajnl-2011-000349. 
 
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perspectives into the personal health record: Implications for care and caring. Perspect 
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efficacy and anxiety in older adults with and without mild cognitive impairment. Alzheimers 
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27. Lavsa, S.M., Holzworth, A., Ansani, N.T. Selection of validated scale for measuring 
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31. Shah, L. C., West, P., Bremmeyr, K., & Savoy-Moore, R. T. (2010). Health literacy 
instrument in family medicine: the “Newest Vital Sign” ease of use and correlates. The 
Journal of the American Board of Family Medicine, 23(2), 195-203. 
 
32. Duell, P., Bhattacharya, D., Wright, D., & Renzaho, A. (2015). Optimal health literacy 
measurement instrument for the assessing health literacy in a clinical setting:-A systematic 
review. Patient Education and Counseling. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX 
 
i. 
Quantitative Data—Risk Factor Scoring 
 
Table 10- CHA2DS2-VASc Stroke Risk Score  
Risk factor-based approach expressed as a point based scoring system, with the 
acronym CHA2DS2-VASc 
(Note: maximum score is 9 since age may contribute 0, 1, or 2 points) 
Risk factor  
Score 
Congestive heart failure/LV dysfunction  
1 
Hypertension  
1 
Age ≥75  
2 
Diabetes mellitus  
1 
Stroke/TIA/systemic embolism  
2 
Vascular disease*  
1 
Age 65-74  
1 
Sex category (i.e. female sex)  
1 

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Maximum score  
9 
* Myocardial infarction, complex aortic plaque and peripheral artery disease (PAD 
 
Table 11- HAS-BLED Score 
Risk Score to Predict Bleeding in Anticoagulated Patients with Atrial Fibrillation 
 
Risk factor  
Score 
Hypertension (>160 mmHG systolic) 
1 
Abnormal renal or hepatic function 
1-2 
Stroke 
1 
Bleeding or history of anemia 
1 
Labile INR (TTR <60%)  
1 
Elderly (age >75 years) 
1 
Drugs (antiplatelet, NSAID) or alcohol  
1-2 
Maximum score  
9 
* High risk total score ≥ 4; Moderate risk total score 2-3; Low risk total score 0-1 
 
 
 
 
 
 
 
 
 
 
 
 
ii. 
Management of Safety Data 
 
For the purposes of this study, the Janssen medicinal product is:  
 
Xarelto (rivaroxaban) 
 
Definitions 
Adverse Event (AE) 
An adverse event is any untoward medical occurrence in a clinical study subject 
administered a medicinal (investigational or non-investigational) product. An adverse event 
does not necessarily have a causal relationship with the treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational or 
non- investigational) product, whether or not related to that medicinal (investigational or non-
investigational) product. (Definition per International Conference on Harmonisation [ICH]) 

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This includes any occurrence that is new in onset or aggravated in severity or frequency 
from the baseline condition, or abnormal results of diagnostic procedures, including 
laboratory test abnormalities. 
 
Adverse Events of Special Interest  
Adverse events of special interest are events that Janssen Scientific Affairs is actively 
monitoring as a result of a previously identified signal (even if non-serious). These 
adverse events are: 
•  Suspected severe toxic effect on the bone marrow, such as severe thrombocytopenia (platelet 
count less than 50,000/μL), severe neutropenia (white blood cell count less than 500/μL), 
pancytopenia, aplastic anemia  
•  Suspected severe hypersensitivity reaction (eg, anaphylaxis, angioedema, severe urticaria, 
bronchospasm, etc.)  
•  Severe skin reactions such as Stevens-Johnson Syndrome  
•  Suspected severe liver injury 
 
Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet regulatory 
reporting requirements. 
• 
an identifiable subject (but not disclosing personal information such as the subject’s 
name, initials or address) 
• 
an identifiable reporter (investigational site) 
• 
a Janssen medicinal product 
• 
an adverse event, outcome, or certain special situations 
 
The minimum information required is: 
• 
suspected Janssen medicinal product (doses, indication) 
• 
date of therapy (start and end date, if available) 
• 
batch or lot number, if available 
• 
subject details (subject ID and country) 
• 
gender 
• 
age at AE onset 
• 
reporter ID 
• 
adverse event detail (AE verbatim in English), onset date, relatedness, causality, 
action taken, outcome, (if available) 
• 
Janssen protocol ID 
 
1.1. Product Quality Complaint (PQC) 
A product quality compliant is defined as any suspicion of a product defect related to a 
potential quality issue during manufacturing, packaging, release testing, stability 
monitoring, dose preparation, storage or distribution of the product, or delivery system.  
Not all PQCs involve a subject.  Lot and batch numbers are of high significance and 
need to be collected whenever available. 
 
Examples of PQC include but not limited to: 
• 
Functional Problem: e.g., altered delivery rate in a controlled release product 
• 
Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 

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• 
Potential Dosing Device Malfunction: e.g.,  autoinjector button not working, needle 
detaching from syringe 
• 
Suspected Contamination 
• 
Suspected Counterfeit 
 
1.2. Serious Adverse Event (SAE) 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use is any untoward medical occurrence that at any dose: 
 
• 
Results in death 
• 
Is life-threatening 
(The subject was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe.) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is a suspected transmission of any infectious agent via a medicinal product 
• 
Is medically important* 
 
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject or 
may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious. 
 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS ADVERSE 
EVENT. 
 
Hospitalization 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the 
hospitalization that is the serious event for which details must be provided. 
 
Any event requiring hospitalization or prolongation of hospitalization that occurs during 
the study must be reported as a serious adverse event, except hospitalizations for the 
following: 
• 
Hospitalizations not intended to treat an acute illness or adverse event (e.g., social 
reasons such as pending placement in long-term care facility) 
• 
Surgery or procedure planned before entry into the study 
 
Life-Threatening Conditions 
The cause of death of a subject in a study within 30 days of the last dose of study drug, whether 
or not the event is expected or associated with the study drug, is considered a serious adverse 
event. 
 
 
Unlisted (Unexpected) Adverse Event/Reference Safety Information 
 
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For a medicinal product(s) with a marketing authorization, the 

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expectedness of an adverse event will be determined by whether or not it is listed in the applicable 
product information.  
 
XARELTO®: https://www.xarelto-us.com 
 
Special Reporting Situations  
Safety events of interest for a Janssen medicinal product that require expediting reporting and/or 
safety evaluation include, but are not limited to: 
• 
Drug exposure during pregnancy (maternal and paternal) 
• 
Overdose of a Janssen medicinal product  
• 
Exposure to a Janssen medicinal product from breastfeeding  
• 
Suspected abuse/misuse of a Janssen medicinal product 
• 
Inadvertent or accidental exposure to a Janssen medicinal product  
• 
Medication error involving a Janssen medicinal product (with or without patient exposure to 
the Janssen medicinal product, e.g., name confusion) 
• 
Suspected transmission of any infectious agent via administration of a medicinal product 
 
These safety events may not meet the definition of an adverse event; however, from a 
Janssen Scientific Affairs perspective, they are treated in the same manner as adverse 
events. Special situations should be recorded on the Adverse Event page of the CRF. 
 
Any special situation that meets the criteria of a serious adverse event should be 
recorded on a Serious Adverse Event Report Form and be reported to Janssen Scientific 
Affairs within 24 hours of becoming aware of the event. 
 
 
Pregnancy  
 
All initial reports of pregnancy must be reported to Janssen Scientific Affairs by the Sponsor 
Investigator within 24 hours of becoming aware of the event using the Serious Adverse Event 
Form. Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital 
anomaly, ectopic pregnancy) are considered serious adverse events and must be reported using the 
Serious Adverse Event Form.  
 
Because the effect of the Janssen medicinal product on sperm is unknown, pregnancies in partners 
of male subjects exposed to a Janssen medicinal product will be reported by the Sponsor 
Investigator within 24 hours of their knowledge of the event using the Serious Adverse Event 
Form.  Depending on local legislation this may require prior consent of the partner. 
 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the infant 
will be required 
 
Maintenance of Safety Information: 
 
All safety data should be maintained in a clinical database in a retrievable format. The Institution and 
Sponsor Investigator shall provide all adverse events, both serious and non-serious, in report format. 
However, in certain circumstances more frequent provision of safety data may be necessary, e.g. to fulfill 
a regulatory request, and as such the data shall be made available within a reasonable timeframe at 
Janssen Scientific Affair’s request. 
 

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Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for 
Janssen Medicinal Products to Janssen Scientific Affairs 
All adverse events and special situations whether serious or non-serious, related or not related, 
following exposure to a Janssen medicinal product are to be documented by the investigator and 
recorded in the CRF and in the subject’s source records. Investigators must record in the CRF their 
opinion concerning the relationship of the adverse event to a Janssen medicinal product.  
All (serious and non-serious) adverse events reported for a Janssen medicinal product should be 
followed-up in accordance with clinical practice. 
 
SAEs and Special Reporting Situations 
All serious adverse events that have not resolved by the end of the study, or that have not resolved 
upon discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs: 
• 
The event resolves 
• 
The event stabilizes 
• 
The event returns to baseline, if a baseline value/status is available 
• 
The event can be attributed to agents other than the study drug or to factors unrelated to study 
conduct 
• 
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts) 
 
The Sponsor Investigator will transmit all SAEs and special situations following exposure 
to a Janssen product under study in a form provided by Janssen Scientific Affairs in 
accordance with the Transmission Methods noted below, in English within 24-hours of 
becoming aware of the event(s). 
 
 
All follow-up information for serious adverse events that are not resolved at the end of the study 
or by the time of patient withdrawal must be reported directly by the Sponsor Investigator, within 
24 hours becoming aware, to Janssen Scientific Affairs using Janssen Scientific Affairs’ Serious 
Adverse Event Report  
 
All available clinical information relevant to the evaluation of a related SAE or special 
situation is required. 
 
• 
The Sponsor Investigator is responsible for ensuring that these cases are complete 
and if not, are promptly followed-up. A safety report is not considered complete until 
all clinical details needed to interpret the case are received. Reporting of follow-up 
information should follow the same timeline as initial reports. 
 
• 
Copies of any and all relevant correspondences with regulatory authorities and ethics 
committees regarding any and all serious adverse events, irrespective of association 
with the Janssen Product under study, are to be provided to Janssen Scientific Affairs 
using a transmission method noted below within 24 hours of such report or 
correspondence being sent to applicable health authorities. 
 
Non-Serious AEs 
All non-serious adverse events should be reported to Janssen Scientific Affairs according to the 
timeframe outlined in the Research Funding Agreement section entitled Reporting of Data. 

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PQC Reporting 
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, 
and complete reporting and analysis of PQC information from studies are crucial for the 
protection of patients, investigators, and Janssen Scientific Affairs, and are mandated by 
regulatory agencies worldwide. Janssen Scientific Affairs has established procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of 
PQC information. Lot and/or Batch #s shall be collected or any reports failure of 
expected pharmacological action (i.e., lack of effect). The product should be quarantined 
immediately and if possible, take a picture. 
 
All initial PQCs involving a Janssen medicinal product under study must be reported to 
Janssen Scientific Affairs by the Sponsor Investigator within 24 hours after being made 
aware of the event. The Janssen contact will provide additional information/form to be 
completed. 
 
If the defect for a Janssen medicinal product under study is combined with either a 
serious adverse event or non-serious adverse event, the Sponsor Investigator must 
report the PQC to Janssen Scientific Affairs according to the serious adverse event 
reporting timelines.  A sample of the suspected product should be maintained for further 
investigation if requested by Janssen Scientific Affairs. 
 
Reporting Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) 
for Non-Janssen Medicinal Products  
For SAEs, special reporting situations and PQCs following exposure to a non-Janssen medicinal 
product under study, the Sponsor Investigator should notify the appropriate regulatory/competent 
authority or the manufacturer of that medicinal product (in the absence of appropriate local legislation) 
as soon as possible. 
 
Transmission Methods: 
 
The following methods are acceptable for transmission of safety information to Janssen 
Scientific Affairs: 
• 
Electronically via Janssen SECURE Email service (preferred) 
• 
For business continuity purposes, if SECURE Email is non-functional: 
o Facsimile (fax), receipt of which is evidenced in a successful fax transmission report 
• 
Telephone (if fax is non-functional). 
 
Please use the contact information and process information provided by Janssen Scientific 
Affairs. 
 
Due to the nature of this study, Janssen Scientific Affairs will not be providing to the Sponsor 
Investigator IND safety reports for the Study Product.