Fostering Medication Adherence in Children With Epilepsy Using mHealth Technology
Phase: NA
Conditions: Epilepsy
Sponsor: Children's Hospital Medical Center, Cincinnati

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Epilepsy Adherence in Children and Technology (eACT): Fostering 
Medication Adherence in Children With Epilepsy Using mHealth Technology 
 
Clinicaltrials.gov NCT03817229 
 
Unique Protocol ID: 2018-8411 
 
Protocol Version 10 - March 8, 2023 
 
 

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CINCINNATI CHILDREN’S HOSPITAL MEDICAL CENTER 
STUDY PROTOCOL 
Study Title: EPILEPSY ADHERENCE IN CHILDREN AND TECHNOLOGY: A SEQUENTIAL, 
MULTIPLE ASSIGNMENT, RANDOMIZED TRIAL (SMART) 
 
Principal Investigator: Avani C. Modi, Ph.D. 
 
1. ABSTRACT 
Non-adherence to antiepileptic drugs (AEDs) is a common problem (i.e., 58% of patients have 
some level of non-adherence) for young children with newly diagnosed epilepsy, with potentially 
devastating consequences. AED non-adherence is associated with a 3-fold increased risk of 
seizures, poor quality of life, inaccurate clinical decision-making, and higher health care 
utilization and costs. One of the primary barriers to adherence is forgetting, which may be 
particularly amenable to mHealth (mobile technology in healthcare) interventions. Despite the 
critical need to develop and implement interventions to improve adherence, there are few 
family-based interventions for young children with epilepsy and their families, with the exception 
of our work. Although highly promising, this intervention requires six in-person sessions, which 
can be impossible for families who lack routine access to tertiary specialty care due to time, 
financial, or transportation constraints. Thus, unmet medical and psychosocial needs of the 
underserved pediatric epilepsy population are perpetuated and compounded by limited access 
to this state of the art care. Our overall goal in this multisite study is to test an mHealth 
adherence intervention that is easily accessible using a stepped up care model based on 
individual needs. This stepped up care model will conserve patient, family, and provider time, 
costs and resources. We have completed the first phase of this work and incorporated the 
feedback we gathered from caregivers during focus groups and usability studies to develop the 
individualized adherence feedback reports, and all modules of the intervention (e.g., education 
and problem-solving web-based modules) to improve adherence. 
 
The second phase of this study will consist of a 2-stage, sequential, multiple-assignment, 
randomized trial (SMART) to evaluate the effectiveness of mHealth intervention strategies for 
improving AED adherence in parents/legal guardians of young children with epilepsy. We plan 
to recruit a total of 600 participants across all collaborating study sites, with approximately 150 
at each site. Enrolled caregivers will complete study questionnaires and be asked to start using 
electronic adherence monitors (e.g., pillbox or pill bottle) at the time of data enrollment during 
the baseline period. Only participants who demonstrate adherence <95% will be randomized to 
either the control group or treatment group in Stage 1. At the end of Stage 1, participants who 
demonstrate adherence <95% will undergo a second randomization to either stay in their 
original group or receive the stepped up intervention. The primary outcome is electronically- 
monitored adherence. Secondary outcomes include seizure severity/frequency, quality of life 
and healthcare utilization. These data will then be examined, analyzed, and used to evaluate 
study aims including efficacy, effectiveness, and predictors of treatment responsiveness. 
 
2. PURPOSE OF STUDY 
The purpose of this study is to evaluate the efficacy of a mHealth adherence intervention in 
caregivers of children with newly diagnosed epilepsy, to compare the effectiveness of three 
different intervention strategies, and to identify predictors of treatment responsiveness. 
 
Specifically, our aims are as follows: 

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Aim 1: Examine the efficacy of the mHealth adherence intervention in caregivers of children 
(ages 2-12) with newly diagnosed epilepsy (< 2 years) on electronically monitored adherence. 
 
Aim 2: To compare the effectiveness of the three intervention strategies on adherence, seizure 
severity/frequency, quality of life, and healthcare utilization at 1-, 6-, and 12-months post- 
intervention. 
 
Aim 3: To identify individual and family characteristics that predict responsiveness to the three 
intervention strategies and to derive an optimal, adaptive intervention strategy for tailoring 
selection of initial and subsequent intervention in the case of nonresponse based on individual 
characteristics. 
 
3. BACKGROUND 
Children with epilepsy represent a high-risk and underserved population. Epilepsy is a 
common chronic neurological condition that affects 1%2 of the US population and 
disproportionately affects children3 (750,000 youth).4,5 Epilepsy is characterized by recurrent 
unprovoked seizures. Children with epilepsy are 3-6 times more likely to have 
neurodevelopmental (e.g., autism) disorders,6 and/or psychological (e.g., depression) 
comorbidities than the general population and children with non-neurological conditions.7-10 
Children with epilepsy are at 4-fold increased risk11 for premature death, with higher risk linked 
to comorbidities.11-14 Further, 54-59% of youth with epilepsy live in poverty (i.e., household 
income < $36,000),15-17 53% have public insurance,16 32% live in rural locations,17 and 64% of 
caregivers have low health literacy.15 Unfortunately, federal programs/agencies have historically 
allocated considerably less funding to epilepsy than far less prevalent conditions.18 
Despite the heavy burden of epilepsy4, children with epilepsy are an underserved and 
vulnerable population with many unmet medical and behavioral health needs.18,34-39 Only 
30% of children with epilepsy receive psychosocial/behavioral health care including adherence 
interventions, likely due to barriers inherent in the delivery or context of the intervention 
itself.34,35 Furthermore, ~60% of children with newly diagnosed epilepsy and their caregivers 
demonstrate non-adherence,40 a significant risk factor for poor health outcomes. In particular, 
children with lower socioeconomic,40 African American race status,41 and lower parental health 
literacy15 are at increased risk for antiepileptic drug (AED) non-adherence. This may be due to 
greater concerns about the AEDs, including whether they are more harmful than beneficial.42 
Similarly, lower socioeconomic status, African American race, and rural residency are 
associated with increased risk of early death,11,17 likely due to lack of resources and access to 
comprehensive multidisciplinary epilepsy care.38,43 Overall, these findings highlight that children 
with epilepsy are an underserved population, with some subgroups exhibiting multiple risk- 
factors and vulnerabilities contributing to non-adherence. 
Consequences of non-adherence are significant. Non-adherence makes seizure control 
more difficult,44,45 leading to increased healthcare utilization,46,47 unnecessary AED changes,48 
and even death.13 Children who demonstrate AED non-adherence in the first six months of 
treatment are >3 times more likely to have seizures 4-years post-diagnosis compared to 
children with near-perfect adherence.45 Our research also demonstrates that both biology and 
adherence play critical roles in health outcomes and that variable non-adherence appears to 
increase the likelihood of having seizures.44 Non-adherence has also been shown to impact 
patient-reported outcomes (e.g., quality of life).49 Despite the known impact of non-adherence 
on health and patient-reported outcomes for children with epilepsy, few adherence interventions 
have been developed. 
Adherence interventions are critically necessary, need to target caregivers, and must 
be individualized. A 2017 Cochrane review indicated a lack of well-designed randomized 
controlled clinical trials (RCT) to improve adherence in epilepsy, especially in young children.50 

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Based on this Cochrane review, we are the only researchers to develop and pilot test 
interventions for young children with epilepsy and their caregivers. In our first pilot study, 
families receiving an education and problem-solving intervention had a 32% adherence 
improvement from baseline to post-intervention.51 In the second pilot study, statistically 
significant differences between treatment versus controls were noted following the second 
problem-solving session.52 Both interventions focused on education and problem-solving and 
demonstrated excellent preliminary efficacy and feasibility/acceptability among families. The 
problem-solving approach targeted family-specific adherence barriers, which varied by family, 
suggesting the need for individualized treatment. Furthermore, improvement in adherence 
varied based on the number and types of barriers endorsed. For example, some families who 
endorsed forgetting chose text reminders and had significantly improved adherence while others 
required further problem-solving around more difficult barriers, such as behavior problems. This 
highlights the need for both tailored and stepped up care to match the family’s specific barriers 
and needs. Further, scheduling face-to-face sessions was challenging; thus, a model utilizing 
mHealth could improve dissemination of adherence interventions. The proposed intervention will 
translate the education and problem-solving content from our pilot studies to mHealth modules 
for families. Notably, these modules will be provided in a stepped up care approach, such that 
non-responders will receive more time and resource-intensive problem-solving sessions 
followed by therapist-guided telehealth sessions to address family-identified adherence barriers. 
Targets for adherence intervention. Previously identified targets for adherence 
intervention in young children with epilepsy and their caregivers include epilepsy knowledge, 
adherence barriers (e.g., forgetting to take AEDs), problem-solving, communication, and 
effective self-management skills.52-54 These studies highlight that we have identified optimal 
targets (mechanisms of action) for the proposed intervention. 
Knowledge: Caregivers of children with epilepsy reported lacking information about their 
child’s epilepsy.55 Only 29% of caregivers of children with epilepsy knew the name or dose of 
their child’s AED,56 and some did not believe that AEDs were beneficial.57-59 Increasing adult 
knowledge of epilepsy and the perceived benefits of AEDs may be associated with adherence 
gains.60-63 However, knowledge is necessary but not sufficient to improve and sustain treatment 
adherence.64-66 Teaching children and families the skills to apply this knowledge (e.g., how to 
implement an AED titration schedule, when to take AEDs) is critical to improve adherence and 
will be provided to both control and treatment groups in the current proposal. 
Forgetting: Forgetting is a major adherence barrier across many pediatric and adult chronic 
conditions.42,59 mHealth solutions may address this barrier because 92% of adults have cell 
phones (67% are smartphones), with 97% using text messaging and 89% using it for the 
internet.67 Individuals with lower income or of minority status increasingly depend on 
smartphones for internet access.67 As such, the number of mHealth tools focused on improving 
adherence via automated digital reminders have increased, with 160 commercial adherence 
tools currently available.68 These reminder systems have high feasibility, satisfaction, cultural 
acceptability, ease of use, and are low-cost. A recent meta-analysis of text-messaging 
interventions to improve adherence revealed significant benefits in 18 of 29 studies; however, 
only three of the 18 studies were pediatric and none were in epilepsy.69 Another review of 
electronic medication packaging and digital reminders found variable improvements in 
adherence, but studies lacked scientific rigor (e.g., small sample, non-randomization) and were 
primarily adult-focused.70 Notably, both reviews concluded that long-term rigorous RCTs, with 
objective adherence measures, are still needed to determine the efficacy of mHealth adherence 
interventions, especially in pediatrics. Further, a 2017 review of all mHealth pediatric 
interventions found that caregiver involvement was a significant positive moderator of treatment 
effects, suggesting the need to focus on caregivers of children with chronic diseases.71 
Individualized Adherence Feedback: These meta analyses also found that the best 
performing interventions tailored content to the specific needs of an individual,69 indicating that 

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individualized adherence feedback is critical to the success of this type of intervention. For 
example, an HIV adherence intervention study that provided electronically-monitored adherence 
feedback to non-adherent patients (< 95%) found a 10% improvement (i.e., 86.8% to 96.5%) in 
the treatment group versus 1% improvement (83.8% to 84.5%) in the control group.72 
Interventions using individualized feedback in pediatric asthma have also resulted in short-term 
adherence improvements.73,74 Several adult studies have demonstrated significant 
improvements in adherence relative to control conditions with the provision of individualized 
adherence feedback,75 suggesting this is a beneficial method to improve adherence in 
caregivers of children with epilepsy. 
Problem-solving: Beyond forgetting, caregivers of children with epilepsy identify general 
barriers, including competing extracurricular activities, difficulty swallowing pills, and poor family 
communication, as well as epilepsy-specific barriers such as AED side effects and the stigma 
associated with having epilepsy and taking AEDs.59 Tailored problem-solving around these 
more complex adherence barriers can be provided to children with epilepsy and their caregivers 
who most need it. For example, if caregivers report oppositional behaviors as a primary barrier, 
problem-solving would focus on identifying solutions, such as giving rewards for taking AEDs, to 
reduce oppositional behaviors. Our intervention studies demonstrate that face-to-face problem- 
solving is efficacious in improving adherence but does not reach many families with children 
with epilepsy. Thus, one goal of this proposal is to translate problem-solving content into a 
mHealth module with therapist-guided telehealth sessions. These problem-solving sessions 
require trained professionals; thus, this component is reserved for participants who are non- 
responsive to the initial, less time-intensive and costly adherence intervention dose (e.g., 
automated digital reminders, individualized adherence feedback) and need stepped-up, tailored 
care. Because clinician time is not required for the initial intervention, our intervention has 
considerable potential for sustainability and broad dissemination for epilepsy and other chronic 
conditions. 
Overall Impact. If successful, the results of this study would have a large impact on 
pediatric epilepsy and other chronic pediatric conditions, with the potential to change clinical 
practice for treating non-adherence. The provision of mHealth adherence interventions will have 
greater reach, especially to those at highest risk within pediatric epilepsy, reducing common 
barriers to behavioral health care. The study design will allow us to identify patients who are 
most likely to respond to interventions and step up care with more time- and resource-intensive 
interventions (i.e., therapist-guided telehealth sessions), when necessary. In the future, front- 
line health care providers, including nurses and social workers, could provide these therapist- 
assisted telehealth sessions. A tailored intervention that uses minimal resources will also 
maximize cost-savings. If efficacious, mHealth adherence interventions could be presented 
proactively to caregivers at diagnosis to promote high adherence behaviors initially, resulting in 
substantial cost-savings and prevention of poor health outcomes. 
 
Our group conducted the first aims of this grant, in which we conducted focus groups and 
usability testing across the four sites to develop the Education microlearning sessions, Problem- 
solving module, and individualized adherence feedback reports with input from caregivers of 
young children with epilepsy. Their input provide significant feedback related to the design and 
infrastructure of the intervention, which directly informs this SMART trial. 
 
4. STUDY DESIGN 
We are conducting a sequential, multiple assignment, randomized clinical trial with caregivers of 
youth with epilepsy (n=600) in order to evaluate the efficacy and effectiveness of a mobile 
health adherence intervention to improve adherence to antiepileptic medications in children with 
newly diagnosed epilepsy. For the purposes of this protocol, CCHMC will serve as the Primary 
Site. The term “Collaborating Site” refers to external children’s hospital sites working in 

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collaboration with CCHMC on the study, including Medical University of South Carolina, 
Nationwide Children’s Hospital, and Children’s Hospital of Orange County. 
 
5. DURATION 
The anticipated duration of the study is approximately 5 years. The duration for participants is 
variable depending on their level of adherence during the baseline period and their enrollment 
date as the follow-up period was shortened twice to continue enrollment and allow participants 
to complete the study by the end of the grant period.  
 
• For enrolled participants who achieve electronically monitored adherence >95% in the 
baseline period, their study participation will be approximately 2 months, with conclusion at 
the end of the baseline period.  
• For participants with adherence < 95% in the baseline period, their participation will be: 
o 20 months (2 months baseline, 5 months of active intervention, and 13 months of 
follow-up) if they enrolled before 12/9/2022. 
o 14 Months (2 months baseline, 5 months of active intervention, and 7 months of follow-
up) if they enrolled between 12/9/2022 and 3/8/2023. 
o 8 months (2 months baseline, 5 months of active intervention, and 1 month of follow-
up) if they enroll after 3/8/2023. 
 
6. SELECTION & RECRUITMENT OF PARTICIPANTS 
Study Participants 
Study participants will include up to 600 caregivers of youth with epilepsy between 2-12 years 
old at CCHMC and collaborating sites. Caregivers will be recruited during routine medical 
appointments with neurology or epilepsy-related hospital visits and will meet the following 
inclusion/exclusion criteria: 
 
Inclusion criteria 
• Child age 2-12 years old 
• Diagnosis of epilepsy within the last 2 years 
• On ≤2 antiepileptic drugs (AEDs) 
• Ability to read and speak English 
 
Exclusion criteria 
• Diagnosis of non-epilepsy medical disorders requiring daily medications (Asthma,  
   allergies, ADHD, and daily vitamins are okay)  
• Diagnosis of severe behavioral disruption, developmental delays (global), and Autism 
Spectrum Disorder (DSM 5 Level 2 or 3 severity) based on medical chart review and/or parent 
report.  “Severe” is defined as children who: 
1) have an IQ < 70 if documented 
2) are nonverbal 
3) have impaired thinking 
4) have aggressive behaviors 
5) have “global developmental delay” 
6) use a school aide (i.e. someone providing 1:1 help in the classroom) 
 
Recruitment Procedures 
Potential participants meeting eligibility criteria will be identified by a trained research 
coordinator in collaboration with the epilepsy team. If potential participants are eligible, a trained 
research coordinator will approach families during their medical clinic visit. A thorough overview 
of the study will be provided, including study procedures, benefits, and risks. Research 
coordinators will verify all inclusion/exclusion criteria as noted above. A study figure will also be 
given to families to understand the design and timeline of the trial (See Appendix A). All 
questions will be addressed and informed consent/assent will be obtained (see Section 7). 

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Following informed consent from the caregiver/legal guardian and child assent (11 years and 
older), electronic pillbox and pill bottles will be provided, and baseline questionnaires will be 
completed via REDCap. The recruitment script can be found in Appendix B and other 
recruitment materials can also be found in the appendices, including flyers, study magnets 
(Appendix C). Recruitment materials will be used in various places to help recruit participants 
(e.g. flyers posted on hospital specific social media sites, distributed in clinic, etc.). Notably, 
this trial is focused on serving at least 30% of those that are underrepresented. 
Underrepresentation is defined as minority race/ethnicity, public/no insurance status, and 
living in a region that is rural or medically underserved based on HRSA maps. We will track 
the number of participants that meet these criteria throughout the trial to ensure at least 30% 
of our participants are underrepresented. The medical chart review will provide data on this 
status. 
 
7. PROCESS OF OBTAINING CONSENT 
 
As noted above, once participants are identified as study eligible, they will be approached 
during their epilepsy clinic visit and provided a description of the study (e.g., study procedures, 
benefits, risks) by a trained research coordinator included on the approved IRB protocol. After 
addressing all questions from potential participants, informed consent/assent will be obtained 
by trained research staff. Consent forms will be signed electronically using REDCap, a secure 
web- based interface supported by the CCHMC Division of Biomedical Informatics in 
compliance with HIPAA designed to protect PHI in the electronic transfer and storage of the 
consent form. 
Should technical issues arise with the REDCap interface, hard copies of consent forms may 
also be used. For all consent visits, all pertinent aspects of consent will be covered including 
study purpose, risks/benefits, confidentiality, and right to withdraw. Patients will be informed that 
their care at CCHMC or other collaborating study sites will not be affected by whether they 
choose to participate in the study. 
 
If the caregiver agrees to participate and is signing an electronic consent form via REDCap, 
they will have an opportunity to check a box stating that they agree to provide their consent. 
There will also be fields for their typed name, date, and electronic signature to document the 
informed consent process. Once the electronic form has been submitted, caregivers will receive 
a copy of the electronically signed and dated consent form via email. 
 
Participants recruited in-person will complete the informed consent document in-person. For 
participants who decide to participate after the clinic visit, we will use telephonic electronic 
consent. Specifically, a member of the study team will provide a link to access the consent form 
in REDCap via email or text message. A hard copy of the consent form may also be mailed if 
necessary. During the consent/assent phone call, research staff will ensure all questions are 
answered. In compliance with CCHMC SOP Number 41-1.6, study staff will sign and date 
accordingly on the signature page of each form corresponding to the date the forms were 
received, not necessarily reviewed with the family. The method used to obtain participant 
consent will also be written on the Informed Consent Process Note. 
 
8. STUDY PROCEDURES 
This is a longitudinal study of caregivers of children with epilepsy that will employ SMART 
methodology to test the efficacy and effectiveness of a mHealth adherence intervention. 
Potential participants will be identified by the study coordinator in collaboration with the epilepsy 
team at each site as noted above. After caregivers provide informed consent (see Section 7), 
baseline questionnaires will be completed via REDCap, including a demographics form and 
study measure questionnaires (see Measures section below). All measures will be hosted on 
REDCap, a secure web-based interface. The PI and her team have fully tested REDCap 
questionnaires and will test prior to study implementation across all sites to ensure functionality. 
A medical chart review will also be conducted to gather information about seizures, medications, 

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seizure etiology, comorbidities, and time since diagnosis. It is notable that the participant must 
provide an email address for the online questionnaires. If they do not have one, we will help 
them create one or we will text the link to their cellular phones, if needed. 
 
The eACT SMART design is illustrated in Figure 1 below. All participant families will complete a 
2-month baseline period during which they will use electronic adherence monitoring (i.e., pillbox 
or pill bottle) to measures adherence. Participants who demonstrate adherence < 95% will move 
on to Stage 1 SMART for randomization. In SMART Stage 1 (3-months), caregivers will be 
randomized to control group (mHealth education microlearning sessions and module and 
automated digital reminders) or treatment (control condition plus individualized adherence 
feedback reports) 
 
 
 
 
• Education microlearning sessions: The 4-5 education microlearning sessions will take 
approximately 5-10 minutes to complete on any mobile device, tablet or computer. All 
caregivers will be provided with a link to the portal with their log-in information following 
the baseline period to obtain access to the microlearning sessions. These sessions have 
information regarding the diagnosis of epilepsy, treatment, rationale for adherence, and 
other epilepsy facts that caregivers have found beneficial. 
 
• Automated Digital Reminders – Each adherence electronic monitor has the capability 
to provide automated digital reminders. As a part of the intervention, all caregivers 
randomized to intervention will have to option of selecting the type of automated digital 
reminders that they receive, which could include text messages and/or device 
sounds/lights. These will be turned on immediately following the baseline period based 
on the participant’s preferences. 
 
• Individualized Adherence Feedback Reports - Individualized adherence feedback will 
be received by families once a week where they will be provided with information about 

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adherence levels over the previous 7 days based on their electronic adherence monitors. 
All individualized adherence feedback reports will be received on Monday. A separate 
portal has been developed by Bioinformatics at CCHMC to create the adherence 
feedback reports. Data from the SimpleMed pillbox via open API and AdhereTech via 
excel spreadsheets are merged to provide a calendar plot with the participant’s 
adherence data from the past week. The participant will receive a push notification to 
view their adherence from the past week. The portal with this information will use the 
same log-in information as the education and problem-solving sessions. It is notable that 
the participant must provide a cell phone number for the push notifications. 
 
At the beginning of SMART Stage 2 (2-months), caregivers randomized to the treatment group 
who demonstrate continued non-adherence (<95%; non-response) by the end of Stage 1 will 
undergo a second randomization to either 1) continued individualized adherence feedback or 2) 
individualized adherence feedback augmented with a mHealth problem-solving module and two 
therapist-guided sessions using Zoom for healthcare. The mHealth problem-solving module 
incorporates a video and reviews skills of problem-solving for caregivers of young children with 
epilepsy and takes approximately 10 minutes to view from any mobile device, tablet or 
computer. The same log-in information for the education microlearning sessions will be used to 
access the problem solving modules. Following completion of the problem-solving module, a 
therapist will contact the family to review and apply the problem-solving skills. Two sessions will 
occur one month apart via teleconferencing (i.e., Zoom for Healthcare-Appendix D), which is a 
HIPAA-compliant teleconferencing site. 
 
After completion of Stage 2, automated digital reminders will be turned off and adherence 
feedback reports will cease to be provided. Additional questionnaires will be completed via 
REDCap at Post-Treatment (1-Month Follow-Up in Month 8), Follow-Up 1 (6 months post-
treatment in Month 14)*, and Follow-Up 2 (12 months post-treatment in Month 20)**. 
 
Data collection procedures and measures: Participants will complete a demographic questionnaire  
that provides general information about the child’s age, caregiver work history, family composition, 
socio-economic status, family history of seizures, history of seizures (e.g., type, who witness, when  
they occurred), and comorbid illnesses (e.g., learning disorders). In addition, caregivers will complete  
the questionnaires detailed in the table below.  
 
Construct Measured 
Respondent 
Stages and Time points 
C=Caregiver; 
M=Medical Chart 
Review 
D=Doctor/Clinician 
Baseline 
Post 
(1 month post- 
treatment) 
Follow-Up 1 
 (6 months post-
treatment) * 
Follow-Up 2  
(12 months post-
treatment) ** 
ORDER OF MEASURES (As 
applicable) 
Background Form (Demographic) 
C 
X 
Pediatric Epilepsy Medication 
Self-Management Questionnaire 
(PEMSQ) 
• 
PEMSQ: Self-reported 
Adherence 
C 
X 
X 
X 
X 
Behavior Assessment System 
for Children-3 Parent-Rating 
Scales 
C 
X 
X 
X 
X 
Short Test of Functional 
Health Literacy in Adults 
C 
X 
X 
X 
X 
Pediatric Quality of Life in Epilepsy 
Module 
C 
X 
X 
X 
X 
Brief Symptom Inventory-18 (BSI-
18) 
C 
X 
X 
X 
X 
Epilepsy Knowledge 
Questionnaire-Adapted (EKQ) 
C 
X 
X 
X 
X 

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Social Problem-Solving 
Inventory-Revised Short 
(SPSI-Revised Short) 
C 
X 
X 
X 
X 
Pediatric Epilepsy Side Effects 
Questionnaire (PESQ) 
C 
X 
X 
X 
X 
Seizure Severity Scale 
Adapted for Children (SSSC) 
C 
X 
X 
X 
X 
Family Assessment Device (FAD) 
C 
X 
X 
X 
X 
Global Assessment of the 
Severity Scale of Epilepsy in 
Children (GASE) 
D 
X 
X 
X 
X 
Healthcare utilization 
C 
X 
X 
X 
X 
Medical Chart Review 
M 
X 
X 
X 
X 
Feasibility/Acceptability 
Questionnaire (FAQ) 
C 
X 
 
 
Impact of COVID-19 on Pediatric 
Epilepsy Management (ICPEM) 
C 
X 
X 
X 
X 
*Follow-Up 1 Questionnaires will only be completed by participants enrolled before 3/8/2023 
**Follow-Up 2 Questionnaires will only be completed by participants enrolled before 12/9/2022  
 
 
An additional questionnaire related to the child’s seizure severity (one item) will be obtained 
from the child’s epilepsy provider. A medical chart review will also be conducted to describe 
key patient medical characteristics (e.g., epilepsy type and treatment, seizure frequency, 
quality of life, side effects, hospitalizations, emergency room visits, and telephone contacts to 
clinic staff between routine clinic visits). Chart reviews will cover the entire study period. Due to 
the unexpected COVID-19 pandemic, we are also including a newly-developed measure, the 
Impact of COVID-19 on Pediatric Epilepsy Management (ICPEM) to understand how COVID-
19 is impacting our research participants and the outcomes of our study.   
 
Raw adherence data will be obtained from the SimpleMed pillbox and AdhereTech bottles and 
will be used as the primary outcome variable. Data from these devices is obtained real-time via 
blue-tooth and 4G technology and thus will require no additional burden for participants. They 
will simply put their anti-seizure medicine in the electronic monitor (those who already use 
bottles will be given an AdhereTech bottle and those who use pillboxes will be given SimpleMed 
pillboxes). 
To increase retention, we will be sending thank you letters, birthday cards and holiday cards 
(See Appendix E). We will also be providing all participants with a study folder with materials 
that may be helpful during the study, such as an introductory letter, study timeline, information 
about their electronic monitor, and our contact information (See Appendix F). 
 
8.1 Sample Size Considerations and Power Analysis: Power analysis was conducted based 
on SMART Stage 1, assuming ~180 participants randomized to treatment and ~90 to control 
group. Effect sizes for education-focused adherence interventions with reminders in other 
chronic conditions relative to controls (e.g., treatment as usual, pre-post) range from 0.08- 
0.20,72,170 while those with adherence feedback range from 0.78-1.03.80,171 Power for the primary 
analysis (Aim 1 below) will be 80% to detect a small-to-moderate standardized effect size 
(Cohen’s d=0.36) and 97% to detect a moderate standardized effect size (Cohen’s d=0.50). 
These detectable effect sizes reflect clinically meaningful changes in adherence. Power 
analyses require known and unknown assumptions, such as the anticipated response rate to 
Education + Automated Digital Reminders + Individualized Adherence Feedback at the end of 
Stage 1. Effect sizes for our face-to-face problem-solving adherence intervention, which 
incorporates IAF relative to treatment as usual, ranged from 0.95 (1st problem-solving session) 
to 1.59 (2nd problem-solving session).15 Assuming a 50% response rate to SMART Stage 1 
treatment and a Bonferroni multiplicity adjustment, the proposed sample size provides 80% 
power with alpha at 0.05 to detect a standardized effect size of d=0.69 between any pair of 
embedded strategies (SMART Stage 2). 
 

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8.2. 
Data Analysis: All data analysis and management will also occur at North Carolina 
State University (NC State), which is the primary data analysis site. The Division of Behavioral 
Medicine and Clinical Psychology at CCHMC has developed a Divisional Data Core (DDC) in 
cooperation with the divisions of Biostatistics and Epidemiology and Bioinformatics to share the 
de-identified data with NC State. The CCHMC DDC will provide quality reports to audit the data 
routinely, provide data for safety monitoring committee reports for the biostatisticians at NC 
State, and cleaning of the data. 
 
Aim 1: Examine the efficacy of the mHealth adherence intervention in caregivers of 
children (ages 2-12) with newly diagnosed epilepsy (< 2 years) on electronically 
monitored adherence. Electronically-monitored adherence, measured on a scale of 0-100%, 
will be calculated for the final 30 days of Stage 1 SMART. The primary outcome is percent 
change in adherence from baseline, calculated using the baseline and final 30-day adherence. 
The primary hypothesis is that participants initially randomized to treatment (E+ADR+IAF) will 
exhibit significantly greater improvements in adherence compared to those randomized to 
control (E+ADR) from baseline to end of Stage 1 (i.e., last 30 days). A two-sided, two-sample 
t- test with unequal sample sizes will be used for the primary analysis. Exploratory Analyses: 
Daily electronically-monitored adherence will be available on each participant throughout the 
SMART. To gain insight into the possible differences in the evolution of adherence following 
introduction of each intervention strategy, we will use functional data analysis methods172 to 
evaluate and contrast patterns of longitudinal adherence. Functional principal components will 
be used to estimate a small set of representative adherence patterns associated with each 
treatment; these patterns will improve understanding of patient trajectories and inform future 
interventions (e.g., identifying when ADR might be most effective). 
 
Aim 2: To compare the effectiveness of the three intervention strategies on adherence, 
seizure severity/frequency, quality of life, and healthcare utilization at 1-, 6-, and 12- 
months post-intervention. We will carry out secondary analyses to compare the three 
intervention strategies embedded in the SMART: #1 E+ADR (control), continuing regardless of 
response at three months; #2 E+ADR+IAF (treatment), continuing regardless of response; and 
#3 E+ADR+IAF+Problem-solving if not responsive. Strategies #1 and #2 are non-adaptive 
intervention strategies in that treatment is not modified in accordance with response status (or 
any other participant characteristics); #3 is an adaptive intervention strategy in that treatment is 
augmented by problem-solving only among non-responders. The pairwise comparison of the 
non-adaptive strategy #1 to the adaptive strategy #3 represents comparison of the least 
resource-intensive, least burdensome strategy to the most resource-intensive, most 
burdensome strategy. Note that the actual experience of a participant may be consistent with 
more than one embedded strategy; in particular, a participant who receives E+ADR+IAF initially, 
responds, and continues to receive E+ADR+IAF is consistent with having followed either 
strategy #2 or #3. Thus, such a participant’s data contribute to assessment of improvement in 
adherence for both of these strategies. Comparison of strategies #1, #2, and #3 requires the 
use of specialized methods133 that account for the fact that actual experiences of participants 
may be consistent with more than one strategy. We will conduct pairwise comparisons of the 
three embedded strategies on the basis of adherence, seizure severity/frequency, quality of life, 
and healthcare utilization at 1-, 6-, and 12-months post-intervention. Appropriate methods will 
be used based on the type of outcome measure: binary, count, and continuous variables. 
 
Aim 3: To identify individual and family characteristics that predict responsiveness to the 
three intervention strategies and to derive an optimal, adaptive intervention strategy for 
tailoring selection of initial and subsequent intervention in the case of nonresponse 
based on individual characteristics. The data collected in the SMART will provide a rich 
resource for investigating participant baseline characteristics and post-randomization 
characteristics ascertained prior to response status that can inform tailored selection of initial 
(E+ADR+IAF or control) and subsequent adherence strategies (continue E+ADR+IAF or 
augment with problem-solving) for children who do not initially respond to E+ADR+IAF. We will 

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carry out several exploratory, hypothesis-generating analyses. We will use standard methods 
based on linear models for percent improvement in adherence to evaluate baseline 
characteristics that are moderators of participants’ adherence status following initial intervention. 
We will also use standard tests for qualitative interactions173 and more recent variable selection 
methods for qualitative interactions that adjust for multiplicity.174,175 Evaluation of moderators of 
outcomes at 1-, 6-, and 12-months post-intervention is complicated by the sequential nature of 
the interventions, requiring the use of specialized statistical methods. We will use Q-learning176 
and value-search estimation129,130 to test for moderators of the initial and stepped up 
interventions. We will first conduct an overall test of the null hypothesis that there are no 
moderators at either stage. If the test rejects this null hypothesis, we will conduct appropriate 
multiplicity-adjusted statistical tests to identify specific baseline and intermediate moderators of 
outcomes at 1-, 6-, and 12-month follow-ups. Because of the sequential nature of the 
interventions, standard statistical tests are invalid without appropriate modification.132,177 We will 
use suitable bootstrap methods to ensure that the tests are valid (i.e., have correct control for 
Type 1 error). We will also use Q-learning and value-search estimation111,112 to estimate an 
optimal adaptive intervention strategy for personalizing selection of initial intervention and the 
need for stepped up care following E+ADR+IAF based on child/caregiver characteristics. We will 
evaluate the potential improvement in adherence that could have been realized for each 
participant in the SMART if s/he had received initial and secondary interventions via the optimal 
adaptive intervention strategy. We will also carry out Monte Carlo simulations to compare the 
average percent improvement in adherence achievable using the optimal adaptive intervention 
strategy to those achievable using the simpler embedded strategies #1- #3. This analysis will 
provide valuable insight on key characteristics implicated in heterogeneous intervention effects 
and subgroups and form the basis for formulation of personalized intervention strategies for 
subsequent study. 
 
9. POTENTIAL BENEFITS 
No immediate or direct benefits to patients participating in this study are expected. However, it 
is possible that participants will learn more information about epilepsy and have improved 
adherence. The information obtained from this study can ultimately be used to increase 
knowledge in the scientific community about how to improve adherence in diverse youth with 
epilepsy. 
 
10. POTENTIAL RISKS, DISCOMFORTS, INCONVENIENCES, & PRECAUTIONS 
There are minimal potential risks/discomforts/inconveniences to participants in this study, no 
greater than those encountered in routine behavioral assessment and clinical care. There are 
no medical risks. All the questionnaires have been used in research, including our own, without 
any reported negative effects; however, it is possible that a small group may feel uncomfortable 
responding to questions. Participants may decline answering questions that cause them to feel 
uncomfortable and will be reminded of this prior to each study visit. Participants may also 
withdraw from the study at any time and will be informed of this right during the consent 
process. 
 
If a participant is distressed by any study procedures, the site PI or designee (CCHMC- Avani C. 
Modi, PhD or Shanna Guilfoyle, Ph.D., licensed clinical psychologists) at CCHMC will be 
contacted immediately to assess the situation. The study PI or their designee will provide 
appropriate referrals and/or intervention. In addition, questions on the questionnaires inquire 
about suicidal ideation by the caregiver, as well as the caregiver’s perception of suicidal ideation 
for their child. These critical items are automatically flagged by the REDCap system, which will 
alert the clinical research coordinator at each site when a participant completes the 
questionnaire and endorses critical risk items. Safety procedures for suicidal ideation and 
reports of abuse/neglect are delineated in our safety monitoring committee plan (See Appendix 
G). In both cases and similar to above, the study PI or their designee at each site will be 
contacted immediately and he/she will assess the risk profile of the caregiver and/or child 
participant with subsequent recommendations based on the level of risk. 

Version 10 (3/8/2023) - Page 13 of 18 
 
 
There is also the risk of possible loss of privacy of data or loss of confidentiality. These risks are 
inherent in all research studies, and a statement to this effect will be included in the informed 
consent. Every effort will be made to ensure that all participant information will be kept 
confidential. A majority of this study is going to be conducted via mHealth. Participants will be 
accessing or receiving information from several different sources, including REDCap, 
education/problem solving modules Wordpress site, Zoom for healthcare for Problem-solving 
with a therapist, a portal created by CCHMC to receive push notifications related to their 
adherence feedback reports, and the adherence monitoring portals for AdhereTech and 
SimpleMed. For each of these sites, we will use the participant’s ID number and not their name. 
For example, enrolled participants will be assigned a secure login ID and password by the study 
staff to access measures via REDCap. Each site will only be able to see their own site’s 
participants in REDCap, with the exception of the lead site (CCHMC). Participants will be asked 
not to share their ID or password with anyone else. Use of Protected Health Information (PHI) 
on online measures will be minimized and participants will not be asked to enter their last name, 
date of birth, or medical record number on the online measures. When the study is complete, 
the content of the site will be taken down. Setup is consistent with HIPAA guidelines and was 
designed to support projects that contain PHI and are subsequently subject to compliance with 
federal and state regulations regarding data of this type. Similarly, the Wordpress site for the 
modules will be linked to their study ID and there will be no identifying information listed in this 
site. However, for the individual adherence feedback reports, participants will be asked to 
provide a cell phone number to receive push notifications. Similarly, although Zoom-healthcare 
is HIPAA compliant, participants will be required to log-in to the secured Zoom server for 
Problem-solving sessions. This information and protection of the participant’s identify will be 
clarified in the informed consent and assent forms. 
Additionally, we will be geocoding their home address to quantify if the patients live in rural or 
medically underserved areas using a combination of HRSA maps and an app created by 
CCHMC. We will obtain parental permission to use the patient’s address for this purpose.  
 
Finally, to communicate study related information across sites, our team will be using trello, a 
task management system that is frequently used by research teams. No identifying information 
will be entered into the trello system; however, we will be tracking participants through the study 
procedures using their study ID. 
 
Notably, the only place the study ID will be linked to the name and demographics is the 
participant database, which is password protected, individually, at each site by the research 
team. No other individuals outside of the IRB-approved research team will have access to this 
participant database and these databases will NOT be shared across study sites. 
 
11. RISK/BENEFIT ANALYSIS 
There is minimal risk associated with study participation. If participants feel distressed as a 
result of their participation, they will be encouraged to discontinue. The PI (Avani C. Modi, PhD) 
and site PIs or their designee will be available to participants during study participation to 
assess for discomfort, safety, and risk, as needed. The minimal risks of this study do not 
outweigh the potential indirect benefits that may be gained through increasing knowledge about 
best practices for improving adherence to treatment and quality of life of children with pediatric 
epilepsy. 
 
12. DATA SAFETY AND MONITORING 
This is a multisite observational study and is considered minimal risk. A Safety Monitoring 
Committee (SMC) is in place for this study and will review randomization, safety events, and 
study progress every 6 months following trial initiation. In addition, each site’s research team will 
monitor for safety and adverse events at each study visit. The SMC plan, which was approved 
by the National Institutes of Nursing Research, is attached in Appendix G. Dr. Modi (PI) and site 
PIs, and the members of the Data Safety Monitoring Plan will be responsible for monitoring the 

Version 10 (3/8/2023) - Page 14 of 18 
 
safety of participants and complying with all reporting requirements. Any serious adverse events 
will be reported immediately to the IRB as required by the hospital’s policy, as well as NINR. 
 
13. PRIVACY AND CONFIDENTIALITY 
All study personnel have been trained in data safety and monitoring, privacy and confidentiality, 
minimizing risks related to loss of privacy and confidentiality. We will closely monitor 
performance of our research personnel to ensure the strictest standards. Additional information 
related to privacy and confidentiality is noted above in section 10. 
 
13.1 Data De-Identification: All data will be de-identified with the use of unique assigned study 
identifier codes. No other identifying data such as address, phone numbers, social security 
number, or zip code will be entered on electronic measures. Electronic data files (including 
downloads of data from REDCap measures) will only identify participants via study identifier 
codes and will be password protected. Electronic data files will be maintained on CCHMC hard 
drives. 
 
Because this research study involves payment for participation, we are required by Internal 
Revenue Service (IRS) rules to collect and use participant’s social security number (SSN) or 
taxpayer identification number (TIN) in order to track the amount of money that we pay them. 
Unless they have given specific permission for another use of their SSN or TIN related to this 
research study, we will only use their SSN or TIN to keep track of how much money we pay 
them and their SSN or TIN will not be used as part of this research study. 
 
13.2 Data Storage and Management: Informed consent documents and all electronically 
collected data will be maintained in REDcap, a secure web-based platform, and in a password- 
protected electronic database on CCHMC hard drives. Although CCHMC, as the Primary Site, 
will be the study management location, no patient information from other sites will be shared 
other than de-identified IDs. Paper informed consent documents will be maintained in locked 
storage cabinets, if they are needed, and will be kept separate from participant data. 
 
Deidentified adherence data will be stored on their respective portals (AdhereTech, SimpleMed) 
and these data will be triangulated with a CCHMC developed portal to provide individualized 
adherence feedback reports, based on the participant’s cell phone number. 
 
Trello (www.trello.com), a web-based project management tool, will be used to coordinate 
study-related tasks across sites. No identifiable patient information will be saved in this platform. 
Medical chart data will be collected by trained study staff under the supervision of the PI. These 
risk protection methods have been effectively used by the PI and her collaborators for numerous 
studies. 
 
Individual data will not be available to anyone not directly associated with the study. All study 
personnel have been trained in data safety and monitoring, privacy and confidentiality, 
minimizing risks related to loss of privacy and confidentiality. We will closely monitor 
performance of our research personnel to ensure the strictest standards. Study-related 
information will not be released without written permission of the participant. 
 
14. COST OF PARTICIPATION 
There are no costs for participation in this research study. Participants will be responsible for the 
usual costs of medical care. 
 
15. PAYMENT FOR PARTICIPATION 
Caregivers will be compensated for participation in the study in the form of a reloadable debit 
card (ClinCard).They will receive a handout that will explain how to use this card. A graduated 

Version 10 (3/8/2023) - Page 15 of 18 
 
incentive schedule will be used:  
 
Study Task 
Compensation 
Baseline Questionnaires 
$20 
Post-Intervention 
Questionnaires 
$25 
Follow-Up 1 Questionnaires 
Only participants enrolled before 
3/8/2023 will complete these measures 
$30 
Follow-Up 2 Questionnaires 
Only participants enrolled before 
12/9/2022 will complete these 
measures 
$35 
Use & Return of Electronic 
Monitoring Device 
$40 
TOTAL COMPENSATION 
Up to $150 for participants enrolled before 
12/9/2022. 
 
Up to $115 for participants enrolled between 
12/9/2022 and 3/8/2023. 
 
Up to $85 for participants enrolled after 3/8/2023 
 
 
 
 

Version 10 (3/8/2023) - Page 16 of 18 
 
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