A Feasibility Study of a Step-goal Based Physical Activity Intervention in People With Epilepsy
Phase: NA
Conditions: Epilepsy
Sponsor: Wake Forest University Health Sciences

Official Title:  A feasibility study of a step-goal based physical activity intervention in people with epilepsy
NCT05359003
IRB Approval Date:  06/21/2024

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Study Title: A feasibility study of a step-goal based physical activity intervention in people with epilepsy 
 
Principal Investigator, Co-investigator(s): Halley Alexander, MD 
 
Sponsor or funding source: CTSI KL2 Mentored Career Development Award 
 
Background, Rationale and Context 
Epilepsy affects over 3 million people in the United States and over 65 million people worldwide.[1]  
One third of people with epilepsy (PWE) continue to have disabling seizures despite treatment with anti-
seizure medications.[2] Even worse, currently available treatments often result in side effects that worsen 
epilepsy-associated comorbidities – including mood disorders[3] and cardiovascular disease.[4-6] These 
comorbidities are undertreated and significantly worsen quality of life (QOL) and health outcomes, 
complicate epilepsy management, increase health care costs, contribute to unemployment, and shorten the 
lifespan.[7-9]  
Up to 80% of PWE exhibit cardiovascular comorbidities, increasing the risk of sudden cardiac 
death by threefold.[6] The “epileptic heart” is characterized in part by altered autonomic tone, resulting in 
increased rates of arrhythmia, myocardial infarction, and premature death.[10]  A standard marker of 
autonomic tone is heart rate variability (HRV), which has consistently shown dysfunction and 
sympathetic dominance in PWE.[11]  This is associated with increased mortality and sudden unexpected 
death in epilepsy.[12, 13] Exercise can improve HRV in other populations but has not been studied in 
PWE.  Moreover, acute changes in HRV are associated with seizure occurrence[14] suggesting that 
altering HRV in PWE via exercise could translate to reduced seizure tendency. We plan to evaluate the 
potential of HRV as a biomarker in our future studies.  
THE PROMISE OF PHYSICAL ACTIVITY  
Animal studies show that physical activity (PA) can reduce seizure frequency across several models 
of epilepsy.[15-18] While small preliminary studies in humans have shown promising effects on seizure 
control,[19, 20] these effects have not been studied in large randomized clinical trials.[21] In other 
populations, PA has been shown to improve mood, cardiovascular health, and quality of life.[22-27] In 
some small prospective studies, PA interventions in PWE have shown improvement in depression, mood 
state, and QOL[28, 29] Thus, physical activity interventions have the potential to improve epilepsy across 
all dimensions of the disease, by improving seizure control and improving, instead of worsening, 
common epilepsy-associated comorbidities.   
BARRIERS TO EXERCISE AND SEDENTARY BEHAVIOR IN PWE 
There is a need for a paradigm shift to improve PA in PWE. Though PWE report that PA makes 
them feel physically healthy and happier, relieves stress and increases social interaction, they are still 
significantly less likely than the general population to follow physical activity guidelines.[30, 31] This 
may be due to a number of factors including lack of transportation, cognitive impairment, fear of having a 
seizure during exercise, medication effects, and stigma.[32, 33] A common worry among patients (and 
some providers) is that PA may trigger seizures, an outdated theory that has been disproven. In fact, 
current epilepsy guidelines reflect the importance of, and encourages, PA in this population.[34] Our and 
others’ work have shown that exercise is safe in PWE,[20, 35, 36] but that neurologists rarely discuss PA 
with their epilepsy patients.[32, 33, 37]  
RIGOR OF THE PRIOR RESEARCH 
Previous small studies of exercise in PWE were not theory-driven and did not consider the unique 
barriers in this population, and as such were not sustainable.[20, 29, 36] In a prospective outpatient study, 
15 women with drug resistant epilepsy underwent in-person guided aerobic exercise for 15 weeks, and 
showed a significant decrease in seizure frequency compared to baseline (mean seizures/week decreased 
from 2.9 to 1.7, a 40% reduction), but there was no control group for comparison.[20] Unfortunately, the 
intervention could not be sustained after the study ended, reducing the generalizability and 
implementation of such an intervention. Additional small (n ~20) randomized, controlled studies of 
exercise in PWE have demonstrated safety, improvement in QOL, mood, and cognition, but none have 
been shown sustainable behavior change in PWE, and have never investigated pathophysiological 

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mechanisms.[29, 38, 39] While small studies have shown that PA may be able to improve seizure control, 
mood, and QOL, larger trials for definitive efficacy are needed.[21] 
SUPPORT FOR A STEP-GOAL BASED PA INTERVENTION 
Steps are easily quantified by inexpensive monitors and are an easy metric to comprehend, which is 
particularly important given the cognitive limitations in PWE. Walking is the most preferred form of PA 
in PWE, can be undertaken in most locations without expensive equipment, and be achieved flexibly 
throughout the day (e.g., in a single sustained bout or several shorter bouts). Therefore, a walking 
intervention with an explicit volumetric target is the most likely to lead to long-term behavior change as 
individuals develop repertoires of personally-enjoyable walking activities (intrinsic motivation being a 
key driver of long-term behavior) that can be achieved during exercise, transport, sport, occupational 
ambulation, or home care. Most importantly, people learn to be active in the contexts in which they live 
and as such removal of the intervention does not mean removal of all of the supports they received during 
the intervention.  
 Consistent data support the use of a 7,000-8,000 step per day goal to achieve current 
recommendations for moderate-to-vigorous-intensity PA.[40]  In numerous studies, self-selected PA 
intensity approximates or exceeds the minimum range recommended by the American College of Sports 
Medicine (ACSM).[41] In contrast, prescribed exercise intensities often result in feelings of displeasure 
and loss of autonomy, which interfere with the tenets of self-determination theory, thereby limiting uptake 
and sustainability.[42, 43] Thus, a step-goal based intervention with self-selected intensity is designed to 
address the unique barriers of this population, avoid undue stress (a common seizure trigger), and 
encourage uptake and sustainability. Our work and that of others has shown feasibility of remote 
interventions and wearables in PWE.[28, 44]  
 
 
Objectives 
Aim 1: To assess feasibility (adherence and sustainability) of a telehealth delivered, step-goal 
based PA intervention as measured by average daily steps achieved compared to steps assigned 
during the final 4 weeks of the intervention period (adherence) and the final 4 weeks of the 
maintenance period post-intervention (sustainability). 
 
Aim 2: To assess the self-selected intensity distribution of activity in the intervention arm (time 
spent in objectively-assessed sedentary behavior, light-intensity, or moderate to vigorous intensity 
activity) to determine if they achieve intensities within the American Heart Association (AHA) 
guidelines. 
 
Exploratory Aim 3: To explore estimates of variability of the effect size of a telehealth delivered, 
step-goal based PA intervention on seizures (measured by frequency and severity) and epilepsy-
associated comorbidities (anxiety, depression, QOL, and measures of fitness/cardiovascular 
health) in the exercise group compared to the control group. 
 
Methods and Measures 
Design 
A randomized, controlled trial with a two-arm, parallel group design with a wait-list education 
control 
Visit 1: Enrollment 
-Consent 
-Baseline assessments 
-HRV 
-Distribute activity trackers 
-Distribute study diary 
Recruit 
  and 
 Phone 
Screen 
Visit 4 
(Remote): 
Sustainability 
assessments 
Visit 3:  
Post-
Intervention 
assessments  
PA 
n=27 
Control 
n=13 
4-week 
baseline 
Period 
    Week 0 
-Baseline- 
Week 4                -Intervention- 
       Week 16 -Maintenance- Week 28 
Visit 2:  
-HRV (optional if 
time permitting) 
-Exercise Test 
-Randomization 

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Setting 
Academic medical center, Atrium Health Wake Forest Baptist  
 
Subjects selection criteria 
Adults with epilepsy will be actively recruited from the Comprehensive Adult Epilepsy 
Clinic at Atrium Health Wake Forest Baptist, and passively recruited from the community 
 
Inclusion Criteria 
•Age 18 or older 
•Focal or generalized epilepsy, as determined clinically by a WFBH epileptologist with no 
significant consideration of an alternative diagnosis 
•Active epilepsy with at least 1 observable seizure in the  6 months prior to screening  
•Access to a smartphone with application capabilities 
•Internet access or cellular data plan to attend virtual sessions 
• 
Able to ambulate independently 
 
Exclusion Criteria 
• Diagnosis of nonepileptic or psychogenic spells 
• Seizures associated with falls with injury (such as atonic seizures) 
• Currently active >/= 30 min on 3 or more days per week or > 5000 steps/day during the 
baseline period  
• Medical conditions that would limit ability to participate in an exercise intervention 
including: 
o Stage III or IV Congestive Heart Failure (CHF) 
o End-stage Renal Disease 
o Severe dementia or significant cognitive impairment that precludes participation 
in the intervention or limits ability to follow the study protocol 
o Uncontrolled hypertension (HTN) defined as systolic blood pressure greater than 
180 mmHg and diastolic blood pressure greater than 110 mmHg at rest  
o Severe arthritis, amputations, or orthopedic problems that limit ambulatory ability 
• Currently pregnant or plan to become pregnant during the study period (16 weeks) 
• An active Central Nervous System (CNS) infection, demyelinating disease, degenerative 
neurologic disease or any CNS disease deemed to be progressive during the course of the 
study that may confound the interpretation of the study results 
• Any clinically significant psychiatric illness, psychological, or behavioral problems that 
would interfere with the subject's ability to participate in the study. 
• Unwilling or unable to comply with all study visits and procedures 
• Participants who have <75% complete days of seizure recording in the study diary or step 
data via the Garmin device will not be randomized. 
 
Sample Size 
Up to 40 subjects will be enrolled, with a 2:1 ratio of intervention to control group 
randomization to best address aims 1 and 2.    
 
 
 
Interventions and Interactions 

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All participants will wear a Garmin device and keep a study diary throughout the duration of the study.  In 
addition, they will wear an ActivPAL 4 for 1 week at the end of the baseline, intervention, and 
maintenance periods. This will be mailed to them for each of the three recording periods along with 
written instructions (attachment 8).  
 
Baseline Period: During a 4-week baseline period, the participants will continue their usual activity but 
will wear the Garmin and ActivPAL 4 and keep a study diary.  We will use this to assess their baseline 
PA profiles and seizure frequency and to screen for adherence with device and diary use, as participants 
who have <75% complete days of seizure recording or step data via the Garmin will not be randomized. 
A 4-week baseline period and self-report of seizures are both standard protocol in epilepsy clinical 
trials.[45] 
 
 
Batched enrollment will be utilized to ensure large enough groups for the group coaching exercise 
intervention. Due to this, the time between visits may vary.   
 
 
Arm 1 Exercise Intervention:  
Participants in this arm will undergo a 12-week physical activity program aimed to achieve the 
equivalent of 8,000 steps per day (56,000 weekly steps). To ensure uptake, our intervention is 
rooted in social cognitive theory and led by a trained health coach, trained within the Wake 
Forest Behavioral Medicine Lab’s Behavioral Coaching program, which follows principles of 
group dynamics, social cognitive theory, and self-determination theory to develop self-efficacy 
for behavior change, which is instrumental to building lasting behavior. 

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Participants will meet in small groups of 2-8 participants facilitated by a behavioral coach and, 
when available, a patient-stakeholder. Following randomization, the behavioral coach will 
contact the participants in this arm, to set up a time for each weekly video meeting. Each weekly 
meeting will occur within the coach’s locked Webex room using a single link that will be 
provided to participants digitally via email. In the event of any unforeseen technical difficulties, 
participants can call into the Webex meeting, but this is not preferred. These sessions are 
developed using group dynamics principles and founded in social cognitive theory, utilizing the 
group structure as a tool of behavior change. Participants will act as models to one another, 
provide an avenue for addressing exercise barriers that arise daily, and foster a sense of 
accountability toward weekly activity goals.  
 
During each weekly video meeting, the coach and participants will review the timing of the next 
week’s meeting, modifying the timing as needed, and setting reminders if applicable.  
 
Each group session will progress through the following tasks: 
1. Introduction and ice breaker: Participants will engage in brief tasks requiring self-
disclosure as a means of opening communication for the remainder of the session. 
2. Didactic content: Next, the coach will guide participants through weekly didactic 
content related to health and physical activity. These sessions are designed to reduce 
negative outcome expectencies related to activity (e.g., activity is unsafe, addressing how 
different types of movement improve health), to highlight facilitators in the environment 
while addressing common barriers to activity, and providing education on how activity 
improves health. 
3. Discussion: Building on weekly didactic content, each session will end with a guided 
discussion designed to provide positive reinforcement of weekly successes, opportunities 
to address barriers as a group, and repertoire-development in which participants share 
exercise experiences they have enjoyed recently. 
 
In addition to weekly group sessions, participants will communicatie briefly one-on-one with the 
behavioral coach using a medium of their choosing (webex, telephone, email) to address any 
private concerns and to review and revise goals. Key facets of these exchanges include: 
1. Review of the previous week’s goal: The coach will review with the participant progress 
toward the previous week’s goal. To do this, the coach will log into the Garmin Connect 
website using the credentials provided to the participant by the study team. The coach 
will emphatically congradulate goal success—thus enhancing self-efficacy through 
mastery experiencess—and adopt a proactive tone during failures with the aim of 
mitigating feelings of guilt. During week 1, the conversation will instead center on 
understanding previous experiences with activity to guide selection of the initial goal. 
2. Selection of a new goal: Participants will aim to progress in both intensity and duration 
over the course of the program. The participant and coach will select a progressive 
stepping goal that is challenging but attainable (increase in ~20-30% increments 
depending on baseline steps). They will objectively self-monitor progress toward step 
goals, a key self-regulatory behavior. Acheivement of goals is a key mastery experience, 
the most potent input to self-efficacy, and consistently identified as the key behavioral 
predictor of activity behavior.[46]. Goals will be revised weekly until at least 8000 

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steps/day is achieved and it is not feasible to continue increasing.When the individual 
fails to meet a weekly goal, conversation will center on identifying true barriers (e.g., 
where “too busy” is commonly cited as a barrier, this is assigned by the participant 
retrospectively, where momentary hunger or fatigue states were the true barriers), and 
then developing strategies for addressing these barriers. As appropriate, the coach may 
suggest the participant brings these barriers to group conversations. Goals will be 
progressed only following successful weeks. Maintenance goals will be set once 
participants achieve 8000 steps/day is achieved and it is not feasible to continue 
increasing. 
 
 
Key theoretical constructs that are addressed within each communication include: 
• Verbal persuasion: The coach will emphasize the term physical activity over exercise 
(negative implicit associations) and provide kind encouragement. 
• Intrinsic motivation: The coach will emphasize methods of aerobic physical activity that 
are enjoyable, placing emphasis on walking behaviors. A key educational technique 
involves clueing participants into the “family” of walking behaviors, noting that there are 
different psychosocial benefits to social versus solo walking, urbana versus rural walking, 
and more. Conversations emphasize enhancing enjoyment the addition of a social 
component or enjoyable audio, structuring the activity so that it is enjoyable (e.g., 
walking in the morning, walking during lunch), and avoiding tying walking to unpleasant 
sensations. 
• Mastery: Goal reviews will highlight and emphasize even small successes. Participants 
will be made to reflect weekly on their own successes and will be asked explicitly to 
savor these sensations while letting go of any perceived failures. 
• Interpretation of psychophysiological responses: The coach will help individuals to re-
interpret physical stimuli as needed (e.g., anxiety over elevated heart rate). 
• Outcome expectencies: Discussions will target negative outcome expectencies around 
safety as they arise and downplay conventional ideas about “exercise”. 
• Barriers: The coach will not query for barriers to avoid generation of new barriers, but 
will troubleshoot barriers as they arise in a manner that is non-negative and action 
oriented. Conversations will guide the participant to self-discover strategies. 
• Facilitators: The coach will include purposeful discussion of environmental and social 
facilitators during each session. 
 
To ensure fidelity, the coach will audio/video record each group session, and these sessions will 
be spot checked by a member of the research team using a coaching checklist to ensure each 
theoretical element is being addressed. The coach will also self-rate adherence to these principles 
on a checklist following each session. This will serve as a second fidelity check, but will also 
continuously remind the coach of these important coaching principles. 
 
The use of the Garmin for Goal Review and Selection 
Prior to the start of the 1:1 session, the coach will sign into the Garmin Connect web page for the 
participant using the credentials provided to the participant from the study team. The coach will 
review step data and any exercise bouts ahead of time to estimate whether the participant 
achieved the previous week’s goal. This will provide a sense of familiarity to the participant 

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during the phone call, and will also prepare the coach to troubleshoot Garmin usage for days 
with missing data.  
 
Arm 2 Control:  
Participants randomized to the wait-list attention control group will continue to undergo standard 
care for 12 weeks.  They will contine to wear the Garmin activity tracker and can view their 
activity but will not be given an exercise program. They will be contacted by a study staff 
member via telephone every 2 weeks for health education.  If for some reason they need to miss 
a session, the information will be emailed to them. During this time, they will review resources 
and healthy lifestyle guidelines for people with epilepsy, including healthy diet, medication 
compliance, seizure precautions, stress management, and sleep hygeine. At the end of study, if 
they complete all study visits, they have the opportunity to receive a personalized exercise 
program.   
 
Changes to anti-seizure therapy (including medications or devices) during the study will be 
discouraged in both groups. However, participants who do report medication or device changes 
will be allowed to continue in the study but will be analyzed separately in the results.  
Medications and medication compliance will be reviewed at each study visit. 
 
Strategies to support fidelity of the intervention: 
• Design: This is a randomized trial of an exercise intervention in people with epilepsy.  It 
is specifically designed to be a simple, individually tailored intervention that can be 
accomplished at home and measured easily with the use of a wearable device.  This 
design supports the fidelity of the intervention and the ability to measure the fidelity 
using the device output instead of relying on self-report alone. 
• Training: All coaches for the weekly virtual sessions will complete the Behavioral Coach 
Training provided by Dr. Fanning’s Behavioral Medicine Lab. Coaching centers on 
effective communication and coaching methods to develop strong social bonds, self-
efficacy, and intrinsic motivation for the behavior, thus enhancing uptake and 
maintenance of the behavior.  In the final sessions of this training, coaches complete 
behavioral simulations to determine readiness to coach.  
• Delivery: The brief social cognitive theory based module that is given at the start of each 
weekly session will be consistent for all participants.  Strategies to revise and reset goals 
for the coming week will follow standard social cognitive therapy practice, as outlined in 
the training.  Dr. Fanning and the coaches will meet at least once monthly to discuss 
participant progress and to ensure coaches are following evidence-based social cognitive 
practices in their communications with participants.  Sessions will be recorded and Dr. 
Fanning will review a random session each month and provide feedback to the coach to 
ensure fidelity of the delivery.  In addition, coaches will self-rate their coaching 
following each coaching session.  
• Receipt: The instructors will observe participants during weekly virtual sessions to ensure 
they understand how to use their Garmin device. 
• Enactment: The participants will use the practices learned in the weekly sessions to 
perform continuous walking in their home environment (or environment of their choice).  
Their activity will be recorded on the Garmin device and then revieiwed with the coach at 
the next weekly session. 

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Strategies to support adherence: 
• Coaches will work with participants to set reminders for weekly sessions, and will 
follow-up for any missed contacts. 
• Self-efficacy and socially-driven goal setting are the two key constructs driving activity 
adherence, and thus these are the focus of the coaching intervention. 
• Participants with significant cognitive impairment (dementia) will be excluded from the 
study. 
• The study intervention is simple and the weekly step goal is clearly explained to the 
participant. 
• The weekly step goal is individualized, and is created each week during a 1:1 session 
with the coach while taking into account the participant’s individual barriers. 
• Participants will be encouraged to seek social support from family and friends and walk 
with family and friends when able. 
• The intervention period is relatively short (only 12 weeks). 
• Participants in the control group will be given a personalized physical activity plan if they 
complete the study 
• All participants will be compensated $50 per visit (4 visits; for total of $200/participant) 
to help cover the costs of transportation, parking, and any time away from employment 
for each research visit. 
• Eligibility criteria are designed to exclude participants in poor physical or emotional 
health for whom adherence may be challenging. 
• Study appointment reminders will be given to all participants. Reminders to complete the 
study diary will be given daily.  
• For in-person study visits, the participant will be contacted 1-3 days prior to remind them 
and confirm the appointment.  
• The group coaching format will enhance social support, participant engagement, and add 
additional resources to help with troubleshooting barriers. When available, a patient-
stakeholder will join the coaching session to provide additional social support. 
Strategies to support retention: 
• Participants in the control group will be given the opportunity to receive a personalized 
physical activity program if they complete the study.  
• Participants will be compensated $50 per study visit V1-V4  
• Study appointment reminders will be given to both groups.  
 

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BLINDING 
Due to the nature of the intervention, participants will not be blinded as to whether they are in 
the intervention or control group.   
The final analysis of activity data and heart rate variability (HRV) will also be performed by 
blinded assessors.  An unblinded investigator or sub-investigator will gather the data and de-
identify the information such that those processing the data will not be privy to which arm is 
which. The PI will not be blinded in this pilot feasibility study, in order to best track adherence 
and fidelity and help troubleshoot unexpected barriers.  
 
FOLLOW-UP VISITS  
Visit 3, Week 16 End of Intervention:  
At the end of the intervention period, participants will return for post-intervention assessments to 
include assessments of seizure frequency (Study Diary), seizure severity (Liverpool Seizure 
Severity Scale), depression(NDDI-E), Review Assurance of the NNDI-E, anxiety (GAD-7), 
quality of life (QOLIE-31), medication side effects (AEP) cardiorespiratory fitness and mobility 
(maximum oxygen uptake and 6 minute walk test), sleep (PSQI and from Garmin device) and 
autonomic tone (heart rate variability).   
 
At the end of the intervention period, participants in arm 1 will be encouraged to continue their 
current habits. Participants in arm 2 will be offered the opportunity to receive a personalized 
exercise program. Those in arm 1 will also complete a questionnaire about the acceptability, 
tolerance and satisfaction with the exercise intervention.  
 
Visit 4, Week 28.  Sustainability Follow-up and Study end 
This will be a remote visit in order to reduce exposure in the era of COVID-19 as well as 
improve access for PWE. All outcomes will be re-assessed for sustainability, with the exception 
of the exercise test, HRV and the 6MWT due to the remote nature of this visit.  The risks of 
excessive in-person visits and transportation issues outweigh the potential benefit of collecting 
this follow-up data, especiallyin light of COVID-19. At the end of the visit, all participants will 
answer an exit questionnaire on their thoughts about the study, what they liked, and what they 
would change.  
 
All visits will occur either at the Worrel Building or at the Clinical Research Unit (CRU).  Due 
to batched enrollment, time between visits (especially Visits 2 and 3) may vary. 
 
 
Visit 0 
Telephone 
Screen 
Visit 1 
Enrollment 
Week 0 
Visit 2** 
Randomization 
Week 4 
 
Intervention 
Period 
Week 5-16 
 
Visit 3 
End Intervention 
Week 16 
Visit 4 
Follow-up 
Week 28 
(remote) 
Exercise 
Control 
 
Review inclusion/exclusion 
X 
X 
 
 
 
 
 
10 meter walk screen 
 
X 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
Vital Signs 
 
X 
 
 
 
X 
 
Collect demographic and 
baseline medical information 
 
X 
 
 
 
 
 

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Distribute Study Diary 
 
X 
 
 
 
 
 
Distribute Activity Tracker 
 
X 
 
 
 
 
 
Collect/Review Study Diary* 
 
 
X 
 
 
X 
X 
Collect/Review data from 
Garmin 
 
 
X 
X 
X 
X 
X 
Review medications and 
adherence 
 
X 
X 
 
 
X 
X 
Randomization 
 
 
X 
 
 
 
 
Weekly telehealth coaching  
 
 
 
X 
 
 
 
Intervention satisfaction 
questionnaire 
 
 
 
X 
 
 
 
Telephone education Q2 weeks 
 
 
 
 
X 
 
 
Exercise Test 
 
 
X 
 
 
X 
 
Questionnaires: PSS, AEP, 
NDDI-E, Review Assurance of 
the NNDI-E, GAD-7, QOLIE-31, 
EXSE, EGS, MOESS, LSSS 
 
X 
 
 
 
X 
X 
(with exception of 
NDDI-E and 
“Review 
Assurance of the 
NNDI-E”) 
HRV measurement 
 
X 
X 
 
 
X 
 
6 minute walk test 
 
X 
 
 
 
X 
 
Exit Questions 
 
 
 
 
 
 
X 
*in addition to review at these visits, the study diary will also be returned daily and reviewed by weekly 
by a member of the study staff.   
**If scheduling is a challenge, V2 can be completed over the telephone with the exercise test being 
conducted at the first available timepoint and prior to the intervention period 
 
Outcome Measure(s) 
1. Primary Objective: Feasibility of the intervention (Adherence and Sustainability) 
a. Primary Endpoints 
i. Adherence to the intervention 
Adherence will be measured as the number of average daily steps achieved 
compared to steps assigned during the final 4 weeks of the intervention period 
ii. Sustainability of the intervention 
Sustainability will be measured as the number of average daily steps achieved 
compared to steps assigned during the final 4 weeks of the maintenance period 
2. Secondary Objectives: To evaluate the intensity distribution in the intervention arm  
a. Secondary Endpoints: time spend in various activity behaviors (measured by the 
ActivePAL4) 
i. Time spent sedentary  
ii. Time spent in light intensity activity  
iii. Time spent in moderate intensity activity 
iv. Time spent in vigorous intensity activity 
v. Acceptability of the Intervention 
Participants will answer an exit survey at Visit 4 regarding what they liked 
about the study and what they did not like, including reasons for missed visits 
or non-adherence, barriers encountered, and overall satisfaction of various 
aspects of the study. In addition, arm 1 will answer a questionnaire at the end 
of the 12 week intervention about the acceptability, tolerance and satisfaction 

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with the exercise intervention. For the main endpoint, we will use the question 
“How satisfied were you with the exercise intervention?” with scale of 
1=VERY UNSATISFIED, 2=UNSATISFIED, 3=NEUTRAL,  
4=SATISFIED, 5=VERY SATISFIED. We will calculate the proportion of 
subjects who answer 4 or above.  
3. Exploratory Objectives: Exploratory Effectiveness: For exploratory efficacy purposes, we 
will also gather pre- and post- intervention data on seizures, depression, anxiety, physical 
functioning, quality of life, and social cognitive mediators of behavior change via the 
following: 
a. Exploratory Endpoints 
i. Effects on seizures 
1. Seizure frequency via study diary report 
This has been shown to be a reliable and standard way of recording 
seizures in epilepsy studies.  For the purposes of evaluating a change 
in seizure frequency, the number of seizures during the final 4 weeks 
of the intervention will be compared to the number of seizures during 
the 4-week baseline. The diaries will be returned via electronic data 
capture in redcap. Participants will be reminded to complete and return 
the diary via automated text and/or email.  If diaries are not received, 
the participant will be called and prompted to return the study diary. 
2. Seizure severity via the Liverpool seizure severity scale (LSSS) 
ii. Effects on mood:  
1. Depression scores  
Participants will complete the Neurological Disorders Depression 
Inventory for Epilepsy (NDDI-E)[47]. This will be performed in-person at 
visits 1 and 3 only (monitoring and management of expression of suicidal 
ideation is outlined under Section VI below). This will be reviewed by 
study personnel and documented in the Review Assurance of the NNDI-E 
form 
2. Anxiety scores 
Participants will complete the Generalized Anxiety Disorder (GAD-7)[48, 
49]in person at Visits 1 and 3 and remotely via redcap survey at Visit 4. 
3.  Stress scores (PSS) 
Participants will complete the Perceived Stress Scale (PSS) in person at 
Visits 1 and 3 and remotely via redcap survey at Visit 4. 
iii. Effects on quality of life 
1. Quality of Life  
Participants will complete the Quality of Life in Epilepsy-31 (QOLIE-
31)[50]. This will be given in person as Visits 1, and 3, and remotely 
via emailed redcap survey link at Visit 
2. Medication side effects  
Participants will complete the Adverse Event Profile (AEP) at Visits 1 
and 3 and remotely via emailed redcap survey link at Visit 4 
iv. Effects on social cognitive theory constructs 
1. To evaluate the influence of social cognitive constructs on behavior 
change in this population, participants will complete the Exercise Self-

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12 
Efficacy Questionnaire (EXSE)[51], Exercise Goal Setting 
Questionnaire (EGS)[52], and Multidimensional Expectations for 
Exercise Scale (MOEES)[53]. These will be given in person at Visits 1 
and 3 and remotely via redcap survey at Visit 4.  
2.   
v. Effects on physical function 
1. Autonomic tone: Heart rate variability (HRV) 
a. Heart Rate Variability (HRV) measurement: Continuous heart 
rate will be recorded while the participant is breathing 
normally in seated position for 10 minutes using Faros 180 
heart rate monitor (Bittium Corporation, Oulu, Finland)[54]. 
Beat to beat intervals (RRI) files will be generated at 1000 Hz 
via the data acquisition software. The files will be analyzed 
with Nevrokard HRV software (by Nevrokard Kiauta, d.o.o., 
Izola, Slovenia).  The recordings will be visually inspected to 
ensure data quality (dropped beats or gross motion artifacts are 
excluded) and the first 5 minutes of usable tracings will be 
analyzed.  We will obtain measures of HRV in the frequency 
domain and these measures will be integrated over specified 
frequency ranges (LF: 0.04-0.15 Hz; HF: 0.15-0.4 Hz).  Power 
of RRI spectra in LF, HF range (LFRRI and HFRRI) will be 
calculated in normalized units and the ratio of LFRRI/HFRRI 
will be used as a measure of sympatho-vagal balance.  We will 
also calculate the standard deviation of normal-to-normal 
interval (SDNN) and the root mean square of successive 
differences (RMSSD) indexes, given their established study in 
PWE.[11, 12] 
2. Cardiorespiratory Fitness:  
a. Maximum oxygen uptake (VO2 max)  
i. Cardiopulmonary exercise test using a modified Balke 
protocol[55, 56] on a treadmill 
b. 6-minute walk test (6MWT) 
Participants will undergo a 6 minute walk test at Visits 1 and 3, 
according to established guidelines[57].  This is a is cost-
effective and well-documented field test for assessing 
functional exercise capacity and response to medical 
interventions in diverse patient groups, and predicts 
cardiorespiratory fitness among healthy people[58]. 
3. Sleep:  
a. Nightly average total sleep time (TST): will be collected from 
the Garmin activity tracker  
b. Sleep quality will be assessed via the Pittsburgh Sleep Quality 
Index (PSQI) 
c.  
 
 

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Analytical Plan 
Aim 1 To assess Feasibility, we will look at (1) adherence and (2) sustainability.  Adherence, defined as 
the proportion of participants who achieve their assigned step goal (as measured by average daily steps 
via the Garmin device) over the last 4 weeks of the intervention period, will be calculated and 95% 
binomial confidence intervals generated. Sustainability will be calculated similarly for the final 4 weeks 
of the maintenance period.  In each case, we will utilize a one-sided 95% confidence interval to estimate 
the lower bound for adherence and sustainability rates to inform future studies.   
 
Aim 2 To assess exercise intensity, we will use descriptive statistics to describe the time spent in 
sedentary, light, and moderate to vigorous PA. We will generate confidence intervals to evaluate if the 
achieved intensity is within the range recommended by the AHA (150 min of moderate or 75 min of 
vigorous activity per week).[59] To assess acceptability, arm 1 will answer a questionnaire at the end of 
the 12 week intervention about the acceptability, tolerance and satisfaction with the exercise intervention. 
For the main endpoint, we will use the question “How satisfied were you with the exercise intervention?” 
with scale of 1=VERY UNSATISFIED, 2=UNSATISFIED, 3=NEUTRAL,  4=SATISFIED, 5=VERY 
SATISFIED. We will calculate the proportion of subjects who answer 4 or above. 
 
To address Aim 3 (exploratory evaluation of effects epilepsy and epilepsy associated comorbidities), we 
will compute change scores in seizure frequency, severity (LSSS), anxiety (GAD-7), depression (NDDI-
E), medication side effects (AEP), cardiorespiratory fitness (VO2 max and 6MWT), heartrate variability 
(HRV), sleep (total sleep time per night) and quality of life (QOLIE-31) pre- and post-intervention. We 
will use multivariable linear regression models modeling change score as the outcome, with intervention 
assignment as the main effect of interest and baseline scores as a confounding variable.  We will use 
estimates of the effect sizes and variability for planning and power of a larger trial. For HRV parameters, 
we will look at high and low frequency indices, standard deviation of normal-to-normal interval (SDNN) 
and the root mean square of successive differences (RMSSD) indices, given their established study in 
PWE.[11, 12] 
 
Similarly, we will explore for effects on social cognitive mediators of behavior change (scores on EXSE, 
MOEES, and EGS), following the same modeling approach. 
 
Human Subjects Protection 
 
Subject Recruitment Methods 
In order to ensure optimal recruitment, eligible subjects may be identified from the below recruitment 
pools.  Potentially eligible subjects from the groups below will undergo further chart review to refine 
eligibility criteria by reviewing the following: age, epilepsy diagnosis, seizure type and frequency, 
ambulation status, medical history, and medications.  In order to confirm eligibility of patients, the study 
team may review local charts or may ask the patient for copies of their local medical record (only the 
minimum amount of information will be collected by the study team to ensure a diagnosis of epilepsy).  
 
Preliminarily eligible subjects will be contacted via telephone call from study staff, approached in person 
during their epilepsy clinic visit or EMU stay, or sent a message via mywakehealth. If the patient is not 
reached by phone, these individuals will receive, through mail, a letter from clinical PI asking them to 
contact us if interested in participating in the study.  Once the patient is reached, a verbal screening 
consent will be obtained, allowing study staff to ask only screening questions including age, seizure 
frequency, ability to ambulate without difficulty, history of seizures associated with frequent falls or loss 
of muscle tone, current exercise habits, presence of end-stage CHF, ESRD, severe dementia, or presence 
of high blood pressure that is not controlled with medications (over 180/110) (Refer to phone screening 
script for further details).  If contacted via an DComm approved message in mywakehealth, the 
participant can reach out to study staff via phone or email, or choose to click on a redcap link for more 

Protocol version: 
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14 
information and to answer a small subset of preliminary screening questions (“do you have epilepsy” and 
“have you had at least 1 seizure in the past 6 months”). From here, preliminarily eligible participants will 
leave their contact information (phone number and/or email address) and, if eligible by chart review, 
subsequently be called by a member of the study team to perform the complete telephone screen. 
 
Demographic information on the participants age, race, gender, seizure frequency, medications, history of 
epilepsy surgery, employment status, address, and distance from the exercise facility will be recorded on 
all screened subjects. If eligible and willing to participate, the email and/or mailing address will be 
recorded in order to mail or email a copy of the consent form for optional review prior to the enrollment 
visit. For ineligible participants, the reason(s) for ineligibility will be recorded. For eligible participants 
who decline to participate, we will also record the reason for declining.  
• 
Chart review study: Potentially eligible subjects have been identified through a recently conducted 
chart review (IRB00056209).  This database contains over 800 charts from approximately April to 
October 2018 at WFBH Adult Epilepsy Clinic. Charts have been screened for seizure frequency, 
cognitive level and ambulatory status.   Preliminarily eligible patients may be contacted via the 
procedures described above.   
• 
Cross-sectional survey: Potentially eligible subjects have been identified through a recently conducted 
survey (IRB00062580) in the WFBH Adult Epilepsy Clinic and the adult Epilepsy Monitoring Unit 
(EMU).  Participants were surveyed regarding their seizure frequency, baseline activity habits, and 
interest and ability to participate in a monitored physical activity intervention.  They also indicated their 
willingness to be contacted for future studies.  Preliminarily eligible patients may be contacted via the 
procedures described above.   
• 
Observational survey: Potentially eligible subjects will be identified through a recently conducted 
observational study (IRB00062034) using wearable devices to track activity and sleep in epilepsy.  In this 
study they also indicated their willingness to be contacted for future studies. Preliminarily eligible 
patients may be contacted via the procedures described above.   
• 
Prior pilot study: (IRB00068408) participants who were screened for this study but were not eligible 
or did not enroll will be identified from the existing screening database and examined for eligibility. 
Preliminarily eligible patients may be contacted as described above.   
•Further eligible participants will be identified by prospective chart review of all epilepsy patients 
presenting to the adult epilepsy clinic each week for outpatient appointments (in-person or telehealth) or 
epilepsy monitoring unit admissions. We will review the chart for eligibility. Preliminarily eligible 
patients may be approached in clinic by a member of the study team and screened for eligibility or  
contacted via the procedures described above. Any potentially eligible participants communicated to the 
study team via word of mouth may also be contacted as described above. 
 
Eligible subjects who agree to participate will be scheduled for V1 Enrollment.  They will be mailed or 
emailed a copy of the consent form and a study overview handout (attachment 3) to review prior to 
enrollment. 
 
In addition, the study will be added to the “Be Involved” website of WFBMC with contact information of 
the study staff.  Interested participants who email or call will undergo the telephone screening process 
described above.  Informational flyers will be hung in each room in the adult epilepsy clinic (again with 
contact information), inpatient Epilepsy Monitoring Unit, and displayed at the monthly epilepsy support 
group meetings. Lastly, an informational flyer with contact information will be posted on the Epilepsy 
Alliance of North Carolina’s website. Flyers may also be distributed throughout the community and at 
other health clinics in the surrounding areas.   
 
Informed Consent 
 
Signed informed consent will be obtained from each subject. Consent will be obtained by a 

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member of the study staff at the enrollment visit. Those who are scheduled for an enrollment 
visit will be mailed and/or emailed a copy of the informed consent document for optional reading 
prior to enrollment.  
 
Confidentiality and Privacy 
Confidentiality will be protected by collecting only information needed to assess study outcomes, 
minimizing to the fullest extent possible the collection of any information that could directly identify 
subjects, and maintaining all study information in a secure manner.  To help ensure subject privacy 
and confidentiality, only a unique study identifier will appear on the data collection form.  Any 
collected patient identifying information corresponding to the unique study identifier will be 
maintained on a linkage file, store separately from the data.  The linkage file will be kept secure, with 
access limited to designated study personnel.  Following data collection subject identifying 
information will be destroyed 6 years after study completion by deleting the linkage file, consistent 
with data validation and study design, producing an anonymous analytical data set.  Data access will 
be limited to study staff.  Data and records will be kept locked and secured, with any computer data 
password protected.  No reference to any individual participant will appear in reports, presentations, 
or publications that may arise from the study. 
 
In group meetings with participants, respect for the privacy and confidentiality of other group 
attendees will be emphasized.  
 
Data and Safety Monitoring 
The principal investigator will be responsible for the overall monitoring of the data and safety of 
study participants.  The principal investigator will be assisted by other members of the study staff. A 
Data Safety and Monitoring Committee, an independent group of experts, will be reviewing the data 
from this research throughout the study  
 
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol changes 
will be promptly reported by the principal investigator or designated member of the research team to 
the IRB and sponsor or appropriate government agency if appropriate. 
 
SAFETY AND MONITORING PLAN 
 
Adverse Event Definitions: 
Adverse Event: (AE) For the purposes of this trial an adverse event is defined as any untoward or 
unfavorable medical occurrence that is temporally associated with the subject’s participation in the 
research, whether or not considered related to the subject’s participation in the research. 
 
Expected Events: In this study, no serious adverse events are expected.  Expected adverse events 
include temporary muscle soreness, temporary joint pain, and temporary increased physical fatigue 
when starting the exercise regimen or when increasing the exercise.  Other expected events include 
mild discomfort from physical exertion including shortness of breath that improves when ceasing 
exercise and sweating.  In people with asthma, an increase in the need for inhaler use is expected. In 
people who have a very high baseline seizure frequency, and even in those with less frequent 
seizures, seizures are reasonably expected to occur during exercise on occasion and certainly will 
occur during the course of the study.  However, seizures that occur consistently with exercise in a 
single individual is not expected.  In addition, it is not expected for participants to have a large 

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16 
increase in seizure frequency.  A small increase would be within the normal fluctuation of seizure 
frequency in people with epilepsy. 
 
Specifically, the temporal relationship of seizures to exercise will be recorded in the daily study diary. 
Responses will be reviewed by the study team weekly. In participants who demonstrate an increase in 
seizure frequency from their baseline weekly frequency consistently over a 4 week period, the 
temporal relationship to exercise will be further investigated. In those who have increased seizure 
frequency AND who report a clear temporal association with exercise (seizure occurs during or 
immediately after exercise in 50% or more of their seizures), participation in the intervention will be 
halted due to concern for exercise-induced seizure activity. 
  
 
All other events not listed above will be considered unexpected for the purposes of this trial. The 
unblinded investigator will be responsible for determining whether an AE is expected or unexpected.  
An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study intervention. 
 
Adverse Event Classification: 
All AEs will be assessed by the study staff for severity and categorized using the criteria 
described below. 
 
Serious Adverse Events:  (SAE) Any event that results in death, hospitalization or 
prolongation of a hospitalization, significant or persistent disability, a birth defect or 
congenital anomaly, or another significant event or problem requiring medical or surgical 
intervention to prevent one or more of the above.  
 
General Adverse Events: 
Mild Adverse Events: Events that require minimal or no treatment and do not interfere 
with the participant’s daily activities. 
 
Moderate Adverse Events: Events result in a low level of inconvenience or concern with t 
the therapeutic measures. Moderate events may cause some interference with functioning. 
 
Severe Adverse Events: Events that interrupt a participant’s usual daily activity and may 
require systemic drug therapy or other treatment. Severe events are usually potentially 
life-threatening or incapacitating.  Of note, the term “severe” does not necessarily equate 
to “serious”. 
 
All adverse events will also have their relationship to study intervention assessed by one of 
the co-investigators (un-blinded) who will examine and evaluate the participant based on 
temporal relationship and his/her clinical judgment and categorized into one of the following: 
 
Definitely Related: There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or chemicals. 
The response to withdrawal of the study intervention (dechallenge) should be clinically 

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plausible. The event must be pharmacologically or phenomenologically definitive, with use 
of a satisfactory rechallenge procedure if necessary. 
 
Probably Related: There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event, including an abnormal laboratory test result, 
occurs within a reasonable time after administration of the study intervention, is unlikely to 
be attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (dechallenge). Rechallenge information is not required to 
fulfill this definition. 
 
Potentially Related: There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, 
other factors may have contributed to the event (e.g., the participant’s clinical condition, 
other concomitant events). Although an AE may rate only as “possibly related” soon after 
discovery, it can be flagged as requiring more information and later be upgraded to “probably 
related” or “definitely related”, as appropriate. 
 
Unlikely to be related: A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant 
treatments). 
 
Not Related: The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician.] 
 
Adverse Event Tracking: 
 
Adverse Events that are of special interest for this study will be actively tracked.  These 
include worsening of seizure frequency, falls, and injuries.  These will be specifically 
recorded by the participant in their study diary, which will be returned electronically daily.  
 
All other adverse events will be passively collected at each study visit (visits 2-4) by asking 
“have you had any health problems since your last visit?” 
 
All AEs will be captured on the appropriate case report form (CRF). Information to be 
collected includes event description, time of onset, clinician’s assessment of severity, 
relationship to study intervention (assessed only by those with  
the training and authority to make a diagnosis), and time of resolution/stabilization of the 
event. All AEs occurring during the study must be documented appropriately regardless of 
relationship.  
 

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Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s 
condition deteriorates at any time during the study, it will be recorded as an AE. 
 
Management of Suicidal Ideation: 
Given the nature of NDDI-E as a depression screening tool, question 4 pertains to passive suicidality.  
If participants score a 3 or 4 on this question, follow-up questions will be carried out by study staff, to 
determine any possibility of active suicidality. If there is a need for immediate treatment (e.g., active 
suicidal ideation, active psychotic symptoms, disorientation, active substance abuse) at any point in 
time, staff will follow the in-person crisis procedures included in Appendix A.  If, during a remote 
visit, a participant voluntarily expresses suicidal ideation, we will follow the established crisis 
procedures under the remote protocol in Appendix A.  Follow-up questions and any immediate 
treatments will be documented in the “Review Assurance of the NNDI-E” form. 
 
As a safety precaution, we will ask each participant upon study enrollment to identify 1 persons 
whom we can contact in case of an emergency and provide a telephone numbers for this individual.   
 
If suicidality is expressed, we may notify their outpatient neurologist in order to help guide future 
care.  
 
Because this is not a treatment study, and given the low rate of active suicidality previously identified 
during a Wake Forest Baptist Health learning health system trial led by Dr. Munger Clary (included 
screening more than 760 individuals using the NDDI-E instrument), we anticipate that active 
suicidality will be exceedingly rare. All study staff will receive training on the crisis protocol and will 
have regular meetings with the team to discuss clinical issues. 
 
Management of Seizures: 
The principal investigator will provide training to all study staff regarding seizure 
management and seizure first aid.  Staff will be informed the proper way to care for the 
patient during the acute seizure period including how to keep the patient from injuring 
themselves, how to time a seizure, and when to call for help.  The PI will be notified in all 
instances to provide further guidance.  Staff will follow outlined safety procedures on when 
and how to contact any necessary additional emergency care.  It should be noted that most 
seizures do NOT require emergency care and will resolve on their own, but staff will be 
trained to respond to all scenarios. Participants will always be advised to notify their primary 
outpatient epilepsy physician of any seizures and this provider will guide long-term 
management of their care.  
 
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Appendix 
1. Copies of each questionnaires or surveys that will be used 
a. AEP 
b. PSS 
c. NDDI-E 
d. GAD-7 
e. QOLIE-31 
f. EXSE 
g. EGS 
h. MOEES 
i. 
Exercise Satisfaction Survey 
j. 
Exit Survey 
k. Liverpool seizure severity scale 
l. 
PSQI 
2. Consent form  
3. Study Overview Handout 
4. Crisis Procedures – Appendix A 
5. Control group scripts:  
a. Healthy eating script,  
b. Medication script 
c. Emotional Health script 
d. Stress script 
e. Sleep script 
f. Seizure diary script 
6. Garmin Operating Instructions 
7. ActivPAL log and operating instructions 
8. Telephone screening script 
9. Study Advertisement 
10. Study Diary 
11. Coaching manual for the intervention group 
12. Webex instructions 
13. Handout for group instructions after randomization