Anxiety and Depression in Epilepsy: Assessing Outcomes Using the Electronic Medical Record (EMR)
Phase: NA
Conditions: Quality of Life, Anxiety, Depression, Epilepsy
Sponsor: Wake Forest University Health Sciences

Anxiety and depression in epilepsy: assessing outcomes 
using the electronic medical record (EMR) 
NCT03879525  
Date: 6/3/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ii 
 
 
 
 
 
Anxiety and depression in epilepsy: assessing outcomes 
using the electronic medical record (EMR) 
Principal Investigator: Heidi M. Munger Clary, MD, MPH 
 
 
Funded by: NCATS (KL-2 award) 
Version Number:  V.6 
 

ii 
 
Table of Contents 
STATEMENT OF COMPLIANCE.............................................................................................................................................. 1 
1 
PROTOCOL SUMMARY .................................................................................................................................................. 2 
1.1 
Synopsis 
2 
1.2 
Schema 
4 
1.3 
Schedule of Activities (SoA) 
6 
2 
INTRODUCTION.............................................................................................................................................................. 7 
2.1 
Study Rationale 
7 
2.2 
Background 
7 
2.3 
Risk/Benefit Assessment 
9 
2.3.1 
Known Potential Risks ............................................................................................................. 9 
2.3.2 
Known Potential Benefits ........................................................................................................ 9 
2.3.3 
Assessment of Potential Risks and Benefits........................................................................... 9 
3 
OBJECTIVES AND ENDPOINTS ....................................................................................................................................... 9 
4 
STUDY DESIGN .............................................................................................................................................................11 
4.1 
Overall Design 
11 
4.2 
Scientific Rationale for Study Design ........................................................................................................11 
4.3 
End of Study Definition 
12 
5 
STUDY POPULATION....................................................................................................................................................12 
5.1 
Inclusion Criteria 
12 
5.2 
Exclusion Criteria 
12 
5.3 
Screen Failures 
12 
5.4 
Strategies for Recruitment and RetentioN ...............................................................................................12 
6 
STUDY INTERVENTION ................................................................................................................................................14 
6.1 
Study Intervention 
14 
6.2 
Measures to Minimize Bias: Randomization and Blinding ......................................................................14 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL ...................14 
7.1 
Participant Discontinuation/Withdrawal from the Study .......................................................................14 
7.2 
Lost to Follow-UP 
14 
8 
STUDY ASSESSMENTS AND PROCEDURES .................................................................................................................15 
8.1 
Efficacy Assessments 
15 
8.2 
Safety and Other Assessments 16 
8.3 
Events and Serious Adverse Events...........................................................................................................17 
8.3.1 
Definition of Events 17 
8.3.2 
Definition of Serious Adverse Events (SAE)..........................................................................17 
8.3.3 
Classification of an Event or Serious Adverse event ...........................................................17 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ...................................18 
8.3.5 
Event Reporting 
19 
8.3.6 
Serious Adverse Event Reporting .........................................................................................19 
8.3.7 
Reporting Events to Participants ..........................................................................................19 
8.4 
Unanticipated Problems 
19 
8.4.1 
Definition of Unanticipated Problems (UP) .........................................................................19 
8.4.2 
Unanticipated Problem Reporting........................................................................................20 
8.4.3 
Reporting Unanticipated Problems to Participants.............................................................20 
8.5 
CRISIS PROTOCOL/SAFETY 
20 
9 
STATISTICAL CONSIDERATIONS ..................................................................................................................................21 
9.1 
Statistical Hypotheses 
21 

  
9.2 
Sample Size Determination 
21 
9.3 
Populations for Analyses 
22 
9.4 
Statistical Analyses 
22 
9.4.1 
General Approach 22 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s)........................................................................22 
9.4.3 
Analysis of the Secondary Endpoint(s) .................................................................................22 
9.4.4 
Safety Analyses 
22 
9.4.5 
Baseline Descriptive Statistics...............................................................................................22 
9.4.6 
Sub-Group Analyses22 
9.4.7 
Tabulation of Individual participant Data ............................................................................23 
9.4.8 
Exploratory Analyses .............................................................................................................23 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................................................24 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .......................................................................24 
10.1.1 
Informed Consent Process ....................................................................................................24 
10.1.2 
Study Discontinuation and Closure ......................................................................................24 
10.1.3 
Confidentiality and Privacy ...................................................................................................25 
10.1.4 
Future Use of Stored Specimens and Data ..........................................................................25 
10.1.5 
Key Roles and Study Governance .........................................................................................26 
10.1.6 
Safety Oversight 
26 
10.1.7 
Clinical Monitoring 26 
10.1.8 
Quality Assurance and Quality Control ................................................................................26 
10.1.9 
Data Handling and Record Keeping ......................................................................................27 
10.1.10 
Protocol Deviations 27 
10.1.11 
Publication and Data Sharing Policy .....................................................................................28 
10.1.12 
Conflict of Interest Policy ......................................................................................................28 
10.2 
Abbreviations 
29 
10.3 
Protocol Amendment History 
30 
11 
REFERENCES...............................................................................................................................................................31 
 

 
 
 
 
 
 
1 
STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with International Conference on Harmonisation 
Good Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
Investigators and staff who are responsible for the conduct, management, or oversight of this 
study have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

2 
 
 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Anxiety and depression in epilepsy: assessing outcomes using the 
electronic medical record (EMR) 
Study Description: 
This is an observational, randomized study among N=30 individuals with 
epilepsy and high or borderline anxiety or depression symptoms receiving 
usual care at the Wake Forest Comprehensive Epilepsy Center.  
Participants are randomized to one of two outcome assessment methods 
[EMR-based-interventional method vs. telephone-based-standard 
method] for collecting quality of life, anxiety and depression outcomes at 3 
and 6 months, under usual care management. 
The primary aim of the study is to assess feasibility of EMR-based outcome 
assessment by measuring 6-month retention. We hypothesize that the 
primary endpoint, retention within the EMR-outcome assessment arm 
(defined completion of the 6 –month outcome assessment instruments via 
the EMR), will be greater than 60%.  
This hypothesis will be tested by randomizing 30 patients with borderline 
or clinically significant anxiety or depression symptoms [Generalized 
Anxiety Disorder-7 (GAD-7) >7or Neurological Disorders Depression 
Inventory-Epilepsy (NDDI-E) >13] to both outcome assessment methods 
during usual care and assessing 3- and 6-month quality of life, anxiety, and 
depression outcomes using the allocated outcome assessment method 
(N=15 in each arm). 
We will also estimate 6-month change in epilepsy-specific quality of life in 
the entire study group (N=30) during usual care. 
 
Objectives: 
 
Primary Objective:  To assess whether retention in the EMR-based 
outcome method arm at 6 months is sufficient in pilot testing to support 
use of this outcome assessment method in future pragmatic trials of 
management interventions for anxiety and depression in epilepsy. 
 
 
Secondary Objectives:  
- To quantify retention at 3-and 6- months in the study population using a 
standard pragmatic trial outcome measure (telephone outcome 
assessment), and at 3 months using the EMR based outcome assessment 
method 
- To estimate 6-month change in epilepsy-specific quality of life (QOLIE-10, 
primary outcome) and depression and anxiety (secondary) at 3 and 6 
months during usual care, among the feasibility cohort of individuals with 

 
 
 
 
 
 
3 
epilepsy and borderline to high anxiety or depression scores at baseline 
(GAD-7>7 or NDDI-E>13 at time of screening). 
 
 
Outcomes: 
Primary Endpoint:  
--% retention in the EMR outcome arm, defined as the % of participants 
who complete the 6 month outcome instruments in the EMR 
 
Secondary Endpoints:  
--% retention in the telephone outcome arm, defined as the % of 
participants who complete the 6 month outcome instruments via 
telephone 
Quality of life under usual care: 
--6 month change in QOLIE-10 (Quality of Life in Epilepsy-10) from baseline 
--3 month change in QOLIE-10 from baseline 
Other outcomes of usual care: 
--change in anxiety (GAD-7) score from baseline to 3 and 6-month 
outcome assessments 
--change in depression (NDDI-E) score from baseline to 3- and 6-month 
outcome assessments 
 
Study Population: 
30 adults with epilepsy seen in follow-up at the Wake Forest 
Comprehensive Epilepsy Center with borderline or clinically significant 
anxiety and/or depression (GAD-7>7 and/or NDDI-E >13) at baseline 
 
Phase: 
N/A: this is not a treatment study 
 
Description of 
Sites/Facilities Enrolling 
Participants: 
Wake Forest Comprehensive Epilepsy Center, a level IV comprehensive 
epilepsy center in Winston-Salem, NC with a busy outpatient clinic serving 
patients primarily from Western North Carolina and adjacent states.   
 
Study Duration: 
Up to 3 years 
 
Participant Duration: 
6 months 
 
 
 
 
 
 
 
 
 

4 
 
 
 
 
1.2 
SCHEMA 
 
 

 
 
 
 
 
 
5 
 
 
 
 
 
 

6 
 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures* 
Screening 
Clinic Visit  
Post-visit 
screening 
Consent/ Enrollment/ 
Randomization 
3 month outcome 
assessment 
6 month outcome 
assessment 
NDDI-E  
X 
 
 
X 
X 
GAD-7  
X 
 
 
X 
X 
QOLIE-10 
X 
 
 
X 
X 
EMR question to patient: 
interest in research? 
X 
 
 
 
 
Eligibility verification: 
medical chart 
 
X 
 
 
 
Telephone consent 
 
 
X 
 
 
Collect additional brief 
psychiatric history  
 
 
X 
 
 
Randomize  
 
 
X 
 
 
EMR baseline: 
demographics 
 
 
X 
 
 
EMR baseline: medications  
 
 
X 
 
 
Management plan from 
screening usual care visit 
 
 
X 
 
 
Health utilization outcomes 
 
 
 
X 
X 
Feasibility assessments 
X 
 
 
X 
X 
 
Key for Schedule of Activities: 
*: procedures with green X above are administered as part of routine clinical care  
 

 
 
 
 
 
 
7 
2 
 
INTRODUCTION 
2.1 
STUDY RATIONALE  
 
Anxiety and depression are highly prevalent and major contributors to poor quality of life 
and other poor outcomes in epilepsy, including increased mortality, health care cost, cognitive 
dysfunction, medication adverse effects, and poor seizure outcomes1-7. Despite this importance, 
anxiety and depression are under-recognized and undertreated in epilepsy, and a recent 
survey indicated top barriers to addressing anxiety and depression in epilepsy were poor access 
to psychiatrists and other mental health providers8-10. Due to poor access to mental health, 
solutions such as colocation of psychiatrists and psychologist-driven internet behavioral 
approaches are not feasible for most epilepsy or neurology clinics8-12. In response, neurologist-
driven solutions are proposed, including a new epilepsy quality measure for conducting 
validated anxiety and depression screeners at every neurology visit and many expert 
publications encouraging direct medication treatment by neurologists10; 13-17. However, 
significant barriers to screening exist, as >50% of surveyed epileptologists indicated inadequate 
time to administer screeners10. In implementing validated anxiety and depression screening 
during our ongoing learning health system trial, we demonstrated substantial staffing effort is 
needed to administer screeners and document in the medical record. There is also a paucity of 
data on outcomes of screening and/or treatment of anxiety and depression in epilepsy 
populations, especially real-world epilepsy clinic populations. Despite conceptions that most 
epilepsy patients are not receiving treatment for anxiety or depression10; 14 our preliminary data 
indicates nearly half of those with active anxiety or depression symptoms are on 
medication treatment, and thus have inadequate symptom relief despite treatment. 
Considering these challenges, streamlined methods of screening and longitudinal outcome 
assessment are fundamental to assessing outcomes of standard treatment and developing 
effective pragmatic interventions for anxiety and depression in epilepsy. We propose to 
implement and assess a learning health system, electronic medical record (EMR)-based 
screening and outcome assessment for anxiety and depression in the epilepsy clinic.  
 
2.2 
BACKGROUND  
Anxiety and depression in epilepsy are highly prevalent and major independent 
predictors of poor quality of life. Depression and anxiety occur in up to 40-55% of tertiary 
care epilepsy patients18-20, and without structured assessment, anxiety is under-recognized1. 
Although depression and anxiety are more important predictors of poor quality of life than 
seizure frequency2; 21; 22, these symptoms are underdiagnosed and undertreated in epilepsy23; 24. 
Treatment of depression and anxiety in epilepsy is important to prevent suicide25 which 
contributes to excess mortality3, as a potential way to reduce excessive health care use4; 26, and 
to improve quality of life2; 22. However, a substantial unmet mental health care need exists in 
epilepsy8; 9.   
The 2014 American Academy of Neurology Epilepsy Quality Measurement Set introduced a 
measure to screen for “psychiatric or behavioral health disorders” at each visit, and well-
validated, free and brief anxiety and depression screeners exist for epilepsy (the GAD-7 and 
NDDI-E)27-33. Despite this, my 2016 survey of leading epileptologists indicated few used 
validated anxiety and depression screening instruments (<9% and <19%, respectively), due to 

8 
 
poor availability of mental health providers and lack of time to administer validated screeners10.  
Since then, a newly published Epilepsy Quality Measure (2017 Measure) requires using 
validated screeners for anxiety and depression at every visit13. Our experience with an 
ongoing learning health system pilot trial of neurologist treatment for anxiety and depression has 
demonstrated extraordinary manpower efforts are required to accomplish screening in an entire 
epilepsy practice (up to 80-90% effort split among different staff). This validates concern about 
time-related barriers to administering screeners raised in the 2016 epileptologist survey 10 and 
indicates need to develop efficient methods to conduct screening in ways that minimize 
clinical or research staff time. Patient entry of questionnaires directly into the medical record 
via patient portal interfaces, with responses stored as discrete data fields that can then be 
exported for data analyses are a potential timesaving technique to conduct outcomes research 
and achieve clinical quality metrics simultaneously. Through the existing multicenter AHRQ-
funded collaboration, the Neurology Practice Based Research Network (NBPRN), we currently 
utilize EMR-based entry of validated anxiety, depression, and epilepsy-specific quality of life 
measures as discrete data fields34; 35. We also now have access to patient-entered versions of 
these instruments (Generalized Anxiety Disorder-7, GAD-7, Neurological Disorders Depression 
Inventory for Epilepsy, NDDI-E, and Quality of Life in Epilepsy-10, QOLIE-10). Thus, we are 
uniquely poised to test feasibility of these novel tools for conducting EMR-based 
outcomes research. 
Identifying effective interventions for mental health comorbidities and testing treatment 
outcomes are epilepsy research priorities recognized by the Institute of Medicine, and the 
National Institute of Neurological Disorders and Stroke (NINDS) epilepsy benchmarks 
include limiting adverse effects on quality of life for people with epilepsy, including 
mental health36; 37. Approaches to treating anxiety and depression in epilepsy (e.g. colocation 
of a psychiatrist in an epilepsy clinic or internet based cognitive behavioral therapy) may have 
some impact, but their generalizability is limited due to scarcity of and lack of funding for mental 
health providers10-12. Based upon an assumption that medications effective for anxiety and 
depression in the general population are also effective among people with epilepsy (selective 
serotonin reuptake inhibitors, SSRI and serotonin and norepinephrine reuptake inhibitors, 
SNRI), expert publications frequently suggest neurologist treatment of anxiety and depression, 
and many epileptologists report willingness to prescribe a medication for depression or 
anxiety10; 15; 16. However, there is a paucity of data on longitudinal outcomes of anxiety or 
depression treatment in epilepsy (whether under experimental treatment conditions or usual 
care) and a total lack of longitudinal data on those with potentially clinically significant borderline 
symptom scores (GAD-7: 7-9, NDDI-E: 14-15)29; 31. Our preliminary data raise questions 
regarding whether SSRI/SNRI medications are effective to relieve symptoms of anxiety and 
depression in epilepsy, as 47% of 106 epilepsy clinic patients with high anxiety or depression 
scores (GAD-7≥10, NDDI-E>15) were already treated with an SSRI or SNRI (compared to 24% 
of all consecutive patients examined in a prior analysis). Our data also raise concern that many 
patients may be too sick from a psychiatric perspective to be managed by a neurologist, as 28% 
of 106 with high anxiety or depression scores had a prior psychiatric hospitalization. Thus, 
further research to assess longitudinal outcomes of anxiety and depression under usual 
care circumstances is essential for designing appropriate pragmatic interventions to test 
in future trials. 
In this study, we aim to introduce a standard care screening and outcome assessment 
paradigm for anxiety and depression in epilepsy using EMR-based direct patient reported 
measures to overcome high staffing burden of screening, to assess the feasibility of obtaining 

 
 
 
 
 
 
9 
EMR-based research outcome measures, and to generate preliminary longitudinal quality of life 
outcome data in the setting of usual care. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
2.3.1 KNOWN POTENTIAL RISKS  
This is not a treatment study and the risks associated with study participation are minimal.  The 
anxiety and depression instruments used for eligibility screening are already administered as standard 
care in our epilepsy center. The current epilepsy quality measurement set includes using standardized 
instruments to screen for anxiety and depression at each visit, and assessing quality of life at each visit 13.  
 
 
Outcome assessments administered during the trial pose minimal if any risk to participants (use 
of time to complete assessments is the main impact on participants).  Completing questionnaires about 
anxiety or depression may result in awareness of emotional symptoms that participants may not have 
otherwise recognized.   
There is a slight chance that suicidality may be identified during outcome assessment due to the 
underlying anxiety or depression condition we aim to study. We have outlined robust safety measures 
used in prior studies by the investigator team, which go beyond institutional clinical protocols for 
response to these symptoms and thus provide additional safety measures beyond what is typical in 
standard care. We also anticipate that this would be a rare occurrence, especially because our design 
excludes individuals with possible passive suicidal ideation at the time of initial screening. 
Potential breach of confidentiality is an additional risk; we have outlined methods to minimize 
this risk in section 10. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
As this is not a treatment study, there is no expected benefit for the participants. The study is 
expected to yield generalizable knowledge to support future research to improve quality of life 
in epilepsy.  
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
As described above, there is minimal risk and no expected benefit to individual participants. 
 
 
3 
OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To assess whether retention in 
the EMR-based outcome 
method arm at 6 months is 
sufficient in pilot testing to 
support use of this outcome 
assessment method in future 
pragmatic trials of management 
interventions for anxiety and 
depression in epilepsy. 
-% retention in the EMR outcome 
arm, defined as the % of participants 
who complete the 6 month outcome 
instruments in the EMR 
 
 
-obtain realistic 
estimate of feasibility 
of long-term EMR-
based outcome 
assessment in this 
population 
 
 
 

10 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Secondary 
 
 
To quantify retention at 3-and 6- 
months in the study population 
using a standard pragmatic trial 
outcome measure (telephone 
outcome assessment), and at 3 
months using the EMR based 
outcome assessment method. 
-% retention at 6 months in the 
telephone outcome arm, defined as 
the % of participants who complete 
the 6 month outcome instruments via 
telephone 
-% retention at 3 months in the EMR 
outcome arm, defined as the % of 
participants who complete the 6 
month outcome instruments via 
telephone 
-% retention at 3 months in the 
telephone outcome arm, defined as 
the % of participants who complete 
the 6 month outcome instruments via 
telephone 
 
 
-to estimate future 
retention & develop 
retention strategy 
-to assist in 
determining whether 
future studies should 
include telephone-or 
EMR-based outcome 
assessment for shorter 
and longer outcome 
assessment durations 
To estimate 6-month change in 
epilepsy-specific quality of life 
(QOLIE-10, primary outcome) 
and depression and anxiety 
(secondary) at 3 and 6 months 
during usual care, among the 
feasibility cohort of individuals 
with epilepsy and borderline to 
high anxiety or depression 
scores at baseline. 
--6 month change in QOLIE-10 from 
baseline 
--3 month change in QOLIE-10 from 
baseline 
 
--change in anxiety (GAD-7) score 
from baseline to 3 and 6-month 
outcome assessments 
--change in depression (NDDI-E) 
score from baseline to 3- and 6-month 
outcome assessments 
 
-to generate 
preliminary estimates 
of effect for change in 
quality of life (and 
anxiety and depression) 
at 3- and 6-months 
from baseline during 
usual care, inputs that 
will be important for 
future trial planning 
with likely usual care 
control group 
 
Tertiary/Exploratory  
 
 
To explore health utilization 
outcomes among individuals with 
epilepsy and high or borderline 
anxiety and/or depression 
symptoms at baseline. 
-hospitalizations from baseline to 6 
month follow-up 
-Emergency visits from baseline to 6 
months follow up 
 
-explore associations 
between longitudinal 
anxiety and depression 
symptom outcomes 
and health utilization 
 
To assess implementation of point-
of care electronic medical record 
based screening in the epilepsy 
clinic. 
-RE-AIM framework measures 
-to explore 
implementation 
metrics for the clinical 
screening protocol 
 
 

 
 
 
 
 
 
11 
 
4 
STUDY DESIGN  
4.1 
OVERALL DESIGN 
 This is a pilot pragmatic observational study of usual care quality-of life outcomes at 3- and 6-
months among adults seen in a tertiary care epilepsy clinic. It is a feasibility pilot designed to 
specifically assess feasibility (retention) of a novel, EMR-based outcome assessment method 
among 30 adults with epilepsy and high or borderline anxiety and/or depression symptoms.  
Participants will be randomized 1:1 to either a traditional pragmatic outcome collection method 
(telephone interview) versus the EMR-based outcome assessment method. We will consider the 
EMR-based outcome assessment feasible if 60% of subjects in this arm are retained at 6 months. 
We will also assess retention in the telephone based outcome arm. 
The 3- and 6-month outcome assessment instruments are brief and freely available measures 
amenable to future pragmatic trial use in outcome assessments (QOLIE-10, GAD-7, NDDI-E). 
Secondary objectives of the study include generating preliminary estimates of effect of usual care 
on quality of life outcomes (primary) as well as anxiety and depression outcomes (secondary). 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
EMR-based tools to assess patient-reported outcomes are increasingly being proposed and used 
as a streamlined method for obtaining these patient reported measures and using them in care.  
In our previous pilot interventional study of neurologist treatment for anxiety and depression in 
epilepsy, we used IPad screening for anxiety and depression via REDCap to deliver standard care 
symptom screening and simultaneously screen individuals for potential research participation. 
This method required substantial coordinator effort to convey the screening results to clinicians 
for care purposes and to enter the results in the electronic medical record.  Entry of patient 
reported measures directly into the electronic medical record has the potential to streamline 
clinical care while simultaneous pragmatic research is accomplished, because the instruments are 
entered as discrete data fields. Long-term outcome assessment via the patient portal interface of 
the electronic medical record may be feasible and potentially efficient for research staff.  
  
In this study, we will screen patients for eligibility for the observational outcome study via 
implementation of standard care anxiety and depression screening and quality of life assessment 
directly into the patient entered section of the EMR, administered on arrival in the clinic.  We will 
assess feasibility of EMR-based outcome assessment based on the primary endpoint of retention 
in the EMR-outcome arm as described above. We have decided to do a randomized feasibility trial 
comparing EMR outcome assessment to telephone outcome assessment, because the 
information from the telephone arm will also be valuable for future trial planning. This is because 
although telephone outcome assessment is often used in pragmatic trials, typical retention rates 
in epilepsy populations are unclear. Our study design aims to also assess retention using the 
telephone method in addition to the EMR method, to aid in determining future outcome 
assessment methods for interventional trials down the road. We will also use the quality of life 
and anxiety and depression outcome data at 3- and 6-months across the entire study population 
to generate estimates of long term effect of usual care among individuals with high or borderline 
anxiety and/or depression symptoms in epilepsy. 
 
 

12 
 
 
4.3 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the Schedule of Activities 
(SoA), Section 1.3. 
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in 
the trial globally. 
 
5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Male or female, age 18 or older 
2. Adequate cognition (able to complete NDDI-E and GAD-7 independently in clinic) 
3. Diagnosis of epilepsy: EEG with documented seizure or epileptiform discharges OR non-
epileptiform EEG and seizure remission with antiseizure drug OR treating epilepsy specialist’s 
leading clinical impression is epilepsy  
4. NDDI-E score >13 AND/OR GAD-7 score >7 at regular clinic visit at the Wake Forest 
Comprehensive Epilepsy Center 
 
5.2 
EXCLUSION CRITERIA 
1. High risk passive suicidal ideation score on NDDI-E: score on item 4 (I’d be better off dead) 
of 3 or 4 (sometimes OR always or often, respectively)  
 
5.3 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to be screened for the study but are not 
subsequently randomly assigned or entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants, to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse event (SAE).  
 
 
Individuals who do not meet the criteria for participation in this study (screen failure) because of 
a lack of current clinically significant anxiety or depression symptoms or other reasons may be 
rescreened.  
 
 
 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 Target study sample size: 30 to be randomized; up to 40 consented.  Anticipated number of 
participants to be screened: up to 1000  
 
Anticipated accrual rate: 5 per month 

 
 
 
 
 
 
13 
 
Number of sites: 1 
 
Recruitment venue: clinic of Wake Forest Comprehensive Epilepsy Center, adult-focused 
epilepsy practices  
 
Participants will be identified using a learning health system care model which includes ALL 
patients completing the GAD-7, NDDI-E and QOLIE-10 instruments as a part of standard care 
upon check-in for a regular clinic visit. This will occur via a link from the clinic visit workspace to 
questionnaires in the patient portal interface (mywakehealth). Those who have borderline or 
high anxiety or depression (GAD-7 > 7 or NDDI-E >13) will be prompted to answer a question 
about interest in research. 
 
An inbasket message to study team will be triggered if an adult’s GAD-7 and/or NDDI-E scores 
meet eligibility criteria and the individual indicates potential interest in research by answering 
yes to the following prompt. 
o We are doing a research study to see how patients in the epilepsy clinic with possible 
symptoms of anxiety or depression are doing 6 months after a clinic visit. The study 
includes one phone call over the next few days. Then in 3 and 6 months, you would 
answer some questions similar to those you just finished.  Each time might take 5-
10minutes.   
May we contact you to tell you more about this study if you are eligible? 
 
When study staff receive the inbasket message, the medical chart will then be reviewed to 
assess whether a diagnosis of epilepsy is present.  If epilepsy is present, the potential participant 
will be contacted by telephone and consent process will be initiated over the phone. 
 
For those eligible individuals who complete telephone consent for study participation, a brief 
baseline telephone interview focused on past psychiatric treatment history will be completed 
and the participant randomized. If necessary, mywakehealth activation will be done at the time 
of enrollment. Instructions for the allocated outcome assessment process will be provided. 
 
Multiple reminders and communications will be utilized to enhance participation in the outcome 
assessments. Telephone calls will be scheduled at the time of enrollment if possible.  The 
outcome instruments will be mailed to telephone arm participants 10 days before scheduled 
outcome calls, and they will be sent electronically 10 days prior to target completion date for 
EMR-arm participants. Two telephone reminders for telephone arm participants, and two 
electronic reminders for EMR-arm participants will be provided prior to scheduled outcome 
assessment.  Up to 5 attempts to call participants in the telephone outcome assessment arm will 
be made on separate days, starting at the originally scheduled outcome assessment time.  Up to 
5 electronic reminders with survey instructions will be sent via the EMR to the EMR arm 
participants, starting with target date for EMR outcome completion. 
 
After criteria for retention outcome at 6 months is met (5 reminders after due date for outcome 
assessment as described above), to reduce potential missing data for the secondary outcomes 
of 6-month change in quality of life, anxiety and depression, the following will be done. For any 
EMR-arm participants without successful 6-month outcome collection, 3 attempts will be made 
to collect outcomes via telephone.  For any telephone arm participants without successful 6-
month outcome collection, 3 attempts will be made to collect outcomes via EMR. 
 
Subjects will receive incentive of $15 gift card for completing the brief baseline telephone 
interview and $15 for completing each of the two outcome assessments (3 and 6 months).  
 
Efforts will be made to recruit any eligible participant seen in the practice, including women and 
under-represented populations 
 
 

14 
 
6 
STUDY INTERVENTION 
6.1 
STUDY INTERVENTION 
This is not a treatment study, so there is no treatment intervention. The study aims to assess feasibility 
of EMR-based outcome collection method, versus standard telephone collection method.  The below 
descriptions refer to the experimental component of the study, in which the participants are 
randomized to one of two outcome assessment groups. 
 
6.2 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Subjects will be randomized to one of two outcome collection arms: EMR-based or telephone-based at 
the time of enrollment.  Participants will be allocated to study group using fixed allocation 
randomization procedures, with a computer-based random number generating algorithm. Blocked 
randomization will be considered, with planned block sizes greater than the group number, and 
randomization will be stratified by mywakehealth enrollment status at the time of study consent. 
Outcome group assignment will not be blinded to the primary investigator or primary study coordinator, 
as it will be necessary for these individuals to know outcome assessment allocation in order for outcome 
collection to occur.  When possible, outcome group assignment will not be shared with the epilepsy 
provider managing the participant, in an effort to reduce any potential bias in retention that could be 
introduced by the provider in clinical interactions with the participant.  
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
 
Although it is unlikely that a participant would need to be withdrawn from this study given its 
observational nature, the investigator may discontinue or withdraw a participant from the study for the 
following reasons: 
 
If any clinical adverse event (AE) or other medical condition or situation occurs such that 
continued participation in the study would not be in the best interest of the participant 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Discontinuation Case Report Form (CRF). Subjects who consent but are not randomized may be 
replaced.  Subjects who consent, are randomized and receive instructions regarding the allocated 
outcome assessment arm, and subsequently withdraw, or are withdrawn or discontinued from the study 
may be replaced, but will also be included in outcome assessment unless the participant withdrew 
consent. 
7.2 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to complete the 6 -month outcome 
assessment and is unable to be contacted by the study staff.  
 

 
 
 
 
 
 
15 
The following actions must be taken if a participant fails to complete an outcome assessment 
appointment: 
 
Study staff will attempt to contact the participant and reschedule the missed outcome 
assessment within <1 week and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain if the participant wishes to and/or should continue in the 
study. 
 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 5 telephone calls or electronic 
communications in the EMR as outlined above followed by up to 3 attempts by the alternative 
modality (following primary retention outcome assignment as described in recruitment and 
retention section) and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts will be documented in the 
participant’s study file.  
 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
EFFICACY ASSESSMENTS  
Screening Assessment 
-NDDI-E, GAD-7, QOLIE-1038 
 
Implementation Monitoring: 
RE-AIM framework measures 
 
Feasibility assessments: 
Enrollment/Baseline Assessments:  
-accrual assessment 
 
Retention: defined as outcomes collected via randomized modality within 1 week of the final of 5 
scheduled reminders following outcome assessment due date (see recruitment and retention section for 
details of reminder process for each arm). 
-6 month retention in EMR outcome arm 
-6 month retention in the telephone outcome arm 
-3 month retention in EMR and telephone outcome arms, respectively 
 
Other feasibility assessments: 
-# attempts to contact participants in each arm 
-staff time for telephone outcome assessment/telephone contact attempts/preparing mailed survey 
packets vs staff time to send EMR surveys and electronic reminders 
-time for participant completion of EMR surveys 
-delay from survey delivery to completion by participant 
 
 

16 
 
Usual care outcome assessments (3 and 6 months): 
-QOLIE-10 
-NDDI-E 
-GAD-7 
-healthcare utilization (ED visits, hospitalizations) 
 
Review of Clinical Chart: this will be done for preliminary eligibility assessment and for supplementary 
information on medications prescribed and health care utilization during the study period.  
 
Health Insurance Portability and Accountability Act (HIPAA) rules, other relevant federal or state laws, 
and local institutional requirements will be followed, as applicable.   
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
Screening Assessments for Safety: in EMR/routine clinic visit 
-NDDI-E validated passive suicidality question for safety39: if score indicates potential risk of suicidality, 
the electronic record system will be triggered to alert the treating epilepsy provider to assess for 
possible suicidality. These individuals will be excluded from study participation.  
 
Other Enrollment Assessments: 
-demographics, medications, medical history (largely based on EMR review) 
-brief past psychiatric treatment history interview  
 
 
Outcome Assessments 
3-month assessment 
-NDDI-E (validated passive suicidality question for safety) 
 
6-month assessment 
-NDDI-E (validated passive suicidality question for safety) 
 
Safety plan at outcome assessments: 
-further assess for active suicidality if score on suicidal ideation question of NDDI-E is 3 or higher (using 
crisis procedures questions outlined in manual and Appendix A).  This will be done immediately during 
telephone outcome assessments.   
If an EMR outcome assessment results in a high-risk score on the NDDI-E, high priority alerts (red flag 
inbasket message or page to study pager) will be sent to study staff, and study staff will then call the 
participant at the first opportunity available, to assess need for any further action. All efforts will be 
made to send the EMR outcome assessment questionnaires at the start of a business day to allow 
maximal opportunity for rapid responses to occur during hours when study staff are available. 
Participant emergency contacts may be called if the study staff is unable to reach the participant on the 
day that a high-risk score was identified. The proposed response time is faster than what may typically 
occur in standard care practice. For example, new patients to the epilepsy center receive a mailed 
version of the NDDI-E prior to initial visit, for completion, and these results which may be completed 
weeks before the visit are only reviewed by clinical staff at the time of the clinic visit. 
Further details of safety protocol are outlined in section 8.5 and appendix A. 
 
   

 
 
 
 
 
 
17 
8.3 
EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF EVENTS  
As this is not a treatment study, the typical definition of adverse events does not apply, as there is no 
treatment intervention with which adverse events could be associated. 
 
However, untoward medical occurrences (events) may be identified during the course of the study.   
 
Events that are not related to study procedures and that do not meet criteria for serious adverse events 
as described below will not be recorded. Events related to study procedures will be recorded. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An adverse event (AE) or event is considered "serious" if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes:  
 
The following events are considered Serious adverse events (SAE) 
 
death 
 
a life-threatening adverse event (Stroke, MI, fracture, suicide attempt) 
 
inpatient hospitalization  
 
prolongation of existing hospitalization 
 
a persistent or significant incapacity (last more than 48 hours and limits activities of daily living)  
 
a congenital anomaly/birth defect 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition.  
 
 
8.3.3 CLASSIFICATION OF AN EVENT OR SERIOUS ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
For events related to the study procedures, the following guidelines may be used to describe severity.  
 
• Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• Severe – Events 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”. 
 
 
8.3.3.2 
RELATIONSHIP TO STUDY PARTICIPATION 
All serious adverse events (SAEs) must have their relationship to study participation assessed by the 
clinician who examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment.  

18 
 
 
The degree of certainty about causality will be graded using the categories below.  
 
• Possibly related – A “possibly related” serious adverse event reflects a realistic chance of a causal 
relationship between a study procedure and the adverse event.  Reasonable possibility means that 
there is evidence to suggest a causal relationship between the study procedure as suggested by 
an event that follows within a reasonable time after the study procedure (i.e., 24 hours), follows a pattern 
consistent with the study procedure. 
 
 
• Not Related – There is not a reasonable possibility that the administration of the study 
procedure caused the serious adverse event, there is no temporal relationship between the 
study procedure and event onset, or an alternate etiology has been established. 
 
 
8.3.3.3 EXPECTEDNESS  
The Principal Investigator will be responsible for determining whether a serious adverse event (SAE) or a 
study related event is expected or unexpected.   
 
• Expected: Any event that is listed in protocol, consent form, or part of the normal disease 
condition.  
 
• Unexpected: Any event that is not listed in the protocol, consent form, or is not part of the 
normal disease progression.  
 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an event or serious adverse event (SAE) may come to the attention of study 
personnel during outcome assessments or at other contacts between study staff and participants. 
Serious adverse events (SAE) may come to the attention of study personnel during medical record 
review for health utilization outcome assessment. 
 
All study-procedure related events not meeting the criteria for SAEs will be captured on the appropriate 
case report form (CRF). Given the minimal risk of the study procedures, these events are expected to be 
rare.  
Any SAEs will also be captured on the appropriate case report form. 
 
Information to be collected includes:  
 
event description,  
 
time of onset and duration 
 
clinician’s assessment of severity,  
 
time of resolution/stabilization of the event.  
 
All study related events will be followed to adequate resolution. 
 

 
 
 
 
 
 
19 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an event. However, if the study participant’s condition deteriorates at any 
time during the study and then meets the definition of an SAE, it will be recorded as an SAE.  
 
Changes in the severity of an event or SAE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed.  
 
 
The Study team will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious study related events) or 30 days (for SAEs) after the last day 
of study participation.  Events will be followed for outcome information until resolution or stabilization. 
 
 
8.3.5 EVENT REPORTING  
All study related events will be reviewed by the PI and will be reported to the IRB if the events meet 
criteria for IRB reporting via IRB policy, or at a timeframe and in a manner specified by the study 
sponsor. 
 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
Any serious adverse events related to the study procedures will be reported to the IRB within 24 hours 
of knowledge of the event. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the investigator 
deems the event to be chronic or the participant is stable. Other supporting documentation of the event 
may be requested by the study sponsor and should be provided as soon as possible. 
 
Serious adverse events not related to study procedures will be reported to the IRB at the time of 
continuing review. 
 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
N/A as this is not a treatment study. 
 
 
8.4 
UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 

20 
 
• Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the principal investigator (PI). The UP report will include the following information: 
 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• A detailed description of the event, incident, experience, or outcome;  
• An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• UPs that are serious adverse events (SAEs) related to the intervention will be reported to the IRB 
immediately (within 24 hours) upon the investigator becoming aware of the event.  
• Any other UP will be reported to the PI within 7 days of the investigator becoming aware of the 
problem and to the IRB. 
• All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 1 week of the IRB’s receipt of the report of the 
problem from the investigator. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
Study team will not be reporting unanticipated problems to participants. 
 
8.5 
CRISIS PROTOCOL/SAFETY 
Crisis procedures: see Appendix A for instructions/crisis procedures document which pertains to the 
outcome assessments and other interactions with the subjects.  The clinic component of the crisis 
procedures document is provided to clinical study team members as an additional resource for potential 
management of symptoms identified in clinic as part of the clinical care depression screening procedure.  
  
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 notify the PI. In both cases, the 
participant may be referred for psychiatric care. Dr. James Kimball, study psychiatrist, will be available 
for input/guidance if needed.  As an additional safety precaution, we will ask each participant upon 
study enrollment to identify 2 persons whom we can contact in case of an emergency and provide 2 
telephone numbers for each of these 2 individuals; if possible. All participants will receive information 
about safety precautions and procedures to follow in the event that a participant becomes imminently 

 
 
 
 
 
 
21 
suicidal. Each participant will be given telephone numbers for the Wake Forest Baptist Health 
psychiatrist-on-call and crisis hotline.  Participants will be able to reach study staff or the psychiatrist-on-
call 24-hours a day. If it is determined that a participant is not at risk of imminent harm, we may refer 
them for additional psychiatric care. If a participant continues to report active suicidal ideation and is at 
imminent risk, we will ask if there is anyone at home with the participant, speak with that person, and 
have that person take the participant to the nearest emergency room for an immediate evaluation. If 
there is no one with the participant, study staff will contact the person’s emergency contacts and 
instruct them to take the participant to the nearest emergency room for an immediate evaluation. If 
there is no one available to do this, mobile crisis management teams will be contacted and local law 
enforcement will be called to transport the participant to an emergency room.  
 
Because this is not a treatment study, because we are excluding individuals with passive suicidal 
ideation at screening, and given the low rate of active suicidality we identified at baseline during our 
recent learning health system trial (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. 
  
Additional safety procedures for EMR outcome assessments  
If in the EMR outcome assessment arm, a high score on the passive suicidality question of the NDDI-E 
will trigger an alert with high priority to study staff inbasket and/or study team pager indicating that a 
high score was received. 
The study team will call the participant as soon as feasible upon receiving the notification to assess for 
active suicidality and respond with further action as appropriate. 
  
Staff will be instructed to follow the crisis protocol outlined in Appendix A and complete the Crisis 
Protocol Event Form. In both cases, the participant may be referred for psychiatric care by a physician or 
provider: their primary care physician, neurologist, APP, or emergency department physician. 
 
Symptom Worsening 
If there is significant symptom worsening at 3 month follow-up compared to baseline or at 6 month 
follow up compared to the prior assessment, a treatment resource handout will be mailed to the 
participant (see Appendix B).  We will define treatment worsening as worsening in GAD-7 or NDDI-E 
score by 1 standard deviation12; 32. 
 
Specifically, symptom worsening would be defined as the following: 
 
-GAD-7 score increase of 5 points or more 
 
-NDDI-E score increase of 4 points or more 
 
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
 
Primary feasibility hypothesis:  We hypothesize that the primary endpoint, retention at 6 
months in the EMR-based outcome assessment arm, will be greater than 60%. 
 
9.2 
SAMPLE SIZE DETERMINATION 
We are aiming to recruit 30 participants for the randomized outcome assessment feasibility study, with 
15 in the EMR-outcome arm and equal allocation between EMR arm and the telephone arm.  Using a 

22 
 
Bayesian design and a simulation study we assessed the probability of declaring acceptable adherence 
(80% credible interval that true adherence is at least 60%, Pr(X ≥ 0.6) ≥ 0.8) over 10,000 simulated trials 
with sample size 15 in the intervention arm. We then summarized the results across all possible single 
trial outcomes and found if 11 to 15 subjects are retained, we are at least 83% confident that the true 
probability of retention is greater than 0.6.  Thus, if at least 11 EMR arm participants meet the primary 
retention outcome, we will declare acceptable retention for using EMR based outcome assessment in 
future trials. 
 
9.3 
POPULATIONS FOR ANALYSES 
Intention to treat analysis will be carried out.  
 
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
Categorical data will be presented using percentages and continuous data using means and standard 
deviations, unless the data is not normally distributed, in which case medians and ranges will be 
presented. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
The number of EMR-arm participants who meet retention criteria will be calculated, and as described 
above in the sample size determination section, if at least 11 EMR-arm participants meet the primary 
retention outcome, we will declare acceptable retention for using EMR based outcome assessment in 
future trials. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
To estimate change in quality of life (QOL) at 6 months during usual care, we will calculate individual 
level change in QOLIE-10 score from baseline to 6-months among all participants, with positive values 
(increased scores at 6 months) indicating improvement in quality of life. The mean change in QOL at 6 
months (primary) will be compared to zero (no change) using the one-sample T-test with alpha=0.05, 
and 95% and 90% confidence intervals will be calculated. This will provide preliminary estimates of 
effect under usual care, to aid in sample size calculation for future intervention trials with usual care 
control group. Similar exploratory analyses will be carried out for change in QOL at 3 months and change 
in anxiety and depression scores from baseline to 3 and 6-months follow-up 
 
9.4.4 SAFETY ANALYSES 
The proportion of individuals reporting suicidality will be calculated. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Baseline demographics and scaled scores for anxiety, depression, and quality of life will be compared 
between the two groups. Two sample t-test and chi square analyses will be used as appropriate to 
compare the two outcome assessment groups/assess quality of randomization. 
 
9.4.6 SUB-GROUP ANALYSES 
N/A: this small pilot study will not have sufficient power for subgroup analyses 
 

 
 
 
 
 
 
23 
9.4.7 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Individual participant data will be listed by measure and timepoint. 
 
9.4.8 EXPLORATORY ANALYSES 
Exploratory analyses will include assessment of the frequency of major health care utilization events 
(such as ED visits) in the study cohort.  
 

24 
 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
9.5 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
9.5.1 INFORMED CONSENT PROCESS 
9.5.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Telephone consent process describing in detail the study procedures and risks is required prior to 
starting the baseline brief telephone interview and completing randomization. An information sheet will 
be mailed to participants who enroll in the study.   
The following consent materials are submitted with this protocol: 
-telephone consent script  
-study information sheet 
 
9.5.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent procedures will be 
Institutional Review Board (IRB)-approved. The study staff will explain the research study to the 
participant and answer any questions that may arise. A verbal explanation will be provided in terms 
suited to the participant’s comprehension of the purposes, procedures, and potential risks of the study 
and of their rights as research participants. The participants will have the opportunity to discuss the 
study with their family or surrogates, if desired, prior to agreeing to participate. The participant will 
provide verbal telephone consent prior to any procedures being done specifically for the study. 
Participants must be informed that participation is voluntary and that they may withdraw from the 
study at any time, without prejudice. A copy of the study information sheet will be mailed to the 
participants for their records. The informed consent process will be conducted and documented before 
the participant undergoes any study-specific procedures. The rights and welfare of the participants will 
be protected by emphasizing to them that the quality of their medical care will not be adversely affected 
if they decline to participate in this study. 
9.5.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to the study participants, investigators, funding agency, 
and regulatory authorities.  If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and 
sponsor and will provide the reason(s) for the termination or suspension.  Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to participants (very unlikely as 
this is not a treatment study) 
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, and IRB. 

 
 
 
 
 
 
25 
 
9.5.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. Therefore, the study protocol, documentation, data, 
and all other information generated will be held in strict confidence. No information concerning the 
study or the data will be released to any unauthorized third party without prior written approval of the 
sponsor.  
 
All research activities will be conducted in an area where private phone conversations and other 
measures to ensure privacy and confidentiality are possible. 
 
Authorized representatives of the sponsor, representatives of the Institutional Review Board (IRB), or 
regulatory agencies may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy 
records for the participants in this study.  
 
The study participant’s contact information will be securely stored at the clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be stored at the Wake Forest University Department of Neurology. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by the clinical site will be secured and password protected. At the end of the study, all 
study databases will be de-identified and archived. 
 
Certificate of Confidentiality  
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the 
National Institutes of Health (NIH).  This certificate protects identifiable research information from 
forced disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, legislative, 
or other proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research participants, 
Certificates of Confidentiality help achieve the research objectives and promote participation in studies 
by helping assure confidentiality and privacy to participants. 
 
9.5.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study will be analyzed and stored at the Wake Forest University Department of 
Neurology.  
When the study is completed, access to study data will be provided through the Wake Forest University 
Department of Neurology.  
 
 
 
 
 

26 
 
9.5.5 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator 
Heidi Munger Clary, MD, MPH 
Assistant Professor of Neurology 
Wake Forest University  
1 Medical Center Blvd. 
Winston-Salem, NC 27104 
336-716-7110; 333-716-4101 
hmungerc@wakehealth.edu 
 
9.5.6 SAFETY OVERSIGHT 
Safety oversight will be carried out by the Principal Investigator. The 3 and 6-month outcome 
assessments include administration of the NDDI-E instrument, which has a single passive suicidal 
ideation question that has been validated as a suicide screen39. Safety monitoring will include review of 
the proportion of participants reporting high suicidality scores (3 or 4 on the NDDI-E passive suicidality 
question). 
 
9.5.7 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
• 
On-site monitoring early, for initial assessment and training and to a more limited extent later 
in the study will be completed by the primary investigator and the study coordinator. This will 
consist of initially comprehensive (100% data verification) review of the first 5 subjects enrolled 
followed by targeted data verification of endpoints and or random review of a few additional 
subjects and the distribution of monitoring reports. 
 
9.5.8 QUALITY ASSURANCE AND QUALITY CONTROL 
The site will perform internal quality management of study conduct, data collection, documentation and 
completion.  A quality management plan will be developed. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the investigator/coordinator for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the study is 
conducted and data are generated, documented (recorded), and reported in compliance with the 
protocol and International Conference on Harmonisation Good Clinical Practice (ICH GCP).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 

 
 
 
 
 
 
27 
9.5.9 DATA HANDLING AND RECORD KEEPING  
9.5.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the study staff under the supervision of the investigator. The 
investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
 
Clinical data (including study related events, concomitant medications) and self-report instruments will 
be directly entered into RedCap, or exported from the EMR and then transferred to RedCAp, a 21 CFR 
Part 11-compliant data capture system provided by Wake Forest University Health Sciences. The data 
system includes password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly 
from the source documents. 
 
9.5.9.2 STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of 6 years after study closure. These documents 
should be retained for a longer period, however, if required by local regulations. No records will be 
destroyed without the written consent of the sponsor, if applicable.  
 
9.5.10 PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the investigators to use continuous vigilance to identify and report deviations 
requiring notification within 5 working days of identification of the protocol deviation, or within 5 
working days of the scheduled protocol-required activity.  All deviations must be addressed in study 
source documents, reported to the appropriate funding organization Program Official if required, and 
the primary investigator.  Protocol deviations must be sent to the reviewing Institutional Review Board 
(IRB) per their policies. The investigator is responsible for knowing and adhering to the reviewing IRB 
requirements. Further details about the handling of protocol deviations will be included in the MOP.  
 
 
 

28 
 
9.5.11 PUBLICATION AND DATA SHARING POLICY 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
Every attempt will be made to publish results in peer-reviewed journals.  Data from this study may be 
requested from other researchers x 7years after the completion of the primary endpoint by contacting 
Dr. Heidi Munger Clary. 
 
9.5.12 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership, in conjunction with the funding agency, has established policies and procedures for all study 
group members to disclose all conflicts of interest and will establish a mechanism for the management 
of all reported dualities of interest. 
 
 

 
 
 
 
 
 
29 
9.6 
ABBREVIATIONS 
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DRE 
Disease-Related Event 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GAD-7 
Generalized Anxiety Disorder-7 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 
NDDI-E 
Neurologic Disorders Depression Inventory-Epilepsy 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PCP 
Primary Care Provider 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
QOLIE-10 Quality of Life in Epilepsy-10 
SAE 
Serious Adverse Event 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

30 
 
9.7 
PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
2 
June 3 2019 
-As the clinical screener instruments 
can be completed in clinic regardless 
of mywakehealth enrollment, 
enrollment step has moved to 
enrollment stage for any individuals 
who enroll and do not already have 
mywakehealth access. 
-update screening consent text 
-Add exploratory implementation 
monitoring to list of study 
objectives. 
-Based upon updated 
information regarding the 
screening instruments, we have 
modified the planned workflow. 
 
 
 
-better clarity of study info 
-To support generating 
preliminary data for potential 
future studies/dissemination. 
3 
July 31 2019 
-remove W-9 language and modify 
randomization plan to reflect 
stratification by patient portal 
enrollment at baseline rather than 
epilepsy provider, add safety plan 
for significant symptom worsening at 
follow up 
-W-9 is not needed based on 
further information gathered by 
research team 
-it will be more important to 
stratify by patient portal 
enrollment than provider, as this 
factor is more likely to 
introduce potential bias if 
unbalanced for the primary 
outcome assessment 
-to provide additional safety 
measures similar to long-term 
outcome assessment phase of 
other mental health studies 
conducted by study team 
4 
January 29 
2020 
-added “if possible” to the collection 
of two emergency contacts with two 
emergency numbers. (section 8.5)  
Either two emergency contacts 
or two emergency numbers for 
each contact was not feasible for 
all subjects contacted 
5 
March 3, 
2020 
-removed “BPA” from trigger alert 
Page 21 
System unable to actually 
trigger a BPA alert 
6 
June 1 2020 
EMR-arm participants without 
successful 6-month outcome 
collection, 3 attempts will be made 
to collect outcomes via telephone.  
For any telephone arm participants 
without successful 6-month 
outcome collection, 3 attempts will 
be made to collect outcomes via 
EMR 
Reduce potential missing data 
for the secondary outcomes of 
6-month change in quality of 
life, anxiety and depression 
assessments. 

 
 
 
 
 
 
31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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