Anxiety and Depression in Epilepsy: A Pilot Epileptologist-Driven Treatment Study
Phase: PHASE4
Conditions: Anxiety, Depression, Epilepsy
Sponsor: Wake Forest University Health Sciences

 
 
Anxiety and Depression in Epilepsy: A Pilot Epileptologist-
Driven Treatment Study 
 
Principal Investigator: Heidi M. Munger Clary, MD, MPH 
 
 
Funded by: NCATS (CTSI pilot award) 
Version Number:  v.6 
13 May 2019 
NCT03464383 
 
 

  
 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 4 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 8 
2 
INTRODUCTION ............................................................................................................................................ 9 
2.1 
Study Rationale .................................................................................................................................... 9 
2.2 
Background........................................................................................................................................... 9 
2.3 
Risk/Benefit Assessment .................................................................................................................. 10 
2.3.1 
Known Potential Risks ................................................................................................... 10 
2.3.2 
Known Potential Benefits .............................................................................................. 11 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 11 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 12 
4 
STUDY DESIGN ........................................................................................................................................... 14 
4.1 
Overall Design .................................................................................................................................... 14 
4.2 
Scientific Rationale for Study Design.............................................................................................. 14 
4.3 
Justification for Dose ......................................................................................................................... 15 
4.4 
End of Study Definition ..................................................................................................................... 15 
5 
STUDY POPULATION ................................................................................................................................ 16 
5.1 
Inclusion Criteria ................................................................................................................................ 16 
5.2 
Exclusion Criteria ............................................................................................................................... 16 
5.3 
Lifestyle Considerations .................................................................................................................... 16 
5.4 
Screen Failures .................................................................................................................................. 16 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 17 
6 
STUDY INTERVENTION ............................................................................................................................ 19 
6.1 
Study Intervention(s) Administration ............................................................................................... 19 
6.1.1 
Study Intervention Description ..................................................................................... 19 
6.1.2 
Dosing and Administration ............................................................................................ 19 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 21 
6.2.1 
Acquisition and accountability ...................................................................................... 21 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 21 
6.2.3 
Product Storage and Stability ....................................................................................... 21 
6.2.4 
Preparation ...................................................................................................................... 21 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 21 
6.4 
Study Intervention Compliance ........................................................................................................ 21 
6.5 
Concomitant Therapy ........................................................................................................................ 21 
6.5.1 
Rescue Medicine ............................................................................................................ 22 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 23 
7.1 
Discontinuation of Study Intervention ............................................................................................. 23 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 23 
7.3 
Lost to Follow-UP .............................................................................................................................. 23 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 25 
8.1 
Efficacy Assessments ....................................................................................................................... 25 
8.2 
Safety and Other Assessments ....................................................................................................... 26 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 26 

  
 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 26 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 26 
8.3.3 
Classification of an Adverse Event .............................................................................. 27 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 28 
8.3.5 
Adverse Event Reporting .............................................................................................. 29 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 29 
8.3.7 
Reporting Events to Participants ................................................................................. 29 
8.3.8 
Events of Special Interest ............................................................................................. 29 
8.3.9 
Reporting of Pregnancy ................................................................................................ 29 
8.4 
Unanticipated Problems .................................................................................................................... 29 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 29 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 30 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 30 
8.5 
Crisis Protocol/Safety ........................................................................................................................ 30 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 32 
9.1 
Statistical Hypotheses ....................................................................................................................... 32 
9.2 
Sample Size Determination .............................................................................................................. 32 
9.3 
Populations for Analyses .................................................................................................................. 33 
9.4 
Statistical Analyses............................................................................................................................ 33 
9.4.1 
General Approach .......................................................................................................... 33 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 33 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 33 
9.4.4 
Safety Analyses .............................................................................................................. 33 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 34 
9.4.6 
Planned Interim Analyses ............................................................................................. 34 
9.4.7 
Sub-Group Analyses ..................................................................................................... 34 
9.4.8 
Tabulation of Individual participant Data .................................................................... 34 
9.4.9 
Exploratory Analyses ..................................................................................................... 34 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 35 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 35 
10.1.1 
Informed Consent Process ........................................................................................... 35 
10.1.2 
Study Discontinuation and Closure ............................................................................. 35 
10.1.3 
Confidentiality and Privacy ........................................................................................... 36 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 36 
10.1.5 
Key Roles and Study Governance .............................................................................. 36 
10.1.6 
Safety Oversight ............................................................................................................. 37 
10.1.7 
Clinical Monitoring .......................................................................................................... 37 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 37 
10.1.9 
Data Handling and Record Keeping ............................................................................ 38 
10.1.10 
Protocol Deviations ........................................................................................................ 38 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 39 
10.1.12 
Conflict of Interest Policy .............................................................................................. 39 
10.2 
Additional Considerations ................................................................................................................. 39 
10.3 
Abbreviations ...................................................................................................................................... 40 
10.4 
Protocol Amendment History ........................................................................................................... 41 
11 
REFERENCES ............................................................................................................................................. 42 
 

Epileptologist Treatment of Depression and Anxiety 
 
Protocol  
 
 
 
1 
STATEMENT OF COMPLIANCE 
The trial 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 clinical trial site staff who are responsible for the conduct, management, or 
oversight of this clinical trial 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. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Anxiety and Depression in Epilepsy: A Pilot Epileptologist-Driven 
Treatment Study 
Study Description: 
This is a pilot feasibility trial of an epileptologist-driven medication 
treatment intervention for anxiety and depression, carried out directly in 
the epilepsy clinic during a regularly scheduled visit and supported by 
advanced practice provider (APP), compared to psychiatry referral.   
In study phase I, we will enroll up to 5 patients in the intervention arm to 
streamline the recruitment, intervention and outcome assessment 
process. 
In our study phase II randomized pilot, we hypothesize that the primary 
endpoint, adherence within the intervention arm (defined as participant 
report of taking the prescribed medication at 12 weeks and participation 
in at least 2 chronic care management encounters), will be greater than 
60%.  
This hypothesis will be tested in study phase II by randomizing a total of 30 
patients with clinically significant anxiety or depression [Generalized 
Anxiety Disorder-7 (GAD-7) ≥10 or Neurological Disorders Depression 
Inventory-Epilepsy (NDDI-E) >15] to both treatment arms and following 
them for 12 weeks on allocated therapy (N=15 in each arm). 
 
Objectives: 
 
Primary Objective:  To assess whether adherence to intervention study 
regimen developed for a randomized trial of management of anxiety and 

Epileptologist Treatment of Depression and Anxiety 
 
Protocol  
 
 
 
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depression in epilepsy, comparing neurologist/APP-administered 
medication/chronic care management versus usual care with psychiatry 
referral, is sufficient in pilot testing to support advancing to a larger 
definitive trial. 
 
Secondary Objectives:  
- To quantify rates of accrual and retention in a randomized trial of 
neurologist/APP-administered medication/chronic care management of 
anxiety and depression in epilepsy versus usual care with psychiatry 
referral, inputs that will inform the design and sample size calculations for 
a large, definitive trial. 
- To assess 12-week changes in anxiety and depression symptoms in the 
medication intervention group versus usual care/psychiatry referral 
control group, to provide preliminary estimates of effect magnitude to 
inform sample size calculations for a larger randomized trial.  Anxiety and 
depression will be measured by the Beck Anxiety Index (BAI) and Beck 
Depression Inventory-II (BDI) respectively. There will be equal allocation of 
subjects across the 2 groups. 
 
As of May 13, 2019, the active major goal of the study has shifted to the 
original secondary objective related to retention. 
 
Outcomes: 
Primary Outcome:  
-% adherence in the intervention arm, defined as the % of participants 
who report taking the prescribed medication at 12 weeks AND who have 
completed at least 2 of the chronic care management scheduled visits 
(telephone or clinic visit) 
 
Secondary Outcomes:  
-accrual: % of patients screened for the trial who are eligible 
   % of patients eligible who are randomized  
-retention: % of participants from each arm who complete 12-week 
outcome assessment 
Proposed efficacy outcomes: 
 a. 12 week change in Beck Depression Inventory-II (among those with high 
depression at baseline) 
 b. 12 week change in Beck Anxiety Index (among those with high anxiety 
at baseline) 
 
Study Population: 
Phase I: intervention only pre-piloting: up to 5 adults, characteristics 
described below  
Phase II: 30 adults with epilepsy seen in follow-up at the Wake Forest 
Comprehensive Epilepsy Center who screen positive for clinically 
significant anxiety and/or depression (GAD-7≥10 and/or NDDI-E >15) at 
baseline 
 
Phase: 
N/A: Non -FDA regulated 
 

Epileptologist Treatment of Depression and Anxiety 
 
Protocol  
 
 
 
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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.   
 
Description of Study 
Intervention: 
A best practice chronic care management plan for anxiety and depression 
carried out in the epilepsy clinic, characterized by: 
1. epileptologist-initiated selective serotonin reuptake 
inhibitor(SSRI)/serotonin norepinephrine reuptake inhibitor(SNRI) 
therapy 
2. repeated phone calls by an APP (at 2, 4, 8, and 10 weeks post-
enrollment) to assess for side effects and reassess anxiety and 
depression symptoms for potential dose adjustment, and 
3. one 6-week follow-up clinic visit with the APP for potential dose 
adjustment. 
 
Study Duration: 
Up to 2 years 
 
Participant Duration: 
12 weeks 
 
 

Epileptologist Treatment of Depression and Anxiety 
 
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1.2 
SCHEMA 
 
 

Epileptologist Treatment of Depression and Anxiety 
 
Protocol  
 
 
 
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Epileptologist Treatment of Depression and Anxiety 
 
Protocol  
 
 
 
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Epileptologist Treatment of Depression and Anxiety 
 
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Epileptologist Treatment of Depression and Anxiety 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures* 
Screening 
Clinic Visit , Day 1 
Baseline/Randomize#  
 Day 1 
APP Telephone Care 1 
week 2 
APP Telephone Care 2 
week 4 
Intermediate Outcome 
week 6 
APP Clinic Visit 
week 6 
APP Telephone Care 3 
week 8 
APP Telephone Care 4 
Week10 
Final Outcome 
Week 12 
NDDI-E (screening: REDCap 
on iPad for clinical care) 
X 
 
X 
X 
X 
r 
X 
X 
X 
GAD-7 (screening: REDCap on 
iPad for clinical care) 
X 
 
X 
X 
X 
r 
X 
X 
X 
Eligibility questions: REDCap 
on iPad 
X 
 
 
 
 
 
 
 
 
in-person coordinator 
screening 
X 
 
 
 
 
 
 
 
 
Eligibility verification: 
medical chart 
X 
 
 
 
 
 
 
 
 
Informed consent 
(enroll/intervention-phase I, 
enroll/randomize-phase II) 
 
X 
 
 
 
 
 
 
 
Detail demographics 
 
X 
 
 
 
 
 
 
 
Collect additional baseline 
medical history 
 
X 
 
 
 
 
 
 
 
Record all medications  
 
X 
 
 
 
 
 
 
X 
MOCA 
 
X 
 
 
 
 
 
 
 
BDI 
 
X 
 
 
X 
 
 
 
X 
BAI 
 
X 
 
 
X 
 
 
 
X 
QOLIE-10 
 
X 
 
 
X 
 
 
 
X 
PROMIS-10 
 
X 
 
 
X 
 
 
 
X 
Randomize (phase II only) 
 
X 
 
 
 
 
 
 
 
Accrual Outcomes 
X 
X 
 
 
 
 
 
 
 
Prescribe escitalopram 
 
X 
 
 
 
 
 
 
 
Potentially adjust dose/switch 
drug if not tolerated 
 
 
X 
X 
 
X 
X 
X 
 
Brief side effect, adherence 
assessment 
 
 
X 
X 
 
X 
X 
X 
 
Final Adherence Outcomes 
   Taking medication? 
   Modified Morisky-4 
   Review pharmacy records 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Retention Outcome 
 
 
 
 
 
 
 
 
X 
Psychiatry referral order  
 
X 
 
 
 
 
 
 
 
Patient Satisfaction (CAHPS) 
 
 
 
 
 
 
 
 
X 
Medication Adherence 
(Morisky-4) 
 
 
 
 
 
 
 
 
X 
Side Effects (LAEP) 
 
X 
 
 
 
 
 
 
X 
Seizure Frequency  
 
X 
 
 
 
 
 
 
X 
Health Care Utilization/ED 
visits/hospitalization 
 
 
 
 
 
 
 
 
X 
Assess for other 
interventions (psychiatry 
referral in intervention 
group/SSRI prescription by 
epileptologist in control 
group) 
 
 
 
 
 
 
 
 
X 
Assess time to psychiatry visit, 
intervention by psychiatry 
 
 
 
 
 
 
 
 
X 
Key for Schedule of Activities: 

Epileptologist Treatment of Depression and Anxiety 
 
Protocol  
 
 
 
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*: visits listed in bold occur for both intervention and control group; visits not bolded and green apply to intervention group only, procedures in 
blue occur for control group only (and only in phase II), procedures in green occur only for those receiving the intervention 
#: randomization applies only to phase II 
r: review scores collected at the intermediate outcome assessment 
 
2 
 
INTRODUCTION 
2.1 
STUDY RATIONALE  
 
Depression and anxiety are highly prevalent and major contributors to poor outcomes in 
chronic diseases managed by medical specialists, including cancer, congestive heart failure, ischemic 
cardiac disease, chronic obstructive pulmonary disease, and multiple chronic neurologic diseases1-2. 
Depression and anxiety are often undertreated, and solutions such as psychiatrist-supported 
collaborative care models or co-location of psychiatrists are not feasible for many medical specialty 
clinics, nor generalizable to the broad health care system due to poor access to mental health 
specialists3-5. 
 
Epilepsy is a chronic neurologic condition having particularly high prevalence of depression and 
anxiety, and these symptoms are associated with increased mortality, health care cost, cognitive 
dysfunction, medication adverse effects, poor quality of life and poor seizure outcome6-12.  Substantial 
unmet mental health care need exists in epilepsy, and a survey I conducted indicated top barriers to 
addressing anxiety and depression in epilepsy were poor access to psychiatrists and other mental health 
providers4,13. In epilepsy, screening for psychiatric symptoms at every visit is a quality measure, and free, 
valid and brief screeners for anxiety and depression exist (the Generalized Anxiety Disorder-7, GAD-7 
and Neurologic Disorders Depression Inventory-Epilepsy, NDDI-E, respectively)14-16. Measurement-based 
depression care is effective in primary care populations, and Advanced Practice Providers (APPs) 
improve quality of care in mental health settings17-18. Thus, we have launched a research program to first 
pilot, and then definitively test, a neurologist-directed, measurement-based, APP-supported medication 
and chronic care management intervention for depression and anxiety in the epilepsy clinic, utilizing 
FDA-approved medications for anxiety and depression (specifically escitalopram or venlafaxine if 
escitalopram is not tolerated). In the currently proposed pilot trial, after an up to 5 patient intervention-
only phase I, 30 patients will be enrolled and randomized to assess the feasibility of conducting a 
definitive trial of this intervention (study phase II). Specifically, the goals of this trial are to quantify 
recruitment and adherence rates - inputs required for planning the definitive trial; and to provide 
preliminary estimates of effect magnitude to inform sample size calculations for a larger trial.  
 
2.2 
BACKGROUND  
Depression and anxiety 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 patients21-25, and 
without structured assessment anxiety is under-recognized6. Although depression and anxiety are more 
important predictors of poor quality of life than seizure frequency7,22,26, these symptoms are 
underdiagnosed and undertreated in epilepsy27-28. Treatment of depression and anxiety in epilepsy is 
important to prevent suicide29, a contributor to excess mortality8, as a potential way to reduce excessive 
health care use10,30, and to improve quality of life7,26. However, a substantial unmet mental health care 
need exists in epilepsy13.  Despite the American Academy of Neurology Epilepsy Quality Measure to 
screen for psychiatric symptoms at each visit, and existence of well-validated, free and brief screeners 
for anxiety and depression in epilepsy (the GAD-7 and NDDI-E), my recent survey of leading 

Epileptologist Treatment of Depression and Anxiety 
 
Protocol  
 
 
 
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epileptologists indicated that few use validated anxiety and depression screening instruments, largely 
due to poor availability of mental health providers4,14-16,31-33.  
 
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 mental health providers4,5,34. A potential solution to address 
poor mental health care access is neurologist-driven medication treatment of depression and 
anxiety35. Small studies suggest these symptoms improve with standard, FDA-approved therapies 
effective for depression and anxiety in the general population36-37. The majority of epileptologists 
surveyed were willing to prescribe antidepressants (55.9%)4. Repeated use of validated screening tools 
for anxiety and depression facilitate treatment of these symptoms by non-psychiatrists, as has been 
shown in primary care, geriatrics, and large-scale general population studies17,38-39. Given the high 
prevalence and unmet need, it is important to use a learning healthcare system approach to assess 
feasibility and potential impact of measurement-based, neurologist-driven and APP-supported 
medication chronic care management of depression and anxiety, to address these symptoms directly in 
the epilepsy clinic and potentially circumvent substantial barriers to mental health care.  
 
We propose an innovative learning healthcare system approach to translate the concept of 
measurement-based depression care into a specialty clinic setting and extend the concept to treat 
depression and/or anxiety. Our neurologist/APP-administered medication intervention utilizes FDA-
approved drugs with advantageous features for use in epilepsy (escitalopram and venlafaxine)36-37 and a 
telephone-based chronic care management plan for repeated symptom measurement and side effect 
surveillance. The proposed intervention may overcome barriers to implementing mental health 
treatment interventions in generalized clinical settings by using healthcare providers commonly 
present in specialty clinics (physicians and APPs) along with a billable, best practices chronic care 
management intervention package. 
 
To test this idea, we seek to pilot a randomized trial of neurologist/APP medication management 
of depression and anxiety versus usual care with psychiatry referral in our epilepsy clinic, using epilepsy 
as a paradigm for chronic medical illness with high prevalence of psychiatric comorbidity14-15,31-32. The 
goal is to assess feasibility of this pragmatic, learning healthcare system intervention (primary outcome 
adherence, secondary outcomes accrual, retention) and estimate anxiety and depression outcomes to 
explore whether a larger trial would be appropriate.   
 
2.3 
RISK/BENEFIT ASSESSMENT   
2.3.1 KNOWN POTENTIAL RISKS  
 
The risks of participating in this trial are similar to risks encountered in standard clinical practice, 
where FDA-approved SSRI/SNRI medications (escitalopram and venlafaxine XR) are commonly 
prescribed in primary care, psychiatry practices, and by some neurologists/epileptologists.  Potential 
side effects of these drugs are well-known and listed in the package insert for each of the drug, with the 
most common side effects being minor symptoms including headache, nausea, diarrhea, insomnia, 
drowsiness, and sexual dysfunction40-41.  Suicide is a known risk among patients with anxiety and/or 
depression, and there is a black box warning for potential increased suicidal thoughts among children, 
adolescents and potentially young adults treated with antidepressants.  Monitoring is recommended40-
41.  Other serious risks are rare, and overall risks are no higher than in standard clinical practice using 
these drugs. 
 

Epileptologist Treatment of Depression and Anxiety 
 
Protocol  
 
 
 
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Psychiatry referrals are commonly employed in standard/usual care of patients who would be 
eligible for the trial. 
 
 
Outcome assessments and repeated symptoms screening administered during the trial pose 
minimal if any risk to participants (use of time to complete assessments is the main impact on 
participants). 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
The main benefit of prescribing SSRI/SNRI therapy and adjusting dose based on repeated 
assessment of depression and anxiety symptoms is improvement in these symptoms.  Trials of primary 
care prescribing of antidepressant therapy with biweekly repeated symptom screening found that one-
third of patients experienced remission of depression and nearly half responded to therapy17.  Phase III 
trials have shown both escitalopram and venlafaxine XR to be effective in treating major depressive 
disorder and generalized anxiety disorder40-41.  
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
The risk of the intervention in this study is minimal and no more than that experienced during 
standard clinical care (risk actually may be lower, as increased symptom monitoring and patient contact 
will occur in the best practice intervention via re-screening for anxiety and depression every 2 weeks).  
The benefit may be substantial. Since subjects are randomized to a treatment option in phase II, 
although both arms consist of appropriate clinical care for anxiety depression, randomization may pose 
some risk to participants if one arm proves to be more efficacious than the other. 
 
 

Epileptologist Treatment of Depression and Anxiety 
 
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3 
OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To assess whether adherence to 
intervention study regimen 
developed for a randomized trial of 
management of anxiety and 
depression in epilepsy, comparing 
neurologist/APP-administered 
medication/chronic care 
management versus usual care 
with psychiatry referral, is sufficient 
in pilot testing to support 
advancing to a larger definitive 
trial. 
 
-% intervention adherence in the 
intervention arm, defined as the % of 
participants who report taking the 
prescribed medication at 12 weeks 
(escitalopram or venlafaxine) AND 
who have completed at least 2 of the 
chronic care management scheduled 
visits (telephone or clinic visit) 
 
 
-obtain realistic 
estimate of feasibility 
of intervention 
implementation, i.e. 
adherence 
 
 
 
Secondary 
 
 
To quantify rates of accrual and 
retention in a randomized trial of 
neurologist/APP-administered 
medication/chronic care 
management of anxiety and 
depression in epilepsy versus usual 
care with psychiatry referral, inputs 
that will inform the design and 
sample size calculations for a large, 
definitive trial. 
 
-accrual:  
% of patients screened for the trial 
who are eligible 
% of patients eligible who are 
randomized  
 
 
 
-retention:  
% of participants from each arm who 
complete 12 week outcome 
assessment 
 
As of May 13,2019, the main active 
study goal is focused on the retention 
endpoint. 
-to provide more 
accurate estimate of 
future trial accrual rate 
for planning of next 
step trial 
-to develop strategies 
to improve accrual in 
future trial 
-to estimate future 
retention & develop 
retention strategy 
 
To assess 12-week changes in 
anxiety and depression symptoms 
in the medication intervention 
group versus usual care/psychiatry 
referral control group, to provide 
preliminary estimates of effect 
magnitude to inform sample size 
calculations for a larger 
randomized trial.  Anxiety and 
depression will be measured by the 
Beck Anxiety Index (BAI) and Beck 
Proposed efficacy outcomes: 
 a. 12 week change in Beck 
Depression Inventory (among those 
with high depression at baseline) 
 b. 12 week change in Beck Anxiety 
Index (among those with high anxiety 
at baseline) 
 
-these are well 
validated common 
data elements for the 
intervention-targeted 
conditions; by 12wk, 
dose titration & clinical 
effect are expected to 
be achieved 
 

Epileptologist Treatment of Depression and Anxiety 
 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Depression Inventory-II (BDI) 
respectively). 
Tertiary/Exploratory  
 
 
To explore the impact of the 
intervention on potential future 
secondary efficacy measures, 
including 12 week epilepsy-specific 
quality of life, patient reported 
outcome, and 6 week change in 
anxiety and depression. 
 
 
 
 
Potential secondary future efficacy 
measures: 
-change in epilepsy-specific quality of 
life at 12 weeks (QOLIE-10) 
-change in generic patient reported 
outcome at 12 weeks (PROMIS-10) 
-change in depression (BDI) at 6 wk 
-change in anxiety (BAI) at 6 wk 
 
 
 
-brief QOL instrument, 
QOL highly associated 
with anxiety and 
depression 
-brief generalizable 
patient outcome 
-assess whether 
intervention has an 
early impact on 
symptoms compared 
to control condition 
 
To explore the impact of the 
intervention on seizure frequency, 
adverse effects, health care 
utilization, patient satisfaction, and 
overall medication adherence. 
- seizure frequency  
-adverse medication effects 
-health care utilization, particularly 
ED visits and hospitalizations 
-patient satisfaction (CAHPS) 
-medication adherence (Morisky-4) 
-worsened seizures, 
adverse effects and 
health care utilization 
are associated with 
presence of anxiety and 
depression 
-assess impact of 
intervention on care 
satisfaction and overall 
medication adherence 
 
 
 

Epileptologist Treatment of Depression and Anxiety 
 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN 
 
This is a pilot pragmatic, randomized trial of a medication treatment/chronic care management 
intervention for anxiety and depression in epilepsy implemented in the epilepsy clinic vs. psychiatry 
referral.  Treatment is open-label, but secondary and exploratory outcome measures are collected by a 
research assistant blinded to treatment assignment.  The goals of the trial are to assess feasibility of a 
potential larger trial of the intervention versus psychiatry referral and to generate preliminary estimates 
of the proposed primary outcomes of a larger trial (change in anxiety and depression from baseline 
among those with symptoms at baseline).  The study is carried out at a single center (Wake Forest 
University).  Prior to the start of the randomized phase II for the trial, a limited intervention-only pilot 
will be carried out with up to 5 participants (phase I). The purpose of this is to streamline enrollment, 
intervention and outcome assessment procedures to ensure they are optimized by the start of the 
randomized phase. 
 
 
The intervention will consist of initiating a chronic care management plan in the epilepsy clinic 
and an initial prescription for escitalopram 10mg daily. Escitalopram dose adjustment will be made 
based on biweekly repeated screening of anxiety and depression symptoms using the NDDI-E and GAD-7 
brief validated instruments for depression and anxiety, respectively, as well as side effects identified on 
biweekly telephone calls or the 6-week APP follow up visit.  Escitalopram dose may be titrated up to a 
maximum of 20mg daily in 5-10mg increments every 2 weeks for treatment effect, or titrated down to 
5mg if needed for adverse effects. If a participant is unable to tolerate escitalopram, then venlafaxine XR 
37.5mg will be substituted, to be titrated in a similar manner biweekly based on side effects and anxiety 
and depression symptoms (with 37.5-75mg increment dose changes and maximum dose of 225mg 
daily). At the end of the 10 week chronic care intervention, participants will receive a prescription for 
the most recent dose of escitalopram or venlafaxine XR, and there may be a plan to transfer this 
prescription to the participant’s primary care provider (PCP), depending upon epileptologist preference. 
 
 
Participants randomized to control will have a psychiatry referral order placed by the treating 
epileptologist under typical care circumstances. This will be an internal or external referral order based 
on patient preference. If external, the order will be printed along with instructions for the patient to 
follow to find a provider covered by insurance. 
 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
Current usual care for anxiety and depression in epilepsy is highly variable, with underdetection 
of symptoms highly likely, as most epileptologists do not use validated screening instruments for 
depression or anxiety4.  When symptoms are detected, management varies from referral to a mental 
health provider, referral to a PCP for management of symptoms, or epileptologist prescribing of an 
antidepressant or anxiolytic, with referral to mental health providers and epileptologist prescribing 
being the most common management approaches4.  In this study, typical usual care with its current 
variability is not a feasible control condition, as the likely variability would dilute the intervention 
condition, since some control patients could be prescribed intervention drug or related medications.  
Considering the risk of suicide associated with anxiety and depression, it would be unethical to offer no 
treatment to the control group. Referral to psychiatry is a current acceptable standard of care for 
management of anxiety and depression in epilepsy despite the various barriers to access mental health 

Epileptologist Treatment of Depression and Anxiety 
 
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specialists.  Thus, a psychiatry referral control group will reflect the reality of treatment approach for 
many epilepsy patients with anxiety and depression under current care circumstances. 
 
 
4.3 
JUSTIFICATION FOR DOSE 
 
The starting doses for escitalopram and venlafaxine are commonly used, recommended starting 
doses for these agents and titration schedules are consistent with package insert recommended 
titration schedules. The maximal doses are within the FDA approved dosing range40-41. 
 
4.4 
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. 
 
 
 

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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. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
3. Male or female, age 18 or older 
4. Ability to take oral medication and be willing to adhere to the intervention regimen 
5. Minimum 1 prior clinic visit at the Comprehensive Epilepsy Center 
6. Adequate cognition (able to complete NDDI-E and GAD-7 independently) 
7. Diagnosis of epilepsy: EEG with documented seizure or epileptiform discharges OR non-
epileptiform EEG and seizure remission with antiseizure drug OR treating epileptologist’s leading 
clinical impression is epilepsy  
8. NDDI-E score >15 AND/OR GAD-7 score >10 
 
 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Pregnancy or lactation 
2. Known allergic reactions to escitalopram or venlafaxine 
3. Comorbid psychogenic nonepileptic seizures 
4. Prior psychiatric hospitalization 
5. Prior suicide attempt 
6. History of manic or psychotic symptoms (past manic episode (MINI-DSM-IV), or psychotic 
symptom screen positive) 
7. Current treatment by a psychiatrist or counselor/therapist 
8. Active suicidality at the time of screening  
9. Current treatment with buspirone or an SSRI/SNRI/atypical antidepressant (specifically 
bupropion, fluoxetine, levomilnacipran, citalopram, milnacipran, desvenlafaxine, mirtazapine, 
duloxetine, paroxetine, escitalopram, sertraline, fluvoxamine, venlafaxine, vilazodone, 
vortioxetine) 
5.3 
LIFESTYLE CONSIDERATIONS 
N/A 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to be screened for the clinical trial but 
are not subsequently randomly assigned to the study intervention 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).  
 

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Individuals who do not meet the criteria for participation in this trial (screen failure) because of 
a lack of current clinically significant anxiety or depression symptoms or other reasons may be 
rescreened.  
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Target study sample size: phase I: up to 5, phase 2: 30 (30 to be randomized).  Anticipated 
number of participants to be screened: up to 5000  
 
Anticipated accrual rate: 5 per month 
 
Number of sites: 1 
 
Recruitment venue: clinic of Wake Forest Comprehensive Epilepsy Center, adult-focused 
epilepsy physician practices  
 
Participants will be identified using a learning health system care model which includes ALL 
patients completing the GAD-7 and NDDI-E instruments upon check-in for a regular clinic visit in 
REDCap on an ipad. Those who have anxiety or depression (GAD-7 ≥ 10 or NDDI-E >15) will be 
prompted to complete additional eligibility questions in REDCap after brief screening consent, 
followed by in-person screening by the study coordinator if all of the electronic questions 
indicate potential eligibility. If eligible, then the full informed consent process will be completed 
by the study coordinator. If the participant consents, then they will proceed to the epilepsy 
clinic visit with the physician, followed by baseline research assessment and randomization. At 
randomization, the epilepsy physician will be informed of assignment and will either prescribe 
10mg escitalopram or place a psychiatry referral order. See Figure on page 5 for diagram of 
screening/enrollment flow. 
 
Additional screening and enrollment procedures may be completed, including: 
o A post clinic visit screening and enrollment procedure (see figure on page 7) in which 
individuals who appear potentially eligible based on prior medical chart review are 
approached for screening immediately on completion of a regular clinic visit. Verbal 
screening consent is obtained, followed by NDDI-E and GAD-7 instruments, then 
additional screening if GAD-7 ≥ 10 or NDDI-E >15. Consent and enrollment, followed by 
randomization is then completed for those who are eligible and consent.  All ineligible 
individuals with high GAD-7 and/or NDDI-E scores in this screening procedure will be 
offered a psychiatry referral. This model will be primarily utilized in the practices of 
epilepsy physicians newly added to the study team who had not previously participated 
in the learning health care system model described above. 
o New patients with high anxiety or depression symptoms identified via the learning 
health system model, if otherwise eligible and interested in the study will be offered a 
rapid follow-up visit with the epilepsy center physician to address anxiety and 
depression and potentially enroll in the study if still eligible at the time of follow-up. 
o We will expand the learning health system model of care by administering paper or 
electronic versions of the GAD-7 and NDDI-E to patients scheduled to see Kelly Conner, 
PA-C at the epilepsy center. Kelly will then have the option of scheduling patients for a 
fast-track follow up visit with their epileptologist for management of anxiety and/or 
depression/potential study enrollment. 
 
Multiple mailed/written reminders and telephone communications will be utilized to enhance 
participation in the outcome assessment telephone calls. These will also be scheduled at the 
time of enrollment if possible. 
 
Subjects will receive incentive of $25 gift card for completing 6 week outcome assessment call, 
and another $25 gift card for completing the 12-week outcome assessment calls.  

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 
Efforts will be made to recruit any eligible participant seen in the practice, including women and 
under-represented populations 
 
Pregnant women will be excluded due to potential risk to unborn offspring due to introduction 
of a new medication during pregnancy, considering the potential risks associated with SSRI/SNRI 
use in pregnancy (pregnancy category C)40-41. 
 

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6 
STUDY INTERVENTION 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
The study intervention is a complex, chronic care management model of care for anxiety and 
depression in epilepsy characterized by the following components: 
 
prescription for escitalopram 10mg daily initially by the treating epileptologist 
 
Chronic care management: 
 
biweekly APP telephone calls (2 weeks, 4 weeks, 8 weeks and 10 weeks)  
o use of standardized instruments to reassess anxiety and depression symptoms 
(NDDI-E and GAD-7)  
o assess for side effects  
o assess for manic and psychotic symptoms since last contact 
o potential medication dose adjustments/switch to venlafaxine XR based on 
symptom response and side effects identified 
 
6-week follow-up clinic visit with the APP to review NDDI-E and GAD-7 symptom status, 
side effects and potentially adjust dose 
 
Maximal potential daily medication doses: escitalopram 20mg, venlafaxine XR 225mg 
At the 10-week APP call, a prescription will be sent for the intervention medication with sufficient refills 
to last to the next regularly scheduled epilepsy clinic visit, or until a scheduled visit with the participant’s 
primary care provider (PCP). The participant’s epileptologist/APP team will continue to manage the 
medication as appropriate, along with ongoing usual epilepsy care, unless the intervention medication 
prescription was transferred to the participant’s PCP due to epileptologist preference. 
Control condition: psychiatry referral order placed by epileptologist under typical care circumstances 
(internal or external referral based on the participant’s geographic preferences).  Internal referrals will be 
processed by current clinic/institutional protocols.  External referral orders will be printed and provided 
to the patient along with brief instructions on how to find a provider covered by the patient’s insurance. 
6.1.2 DOSING AND ADMINISTRATION 
*see page 18 for definition of symptoms improved 
 
Initial treatment: escitalopram 10mg by mouth daily 
 
2 week call:  
o if no side effects, continue 10mg escitalopram daily 
o if side effects, reduce to 5mg escitalopram daily 
 
4 week call: 
o If symptoms are not improved, increase escitalopram daily dose by 5-10mg  
o If symptoms are improved, continue current dose 
o If side effects, reduce escitalopram daily dose by 5mg 
o If intolerable side effects at 5mg daily, stop escitalopram. Start venlafaxine XR 37.5mg 
daily, then increase to 75mg daily in 1 week. 
 
6 week visit: 
o If symptoms are not improved, increase escitalopram daily dose by 5-10mg (up to 
maximum 20mg daily) 

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o If symptoms are improved, or patient is already taking 20mg escitalopram daily and 
there are no side effects, continue current dose 
o If side effects, reduce escitalopram daily dose by 5mg 
o If intolerable side effects at 5mg daily, stop escitalopram. Start venlafaxine XR 37.5mg 
daily, then increase to 75mg daily in 1 week. 
o If venlafaxine XR was started previously:  
 
If symptoms are not improved, increase daily dose by 75mg 
 
If symptoms are improved, continue current dose 
 
If side effects, reduce daily dose by 37.5mg 
 
8 week call: 
o If symptoms are not improved, increase escitalopram daily dose by 5-10mg (up to 
maximum 20mg daily) 
o 
If symptoms are improved, or patient is already taking 20mg escitalopram daily and 
there are no side effects, continue current dose 
o If side effects, reduce escitalopram daily dose by 5mg 
o If intolerable side effects at 5mg daily, stop escitalopram. Start venlafaxine XR 37.5mg 
daily, then 75mg daily in 1 week. 
o If venlafaxine XR was started previously:  
 
If symptoms are not improved, increase daily dose by 75mg (up to maximum 
225mg daily) 
 
If symptoms are improved, continue current dose 
 
If side effects, reduce daily dose by 37.5mg  
 
10 week call: 
o If symptoms are not improved, increase escitalopram daily dose by 5-10mg (up to 
maximum 20mg daily) 
o 
If symptoms are improved, or patient is already taking 20mg escitalopram daily and 
there are no side effects, continue current dose 
o If side effects, reduce escitalopram daily dose by 5mg 
o If intolerable side effects at 5mg daily, stop escitalopram. Start venlafaxine XR 37.5mg 
daily, then 75mg daily in 1 week. 
o If venlafaxine XR was started previously:  
 
If symptoms are not improved, increase daily dose by 75mg (up to maximum 
225mg daily) 
 
If symptoms improved or already taking 225mg daily and no side effects, 
continue current dose 
 
If side effects, reduce daily dose by 37.5mg  
 
 
 
Definition of symptoms improved:  
o if the GAD-7 and/or NDDI-E scale score(s) for which the patient screened positive for trial 
entry are lower than the score(s) from the most recent measurement (2 weeks prior). 
[ALSO: IF the patient met trial entry criteria based on GAD-7 score alone, then the current 
NDDI-E score must also be ≤15.  OR IF the patient met trial entry criteria based on NDDI-E 
score alone, then the current GAD-7 score must also be <10.] 
OR 
o If the GAD-7 and NDDI-E scores are BOTH <10 and ≤15, respectively 

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6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
N/A: this is a pragmatic trial in which the intervention and control will be carried out during normal 
clinical care, via standard prescribing and referral ordering. 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
N/A 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
N/A 
 
6.2.4 PREPARATION 
N/A 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
In the randomized phase II, subjects will be randomized to medication/chronic care management 
intervention vs. psychiatry referral 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 epilepsy physician. Treatment group 
assignment will not be blinded to the treating physician, primary investigator, and primary study 
coordinator. Outcome assessment phone calls for gathering scaled instrument scores will be carried out 
by a second study coordinator blinded to treatment assignment (for both phases of the study).  In 
discussions between study coordinators with the PI regarding outcome related items while the trial is 
running, all efforts will be made if feasible to prevent the PI from knowing the treatment group 
allocation at that time.  
6.4 
STUDY INTERVENTION COMPLIANCE 
See outcome section for primary adherence outcome. 
Adherence will be assessed by a single question at each chronic care management APP phone call and 
the APP clinic visit.  The primary adherence outcome will be assessed in the intervention group at 12 
weeks by the unblinded primary study coordinator along with a modified Morisky-4 scale. Also, the 
primary study coordinator will contact participant pharmacies to ascertain number of refills obtained for 
the intervention medication to compare to expected number of refills in the setting of complete 
adherence. Time to psychiatry appointment scheduling, whether an appointment was scheduled, and 
whether the participant attended the scheduled psychiatry appointment will be collected at 12 weeks 
by the primary study coordinator (unblinded).  Medication adherence in general will be assessed using 
the Morisky-4 scale at 12 weeks in both groups by the blinded outcome assessment study coordinator.  
 
 
6.5 
CONCOMITANT THERAPY 

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For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications and supplements. 
 
6.5.1 RESCUE MEDICINE 
N/A 
 
 
 
 

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7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Discontinuation from escitalopram or venlafaxine XR does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated by the study protocol.  If a clinically 
significant finding is identified (including, but not limited to changes from baseline) after enrollment, the 
investigator or qualified designee will determine if any change in participant management is needed. 
Any new clinically relevant finding will be reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
 
Reason for discontinuation 
 
6 week (if not yet completed) and 12 week outcome assessment will still be completed unless 
the participant withdraws consent 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
Pregnancy 
 
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 sign the informed consent form but are not 
randomized/do not receive the study intervention may be replaced.  Subjects who sign the informed 
consent form, and are randomized and receive the study intervention, 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. 
 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to complete the 12-week outcome 
assessment and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to complete an outcome assessment 
appointment: 
 
The site 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, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  

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 
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. 
 
 
 

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8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
EFFICACY ASSESSMENTS  
Screening Assessment 
-NDDI-E and GAD-7 
 
Enrollment/Baseline Assessments: 
-BAI 
-BDI 
-QOLIE-10 
-PROMIS-10 
-LAEP (Liverpool adverse events profile); also includes a seizure frequency assessment  
-accrual assessment 
 
Intervention Efficacy Assessments (blinded coordinator completes, except *data points collected by 
unblinded coordinator) 
6 weeks 
-BAI 
-BDI 
-QOLIE-10 
-PROMIS-10 
-NDDI-E 
-GAD-7 
 
12 weeks 
-primary adherence assessment (patient reported medication adherence in intervention group)* 
-secondary adherence assessments* 
 
-review of pharmacy fill records* 
 
-modified Morisky scale for intervention medication* 
-retention assessment (was blinded outcome phone call completed?) 
-BAI 
-BDI 
-QOLIE-10 
-PROMIS-10 
-NDDI-E 
-GAD-7 
-LAEP (Liverpool adverse events profile); includes a seizure frequency assessment as well 
-CAHPS (patient satisfaction) 
-Morisky-4 (medication adherence) 
-time to psychiatry visit/appointment outcomes and psychiatry management plan in control group* 
-healthcare utilization (ED visits, hospitalizations) 
 
Clinical Care/Chronic Care Management (obtained from the medical chart) 
NDDI-E and GAD-7 at 2 weeks, 4 weeks, 8 weeks, and 10 weeks 
APP assessment of side effects: 2 weeks, 4 weeks, 6 weeks, 8 weeks, and 10 weeks 
Dosing of intervention SSRI/SNRI prescribed: 2 weeks, 4 weeks, 6 weeks, 8 weeks, and 10 weeks 
Adherence: whether participant completed the visit 

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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 and Eligibility (on Ipad): 
-assess psychiatric history exclusions: prior psychiatric hospitalization, current treatment by a 
psychiatrist or therapist, current anxiety and depression medications, history of psychogenic 
nonepileptic seizures 
-MINI DSM-IV past manic episode module (2-12 questions depending upon response) 
-psychotic symptom screen (auditory hallucinations) 
 
In-person screening 
-past suicide attempt? 
-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) 
 
Other Enrollment Assessments: 
-detailed demographics 
-MoCA (cognitive assessment) 
-LAEP (Liverpool adverse events profile) 
 
6 week assessment 
-NDDI-E (validated suicidality question for safety) 
-BDI suicidality question 
 
12 week assessment 
-NDDI-E (validated suicidality question for safety) 
-LAEP (Liverpool adverse events profile) 
-BDI suicidality question 
 
Clinical Care/Chronic Care Management (obtained from the medical chart) 
NDDI-E at 2 weeks, 4 weeks, 8 weeks, and 10 weeks (validated suicidality question for safety) 
APP assessment of side effects: 2 weeks, 4 weeks, 6 weeks, 8 weeks, and 10 weeks 
Dosing of intervention SSRI/SNRI prescribed: 2 weeks, 4 weeks, 6 weeks, 8 weeks, and 10 weeks 
 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  

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An adverse event (AE) or suspected adverse reaction 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 ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will 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 INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment.  
 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study intervention must always be suspect.  
 
• 
Related – A “related” adverse event reflects a realistic chance of a causal relationship between a study 
intervention and the adverse event.  Reasonable possibility means that there is evidence to suggest 
a causal relationship between the study intervention as suggested by an event that follows within a 
reasonable time after the intervention (i.e., 24 hours), follows a pattern consistent with the study 
intervention, and improves when the study intervention has stopped and/or the reaction reappears when 
the intervention is readministered. 
 

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• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
 
8.3.3.3 EXPECTEDNESS  
The Principal Investigator will be responsible for determining whether an adverse event (AE) is expected 
or unexpected.   
 
• 
Expected: Any adverse event that is listed in medication package insert, protocol, consent form, 
or part of the normal disease condition.  
 
• 
Unexpected: Any adverse event that is not listed in the current investigator brochure, 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 adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes  
 
event description,  
 
time of onset and duration 
 
clinician’s assessment of severity,  
 
relationship to study intervention (assessed only by those with the training and authority to 
make a diagnosis),  
 
time of resolution/stabilization of the event.  
 
All AEs occurring while on study must be documented appropriately regardless of relationship. All AEs 
will be followed to adequate resolution. 
 
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.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The Study team will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation.  Events will be followed for outcome information until resolution or stabilization. 
 

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8.3.5 ADVERSE EVENT REPORTING  
All adverse events will be reported on a quarterly basis to the Safety Monitoring Committee (I-DSMB) 
and upon continuing review to the IRB, 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 intervention 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. 
 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
N/A as the study intervention involves use of FDA-approved drugs commonly used in standard clinical 
care; potential side effects will be discussed with participants as part of standard clinical care 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
N/A 
 
8.3.9 REPORTING OF PREGNANCY  
If a participant becomes pregnant while receiving the medication treatment intervention, risks and 
benefits of continuing the medication would be discussed with the participant and discontinuation of 
the medication intervention would be offered to the participant after the discussion of risks and 
benefits. 
 
 
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; 
• 
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. 

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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 assessment calls and all clinical encounters with the subjects (in the clinic, during telephone 
based chronic care management, or other clinic telephone encounters). 
  
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 entry to identify 2 persons whom we can contact in case of an emergency and provide 2 
telephone numbers for each of these 2 individuals. All participants will receive information about safety 
precautions and procedures to follow in the event that a participant becomes imminently 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 

Epileptologist Treatment of Depression and Anxiety 
 
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31 
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 active suicidal ideation and history of suicide attempt are exclusion criteria for the study, we 
anticipate that the risk of participants becoming suicidal during the study will be minimal. 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 at outcome assessments (6 and 12 week outcome calls) 
If any participant indicates a significant worsening in anxiety or depression scores (1 standard deviation 
increase on the BDI or BAI from baseline, 11.75 and 9.08, respectively)19-20, the computer software 
system will facilitate identifying the worsening and an e-mail will be sent to the Wake Forest School of 
Medicine Project Manager and to study psychiatrist Dr. James Kimball.  The patient will be assessed to 
determine if there is a need for immediate treatment, under the guidance of Dr. Kimball. 
  
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. 
 
 

Epileptologist Treatment of Depression and Anxiety 
 
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32 
 
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
 
Primary (pertains to randomized study phase II):   We hypothesize that the primary endpoint, 
adherence within the intervention arm (defined as participant report of taking the prescribed 
medication at 12 weeks and participation in at least 2 chronic care management encounters), 
will be greater than 60%. 
 
 
Proposed Outcome Endpoint(s):  
 
Among those with clinically significant depression at baseline (NDDI-E>15), 12-week change in Beck 
Depression Inventory Score will be better in the medication/chronic care management intervention 
group than in the psychiatry referral group. 
 
Among those with clinically significant anxiety at baseline (GAD-7≥10), 12-week change in Beck Anxiety 
Index Score will be better in the medication/chronic care management intervention group than in the 
psychiatry referral group. 
 
 
Proposed Exploratory Endpoint(s): 
 
Improvement in epilepsy-specific quality of life (QOLIE-10) at 12 weeks will be greater in the 
medication/chronic care management intervention group than in the psychiatry referral group. 
 
Improvement in patient-reported outcome (PROMIS-10) at 12 weeks will be greater in the 
medication/chronic care management intervention group than in the psychiatry referral group. 
 
Among those with clinically significant depression at baseline (NDDI-E>15), 6-week change in Beck 
Depression Inventory Score will be better in the medication/chronic care management intervention 
group than in the psychiatry referral group. 
 
Among those with clinically significant anxiety at baseline (GAD-7≥10), 6-week change in Beck Anxiety 
Index Score will be better in the medication/chronic care management intervention group than in the 
psychiatry referral group. 
 
 
9.2 
SAMPLE SIZE DETERMINATION 
Phase I: We will recruit up to 5 individuals in an intervention-only pilot intended to streamline study 
procedures, not for data analysis. 
 
Phase II: We are aiming to recruit 30 participants for the randomized portion of the pilot study, with 15 
in the intervention arm and equal allocation between intervention arm and the control arm.  Using a 
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 adherent, we are at least 83% confident that the true 
probability of adherence is greater than 0.6.  Thus, if at least 11 intervention arm participants meet the 

Epileptologist Treatment of Depression and Anxiety 
 
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33 
primary adherence outcome, we will declare acceptable adherence for proceeding to a larger trial of this 
intervention. 
 
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 intervention arm participants who meet the adherence criteria will be calculated, and as 
described above in the sample size determination section, if at least 11 intervention arm participants 
meet the primary adherence outcome, we will declare acceptable adherence for proceeding to a larger 
trial of this intervention. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Accrual (proportion of participants who screen positive for anxiety or depression symptoms, # 
participants enrolled per month, proportion of total clinic follow-up patients enrolled per 
month, proportion consented and reasons for screen failure) and retention by group 
(proportion of randomized participants completing 12-week outcome assessment), will be 
assessed. These results will be utilized to plan realistic screening and recruitment goals for our 
larger, next-step trial.  
 
We will estimate 12-week change in anxiety and depression symptoms (BAI and BDI-II, 
respectively)19-20 in the medication intervention versus psychiatry referral control groups. To 
estimate effect of the intervention versus psychiatry referral on depression (BDI), we will 
calculate individual-level changes in total scores from baseline to 12 weeks among those with 
significant depression on initial screen. Mean changes in scores will then be compared between 
the two groups, (psychiatry referral vs. intervention group), using a two-sample t test with alpha 
level = 0.05. To estimate the effect of the intervention versus psychiatry referral on anxiety 
(BAI), we will similarly calculate individual-level 12 week change in BAI from baseline among 
those with significant anxiety on initial screening and compare mean changes between the two 
groups in a similar manner. Similar statistical methods will be used to estimate the effect of the 
intervention on other exploratory outcomes shown in Table 2 on page 6 between groups for all 
participants. The primary purpose of this analysis is to provide initial estimates of effect sizes 
and variability to inform sample size calculations for the large, definitive trial.  
 
9.4.4 SAFETY ANALYSES 
Similar statistical methods will be used to test for adverse effects measured by the Liverpool 
Adverse Event Profile (LAEP), as for the secondary outcomes (2 sample t-test comparing mean 
change in score from baseline to 12-week assessment), among the entire study population. Also 
the proportion of individuals in each group reporting suicidality will be compared between 
groups (separately for the NDDI-E suicide screening question and the BDI suicide question). 

Epileptologist Treatment of Depression and Anxiety 
 
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34 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Baseline demographics and scaled scores for anxiety, depression, quality of life, seizure frequency, and 
patient reported outcome measure will be compared between the two groups. Two sample t-test and 
chi square analyses will be used as appropriate to compare the intervention and control groups. 
 
9.4.6 PLANNED INTERIM ANALYSES  
N/A 
 
9.4.7 SUB-GROUP ANALYSES 
N/A: this small pilot study will not have sufficient power for subgroup analyses 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Individual participant data will be listed by measure and timepoint. 
 
9.4.9 EXPLORATORY ANALYSES 
Exploratory analyses will include comparison of patient satisfaction at 12 weeks between the 2 groups, 
comparison of change in seizure frequency by study group, comparison of the frequency of major health 
care utilization events (such as ED visits) between the 2 groups.  Two sample t-test or chi square analysis 
will be used as appropriate.  Kaplan-Meier modeling of time to remission of symptoms measured by 
NDDI-E and GAD-7 (score ≤15 and <10 respectively) will be done in the intervention group.  
 
 

Epileptologist Treatment of Depression and Anxiety 
 
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35 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following consent materials are submitted with this 
protocol: 
-brief screening consent  
-consent for enrollment and intervention in phase I along with outcome assessment 
-consent for treatment randomization and outcome assessment in phase II 
 
10.1.1.2 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 forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator 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.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document 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 informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, 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. 
10.1.2 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 
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
 

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36 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, and IRB. 
 
10.1.3 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 as private a setting as 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 clinical study site will permit access to such records. 
 
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. 
10.1.4 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.  
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator 
Heidi Munger Clary, MD, MPH 
Assistant Professor of Neurology 
Wake Forest University  

Epileptologist Treatment of Depression and Anxiety 
 
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37 
1 Medical Center Blvd. 
Winston-Salem, NC 27104 
336-716-7110 
hmungerc@wakehealth.edu 
10.1.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a Safety Monitoring Committee (SMC) composed of 
individuals with the appropriate expertise, including an independent investigator and a biostatistician. 
We will collaborate with the institutional Data and Safety Monitoring Board (I-DSMB) to establish the 
SMC. Members of the SMC should be independent from the study conduct and free of conflict of 
interest, or measures should be in place to minimize perceived conflict of interest.  The SMC will meet at 
least semiannually to assess safety and efficacy data on each arm of the study. Specifically, the main 
potential serious adverse event in this trial is suicidality. The 6 and 12-week outcome assessment calls 
include administration of the NDDI-E instrument in both the control and intervention groups, which has 
a single passive suicidal ideation question that has been validated as a suicide screen42, and a question in 
the BDI directly assessing suicidality. Data safety monitoring will include review of the proportion of 
participants reporting high suicidality scores (3 or 4 on the NDDI-E passive suicidality question or 2 or 3 
on the BDI suicide question) in each group, presented at each review. The SMC will provide its input to 
the primary investigator and study sponsor. 
 
10.1.7 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. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
The site will perform internal quality management of study conduct, data and biological specimen 
collection, documentation and completion.  A quality management plan will be developed to describe a 
site’s quality management. 
 
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 clinical trial 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).  
 

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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. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff at the site 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 adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and self-report instruments will be entered into 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. 
 
10.1.9.2 STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of 6 years after the last approval of a marketing 
application in an International Conference on Harmonisation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. 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.  
 
10.1.10 
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 
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, 

Epileptologist Treatment of Depression and Anxiety 
 
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39 
reported to the appropriate funding organization Program Official 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.  
 
10.1.11 
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. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, 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. 
 
10.1.12 
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. 
 
10.2 ADDITIONAL CONSIDERATIONS 
N/A 
 
 

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10.3 ABBREVIATIONS 
 
AE 
Adverse Event 
APP 
Advanced Practice Provider 
BAI 
Beck Anxiety Index 
BDI 
Beck Depression Index 
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 
I-DSMB 
Institutional Data and Safety Monitoring Board 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LAEP 
Liverpool Adverse Events Profile 
MedDRA 
Medical Dictionary for Regulatory Activities 
MoCA 
Montreal Cognitive Assessment 
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 
PROMIS-10 
Patient Reported Outcome-10 
QA 
Quality Assurance 
QC 
Quality Control 
QOLIE-10 
Quality of Life in Epilepsy-10 
SAE 
Serious Adverse Event 
SMC 
Safety Monitoring Committee 
SNRI 
Serotonin Norepinephrine Reuptake Inhibitor 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
SSRI 
Selective Serotonin Reuptake Inhibitor 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

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10.4 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 
5/14/2018 
Change manic symptom exclusion 
from SCID-II screen to MINI for DSM-
IV 
Observation that SCID-II was 
oversensitive: many individuals 
were ineligible due to irritability 
but not true past manic episode 
3 
6/21/2018 
Change MoCA to a baseline variable, 
modify cognitive inclusion criteria to 
ability to complete questionnaires 
independently. 
Add 3rd physician Dr. Cormac 
O’Donovan 
To boost recruitment based on 
observations of reasons for 
screen failure and frequency 
during enrollment to date. 
4 
7/21/2018 
Remove strict +/- 2 day timeframe 
for each study activity 
We now recognize that strict 
time windows such as these are 
not practical or commonly used 
in these types of behavioral 
trials. 
5 
9/10/2018 
Add additional recruitment 
strategies and related changes 
We have recognized that 
additional recruitment strategies 
are required due to 
unexpectedly high screen failure 
rate and decline of consent. 
6 
5/13/2019 
Clarify current goals of the project 
related to secondary retention 
endpoint. 
 
 
Add potential for electronic GAD-7 
and NDDI-E administration by study 
team in clinics of Kelly Conner, PA-C. 
Major goals have shifted to 
generating preliminary retention 
data. Clarification of goals 
requested by DSMB. 
 
An electronic tool for 
administering the GAD-7 and 
NDDI-E has become available 
for clinical use in the electronic 
medical record. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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