Clinical trial NCT04417907
Conditions: Epilepsy
Keywords: Perampanel Cognition
Sponsor: Kimford Jay Meador
Start date: 2021-10-20; Completion date: 2023-05-01
Enrollment: 29 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to determine whether there are any differences in the cognitive abilities and/or behavioral response of normal healthy volunteers across different titration rates of perampanel.

Detailed description:
This is a randomized, double-blind, parallel group design across different titration rates of perampanel in healthy volunteers. The study consists of 8 visits, 4 of which will occur at the participant's home, over a 7-week period. One hundred and three (103) normal healthy subjects will be treated with perampanel (PER) at one of four different titration rates: (1) 2mg/day PER for one week followed by 4mg/day PER for five weeks, (2) 2mg/day PER for two weeks followed by 4mg/day PER for four weeks, (3) 4mg/day PER for six weeks, or (4) placebo (0mg/day PER) for six weeks. Cognitive and behavioral function testing along with safety testing will be conducted at screening, pretreatment baseline, the end of each week during the titration and maintenance period.

Arms: arm 1: Participants will take 2mg placebo PO QD for six weeks. arm 2: Participants will take 2mg perampanel PO QD for one week, followed by 4mg perampanel PO QD for five weeks. arm 3: Participants will take 2mg perampanel PO QD for two weeks, followed by 4mg perampanel PO QD for four weeks. arm 4: Participants will take 4mg perampanel PO QD for six weeks
Interventions: intervention 1: Perampanel 1 week titration intervention 2: Perampanel 2 week titration intervention 3: Perampanel 4mg intervention 4: Placebo
Intervention descriptions: intervention 1: Healthy adults will take 2mg perampanel PO QD for one week followed 4mg perampanel PO QD for five weeks. intervention 2: Healthy adults will take 2mg perampanel PO QD for two weeks followed 4mg perampanel PO QD for four weeks. intervention 3: Healthy adults will take 4mg perampanel PO QD for six weeks intervention 4: Healthy adults will take 2mg placebo PO QD for six weeks

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
Perampanel Titration and Cognitive Effects 
 
Protocol Version 1.8 – 02 May 2022 
 
NCT0441797 
 


Version 1.8 Dated 02MAY2022 
 
1
PROTOCOL FOR CLINICAL RESEARCH TRIAL 
 
Protocol Version 1.8 – 02 May 2022 
 
TITLE: Effects of Titration Rate on Cognitive and Behavioral Side Effects of Perampanel 
 
 
BRIEF DESCRIPTION OF STUDY 
 
This is a randomized, double-blind, parallel group design across different titration rates 
of perampanel in healthy volunteers. The study consists of 8 visits, 4 of which will occur at the 
participant’s home, over a 7-week period.  One hundred and three (103) normal healthy 
subjects will be treated with perampanel (PER) at one of four different titration rates: (1) 
2mg/day PER for one week followed by 4mg/day PER for five weeks, (2) 2mg/day PER for two 
weeks followed by 4mg/day PER for four weeks, (3) 4mg/day PER for six weeks, or (4) placebo 
(0mg/day PER) for six weeks. Cognitive and behavioral function testing along with safety testing 
will be conducted at screening, pretreatment baseline, the end of each week during the 
titration and maintenance period.  
 
TIME PERIOD AND NUMBER OF SUBJECTS 
A. 
Anticipated Number of Subjects:  
103 (to obtain 76 evaluable subjects) 
B. 
Anticipated Duration of Study:    
1 Year 
 
 
 
DESCRIPTION OF MEDICATIONS 
Generic 
 
 
 
Strength and   
Therapeutic 
              
 
 
Dosage Form  
Classification 
 
PER 
 
 
 
 
2 mg/capsule  
 
Anticonvulsant 
 
 
Prepared by: 
Kimford J. Meador, MD 
Professor, Department of Neurology & Neurological Sciences 
Stanford Comprehensive Epilepsy Center 
Stanford University School of Medicine 
213 Quarry Road (Room 2856) 
Stanford, CA 94304-5979 
Tel: 650:725-6648 
 
 
Fax: 650:498-6326  
kmeador@stanford.edu


 
2
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
      Page 
I. 
BACKGROUND AND RATIONALE 
 
 
 
 
 
3 
II. 
STUDY QUESTION 
 
 
 
 
 
 
 
 
4 
III. 
STUDY OBJECTIVE 
 
 
 
 
 
 
 
4 
IV. 
STUDY DESIGN 
 
 
 
 
 
 
 
 
4 
V. 
STUDY POPULATION 
 
A. 
Number and type of subjects  
 
 
 
 
4 
 
B. 
Inclusion Criteria 
 
 
 
 
 
 
 
4 
 
C. 
Exclusion Criteria 
 
 
 
 
 
 
 
5 
VI. 
STUDY PROCEDURES 
 
A. 
Overview: time and events 
 
 
 
 
 
 
5 
 
B. 
Blinding and controls  
 
 
 
 
 
6 
 
C. 
Dosage regimen 
 
 
 
 
 
 
 
6 
 
D. 
Enrollment goals 
 
 
 
 
 
 
 
6 
 
E. 
Visit-specific treatment and evaluation sequence 
 
 
6 
 
F. 
Subject Reimbursement Rates 
 
 
 
 
 
8 
VII. 
NEUROPSYCHOLOGICAL TESTS 
 
A. 
Outline 
 
 
 
 
 
 
 
 
9 
 
B. 
Description of Individual Tests 
 
 
 
 
 
9 
VIII. 
STUDY MEDICATION 
 
A. 
Description 
 
 
 
 
 
 
 
 
15 
 
B. 
Packaging and labeling 
 
 
 
 
 
 
15 
 
C. 
Shipment and storage 
 
 
 
 
 
15 
 
D. 
Maintenance of medication dispensing records 
 
 
 
15 
 
E. 
Return of unused medication  
 
  
 
 
15 
 
F. 
Concomitant medication and therapy 
 
 
 
 
15 
VIII. 
CLINICAL AND LABORATORY MEASUREMENTS 
 
 
 
 
 
A. 
Clinical efficacy measurements 
 
 
 
 
 
16 
 
B. 
Clinical safety measurements  
 
 
 
 
16 
 
C. 
Adverse event procedures 
 
 
 
 
 
 
17 
 
D. 
Medication compliance assessment  
 
 
 
18 
 
E. 
Subject discontinuation criteria 
 
 
 
 
 
19 
IX. 
STATISTICAL EVALUATION 
 
A. 
Sample size rationale  
 
 
 
 
 
20 
 
B. 
Methodology for statistical analysis  
 
 
 
20 
 
C. 
Interim analysis 
 
 
 
 
 
 
 
22 
 
D. 
Definition of evaluable subject (safety, efficacy) 
 
 
 
22 
X. 
REFERENCES  
 
 
 
 
 
 
 
22 
XI. 
APPENDICES  
 
 
 
 
 
 
 
 
 
A.  
Study Timetable 
 
 
 
 
 
 
 
27 
 
B. 
Protocol Signature Form 
 
 
 
 
 
 
28 


 
3
I. 
BACKGROUND AND RATIONALE                                                                               
 
 
The efficacy of antiseizure medications (ASMs) in reducing seizures is similar for the 
most common type of seizures (i.e., focal +/- secondary generalized).  Therefore, differential 
side effects play an important role in therapeutic decisions.  In this regard, differential cognitive 
effects of ASMs are of particular interest.  The older ASMs are known to produce untoward 
cognitive effects, which are clinically significant in some patients (Meador, 2001).  The cognitive 
effects of carbamazepine, phenytoin, and valproate are similar while the effects of 
phenobarbital are worse. Several of the newer ASMs are well tolerated and demonstrate fewer 
adverse cognitive effects compared to placebo and to older ASMs, but other new ASMs have 
significant cognitive side effects (Meador, 2020). 
 
Perampanel (PER) is a new generation ASM, which acts as an antagonist of α-amino- 3-
hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Phase II studies in patients with 
focal seizures demonstrated doses from 4-12mg/day are generally well-tolerated, with the 
most common adverse events being CNS-related (Krauss et al., 2012a). Additionally, in phase III 
studies showed that the minimum effective dose for seizure reduction is 4mg/day and that 4-
12mg/day have acceptable tolerability, with adverse events of dizziness, somnolence, and 
fatigue showing dose-dependent effects (French et al., 2013; Krauss et al., 2012b). 
  
Studies examining the cognitive effects of perampanel suggest that measures of 
cognition are minimally affected by perampanel at maintenance therapeutic doses. A 
retrospective comparison of the cognitive effects lacosamide and perampanel suggests that 
neither have negative effects on cognition (Meschede et al., 2018). However, this study was 
confounded by several factors, such as the use of perampanel and lacosamide as adjunctive 
treatments. A prospective, long-term study of the cognitive effects of perampanel in 
adolescents did not show an impact on a global measure of cognition, measured by a change 
from baseline assessments (Piña-Garza et al., 2018). Similar findings were shown in adolescents 
in another randomized, controlled trial in which a global cognitive measure after adjunctive 
treatment with perampanel was not different from placebo (Meador et al., 2016). 
 
Cognitive side effects of drugs are affected by ASM dose and titration, However, the 
effects of titration and habituation on the cognitive and behavioral side effects of drugs are not 
well established for most ASMs, especially in regards to the timing of such effects, with the 
possible exception of topiramate. The present label representation of all drug-related 
treatment emergent adverse effects (TEAEs) across the titration and maintenance phases of 
clinical trials overexpresses the ultimate expected TEAEs once titration is completed and time 
for habituation has occurred. A more realistic and pragmatic view of TEAEs would be to denote 
TEAEs leading to ASM discontinuation and then separate TEAEs occurring during titration and 
the remaining TEAEs at maintenance once titration and time for habituation have occurred. 
 
The present investigation is a post-marketing study in healthy volunteers designed to 
provide more safety information on effects of perampanel dose and titration on cognitive and 
other side effects, employing a randomized double-blind parallel group design at different 


 
4
titration rates. The design provides robust statistical strength and controls for selection bias 
created by individual variability in cognitive performance. The use of healthy subjects will 
control for the effects of epilepsy, underlying brain dysfunction, and changes in seizure 
frequency on cognitive function. In addition, examining ASM cognitive effects in healthy 
subjects allows extrapolation of the results to other patient populations that might be 
potentially treated with ASMs (e.g., tremor, pain). We have conducted multiple studies with 
similar design with an excellent safety record that have provided clear delineation of the 
cognitive side effects of ASMs (Meador, et al. 2019). 
 
II. 
STUDY QUESTIONS 
 
1. What are the behavioral, cognitive or other side effects of perampanel at different 
titration rates in healthy volunteers? 
2. What is the time course of habituation to objective vs. subjective neuropsychological 
(e.g., cognitive and behavioral) side effects of perampanel? 
 
III. 
STUDY OBJECTIVE 
 
 
The objective of this study is to determine whether there are any differences in the 
cognitive abilities and/or behavioral response of normal healthy volunteers across different 
titration rates of perampanel.  
 
IV. 
STUDY DESIGN 
 
The study will employ a randomized, double-blind, parallel group design across different 
titration rates of perampanel in healthy volunteers. Every subject will be treated with 
perampanel (PER) at one of four different titration rates: (1) 2mg/day PER for one week 
followed by 4mg/day PER for five weeks, (2) 2mg/day PER for two weeks followed by 4mg/day 
PER for four weeks, (3) 4mg/day PER for six weeks, or (4) placebo (0mg/day PER) for six weeks. 
A study physician will monitor each subject during ASM treatment period. Subjects will undergo 
cognitive, behavioral, and safety testing at screening, prior to initiation of the first dose, and at 
the end of each week during the titration and maintenance period. Subjects and study 
personnel in direct contact with subjects will be blinded to ASM treatment. 
 
V. 
STUDY POPULATION 
 
 
A. 
Number and type of subjects 
 
 
Healthy males and females between the ages of 18 and 55 who do not require 
concomitant medications that affect study medications or cognitive and behavioral functions.  
One hundred and three subjects across three academic medical centers (Stanford University, 
New York University, and Northwestern University) will be enrolled in the study in order to 
complete 76 subjects. 
 


 
5
B. 
Inclusion Criteria 
 
 
1. Healthy adults between the ages of 18 and 55 years 
 
 
2. Male or female (using approved birth control methods) 
 
 
3. Informed consent obtained 
 
C. 
Exclusion Criteria 
 
 
 
1. Presence of clinically significant cardiovascular, endocrine, hematopoietic, hepatic, 
neurologic, psychiatric, or renal disease. 
 
2. Presence or history of drug or alcohol abuse or positive urine drug test at screening. 
 
3. The use of concomitant medications, which are known to affect perampanel or the 
use of any concomitant medications that may alter cognitive function (see Section VIII.F 
for a partial list). 
 
4. Prior adverse reaction to or prior hypersensitivity to perampanel. 
 
5. Prior participation in studies involving perampanel. 
 
6. Subjects who have received any investigational drug within the previous thirty days. 
 
7. Subjects with IQ < 80 as determined by the Peabody Picture Vocabulary Test after 
enrollment. 
 
8. Positive pregnancy test. Women of childbearing potential will be required to use 
approved birth control methods during the study. 
 
9. Presence of lifetime history of suicide attempt (including an active attempt, 
interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months 
as indicated by a positive response (‘Yes’) to either Question 4 or Question 5 of the C-
SSRS at Screening. 
 
10. Invalid results on computerized cognitive tests at screening as indicated by a ‘No’ on 
any of the validity indicators generated in the CNS Vital Signs report and low effort on 
neuropsychological assessments per investigator judgement. 
 
VI. 
STUDY PROCEDURES 
 
A. 
Overview: time and events 
 
 
 
 


 
6
 
The study will employ a randomized, double-blind, parallel group design across different 
titration rates of perampanel in healthy volunteers. The study consists of 8 visits over an 8-
week time period. Subjects will be screened and tested at baseline, and then randomly assigned 
to receive one of four titration schedules, each lasting 6 weeks. (See Appendix A for a complete 
study timetable). 
 
B. 
Blinding and Controls 
 
 
Subjects and study personnel will be blinded to drug randomization since all study drugs 
will be over-encapsulated in identical capsules.  
 
C. 
Dosage Regimen 
 
 
 
 
 
Subjects will be titrated up to 4mg/day PER or receive placebo according to the dosage 
schedule below: 
 
Event 
1 
2 
3 
4 
5 
6 
7 
8 
Week 
Screen 
BLa 
1 
2 
3 
4 
5 
6 
Clinic Visit 
X 
X 
 
 
X 
 
 
X 
Placebo 
 
 
0mg 
0mg 
0mg 
0mg 
0mg 
0mg 
PERb-1 
 
 
2mg 
4mg 
4mg 
4mg 
4mg 
4mg 
PERb-2 
 
 
2mg 
2mg 
4mg 
4mg 
4mg 
4mg 
PERb-3 
 
 
4mg 
4mg 
4mg 
4mg 
4mg 
4mg 
Partial NPc 
 
 
X 
X 
 
X 
X 
 
Full NPd 
X 
X 
 
 
X 
 
 
X 
TEAEse 
X 
X 
X 
X 
X 
X 
X 
X 
Testing is at the end of each week. 
aBL = baseline visit. 
bPER = perampanel. 
cPartial NP = partial neuropsychological battery on non-clinic visit weeks refers to online CNS-
Vital Signs computerized cognitive tests and behavioral questionnaires (POMS-total, AEP, & 
QOLIE-89 cognitive scores, which will be mailed back). 
dFull NP = full neuropsychological battery includes Non-computerized cognitive tests and the 
Partial NP (questionnaires and online CNS-Vital Signs computer tests). 
eTEAEs = treatment emergent adverse events. 
 
The investigative team will monitor each subject’s progress and safety during ASM 
treatment periods. Subjects will remain in their treatment arm for a total of 6 weeks. 
 
D. 
Enrollment Goals 
 


 
7
 
Previous studies indicate that an enrollment of 103 subjects will be required to obtain 
76 evaluable subjects. See Statistical Section for power analysis. 
 
E. 
Visit-Specific Treatment and Evaluation Sequence 
 
 
 
 
Subjects will be randomly assigned to one of four possible titration schedules. Each 
titration schedule lasts 6 weeks.   
 
At all visits, subjects will be advised on drug compliance and avoidance of medications 
which my adversely effect the results of cognitive function testing. Adverse events will be 
documented on the appropriate case report form.  Appointments will be made for follow up 
visits and care will be taken to schedule all cognitive and behavioral function testing for a given 
subject at the same time of the day. Dosing of the study medication should be at approximately 
the same time of day (e.g., before the participant goes to sleep). However, due to the long half-
life of perampanel, this is not critical. The time of testing and time of last 2 doses will be 
recorded.   
 
 
The timetable for the study is listed in Appendix A.  This is a visit-by-visit description of 
the events scheduled for each visit. 
 
 
Visit 1  
Screening Visit (-1 weeks prior to randomization) 
 
 
Subjects will be screened to assure they meet all of the inclusion criteria and none of 
the exclusion criteria.  All eligible subjects will be required to give informed consent.  A 
complete history, full physical examination, full neurologic examination, vital signs, laboratory 
screening (including urine pregnancy test for women of childbearing potential), urine drug 
screen, IQ screen with Peabody Picture Vocabulary Test, full cognitive battery (see below), and 
lifetime assessment of suicidal ideation/behavior measured by the Columbia-Suicide Severity 
Rating Scale (C-SSRS) will be obtained. 
 
 
 
Visit 2  
Baseline/Randomization (Study week 0) 
 
 
At this visit all subjects who had successfully completed all screening tests and had no 
significant abnormalities on baseline laboratory, physical exam, neurologic exam, or IQ testing 
will be randomized to study drug.  At this visit, neuropsychological testing will be conducted 
before the first dose of study drug is administered.  Subjects will be randomized and study drug 
will be dispensed. 
 
 
 
Visit 3  
Home testing (Study week 1) 
 
 
At this visit, a partial neuropsychological assessment of cognitive function and 
behavioral testing will be performed. The assessments at this visit consist of online CNS-Vital 
Signs computerized cognitive tests and behavioral questionnaires (Profiles of Mood States 


 
8
(POMS), Adverse Events Profile (AEP), & cognitive/behavioral subsets of QOLIE-89). Partial 
neuropsychological assessment will be conducted. Telephone contact will be made to check on 
adverse events and to encourage compliance. 
 
 
Visit 4  
Home testing (Study week 2) 
 
 
At this visit, a partial neuropsychological assessment of cognitive function and 
behavioral testing will be performed. The assessments at this visit consist of online CNS-Vital 
Signs computerized cognitive tests and behavioral questionnaires (Profiles of Mood States 
(POMS), AEP, & cognitive/behavioral subsets of QOLIE-89). Partial neuropsychological 
assessment will be conducted. Telephone contact will be made to check on adverse events and 
to encourage compliance.  
 
 
Visit 5  
Clinic testing (Study week 3) 
 
 
At this visit, a brief physical examination, brief neurologic examination, vital signs, full 
neuropsychological assessment of cognitive function and behavioral testing will be performed. 
Full neuropsychological assessment will be conducted and perampanel blood levels will be 
collected. Time of last dose will be collected, suicidal ideation/behavior since last visit (C-SSRS) 
will be obtained, and adverse events will be assessed. 
 
 
Visit 6  
Home testing (Study week 4) 
 
 
At this visit, a partial neuropsychological assessment of cognitive function and 
behavioral testing will be performed. The assessments at this visit consist of online CNS-Vital 
Signs computerized cognitive tests and behavioral questionnaires (Profiles of Mood States 
(POMS), AEP, & cognitive/behavioral subsets of QOLIE-89). Partial neuropsychological 
assessment will be conducted. Telephone contact will be made to check on adverse events and 
to encourage compliance.  
 
 
Visit 7  
Home testing (Study week 5) 
 
 
At this visit, a partial neuropsychological assessment of cognitive function and 
behavioral testing will be performed. The assessments at this visit consist of online CNS-Vital 
Signs computerized cognitive tests and behavioral questionnaires (Profiles of Mood States 
(POMS), AEP, & cognitive/behavioral subsets of QOLIE-89). Partial neuropsychological 
assessment will be conducted. Telephone contact will be made to check on adverse events and 
to encourage compliance.  
 
 
Visit 8  
Clinic testing (Study week 6) 
 
 
At this visit, a full physical examination, full neurologic examination, vital signs, 
laboratory screening (including urine pregnancy test for women of childbearing potential), 
urine drug screen, full neuropsychological assessment of cognitive function and behavioral 


 
9
testing will be performed. Full neuropsychological assessment will be conducted and 
perampanel blood levels will be collected. Time of last dose will be collected, suicidal 
ideation/behavior since last visit (C-SSRS) will be obtained, and adverse events will be assessed.  
 
F. 
Subject Reimbursement Rates 
 
Subject Reimbursement Rates (total $1300): 
Event 
1 
2 
3 
4 
5 
6 
7 
8 
Week 
Screen 
BL 
1 
2 
3 
4 
5 
6 
Clinic vs Web 
Clinic 
Clinic 
Web 
Web 
Clinic 
Web 
Web 
Clinic 
Payment 
$100 
$100 
$200 
$100 
$200 
$100 
$100 
$400 
Provisions for prorating payment: If perampanel levels tested at visits 5 and 8 are below 
detectable levels, this indicates that the participant was not complying with the protocol and 
they will not receive their final payment of $400 for visit 8. Please note that this only applies to 
participants assigned to the three perampanel groups, not the placebo group. 
 
 
VII. 
NEUROPSYCHOLOGICAL TESTS 
 
A. 
Outline:  
Note that test will be performed in the following order. 
 
Computerized Testing Battery (CNS Vital Signs system) 
• Verbal memory immediate assessment 
• Visual memory immediate assessment 
• Symbol digit coding assessment 
• Shifting attention test 
• Dual task test 
• One- and two-back continuous performance test 
• Verbal memory delay assessment 
• Visual memory delay assessment 
 
Non-computerized cognitive/behavioral testing 
• MCG paragraph memory-immediate recall assessment 
• Symbol digit modalities test 
• Stroop test 
• Profile of mood states (POMS) assessment 
• AEP 
• QOLIE-89 cognitive domains (attention/concentration, language, memory) 
• MCG paragraph memory-delay recall assessment 
• Columbia-Suicide Severity Rating Scale 
 


 
10
B. 
Description of Individual Tests: 
 
1. 
Components for computerized cognitive assessments: 
The computerized cognitive assessments have been used in prior studies (see reference section 
for CNS Vital Signs). It consists of verbal memory immediate assessments, visual memory 
immediate assessments, symbol digit coding, shifting attention tasks, dual task tests, one- and 
two-back continuous performance tests, verbal memory delayed, and visual memory delayed. 
Detailed descriptions of each are below. 
 
1a. 
The order of computerized testing should be as follows: 
• Verbal memory immediate 
o Encoding - 30 seconds 
o Immediate recognition - 1 minute 
• Visual memory immediate 
o Encoding - 30 seconds 
o Immediate recognition-1 minute 
• Symbol digit coding - 2 minutes 
• Shifting attention test - 2 minutes 
• Dual task test - 2 minutes 
• One- and two-back continuous performance test - 5 minutes 
• Verbal memory delayed - 1 minute 
• Visual memory delayed - 1 minute 
 
These are actual test run times and do not include reading instructions or practice tests. 
 
1b. 
Verbal memory immediate assessment: 
 
Fifteen words are presented sequentially for 2 seconds each on the computer screen and 
subjects are instructed to remember the words. Following their presentation, the 15 target 
words are presented in addition to new words, and the subject indicates if the word is new (not 
presented) or old (a member of the original presentation list). The duration of instructions and 
testing is approximately 3 minutes. 
Results are reported as follows: 
• Correct hits (immediate) 
• Correct passes (immediate) 
• Total Correct hits + passes (immediate) – This is a primary measure for Z score. 
 
1c. 
Visual memory immediate assessment: 
 
Fifteen shapes are presented sequentially for 2 seconds each on the computer screen, and 
subjects are instructed to remember the shapes. Following their presentation, the 15 target 
shapes are presented in addition to new shapes, and the subject indicates if the shape is new 


 
11
(not presented) or old (a member of the original presentation list). The duration of instructions 
and testing is approximately 3 minutes. 
Results are reported as follows: 
• Correct hits (immediate) 
• Correct passes (immediate) 
• Total Correct hits + passes (immediate) – This is a primary measure for Z score. 
 
1d. 
Symbol digit coding: 
 
As a measure of processing efficiency, symbols are presented on the computer screen and the 
subject types in numbers that correspond to each symbol based upon a response key. The 
duration of instructions and testing is approximately 4 minutes. 
Results are reported as follows: 
• Correct responses – This is a primary measure for Z score. 
• Errors 
• Correct responses – Errors    – This is a primary measure for Z score. 
 
 
1e. 
Shifting attention test: 
 
As a measure of set shifting attention and executive function, the subject assesses a series of 
targets and rules and responds by pressing the appropriate shift key. The duration of 
instructions and testing is approximately 3 minutes. 
Results are reported as follows: 
• Correct responses 
• Errors 
• Correct responses – Errors    – This is a primary measure for Z score. 
 
1f. 
Dual task test: 
 
This is a test that measures multi-tasking. The subject traces the track of a target with a 
computer mouse while simultaneously monitoring and responding each time a number from a 
series of sequentially presented random numbers (i.e., 1 to 99) is presented which corresponds 
to specific criteria (i.e., between 45 and 55). The duration of instructions and testing is 
approximately 3 minutes. During the test portion, the level of difficulty increases by increasing 
the speed of the target movement. There are 8 levels of difficulty. 
Results are reported for each of 8 levels (X 15 second each) of increasing difficulty as follows: 
• Percent of time cursor in box 
• Correct responses 
• Correct average reaction time 
• Commission errors 
• Omission errors 
 


 
12
Summary across the 8 levels of difficulty includes: 
• Total percent of time cursor in box 
• Average percent of cursor in box 
• Total correct responses 
• Average correct reaction time 
• Total commission errors 
• The primary measure for this test is a Z score averaging Z scores for (% time in box) + 
(Correct RT) + (# Correct – Errors). 
 
1g. 
One- and two-back continuous performance test: 
 
As a measure of working memory and sustained attention, subjects are presented a series of 
shapes of different colors in a sequence on the computer screen. Subjects are required to press 
the spacebar upon seeing the target (e.g., blue square), but only when a matching stimulus 
(e.g., blue square) appears 1 position before (i.e., one-back) or 2 positions before (i.e., two-
back). The duration of instructions and testing is approximately 6 minutes. As an example of 
two-back, correct responses (yes/no) are given for the following sequence of stimuli: 
• Blue square=no 
• Red triangle=no 
• Blue square=yes 
• Blue triangle=no 
 
Results are reported as follows: 
• Correct responses 
• Average correct response time 
• Incorrect responses 
• Average incorrect response time 
• Omission errors 
• The primary measure for this test is a Z score averaging Z scores for (Correct RT) + (# 
Correct – Errors). 
 
1h. 
Verbal memory delayed assessment: 
 
This is a measure of delayed memory in which the 15 target words from the original list are 
presented interspersed with 15 foils. The subject indicates if the word is new (not previously 
presented) or old (a member of the original presentation list). The duration of testing is 
approximately 1 minute. 
Results are reported as follows: 
• Correct hits (delayed) 
• Correct passes (delayed) 
• Total Correct responses– This is a primary measure for Z score. 
 
1i. 
Visual memory delayed assessment: 


 
13
 
This is a measure of delayed memory in which the 15 target shapes from the original list are 
presented interspersed with 15 foils. The subject indicates if the shape is new (not previously 
presented) or old (a member of the original presentation list). The duration of instructions and 
testing is approximately 1 minute. 
Results are reported as follows: 
• Correct hits (delayed) 
• Correct passes (delayed) 
• Total Correct responses– This is a primary measure for Z score. 
 
2. 
Components for non-computerized cognitive and behavioral assessments: 
 
The non-computerized cognitive and behavioral battery performance measures consist of MCG 
paragraph memory, symbol digit modalities test, Stroop test, and POMS. A detailed description 
of each of these follows. 
 
2a. 
Peabody picture vocabulary test: 
 
At Screening, the PPVT (third edition) will be used to assess IQ at enrollment. The PPVT is an 
individually-administered test of receptive vocabulary (of standard English) for children and 
adults from 2.5 through 90 years old. This test requires examinees to examine a series of 4 
pictures and choose which best represents the meaning of a stimulus word that is presented 
orally by the examiner (Dunn and Dunn, 1997). 
 
This is screening measure and is not used in analyses. 
 
2b. 
MCG paragraph memory: 
 
The MCG paragraph memory test includes a matched set of short stories that were previously 
developed and have been shown to be sensitive to the side effects of anticonvulsants (Meador 
et al, 1993). On each test day, the subjects will be read 1 of the short stories. Free immediate 
and delayed (approximately 15-minute) recall will be obtained. 
 
The primary measure for Z score is the % correct for delayed recall. 
 
2c. 
Symbol digit modalities test: 
 
The SDMT is a measure of cognitive processing involving coding which is sensitive to drug 
effects. This is a complex graphomotor transcription task that requires the subject to transcribe 
symbols to numbers as quickly as possible employing a combination of direct visual 
identification and/or short-term memorization. Symbols with empty squares are presented, 
and the subject’s task is to fill in the corresponding number as quickly as possible during a 90-
second interval (Smith, 1973). Results are scored based on number correct in 90 seconds, which 
is the primary measure for Z score. 


 
14
 
2d. 
Stroop test: 
 
The Stroop test is a measure of concentration effectiveness and response inhibition. The test 
consists of 3 pages containing 100 items. One page contains the words “RED,” “GREEN,” and 
“BLUE” arranged randomly and printed in black ink. No word follows itself within a column. The 
second page contains “XXXX”s written in red, green and blue ink. The final page consists of 
word names printed in non-congruent colors. The subject’s task for the first card is to read 
correctly as many of the word names as possible during a 45-second interval. The second task is 
to read the colors of the printed “X”s as quickly as possible during an additional 45-second 
interval. The final task measures an interference effect by requiring the subject to inhibit the 
natural tendency to read the word, and to instead name the color of ink, which is incongruent 
with the word name. This test results in 3 scores: word, color, and word/color contrast 
conditions (Golden, 1978). 
 
The primary measure for Z score is the total # correct across all 3 conditions. 
 
2e. 
Profile of Mood States: 
 
The POMS is a checklist of 65 adjectives describing mood states (Lorr et al, 1971. The subject 
rates the presence of each mood state in the past week on a 5-point scale from “not at all” to 
“extremely.” The POMS is scored for 6 scales (fatigue, vigor, depression-dejection, anger-
hostility, tension-anxiety, and confusion-bewilderment). All scales but the vigor scale are scored 
such that higher scores reflect greater mood disturbance; for the vigor scale, higher scores 
reflect less mood disturbance. The test is scored for each scale as well as for a total mood 
disturbance score derived from summing all scales (with reversal of the negatively scored items 
on the vigor scale). The POMS has been shown to be sensitive to ASMs in prior studies (Meador, 
2020). 
 
The Total score for POMS is the primary measure for Z score for this measure. 
 
2f. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia University 
Medical Center, 2008; Posner et al., 2011). This scale will be used for screening as well as to 
assess suicidal ideation and behavior that may occur during the study.  
 
Subjects who have active suicidal ideation (answering “Yes” to questions 4 and/or 5 on the C-
SSRS) will be evaluated by the Investigator. If the Investigator determines that a subject is at 
risk of suicide or self-harm, appropriate measures to ensure the subject’s safety and obtain 
mental health evaluation must be implemented and the Investigator should evaluate if the 
patient should be discontinued from the study.  
 
This is a safety measure and is not used in the primary analysis. 


 
15
 
2g. 
Adverse Events Profile (AEP) 
 
The AEP measures patients’ perception of adverse effects of antiepileptic drugs (Baker et al, 
1997; Perucca et al, 2012). It has 19 items assessing the frequency of the most common 
adverse effects of antiepileptic drugs during previous weeks, using a four-point Likert scale. 
Item ratings can be added to obtain a total score of 19–76, higher scores indicating a greater 
burden of adverse effects. 
 
2h. 
QOLIE-89 
The QOLIE-89 inventory was developed to assess perception of quality of life issues in patients 
with epilepsy (Devinsky et al., 1995). It has 89 questions covering 17 different scales: health 
perceptions, overall quality of life, physical function, role limitations-physical, role limitations-
emotional, pain, work/driving/social function, energy/fatigue, emotional well-being, 
attention/concentration, health discouragement, seizure worry, memory, language, medication 
effects, social support, and social isolation. These scales also are aggregated into an overall 
score. In the present study, we will employ only questions related to the subject’s perception of 
their attention/concentration, memory, and language (Perrine et al., 1995; Elixhauser et al., 
1999). The purpose of these measures in the present study is to allow us to compare subjective 
perceptions of cognitive side effects to objective performances (Marino et al., 2009). Where 
appropriate, ratings will be made based on the previous week, rather than previous 4 weeks as 
originally written in the QOLIE-89. 
 
 
VIII. 
 
STUDY MEDICATIONS 
 
A. 
Description 
 
 
PER 2mg, 4mg, and placebos will be provided by Eisai or their designee. All ASM doses 
and placebos will be overencapsulated in matched opaque capsules.  
 
B. 
Packaging and Labeling 
 
 
Medications will be provided by Eisai in capsule bulk containers.  Each will be labeled 
with the appropriate contents, PER 2mg capsules, PER 4mg capsules, and matching placebo. All 
drugs will be identical capsules. The clinical research pharmacy will be responsible for 
dispensing and labeling study drug for the study subjects. 
 
C. 
Shipment and storage 
 
 
 
 
 
Eisai or their designee will ship all drug supplies to the site.  A shipping invoice will be 
contained with each shipment and should be kept and matched against received drug.  All 
investigational drug will be stored and locked in the Clinical Research Pharmacy.  All unused 
drug supplies remaining at end of study will be destroyed by the site pharmacy personnel and 


 
16
written notification of the destruction will be sent to Eisai.  Study drug should be stored in the 
drums it is shipped in, in a cool dry area until drug is dispensed to the study subjects. 
 
D. 
Maintenance of medication dispensing records 
 
 
Each clinical pharmacy site will provide medication dispensing instructions and forms for 
recording dispensing of study medications to the pharmacy study personnel.  These records 
should be kept current during the study and be available for inspection.  When medication is 
dispensed, the number of capsules of active and/or placebo are to be listed on the appropriate 
dispensing log.  Returned capsules at each visit will also be recorded. 
 
E. 
Return of unused medication 
 
 
 
 
 
At each visit, subjects must return the medication bottles and all unused study 
medication to the investigator. The accountability for returning of medication is the 
responsibility of the investigator.  Unused study drug returned by subjects will be destroyed in 
accordance with remainder study drug. 
 
F. 
Concomitant medication and therapy 
 
 
Subjects will be instructed to limit alcohol consumption to no more than ½ ounce of 
absolute alcohol equivalents per day (approximately one 12 oz. beer, or 1 mixed drink) and no 
more than 3 ounces per week. Regular consumption of caffeine is allowed but will be limited to 
two cups on test days. Subjects will be instructed not to consume alcohol 12 hours prior to 
cognitive and behavioral testing, , or take any over-the-counter medications for at least 72 
hours prior to cognitive and behavioral testing. All concomitant medications will be recorded on 
the case report forms.  Any concomitant medications and other agents, which are known to 
affect perampanel or have significant effects on cognition may not be taken during this trial. A 
partial list of examples include: anticholinergics, anticoagulants, antidepressants, antiepileptics, 
antipsychotics, anxiolytics, central nervous system depressants, corticosteroids, doxycycline, 
erythromycin, H2 antagonists, lithium, methylphenidate, narcotics, quinidine, reserpine, 
theophylline, and centrally active antihistamines. 
 
IX. 
 
CLINICAL AND LABORATORY MEASUREMENTS 
 
A.  
Clinical Efficacy Measurements (Study weeks -1, 0, 1, 2, 3, 4, 5, & 6) 
 
 
Neuropsychological testing will be completed at screening (visit 1; study week -1), 
baseline (visits 2; study week 0), and each week of the ASM treatment period (visits 3-8; study 
weeks 1-6). The neuropsychological test results from the first screening testing (i.e., visit 1 at -1 
weeks) will not be included in the analyses. All subjects will have at least 7 hours of sleep on the 
evening before the day of cognitive testing. (Note. If the subject does not get the required 
hours of sleep or takes non-approved medication, caffeine, etc., cognitive and behavioral 
testing will be rescheduled). 


 
17
 
For detailed information regarding all of the cognitive tests refer to Section VII. 
 
B. 
Clinical Safety Measurements 
 
 
 
 
 
1. Physical Examinations (Study weeks -1, 3, & 6) 
 
 
 
 
 
 
A complete physical and neurological examination will be performed during pre-
study screening (visit 1; study week -1) and at the completion of the study (visit 8; study 
week 6) or early study discontinuation. Brief physical and neurological examinations will 
be performed at visit 5 (study week 3). 
 
 
A complete physical examination will consist of determinations of sitting blood 
pressure, weight, heart rate, assessment of physical condition (general appearance, skin 
and skin structure, HEENT, abdomen, cardiovascular, respiratory, musculoskeletal, 
genitourinary and central nervous systems).  Brief physical examinations will consist of 
determinations of sitting blood pressure, weight, heart rate, and an assessment of 
physical condition, as required to determine change from the previous visit, and an 
assessment of adverse effects focused on skin and neurological systems. 
 
 
2. Laboratory assessments (Study weeks -1 and 6) 
 
 
 
 
 
 
 
A. Blood and Urine Samples 
 
Blood work assessments will be obtained at visits 1 & 8. 
 
The hematology parameters to be determined are: RBC count, hemoglobin, 
hematocrit, WBC count, platelet count, cell morphology and complete WBC 
differential count (neutrophils, bands, lymphocytes, monocytes, eosinophils and 
basophils). 
 
The chemistry parameters to be determined are: SGOT, SGPT, alkaline 
phosphatase, albumin, total protein, total bilirubin, sodium, potassium, chloride, 
calcium, phosphorous, creatinine, blood urea nitrogen, uric acid and glucose. The 
total chemistry panel will be obtained at visits 1 & 8. 
 
Urine Pregnancy tests will be performed on women of childbearing potential at 
study weeks -1, and 6 (visits 1 & 8). 
 
Blinded PER blood levels will be collected at study weeks 3 and 6 (i.e., visits 5 & 
8).  PER levels will be sent to an outside contract lab. PER levels may be sent to 
the hospital laboratory for immediate analysis if testing is available. Results are 
to be reviewed and stored by a non-blinded investigator. 
 


 
18
C. 
Adverse Event Procedures 
 
 
An ADVERSE EVENT (AE) is a noxious and unintended event observed in, or reported by, 
a subject who is participating in (or has participated in) a clinical study and/or has received 
study medication.  The AE may be related temporarily either to immediate or long-term use of 
the drug; the AE may not necessarily be caused by the drug. Overdose is regarded as an adverse 
event.  Any event meeting these criteria is to be considered an adverse event, regardless of 
whether or not it is considered drug related. 
 
 
All adverse events will be reported on the appropriate Case Report Form; details should 
include the type of event, date of onset, duration, intensity, causality relationship to the study 
drug(s), and outcome.  Wherever possible, a diagnosis rather than symptom(s) should be 
reported. 
 
 
“Serious” means an adverse experience that is fatal or life-threatening, is permanently 
disabling, requires or prolongs inpatient hospitalization, or is a congenital anomaly, cancer or 
overdose. 
 
At enrollment, the subjects will be informed of known perampanel-adverse side effects 
such as dizziness, sleepiness, tiredness, irritability, falls, nausea, problems with muscle 
coordination, problems walking normally, vertigo, weight gain, headache, vomiting, abdominal 
pain, and anxiety. The potential serious adverse side effects of perampanel will be highlighted, 
and subjects advised to immediately contact the investigators if any serious adverse effects 
occur. Subjects who have homicidal or aggressive behavior will be evaluated by the 
Investigator. The drug will be discontinued, and if the Investigator determines that the subject 
or others are at risk, appropriate measures to ensure the safety of the subject and others. 
 
Serious adverse side effects for perampanel in the controlled Phase 3 epilepsy clinical 
trials included hostility- and aggression- related adverse reactions occurred in 12% and 20% of 
patients randomized to receive perampanel at doses of 8 mg and 12 mg/day, respectively, 
compared to 6% of patients in the placebo group (FDA label, 2016). Three patients (0.1%) out of 
4,368 perampanel-treated patients exhibited homicidal ideation or threat in controlled and 
open-label studies, including non-epilepsy studies. These effects were dose-related (less at 
4mg) and generally appeared within the first 6 weeks of treatment. A review of the phase I, II, 
and III studies concluded that the incidence of hostility/anger was not different from placebo in 
doses ≤ 8 mg (Ettinger et al, 2015). 
 
U.S. Prescribing Information for all AEDs includes the following language: “AEDs increase 
the risk of suicidal thoughts or behavior in patients taking these drugs for any 
indication.” 
 
 
The investigators have conducted multiple studies with healthy volunteers on the 
cognitive effects of antiseizure medications with an excellent safety record (see 15 References 


 
19
from Prior Healthy Volunteer ASM Studies by Meador). Almost all side effects are mild or 
moderate and reversable. No long-term sequelae have ever occurred. 
 
 
If any medically serious adverse event occurs (SAE), the study medication may be 
discontinued, and the subject treated at the discretion of the physician investigator. 
 
 
ANY MEDICALLY SERIOUS ADVERSE EVENT REQUIRES IMMEDIATE NOTIFICATION OF THE 
FDA BY THE INVESTIGATOR. 
 
 
 
Any serious adverse event that occurs up to two weeks following study participation 
must also be reported. 
 
 
Serious adverse events must be reported to the lead site principal investigator, Kimford 
Meador, within 24 hours of the site becoming award of the SAE. 
 
 
Serious adverse events must be reported to sites’ institutional review boards (IRB) 
according to their IRB’s regulations. 
 
 
Specific procedures for Double-Blind Studies 
 
 
Site personnel not involved in direct care of study subjects will generate a 
randomization code.  In an acute medical emergency, the randomization code may be broken if 
this is considered essential for subject management.  For this purpose, the sealed 
randomization code will be provided to the investigator by the site pharmacy. If the code is 
broken, a record of the date, time and reason must be put into writing and sent to Eisai.  This 
letter will become part of the permanent study record. 
 
 
All adverse events should be recorded on the appropriate Case Report Forms (CRF’s) 
including date of onset and cessation, intensity and relationship to study drug.  The action 
taken and clinical outcome of the adverse event will also be recorded.   
 
 
The investigator will report all serious AE's to the FDA and to Eisai without delay. 
 
 D. 
Medication Compliance Assessment 
 
 
 
 
Compliance is to be judged by questioning the patient at the clinic visit and by the non-
blinded observer’s inspection of medication returned and recording missed doses on the 
appropriate CRF. Repeated noncompliance, or the missing of all scheduled doses of medication 
for three (3) consecutive days (72-hour period) would be cause for removing the subject from 
the study.  Subjects should take all doses for 3 days before visits when cognitive function 
testing occurs. 
 
E. 
Subject Discontinuation Criteria 
 


 
20
1. 
Although they may withdraw without prejudice at any time, every effort should 
be made to have subjects complete the study within the bounds of safety and 
provisions of informed consent. 
 
2. 
The investigator may discontinue the participation of any subject in this study if: 
 
 
 
 
a. 
Any clinically significant adverse experiences are observed. 
 
b. 
The subject is grossly noncompliant. 
 
c. 
The subject’s health would be jeopardized by continued participation. 
 
d. 
Consent is withdrawn. Subjects will be encouraged to complete the study, 
although they may withdraw at any time without prejudice. 
 
4. 
Subject replacement. 
 
 
Subjects who are dropped from the study prior to completion of all cognitive 
testing will not be replaced. 
 
 
 
Subjects who are withdrawn prior to completion of at least one set of cognitive 
testing on treatment drug (i.e., prior to visit 5/study week 3) may be replaced. 
 
5. 
Follow-up of discontinued patients 
 
 
Subjects who receive study drug and are discontinued from the study will have 
all safety assessments completed, including a complete physical examination and 
laboratory evaluation including chemistry, hematology with differential, 
urinalysis and urine pregnancy test as required at study termination.  This testing 
should be done as soon as possible.  Medical follow-up of any severe adverse 
events or clinically significant abnormal laboratory values will continue until the 
abnormality resolves, and adequate medical explanation is apparent.  Such data 
will be provided to Eisai. 
 
 
X. 
STATISTICAL EVALUATION 
 
A. 
Sample Size 
 
We assume that the 4 groups (3 PER treatments and a placebo group) are equally 
spaced (in terms of z-score) at the time point of maximum drug effects (end week 1 for 4mg 
group and end week 3 for titration to 2mg x2wks then 4mg group), with a maximum difference 
of 0.24 (which is the difference between the placebo group and treatment at max effect). We 
then assume that over the 4 visits after max drug effect the z-scores get closer together until 


 
21
they are equal at the treatment week 6th. The calculation indicates that at least 18 subjects are 
needed in each group to have 80% power. Since there are 4 groups, the total sample at least 
finishing assessment at end of week 6 (event 8) would be 19 X 4 = 76. Enrollment will include 
20% (n=15) more to account for dropouts prior to assessment at end of visit 2 (baseline), and 
~15% (n=12) more for dropouts before end of event 8 (treatment week 6). Thus, the total 
enrollment sample will be 103 subjects. 
 
In summary, the 4 total groups (3 PER treatment, 1 placebo) would need at least 19 
subjects per group (76 total), and total enrollment would be rounded to 105 to account for 
dropouts. 
 
B. 
Methodology for statistical analysis 
 
 
The parameters of interest are listed in Section VII. Descriptive statistics will be used to 
provide an overview of the primary, secondary, and other variable results. For categorical 
parameters, the number and percentage of subjects in each category will be presented. The 
denominator for percentages will be based on the number of subjects appropriate for the 
purpose of analysis. For continuous parameters, descriptive statistics will include number of 
subjects, mean, standard deviation (SD), median, minimum, and maximum. Unless otherwise 
specified, baseline neuropsychological data will be based on the Visit 2 assessments. 
 
Study question 1: What are the behavioral, cognitive or other side effects of perampanel 
at different titration rates in healthy volunteers? 
The primary outcome variable will be the overall neuropsychological composite z-scores 
for the objective and subjective measures combined. 
 
Study question 2: What is the time course of habituation to objective vs. subjective 
neuropsychological (e.g., cognitive and behavioral) side effects of perampanel? 
The primary outcome variable will be the neuropsychological composite z-scores for the 
objective and subjective measures, which will be analyzed separately.  
 
The objective measure z-score will be calculated by averaging overall computerized and 
noncomputerized cognitive z scores, which are calculated by averaging individual z-scores of 
selected performance measures from the computerized cognitive test battery (i.e., average of 
z-scores for the domain scores for executive function and for processing speed) and from the 
noncomputerized cognitive test battery (i.e., average of individual z-scores for MCG immediate, 
MCG delayed, SDMT, and Stroop-average score). The subjective measure z-score will be 
calculated by averaging the individual z-scores for AEP, POMS, and QOLIE-cognitive questions 
(average of 3 scores from QOLIE). These z-scores will be assessed by a 4 (titration rate) X 6 
(time: weeks 1-6) ANCOVA controlling for scores at Baseline (visit 2) using an intent-to-treat 
analysis for those receiving neuropsychological testing at least at the end of week one. 
Imputations will be employed for dropout after week one.  
 


 
22
We will control for differences across groups in age, gender, and personal/family history 
of psychiatric disorders. 
 
This method with a similar overall score has been employed in prior investigations. This 
approach avoids potential Type I errors from multiple statistical comparisons and Type II errors 
resulting from reduced statistical sensitivity as a result of correcting for multiple comparisons. 
Analyses of individual components of the computer and neuropsychological assessment are 
secondary endpoints meant to evaluate sensitivity of the primary endpoint and examine the 
pattern of neuropsychological effects. All other endpoints are supportive and are safety 
assessments. Hence no adjustments for multiplicity are planned. P-values for these safety 
variables are not meant to show superiority and thus testing each of these variables at the 
p=0.05 level without multiplicity adjustment is a more conservative approach, which is 
appropriate for safety assessments and for secondary analyses of the pattern of impairments. 
The importance of the results should be evaluated in terms of actual differences and the 
risk/benefits offered by the drug to the patients. 
 
The secondary outcome variables will be: 
 
1. Compare titration rates for changes from Baseline (visit 2) to the end of titration (study 
week 3) and end of maintenance (study week 6) using Z-scores from full 
neuropsychological battery. The outcome variable for this analysis will be an overall 
neuropsychological composite Z-score, calculated by averaging individual z-scores of the 
selected performance measures from the computerized cognitive test battery (i.e., z-
scores for the domain scores for executive function and processing speed), the average 
for individual Z-scores for AEP, POMS, QOLIE-cognitive questions (average of 3 scores), 
and the noncomputerized cognitive scores (i.e., average of z-scores for MCG immediate, 
MCG delayed, SDMT, Stroop-average score). 
2. Compare titration rates for TEAEs and dropouts due to TEAEs across visits 3-8 (i.e., 
weeks 1-6). 
3. Separate comparisons of titration rates for behavioral overall scores and cognitive 
overall scores. 
4. Comparisons of titration rates and habituation over time for individual measures. 
 
 
Summary statistics will be calculated by treatment for each evaluation of antiepileptic 
blood levels (ABLs). Additional analyses of data will be performed which take the ABLs into 
account. Linear correlations of plasma concentrations and the overall composite and individual 
score variables will be plotted with a fitted regression line superimposed for each condition. 
 
 
The incidences of all adverse events reported during the trial will be tabulated by 
treatment and study period.  The other safety variables, which include changes in hematology, 
clinical chemistry, and urinalysis parameters, and vital signs will be analyzed descriptively. The 
actual measurement and its change from baseline will be presented by visit and period of 
collection. In addition, shift tables may be used to evaluate the number and percentage of 
subjects having a different post-baseline status when compared with their baseline status. 


 
23
 
 
 
C. 
Interim Analysis 
 
No interim analyses are planned. 
 
D. 
Definition of Evaluable Subjects 
 
 
 
Any subject who ingested one or more doses of blinded study medication and provided 
follow-up information will be evaluable for the analysis of the safety data. The primary analysis 
will include subjects who complete all visits or at least one set of cognitive/behavioral testing 
on treatment drug and who did not have any important deviations, which may have an impact 
on cognitive function. Subjects who prematurely discontinue the study will be evaluated based 
on the data collected at each visit attended. Any subject who is evaluable for the safety analysis 
who also has baseline and end of drug period cognitive/behavioral data available will be 
evaluable for the intent-to-treat analysis of the parameters of interest. Any subject evaluable 
for the intent-to-treat analysis will be evaluable for the per-protocol analysis of the parameters 
of interest provided that the subject was compliant with the protocol with regard to the study 
medication regimen, use of concomitant medications, sleep requirements prior to cognitive 
testing, alcohol consumption, caffeine consumption, and use of OTC medications prior to 
cognitive testing. All data will be used to their maximum possible extent, but without any 
imputations for missing data for any parameter.  
 
 
XI. REFERENCES: 
 
1. Background References. 
French, J. A., Krauss, G. L., Steinhoff, B. J., Squillacote, D., Yang, H., Kumar, D., & Laurenza, A. 
Evaluation of adjunctive perampanel in patients with refractory partial‐onset seizures: results of 
randomized global phase III study 305. Epilepsia 2013;54(1), 117-125. 
Krauss, G. L., Bar, M., Biton, V., Klapper, J. A., Rektor, I., Vaiciene‐Magistris, N., ... & Kumar, D. 
Tolerability and safety of perampanel: two randomized dose‐escalation studies. Acta Neurol 
Scand 2012a;125(1):8-15. 
Krauss, G. L., Serratosa, J. M., Villanueva, V., Endziniene, M., Hong, Z., French, J., ... & Laurenza, 
A. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset 
seizures. Neurology 2012b;78(18), 1408-1415. 
Meador KJ.  Cognitive effects of epilepsy and its treatments, Chapter 93. In: Wyllie E, Cascino 
GD, Gidal BE, Goodkin HP, Loddenkemper T, Sirven JI (eds). Wyllie’s Treatment of Epilepsy: 
Principles & Practice, 7th Edition. Philadelphia: Lippincott Williams & Wilkins, 2020: 1058-63. 
Meador, K. J., Gilliam, F. G., Kanner, A. M., & Pellock, J. M. (2001). Cognitive and behavioral 
effects of antiepileptic drugs. Epilepsy Behav 2001;2(4), SS1-SS17. 


 
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Meador, K. J., Yang, H., Piña‐Garza, J. E., Laurenza, A., Kumar, D., & Wesnes, K. A. Cognitive 
effects of adjunctive perampanel for partial‐onset seizures: a randomized 
trial. Epilepsia 2016;57(2), 243-251. 
Meschede, C., Witt, J. A., Rademacher, M., von Wrede, R. D., Elger, C. E., & Helmstaedter, C. 
Evaluating the longer-term cognitive effects of adjunctive perampanel compared to lacosamide 
in a naturalistic outpatient setting. Seizure 2018;58, 141-146. 
Piña-Garza, J. E., Lagae, L., Villanueva, V., Renfroe, J. B., Laurenza, A., Williams, B., ... & Meador, 
K. J. Long-term effects of adjunctive perampanel on cognition in adolescents with partial 
seizures. Epilepsy Behav 2018;83:50-58. 
 
2. References Related to Safety Issues 
Fycompa FDA label (2016). 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202834s011lbl.pdf (accessed 5-
14-2020). 
Ettinger AB, LoPresti A, Yang H, Williams B, Zhou S, Fain R, Laurenza A. Psychiatric and 
behavioral adverse events in randomized clinical studies of the noncompetitive AMPA receptor 
antagonist perampanel. Epilepsia. 2015 Aug;56(8):1252-63. 
 
3. References for 15 Articles on Prior Healthy Volunteer ASM Studies by Meador 
Meador KJ, Loring DW, Allen ME, Zamrini EY, Moore EE, Abney OL, King DW.  Comparative 
cognitive effects of carbamazepine and phenytoin in healthy adults. Neurology 1991;41:1537-
1540. 
Meador KJ, Loring DW, Abney OL, Allen ME, Moore EE, Zamrini EY, King DW.  Effects of 
carbamazepine and phenytoin on EEG and memory in healthy adults. Epilepsia 1993;34:153-
157. 
Meador KJ, Loring DW, Moore EE, Thompson WO, Nichols ME, Oberzan RE, Durkin MW, 
Gallagher BB, King DW.  Comparative cognitive effects of phenobarbital, phenytoin, and 
valporate in healthy adults. Neurology 1995;48:1494-1499. 
Meador KJ, Loring DW, Ray PG, Murro AM, King DW, Nichols ME, Deer EM, Goff WT.  
Differential cognitive effects of carbamazepine and gabapentin. Epilepsia 1999;40(9):1279-
1285. 
Meador KJ, Loring DW, Ray PG, Murro AM, King DW, Perrine KR, Vazquez BR, Kiolbasa T. 
Differential cognitive and behavioral effects of carbamazepine and lamotrigine. Neurology 
2001;56:(9):1177-1182. 
Meador KJ, Loring DW, Vahle VJ, Ray PG, Werz MA, Fessler AJ, Ogrocki P, Schoenberg MR, 
Miller JM, Kustra RP. Cognitive and behavioral effects of lamotrigine and topiramate in healthy 
volunteers. Neurology 2005;64(12):2108-14. 


 
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Werz MA, Schoenberg MR, Meador KJ, Loring DW, Ray PG, Kaul-Gupta R, Ogrocki P. Subjective 
preference for lamotrigine or topiramate: Relationship with cognitive and behavioral 
functioning. Epilepsy Behav 2006;8:181-91. 
Smith ME, Gevins A, McEvoy LK, Meador KJ, Ray PG, Gilliam F. Distinct cognitive 
neurophysiologic profiles for lamotrigine and topiramate. Epilepsia 2006;47:695-703. 
Meador KJ, Gevins A, Leese PT, Otoul C, Loring DW. Neurocognitive effects of brivaracetam, 
levetiracetam, and lorazepam. Epilepsia 2011;52(2):264-72. 
Loring DW, Williamson DJ, Meador KJ, Wiegand F, Hulihan J. Topiramate dose effects on 
neuropsychological function: A randomized double-blind placebo-controlled study. Neurology 
2011;76 131-137. PMID: 21148119. 
Loring DW, Marino SE, Drane DL, Parfitt D, Finney GR, Meador KJ. Lorazepam effects on word 
memory test performance: a randomized, double-blind, placebo controlled, cross-over trial. 
The Clinical Neuropsychologist 2011;25(5):799-811. 
Meador KJ, Brashear HR, Wiegand F, Zannikos P, Novak G. Cognitive effects of carisbamate in 
randomized, placebo-controlled, healthy-volunteer, multidose studies. Epilepsy & Behavior 
2011;22(2):324-30. 
Loring DW, Marino SE, Parfit D, Finney GR, Meador KJ. Acute lorazepam effects on 
neurocognitive performance. Epilepsy & Behavior 2012;25(3):329-33. 
Meador KJ, Loring DW, Boyd A, Echauz J, LaRoche S, Velez-Ruiz NJ, Korb P, Byrnes W, Dilley D, 
Borghs S, De Backer M, Story T, Dedeken P, Webster E. Randomized double-blind comparison of 
cognitive and EEG effects of lacosamide and carbamazepine. Epilepsy & Behavior 2016;62:267–
275. 
Meador KJ, Seliger J, Boyd A, Razavi B, Falco-Walter J, Le S, Loring DW. Comparative 
neuropsychological effects of carbamazepine and eslicarbazepine acetate. Epilepsy & Behavior 
2019 Mar 30;94:151-157. 
 
4. References for Cognitive/Behavioral Tests 
Adverse Events Profile (AEP): 
Baker GA, Jacoby A, Buck D, Stalgis C, Monnet D. Quality of life of people with epilepsy: a 
European study. Epilepsia. 1997;38:353–62 
Perucca P, Gilliam FG. Adverse effects of antiepileptic drugs. Lancet Neurol. 2012;11:792–802. 
CNS Vital Signs: see reference section #3 below. 
Columbia-Suicide Severity Rating Scale:  
Columbia University Medical Center. Columbia-Suicide Severity Rating Scale, 
http://www.cssrs.columbia.edu/, 2008. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, 
Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity and 


 
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internal consistency findings from three multisite studies with adolescents and adults. Am J 
Psychiatry. 2011 Dec;168(12):1266-77. 
MCG Paragraphs:  
Meador KJ, Loring DW, Abney OL, et al.  Effects of Carbamazepine and phenytoin on EEG and 
memory in healthy adults.  Epilepsia 1993;34:153-157. 
Peabody Picture Vocabulary Test (PPVT):  
Dunn, LM and Dunn, LM. Peabody Picture Vocabulary Test, 3d ed. Circle Pines, MN: American 
Guidance Service, 1997 
Profile of Mood States:  
Lorr M, McNair DM, Droppleman LF. Manual: Profile of Mood States. San Diego, CA: 
Educational and Industrial Testing Service, 1971. 
QOLIE-89: 
Devinsky O, Vickrey BG, Cramer J, Perrine K, Hermann B, Meador K, Hays RD. Development of 
the quality of life in epilepsy inventory. Epilepsia. 1995 Nov;36(11):1089-104. 
Perrine K, Hermann BP, Meador KJ, Vickrey BG, Cramer JA, Hays RD, Devinsky O. The 
relationship of neuropsychological functioning to quality of life in epilepsy. Arch Neurol. 1995 
Oct;52(10):997-1003. 
Elixhauser A, Leidy NK, Meador K, Means E, Willian MK. The relationship between memory 
performance, perceived cognitive function, and mood in patients with epilepsy. Epilepsy Res. 
1999 Oct;37(1):13-24. 
Marino SE, Meador KJ, Loring DW, Okun MS, Fernandez HH, Fessler AJ, Kustra RP, Miller JM, 
Ray PG, Roy A, Schoenberg MR, Vahle VJ, Werz MA. Subjective perception of cognition is 
related to mood and not performance. Epilepsy Behav. 2009 Mar;14(3):459-64. 
Symbol Digit Modalities:  
Smith A. Symbol Digit Modalities Test. Manual. Los Angeles: Western Psychological Services, 
1973. 
Stroop Test:  
Golden CJ. Stroop Color and Word Test. A Manual for Clinical and Experimental Uses. Chicago: 
Stoelting, 1978. 
 
5. CNS Vital Signs References 
Meador KJ, Loring DW, Boyd A, Echauz J, LaRoche S, Velez-Ruiz NJ, Korb P, Byrnes W, Dilley D, 
Borghs S, De Backer M, Story T, Dedeken P, Webster E. Randomized double-blind comparison of 
cognitive and EEG effects of lacosamide and carbamazepine. Epilepsy & Behavior 2016;62:267–
275.  


 
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Loring DW, Marino SE, Parfitt D, Finney GR, Meador KJ. Acute lorazepam effects on 
neurocognitive performance. Epilepsy Behav. 2012;25(3):329-33. 
 
Kane JM, Yang R, Youakim JM. Adjunctive armodafinil for negative symptoms in adults with 
schizophrenia: a double-blind, placebo-controlled study. Schizophr Res. 2012;135(1-3):116-22. 
 
Brooks BL, Sherman EM, Iverson GL. Embedded validity indicators on CNS vital signs in youth 
with neurological diagnoses. Arch Clin Neuropsychol. 2014;29(5):422-31. 
 
Iverson GL, Brooks BL, Ashton Rennison VL. Minimal gender differences on the CNS vital signs 
computerized neurocognitive battery. Appl Neuropsychol Adult. 2014;21(1):36-42. 
 
Levy B. Autonomic nervous system arousal and cognitive functioning in bipolar disorder. Bipolar 
Disord. 2013;15(1):70-9. 
 
Olofsen E, Noppers I, Niesters M, Kharasch E, Aarts L, Sarton E, Dahan A. Estimation of the 
contribution of norketamine to ketamine-induced acute pain relief and neurocognitive 
impairment in healthy volunteers. Anesthesiology. 2012;117(2):353-64. 
 
Iverson GL, Brooks BL, Langenecker SA, Young AH. Identifying a cognitive impairment subgroup 
in adults with mood disorders. J Affect Disord. 2011;132(3):360-7. 
 
Brooks BL, Sherman EM. Computerized neuropsychological testing to rapidly evaluate cognition 
in pediatric patients with neurologic disorders. J Child Neurol. 2012;27(8):982-91. 
 
Crowgey T1, Peters KB, Hornsby WE, Lane A, McSherry F, Herndon JE 2nd, West MJ, Williams 
CL, Jones LW. Relationship between exercise behavior, cardiorespiratory fitness, and cognitive 
function in early breast cancer patients treated with doxorubicin-containing chemotherapy: a 
pilot study. Appl Physiol Nutr Metab. 2014;39(6):724-9. 
 
Gualtieri CT, Johnson LG. Reliability and validity of a computerized neurocognitive test battery, 
CNS Vital Signs. Arch Clin Neuropsychol. 2006;21(7):623-43. 
 
Gualtieri CT, Johnson LG. Comparative neurocognitive effects of 5 psychotropic anticonvulsants 
and lithium. MedGenMed. 2006;8(3):46. 
 
Mihalik JP, Lengas E, Register-Mihalik JK, Oyama S, Begalle RL, Guskiewicz KM. The effects of 
sleep quality and sleep quantity on concussion baseline assessment. Clin J Sport Med. 
2013;23(5):343-8. 
 


 
28
APPENDIX A - STUDY TIMETABLE 
Event 
1 
2 
3 
4 
5 
6 
7 
8 
Week 
Screena 
-1 
BLb 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
Dayc 
-7 
0 
7 
14 
21 
28 
35 
42 
Clinic Visit 
X 
Xm 
 
 
X 
 
 
X 
Home Testing 
 
 
X 
X 
 
X 
X 
 
Informed Consent 
X 
 
 
 
 
 
 
 
PMHx & Fam Hxd 
X 
 
 
 
 
 
 
 
Vital Signs 
X 
 
 
 
X 
 
 
X 
Full PEe 
X 
 
 
 
 
 
 
X 
Neuro Examf 
 
 
 
 
X 
 
 
 
CBC & Chemsg 
X 
 
 
 
 
 
 
X 
PER Levelh 
 
 
 
 
X 
 
 
X 
Urine drug screen 
X 
 
 
 
 
 
 
X 
Urine pregnancy testi 
X 
 
 
 
 
 
 
X 
C-SSRSj 
X 
 
 
 
X 
 
 
X 
Partial NPk 
 
 
X 
X 
 
X 
X 
 
Full NPl 
X 
X 
 
 
X 
 
 
X 
TEAEs 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Drug 
 
X 
 
 
 
 
 
 
aScreening visit may occur 1-3 weeks prior to baseline visit. 
bBL = baseline visit. 
cVisits may occur +/- 3 days from target day. 
dPMHx & Fam Hx = psychiatric history for subject and their family 
ePE = complete physical exam including full neurologic exam 
fNeuro Exam = brief neurological exam including brief physical exam 
gCBC & Chems = CBC with differential and Chemistries (comprehensive metabolic panel) 
hPER Level = perampanel blood level 
iWomen of childbearing potential only 
jC-SSRS = Columbia-Suicide Severity Rating Scale 
kPartial NP = partial neuropsychological battery on non-clinic visit weeks refers to online CNS-Vital Signs 
computerized cognitive tests and behavioral questionnaires (POMS-total, AEP, & QOLIE-89 cognitive 
scores, which will be mailed back). Note phone calls will be made for each home testing visit to assure 
adherence to the protocol. 
lFull NP = full neuropsychological battery includes non-computerized cognitive tests and the items from 
the Partial NP (questionnaires and online CNS-Vital Signs computer tests). Peabody Picture Vocabulary 
Test (PPVT) given only at screening visit. 
mThis week does not require clinic room or to see physician unless necessary. 
 
 


 
29
APPENDIX B - PROTOCOL SIGNATURE FORM 
 
 
PROTOCOL TITLE: Effects of Titration Rate on Cognitive and Behavioral Side Effects of 
Perampanel 
 
VERSION: 1.8 
 
VERSION DATE: 02 May 2022 
 
I have read the protocol described above and agree to conduct this study in accordance with 
the procedures described therein. I also agree to conduct the study in compliance with all 
applicable regulations.  
 
 
________________________________  
Investigator’s Name  
 
 
________________________________        ________________________________ 
Investigator’s Signature  
 
 
       Date