Conditions: Epilepsy Seizures
Keywords: Partial Onset Seizures Secondarily Generalized Seizures Primary Generalized Tonic-Clonic Seizures
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
The purpose of the study is to evaluate the safety and tolerability of perampanel administered as a 30-minute intravenous infusion after switching from oral tablets (8 to 12 milligrams per day \[mg/day\]) as an adjunctive therapy in participants with epilepsy with partial onset seizures (POS) (including secondarily generalized seizures) or primary generalized tonic-clonic (PGTC) seizures.

Detailed description:

Arms:
arm 1: Participants with POS with or without secondarily generalized seizures or PGTC seizures will receive perampanel 8 to 12 milligram (mg), tablets, orally, once daily for 28 days (Day -28 to Day -1) in Pretreatment Phase and followed by 8 to 12 mg dose of perampanel as intravenous infusion for 30 minutes, once daily from Day 1 to Day 4 in Treatment Phase, and then again 8 to 12 mg, tablets, orally, once daily from Day 5 to Day 11 in Follow-up Phase as an adjunctive therapy, along with 1 to a maximum of 3 marketed concomitant antiepileptic drugs (AEDs).

Interventions: intervention 1: Perampanel intervention 2: Perampanel
Intervention descriptions: intervention 1: Oral tablets. intervention 2: Intravenous infusion.

Protocol document:
Prot_000.pdf: 
 
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1. TITLE PAGE 
 
 
Clinical Study Protocol 
 
Study Protocol 
Number: 
E2007-J081-240 
Study Protocol 
Title: 
A multicenter, uncontrolled, open-label study to evaluate the safety 
and tolerability of intravenous perampanel as substitute for oral 
tablet in subjects with partial onset seizures (including secondarily 
generalized seizures) or primary generalized tonic-clonic seizures 
Sponsor: 
Eisai Co., Ltd. 
4-6-10 Koishikawa, Bunkyo-Ku, Tokyo 112-8088, Japan 
Investigational 
Product Name: 
E2007/ Perampanel Hydrate (Japanese Accepted Names for 
Pharmaceuticals [JAN]) 
Indication: 
Partial-onset seizures with or without secondarily generalized 
seizures or primary generalized tonic-clonic seizures 
Phase: 
2 
Approval Date: 
V1.0 
07 Sep 2018 
V2.0 
09 Oct 2018 
GCP Statement: 
This study is to be performed in full compliance with all applicable 
local Good Clinical Practice (GCP) and regulations.  All required 
study documentation will be archived as required by the regulatory 
authorities. 
Confidentiality 
Statement: 
This document is confidential.  It contains proprietary information 
of Eisai (the sponsor).  Any viewing or disclosure of such 
information that is not authorized in writing by the sponsor is 
strictly prohibited.  Such information may be used solely for the 
purpose of reviewing or performing this study. 
 
 
 


 
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2. CLINICAL PROTOCOL SYNOPSIS 
Compound No. 
E2007 
Name of Active Ingredient 
perampanel 
Study Protocol Title 
A multicenter, uncontrolled, open-label study to evaluate the safety and tolerability of intravenous 
perampanel as substitute for oral tablet in subjects with partial onset seizures (including secondarily 
generalized seizures) or primary generalized tonic-clonic seizures 
Sites 
Japan, approximately 15 sites 
Study Period and Phase of Development 
Study Period:  October 2018 to April 2020 (planned) 
Phase 2 
Objectives 
Primary Objective: 
To evaluate the safety and tolerability of 30-minute intravenous infusions of perampanel after switching 
from oral perampanel (8 to 12 mg/day) as an adjunctive therapy in subjects with partial-onset seizures 
(POS) with or without secondarily generalized seizures or primary generalized tonic-clonic (PGTC) 
seizures 
Secondary Objectives: 
• To evaluate the plasma concentration of perampanel before and after switching from oral 
perampanel to 30-minute intravenous infusions of perampanel 
• To evaluate the seizure frequency before and after switching from oral perampanel to 30-minute 
intravenous infusions of perampanel 
Study Design 
This is a multicenter, uncontrolled, open-label study in subjects with POS with or without secondarily 
generalized seizures or PGTC seizures.  This study will consist of 3 phases:  the Pretreatment Phase, 
Treatment Phase, and Follow-up Phase. 
During the Pretreatment Phase, subjects will be screened and assessed for eligibility to participate in 
the study.  Subject informed consent/assent will be obtained before the screening, after which protocol 
eligibility will be established on any day from Day –28 to Day –7.  Eligible subjects must be on a 
stable dosage (8 to 12 mg/day) of oral perampanel as an adjunctive therapy with 1 to a maximum of 3 
marketed concomitant antiepileptic drugs (AEDs) for at least 28 days before the first dose of the study 
drug (ie, intravenous infusion of perampanel).  Eligible subjects will return to and remain onsite (be 
“hospitalized”) 1 day before switching from oral perampanel to intravenous infusion of perampanel (ie, 
on Day –1 [Visit 2]). 
During the Treatment Phase, hospitalized subjects will be switched from oral perampanel to intravenous 
infusion of perampanel at a dose equivalent to the oral perampanel dose.  Subjects will receive 30-
minute intravenous infusions of perampanel once a day for 4 days under inpatient conditions. 
Afterwards, the subject must be switched back to oral perampanel at the equivalent daily dose of the 


 
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intravenous infusion of perampanel. 
If subjects cannot continue intravenous infusion of perampanel for any reason(s), they must discontinue 
the study. 
Subjects will be discharged from the hospital the day after the last intravenous infusion of perampanel, 
and treatment must be switched back to their original dose of oral perampanel.  The assessments at the 
Follow-up Visit will be conducted 7 days (allowance window: +7 days) after the last intravenous 
infusion of perampanel. 
The study design is shown below. 
 
 
Number of Subjects 
20 subjects will be enrolled and treated. 
Inclusion Criteria 
(1)Male or female aged 12 years or older at the time of informed consent/assent 
(2)Have a diagnosis of epilepsy with POS with or without secondarily generalized seizures or PGTC 
seizures according to the International League Against Epilepsy (ILAE) Classification of Epileptic 
Seizures (1981) 
(3)Have been receiving a stable dosage of oral perampanel (8 to 12 mg/day) for at least 28 days before 
Day 1 in the Treatment Phase 
(4)Have been receiving a concomitant stable dosage of 1 to a maximum of 3 marketed AED(s) (regarding 
phenobarbital used as an AED, phenytoin, and carbamazepine, only one is allowed) for at least 28 days 
before Day 1 in the Treatment Phase.  No change of dosing regimen for concomitant AED(s) is 
planned during the Treatment and Follow-up Phases. 
(5)Are considered reliable and willing to be available for the study period by the investigator, and are 
able to record seizures and report adverse events (AEs) by themselves or have a caregiver who can 
record seizures and report AEs for them 
Exclusion Criteria 
(1)Have a history of drug or alcohol dependency or abuse within the last 2 years before Visit 1 
(2)Have a history of status epilepticus within 6 months before Day 1 in the Treatment Phase 
(3)Are unsuitable for venipuncture and intravenous administration 
(4)Require medical intervention due to safety issues related to the concomitant administration of 1 to 


 
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3 AEDs 
(5)Have a history of suicidal ideation/attempt within 2 years before Day 1 in the Treatment Phase 
(6)Have clinically problematic psychological or neurological disorder(s) 
(7)Clinical symptoms or imaging suggest a progressive central nervous system (CNS) abnormality, 
disorder, or brain tumor 
(8)Current evidence of a clinically significant disease (eg, cardiac, respiratory, gastrointestinal, or 
renal disease) that in the opinion of the investigator(s) could affect the subject’s safety, interfere 
with the study assessments, or require prohibited medications as specified in the study protocol 
(9)Clinically significant abnormal laboratory values 
(10)Concomitant use of the following drugs except for carbamazepine and phenytoin or foods known 
to induce CYP3A (not limited to these drugs or foods) within 14 days before Day 1 in the 
Treatment Phase: 
enzalutamide, mitotane, phenobarbital (except for use as an AED), amobarbital, secobarbital, 
rifabutin, rifampicin, food containing St. John’s Wort (hypericum perforatum), bosentan, 
efavirenz, etravirine, modafinil, aprepitant, echinacea, pioglitazone, vemurafenib, nevirapine, and 
glucocorticoid (except for topical use) 
(11)Hypersensitivity to the study drug or any of its excipients 
(12)A history of multiple drug allergies or a severe drug reaction to an AED(s), including 
dermatological (eg, Stevens-Johnson syndrome), hematological, or organ toxicity reactions 
(13)Females of childbearing potential who: 
• In the Pretreatment Phase, are breastfeeding or pregnant (as documented by a positive beta-human 
chorionic gonadotropin [β-hCG] test). 
• Within 28 days before Visit 1, did not use a highly effective method of contraception, which 
includes any of the following: 
˗ total abstinence (if it is their preferred and usual lifestyle) 
˗ an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) 
˗ a contraceptive implant 
˗ an oral contraceptive (with additional barrier method) 
(Subject must be on a stable dose of the same oral contraceptive product for at least 28 days 
before Day 1 in the Treatment Phase and throughout the entire study period, and for 28 days 
after the last dose of the study drug) 
˗ have a vasectomized partner with confirmed azoospermia. 
• Do not agree to use a highly effective method of contraception (as described above) throughout 
the entire study period and for 28 days after the last dose of the study drug. 
 
It is permissible that if a highly effective method of contraception is not appropriate or acceptable 
to the subject, then the subject must agree to use a medically acceptable method of contraception, 
ie, double-barrier methods of contraception such as latex or synthetic condom plus diaphragm or 
cervical/vault cap with spermicide. 
 
NOTE: All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, 
and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal 
ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before 


 
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dosing). 
(14)Be considered inappropriate for evaluation in the investigator’s judgment 
(15)Have participated in a study involving administration of an investigational drug or device within 
28 days before Visit 1, or within approximately 5 half-lives of the previous investigational drug, 
whichever is longer 
(16)Have a prolonged QTcF interval (>450 ms) 2 or more times as demonstrated by a repeated 
electrocardiogram (ECG) 
(17)Have a vagal nerve stimulation (VNS) device implanted less than 5 months before Visit 1 or 
changes in stimulation parameters less than 28 days before Visit 1 
Study Treatment 
Test drug: 
Perampanel will be administered as an intravenous infusion for 30 minutes once a day on Days 1 
through 4 under inpatient conditions. 
Comparator drug: 
Not applicable 
Duration 
• Pretreatment Phase:  Up to 29 days  
• Treatment Phase:  4 days (the period beginning at the start of intravenous infusion of perampanel 
on Day 1 to immediately before the oral perampanel administration on Day 5) 
• Follow-up Phase:  Assessments at the Follow-up Visit will be conducted 7 days (allowance window: 
+7 days) after the last intravenous infusion of perampanel. 
Concomitant Drug/Therapy 
For at least 28 days before Day 1 in the Treatment Phase and throughout the study (or until the visit at 
the time of early discontinuation for discontinued subjects), subjects must be on a stable dosage of 1 to 
a maximum of 3 marketed concomitant AEDs. 
Prohibited Concomitant Medications and Foods 
For 14 days before Day 1 in the Treatment Phase and throughout the study (or until the visit at the time 
of early discontinuation for discontinued subjects), concomitant use of the following drugs and foods 
is prohibited. 
• Other than carbamazepine and phenytoin, concomitant use of the following drugs or foods known 
to induce CYP3A (not limited to these): 
enzalutamide, mitotane, phenobarbital (except for use as an AED), amobarbital, secobarbital, 
rifabutin, rifampicin, food containing St. John’s Wort (hypericum perforatum), bosentan, 
efavirenz, etravirine, modafinil, aprepitant, echinacea, pioglitazone, vemurafenib, nevirapine, 
and glucocorticoids (except for topical use) 
The use of the following drugs is prohibited within 28 days or approximately 5 half-lives of the previous 
investigational drug (whichever is longer) before Visit 1, as well as during the study (or until the visit 
at the time of early discontinuation for discontinued subjects). 
• Other investigational drugs 
The use of the following drug is prohibited during the Treatment Phase: 
• Oral perampanel 
 


 
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Prohibited Concomitant Therapies 
The following therapies must not be implemented during the study (or until the visit at the time of early 
discontinuation for discontinued subjects). 
• Brain surgery 
• Neuromodulation therapy except for VNS (transcranial magnetic stimulation, etc.) 
The following therapies must not be implemented within 28 days before Visit 1, as well as throughout 
the study (or until the visit at the time of early discontinuation for discontinued subjects). 
• Therapies with a medical device under clinical study 
Restricted Concomitant Drugs 
The dosing regimens of the following drugs must not be altered, newly introduced, or discontinued 
during the study (or until the visit at the time of early discontinuation for discontinued subjects). 
• Antidepressants 
• Antipsychotics 
• Antianxiety drugs 
• Benzodiazepine hypnotics 
Restricted Concomitant Therapies 
• A ketogenic diet must not be changed, initiated, or discontinued during the study (or until the visit 
at the time of early discontinuation for discontinued subjects). 
• A VNS is allowed, however, stimulation parameters cannot be changed for 28 days before Visit 1 
and throughout the study (or until the visit at the time of early discontinuation for discontinued 
subjects). 
Assessments 
Safety Assessments 
Safety assessments will consist of monitoring and recording all adverse events (AEs), clinical 
laboratory evaluations (biochemistry, hematology, urinalysis), vital signs, weight, 12-lead 
electrocardiogram (ECG), and physical examinations. 
Efficacy Assessments 
Seizure diaries will be used to collect all seizure counts and types. 
Pharmacokinetic Assessments 
The plasma concentration of perampanel will be determined. 
Bioanalytical Method 
The plasma concentration of perampanel will be measured by a validated liquid chromatography with 
tandem mass spectrometry (LC/MS/MS) assay. 
Statistical Methods 
Study Endpoints 
The safety endpoints are AEs, clinical laboratory tests (biochemistry, hematology, and urinalysis), vital 
signs, weight, and 12-lead ECG. 
The efficacy endpoint is the seizure frequency per day in each of the 3 phases (Pretreatment Phase, 
Treatment Phase, and Follow-up Phase).  Seizure frequency per day will be derived from the 
information recorded in the subject diaries. 
The pharmacokinetic endpoint is the plasma concentration of perampanel. 


 
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All observed data will be reported with no adjustments for missing data. 
Analysis Sets 
The Safety Analysis Set is the group of subjects who received at least 1 intravenous infusion of 
perampanel. 
The Efficacy Analysis Set is the group of subjects who received at least 1 intravenous infusion of 
perampanel and had at least 1 postdose efficacy measurement. 
The Pharmacokinetic Analysis Set is the group of subjects who received at least 1 intravenous infusion 
of perampanel and had at least 1 evaluable measurement of plasma perampanel concentration. 
Efficacy Analyses 
The efficacy analyses will be performed on the Efficacy Analysis Set.  The seizure frequency per day 
for each of the 3 phases (Pretreatment Phase, Treatment Phase, and Follow-up Phase) will be 
summarized using descriptive statistics (eg, mean, SD, median, minimum, and maximum).  The 
seizure frequency per day from the Pretreatment Phase to the Follow-up Phase for each subject will be 
displayed using a spaghetti-plot. 
Pharmacokinetic Analyses 
The PK analyses will be performed on the Pharmacokinetic Analysis Set using the plasma 
concentrations of perampanel.  Summary statistics for the plasma concentrations will be obtained by 
sampling time point and dose.  The plasma concentrations of perampanel before and after switching 
from oral tablet to intravenous infusion will be plotted.  A similar analysis may be conducted using 
dose-normalized plasma concentration data. 
Safety Analyses 
The safety analyses will be performed on the Safety Analysis Set.  Safety data will be summarized 
using descriptive statistics (eg, n, mean, SD, median, minimum, and maximum for continuous variables; 
n [%] for categorical variables).  Safety variables include AEs, clinical laboratory parameters 
(biochemistry, hematology, and urinalysis), vital signs, weight, and 12-lead ECG results. 
Interim Analysis 
No interim analysis is planned for this study. 
Sample Size Rationale 
This is an uncontrolled, open-label study for the safety evaluation of intravenous infusion of perampanel 
and the sample size (20 subjects) is not based on statistical power considerations, but rather on 
feasibility.  It is considered that a sufficient number of subjects will be obtained for the safety 
evaluation of intravenous infusion of perampanel if the sample size is 20. 
 


 
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3. TABLE OF CONTENTS 
1. TITLE PAGE .............................................................................................................................................. 1 
2. CLINICAL PROTOCOL SYNOPSIS ........................................................................................................ 2 
3. TABLE OF CONTENTS ............................................................................................................................ 8 
4. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................................ 11 
5. ETHICS .................................................................................................................................................... 12 
5.1 Institutional Review Boards/Independent Ethics Committees ........................................................... 12 
5.2 Ethical Conduct of the Study .............................................................................................................. 12 
5.3 Subject Information and Informed Consent........................................................................................ 12 
6. INVESTIGATORS AND STUDY PERSONNEL .................................................................................... 14 
7. INTRODUCTION .................................................................................................................................... 15 
7.1 Indication ............................................................................................................................................ 15 
7.1.1 Current Drug Treatment ............................................................................................................... 15 
7.1.2 E2007 ........................................................................................................................................... 15 
7.2 Study Rationale .................................................................................................................................. 16 
8. STUDY OBJECTIVES ............................................................................................................................ 17 
8.1 Primary Objective ............................................................................................................................... 17 
8.2 Secondary Objectives ......................................................................................................................... 17 
9. INVESTIGATIONAL PLAN ................................................................................................................... 18 
9.1 Overall Study Design and Plan ........................................................................................................... 18 
9.1.1 Pretreatment Phase ...................................................................................................................... 18 
9.1.2 Treatment Phase ........................................................................................................................... 19 
9.1.3 Follow-up Phase .......................................................................................................................... 19 
9.2 Discussion of Study Design, Including Choice of Control Groups .................................................... 19 
9.3 Selection of Study Population ............................................................................................................ 20 
9.3.1 Inclusion Criteria ......................................................................................................................... 21 
9.3.2 Exclusion Criteria ........................................................................................................................ 21 
9.3.3 Removal of Subjects From Therapy or Assessment .................................................................... 23 
9.4 Treatment ............................................................................................................................................ 23 
9.4.1 Treatment Administered............................................................................................................... 23 
9.4.2 Identity of Investigational Product .............................................................................................. 24 
9.4.2.1 Chemical Name of E2007 ..................................................................................................... 24 
9.4.2.2 Comparator Drug .................................................................................................................. 24 
9.4.2.3 Labeling for Study Drug ....................................................................................................... 24 
9.4.2.4 Storage Conditions ............................................................................................................... 24 
9.4.3 Method of Assigning Subjects to Treatment Groups ................................................................... 24 
9.4.4 Selection of Doses in the Study ................................................................................................... 24 
9.4.5 Selection and Timing of Dose for Each Subject .......................................................................... 25 


 
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9.4.6 Blinding ....................................................................................................................................... 25 
9.4.7 Prior and Concomitant Therapy ................................................................................................... 25 
9.4.7.1 Antiepileptic Drugs Other Than Perampanel ........................................................................ 25 
9.4.7.2 Prohibitions and Restrictions During Study Period .............................................................. 25 
9.4.8 Treatment Compliance ................................................................................................................. 26 
9.4.9 Drug Supplies and Accountability ............................................................................................... 26 
9.5 Study Assessments .............................................................................................................................. 27 
9.5.1 Assessments ................................................................................................................................. 27 
9.5.1.1 Demography ......................................................................................................................... 27 
9.5.1.2 Pretreatment Assessments ..................................................................................................... 27 
9.5.1.3 Efficacy Assessments ............................................................................................................ 28 
9.5.1.4 Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
 .......................................................................................................................................................... 28 
9.5.1.5 Safety Assessments ............................................................................................................... 28 
9.5.1.6 Other Assessments ................................................................................................................ 34 
9.5.2 Schedule of Procedures/Assessments .......................................................................................... 34 
9.5.2.1 Schedule of Procedures/Assessments ................................................................................... 34 
9.5.3 Appropriateness of Measurements ............................................................................................... 37 
9.5.4 Reporting of Serious Adverse Events, Pregnancy, and Events Associated With Special Situations
 .............................................................................................................................................................. 37 
9.5.4.1 Reporting of Serious Adverse Events ................................................................................... 37 
9.5.4.2 Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding .................... 37 
9.5.4.3 Reporting of Events Associated With Special Situations...................................................... 38 
9.5.4.4 Expedited Reporting ............................................................................................................. 39 
9.5.4.5 Breaking the Blind ................................................................................................................ 39 
9.5.4.6 Regulatory Reporting of Adverse Events ............................................................................. 39 
9.5.5 Completion/Discontinuation of Subjects ..................................................................................... 39 
9.5.6 Abuse or Diversion of Study Drug .............................................................................................. 40 
9.5.7 Confirmation of Medical Care by Another Physician.................................................................. 40 
9.6 Data Quality Assurance ...................................................................................................................... 40 
9.6.1 Data Collection ............................................................................................................................ 40 
9.6.2 Clinical Data Management .......................................................................................................... 41 
9.7 Statistical Methods ............................................................................................................................. 41 
9.7.1 Statistical and Analytical Plans .................................................................................................... 41 
9.7.1.1 Study Endpoints .................................................................................................................... 41 
9.7.1.2 Definitions of Analysis Sets .................................................................................................. 41 
9.7.1.3 Subject Disposition ............................................................................................................... 42 
9.7.1.4 Demographic and Other Baseline Characteristics ................................................................ 42 
9.7.1.5 Prior and Concomitant Therapy ............................................................................................ 42 


 
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9.7.1.6 Efficacy Analyses ................................................................................................................. 42 
9.7.1.7 Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses . 43 
9.7.1.8 Safety Analyses ..................................................................................................................... 43 
9.7.2 Determination of Sample Size ..................................................................................................... 45 
9.7.3 Interim Analysis ........................................................................................................................... 45 
9.7.4 Other Statistical/Analytical Issues ............................................................................................... 45 
9.7.5 Procedure for Revising the Statistical Analysis Plan ................................................................... 45 
10. REFERENCE LIST ................................................................................................................................ 46 
11. PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) ............................... 47 
11.1 Changes to the Protocol .................................................................................................................... 47 
11.2 Adherence to the Protocol ................................................................................................................. 47 
11.3 Monitoring Procedures ..................................................................................................................... 47 
11.4 Recording of Data ............................................................................................................................. 48 
11.5 Identification of Source Data ............................................................................................................ 48 
11.6 Retention of Records ........................................................................................................................ 48 
11.7 Auditing Procedures and Inspection ................................................................................................. 49 
11.8 Handling of Study Drug .................................................................................................................... 49 
11.9 Publication of Results ....................................................................................................................... 49 
11.10 Disclosure and Confidentiality ....................................................................................................... 49 
11.11 Discontinuation of Study ................................................................................................................ 50 
11.12 Subject Insurance and Indemnity .................................................................................................... 50 
12. APPENDICES ........................................................................................................................................ 51 
LIST OF TEXT TABLE 
Table 1 Clinical Laboratory Tests .................................................................................................. 33 
Table 2 Schedule of Procedures / Assessments in Study E2007-J081-240 ................................... 35 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design ................................................................................................................. 18 
 
LIST OF APPENDICES 
Appendix 1 Sponsor’s Grading for Laboratory Values ................................................................. 52 


 
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4. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMPA 
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
β-hCG 
beta-human chorionic gonadotropin 
BUN 
blood urea nitrogen 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
GABA 
gamma-aminobutyric acid 
GGT 
gamma-glutamyl transferase 
ICH 
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ILAE 
International League Against Epilepsy 
IUD 
intrauterine device 
IUPAC 
International Union of Pure and Applied Chemistry 
IUS 
intrauterine hormone-releasing system 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
LLT 
lowest level term 
LNH 
low/normal/high 
MedDRA 
Medical Dictionary for Regulatory Activities 
PT 
preferred term 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SBECD 
Sodium Sulphobutylether-beta-cyclodextrin 
SI 
Système International 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory value 
ULN 
upper limit of normal 
VNS 
vagal nerve stimulation 
WHO DD 
World Health Organization Drug Dictionary 
 


 
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5. ETHICS 
5.1  Institutional Review Boards/Independent Ethics Committees 
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) constituted and functioning in 
accordance with Japan’s Good Clinical Practice (J-GCP).  Any protocol amendment or 
revision to the ICF will be resubmitted to the IRB for review and approval, except for changes 
involving only logistical or administrative aspects of the study (eg, change in clinical research 
associate [CRA], change of telephone number).  Documentation of IRB compliance with J-
GCP regarding constitution and review conduct will be provided to the sponsor. 
A signed letter of study approval from the IRB chairman must be sent to the head of the medical 
institution with a copy to the sponsor before study start and the release of any study drugs to 
the site by the sponsor or its designee.  If the IRB decides to suspend or terminate the study, 
the head of the medical institution will immediately send a notice of study suspension or 
termination by the IRB to the sponsor. 
Study progress is to be reported to the IRB annually (or as required) by the investigator via the 
head of the medical institution, depending on J-GCP.  The sponsor will submit, depending on 
the regulations, periodic reports and inform the investigator, the head of the medical institution, 
and the relevant IRB (directly or via the head of the medical institution) of any reportable 
adverse events (AEs) per J-GCP guidelines and local IRB standards of practice.  Upon 
completion of the study, the investigator will provide the sponsor and the relevant IRB via the 
head of the medical institution with a brief report of the outcome of the study, if required. 
5.2  Ethical Conduct of the Study 
This study will be conducted in accordance with the standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following: 
• 
Principles of the World Medical Association Declaration of Helsinki 
• 
J-GCP guidelines 
• 
Other applicable regulatory authorities’ requirements or directives 
5.3  Subject Information and Informed Consent 
As part of administering the informed consent, the investigator must explain to each subject or 
the subject’s legally acceptable representative the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits involved, any 
potential discomfort, potential alternative procedure(s) or course(s) of treatment available to 
the subject, and the extent of maintaining confidentiality of the subject’s records.  Each 
subject must be informed that participation in the study is voluntary, that he/she may withdraw 
from the study at any time, and that withdrawal of consent will not affect his/her subsequent 
medical treatment or relationship with the treating physician. 


 
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This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to the subjects is read and 
explained to the subject or the subject’s legally acceptable representative, and after the subject 
or the subject’s legally acceptable representative has signed and personally dated the ICF, the 
witness should sign and personally date the consent form.  The subject will be asked to sign 
an ICF before any study-specific procedures are performed.  No subject can enter the study 
before his/her informed consent has been obtained. 
If an underage subject is able to understand participation in the study, the investigator should 
explain the nature of the study and other information to the subject with the ICF or an informed-
assent document prepared separately from the ICF, and should obtain the written informed 
consent/assent.  In such cases, the written informed consent for the subject’s participation in 
the study must be obtained from the subject’s legally acceptable representative (ie, an 
individual who exercises parental rights over the subject). 
If a subject is unable to give a written informed consent/assent, the investigator should confirm 
that the subject has orally consented to the subject’s participation in the study, and must obtain 
the written informed consent from the subject’s legally acceptable representative, and record it 
in the ICF. 
An unsigned copy of an IRB-approved ICF and an informed-assent document must be prepared 
in accordance with J-GCP and other applicable regulations.  Each subject must sign an 
approved ICF/informed assent form before study participation.  The form must be signed and 
dated by the appropriate parties.  The original, signed ICF/informed assent form for each 
subject will be verified by the sponsor and kept on file according to the local procedures at the 
site. 
The subject or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s willingness 
to continue participation in the study.  The communication of this information should be 
documented. 


 
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6. INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of Eisai Co., Ltd. 
(the sponsor) at investigational sites in Japan (See Attachment 2). 
The name, and telephone and fax numbers of the sponsor are listed in Attachment 1. 
 


 
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7. INTRODUCTION 
7.1  Indication 
Epilepsy is a common serious neurological disorder with an overall prevalence of 0.5% to 1%.  
Epilepsy is characterized by the spontaneous recurrence of seizures and requires long term, 
often life-long pharmacological management.  There are 3 major types of clinical seizures: 
generalized, partial (focal), and unclassified seizures.  The most frequent type is partial-onset 
seizures (POS). 
Patients suffering from POS often have poor seizure control.  Uncontrolled seizures lead to a 
wide variety of medical consequences (eg, severe trauma due to seizures, sudden death, 
depression, or intermittent psychotic disorders).  In addition, uncontrolled seizures lead to 
significant lifestyle limitations and social handicaps (eg, loss of driving privileges, difficulties 
getting and maintaining a job). 
Like other types of seizures, primary generalized tonic-clonic (PGTC) seizures are caused by 
a paroxysmal, uncontrolled discharge of cerebral cortical neurons, leading to neurologic 
dysfunction.  Unlike most other types of seizures, however, this cerebral hyperactivity is not 
confined to a localized area, but extends to the entire brain.  The onset of PGTC seizures is 
age-related and typically starts in older children, adolescents, and young adults.  PGTC 
seizures are associated with an increased risk of injury and death.  Therefore, effective control 
of PGTC seizures is necessary to reduce epilepsy-related morbidity and mortality. 
7.1.1  Current Drug Treatment 
In the guidelines for the drug treatment of adult patients with epilepsy by the Japan Epilepsy 
Society, carbamazepine and valproic acid are recommended as the first-line drugs for POS and 
generalized seizures, respectively. 
Intravenous formulations of levetiracetam and fosphenytoin sodium hydrate are the only 
marketed drugs which have an indication for short-term replacement therapy when oral 
administration is temporarily infeasible (eg, in cases of patients undergoing surgical procedures, 
experiencing difficulty swallowing, suffering from consciousness disturbance, or acute 
gastrointestinal disorders). 
7.1.2  E2007 
E2007/perampanel is a first-in-class noncompetitive and highly selective α-amino-3-hydroxy-
5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist that was discovered and 
developed by Eisai. 
Perampanel was approved for marketing as an adjunctive therapy for the treatment of POS with 
or without secondarily generalized seizures in patients aged 12 years and older in Europe and 
the United States in 2012, and in subsequently more than 59 countries.  Perampanel was also 
approved for marketing as an adjunctive therapy for the treatment of PGTC seizures in patients 


 
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with epilepsy aged 12 years and older in Europe and the United States in 2015.  In Japan, the 
above 2 indications were approved in March 2016.  Furthermore, perampanel was approved 
for marketing as a monotherapy for the treatment of POS with or without secondarily 
generalized seizures in patients aged 12 years and older in the United States in 2017.  In 
addition, Eisai applied for approval in the United States to expand the indications of adjunctive 
therapy for the treatment of POS with or without secondarily generalized seizures and PGTC 
seizures in patients aged 2 years and older in 2018. 
Depending on the mechanism of action, existing antiepileptic drugs (AEDs) are divided into 2 
groups, the first of which decrease neuronal excitation, and the second of which enhance 
inhibition.  Major target sites for AEDs are blockage of voltage-operated sodium channels or 
calcium channels, regulation of neuronal transmitter release, inhibition of glutamatergic neural 
transmission, and facilitation of gamma-aminobutyric acid (GABA)-ergic neurotransmission.  
Current major AEDs are speculated to have a selective or mixed action on these targets.  
Perampanel is the only available drug showing noncompetitive and selective antagonism to 
AMPA receptors. 
Further detailed information on perampanel including the data of the nonclinical and clinical 
studies that have been completed so far are provided in the Investigator's Brochure. 
7.2  Study Rationale 
In advance of this study, Eisai conducted a survey that aimed to investigate the needs of 
antiepileptic-injection use among epileptologists, and the results suggested that a need for 
antiepileptic-injection use exists for patients for whom it is temporarily not feasible to receive 
oral AEDs due to undergoing surgical procedures or other reasons. 
Perampanel is the only available noncompetitive and selective AMPA receptor antagonist.  
For that reason, when patients cannot temporarily receive a safe and effective dose of oral 
perampanel, and are forced to switch to another oral AED, risks such as poor tolerability and 
seizure control are likely to result for the patients.  Therefore, the development of a 
perampanel intravenous formulation to be used as an alternative to the oral formulation is 
significant. 
Thus, conducting this study, which aims to evaluate the safety and tolerability, as well as the 
pharmacokinetics and efficacy of intravenous infusion of perampanel as a substitute for oral 
perampanel, is considered appropriate. 


 
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8. STUDY OBJECTIVES 
8.1  Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of 30-minute 
intravenous infusions of perampanel after switching from oral perampanel (8 to 12 mg/day) as 
an adjunctive therapy in subjects with POS with or without secondarily generalized seizures or 
PGTC seizures. 
8.2  Secondary Objectives 
The secondary objectives of this study are: 
• 
To evaluate the plasma concentration of perampanel before and after switching from oral 
perampanel to 30-minute intravenous infusions of perampanel 
• 
To evaluate the seizure frequency before and after switching from oral perampanel to 30-
minute intravenous infusions of perampanel 




 
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from oral perampanel to intravenous infusion of perampanel (ie, on Day –1 [Visit 2]). 
9.1.2  Treatment Phase 
The Treatment Phase is defined as the period beginning at the start of intravenous infusion of 
perampanel on Day 1 to immediately before the oral perampanel administration on Day 5. 
Hospitalized subjects will be switched from oral perampanel on Day 1 to intravenous infusion 
of perampanel at a dose equivalent to the oral perampanel dose.  Subjects will receive 30-
minute intravenous infusions of perampanel once a day for 4 days under inpatient conditions 
(Days 1 through 4). 
Subjects will be discharged from the hospital the day after the last intravenous infusion of 
perampanel (ie, Day 5), and treatment must be switched back to their original dose of oral 
perampanel. 
If subjects cannot continue intravenous infusion of perampanel for any reason(s), they must 
discontinue the study. 
9.1.3  Follow-up Phase 
The Follow-up Phase is defined as the period after switching back to oral perampanel 
administration. 
The assessments at the Follow-up Visit will be conducted 7 days (allowance window: +7 days) 
after the last intravenous infusion of perampanel. 
9.2  Discussion of Study Design, Including Choice of Control Groups 
Study Design 
This study was designed to be conducted as an open-label, uncontrolled study, as with the 
Japanese study of levetiracetam injection (Inoue Y, et al., 2014), for which the indication as a 
substitute for oral formulation has been approved, in patients with epilepsy taking perampanel 
oral formulation as an adjunctive therapy with other AED(s) to evaluate the safety, tolerability, 
pharmacokinetics, and efficacy when perampanel oral formulation is temporarily replaced with 
perampanel injection. 
Doses of the Study Drug 
Perampanel oral formulation has been approved for the indication as an adjunctive therapy 
with other AED(s) for POS with or without secondarily generalized seizures and PGTC 
seizures, in patients with epilepsy aged 12 years or older, and is used at maintenance doses of 
8 to 12 mg/day. 
In this study, with a view to obtain approval for the indication as a substitute for perampanel 
oral formulation, the doses of the study drug (perampanel injection) are set to the same levels 
(8 to 12 mg/day) as the maintenance doses of perampanel oral formulation taken for at least 28 


 
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days before starting administration of the study drug. 
Duration of Study Drug Administration 
The duration of study drug administration is set at 4 days. 
A review of the data on the prescription of levetiracetam intravenous infusion formulation, 
approved as a substitute for oral formulation (Medical Data Vision Co., Ltd.; Review period: 
November 2016 to October 2017), demonstrated that the mean duration of administration was 
4.8 days, and the percentage of patients with an administration duration of 4 days or shorter 
was 73.1% (7688/10510 patients). 
In consideration of feasibility, this study will be conducted not only in inpatients, but also in 
patients who will be able to be admitted to the hospital to participate in the study.  Because 
an unnecessarily prolonged hospital stay may lead to a disadvantage for these patients, the 
duration of study drug administration is set at 4 days, as a duration of administration for which 
the safety of the study drug can be evaluated appropriately, with reference to the duration of 
administration of the Japanese study of other antiepileptic injections (Inoue Y, et al., 2014). 
Time of Study Drug Administration 
In the United States, a clinical pharmacology study (E2007-A001-050 study, hereinafter the 
“Study 050”) was conducted in Japanese and non-Japanese healthy subjects to evaluate 
bioavailability of a single 12 mg dose of perampanel for 3 intravenous infusion durations (for 
30 minutes [n=20], 60 minutes [n=20], and 90 minutes [n=8]) relative to a single 12 mg 
perampanel oral tablet.  As a result, it was demonstrated that the AUC after intravenous 
administration for 30 minutes and 60 minutes was within the range of the criteria for 
bioequivalence (two-sided 90% confidence interval of 0.8 to 1.25 for the ratio of the means 
after intravenous administration/oral administration) to the AUC after oral administration.  
On the other hand, the Cmax did not satisfy the bioequivalence criteria for the ratio of the means 
after intravenous administration for 30, 60, and 90 minutes versus oral administration.  
Therefore, we developed a population pharmacokinetic model using the plasma concentration 
data in the Study 050, in order to simulate and estimate changes in the plasma concentration 
after switching to intravenous administration under steady-state conditions after multiple oral 
administration.  As a result, it was estimated that, under steady-state conditions, the Cmax after 
intravenous administration for 30 minutes and 60 minutes fell within the range of the criteria 
for bioequivalence to the Cmax after oral administration. 
In addition, based on a hearing from specialists in epilepsy regarding the time of administration 
of antiepileptic injection as an alternative therapy, it was suggested that an injection should be 
administered for no longer than 30 minutes in actual clinical settings. 
Based on the above findings, the time of study drug administration is set at 30 minutes. 
9.3  Selection of Study Population 
Twenty subjects will be randomized and treated in this study.  Subjects who do not meet all 
of the inclusion criteria or who meet any of the exclusion criteria will not be eligible to receive 


 
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the study drug. 
9.3.1  Inclusion Criteria 
Subjects must meet all of the following criteria to be included in this study: 
1. Male or female aged 12 years or older at the time of informed consent/assent 
2. Have a diagnosis of epilepsy with POS with or without secondarily generalized seizures 
or PGTC seizures according to the International League Against Epilepsy (ILAE) 
Classification of Epileptic Seizures (1981) 
3. Have been receiving a stable dosage of oral perampanel (8 to 12 mg/day) for at least 28 
days before Day 1 in the Treatment Phase 
4. Have been receiving a concomitant stable dosage of 1 to a maximum of 3 marketed 
AED(s) (regarding phenobarbital used as an AED, phenytoin, and carbamazepine, only 
one is allowed) for at least 28 days before Day 1 in the Treatment Phase.  No change of 
dosing regimen for concomitant AED(s) is planned during the Treatment and Follow-up 
Phases. 
5. Are considered reliable and willing to be available for the study period by the 
investigator, and are able to record seizures and report adverse events (AEs) by 
themselves or have a caregiver who can record seizures and report AEs for them 
9.3.2  Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Have a history of drug or alcohol dependency or abuse within the last 2 years before 
Visit 1 
2. Have a history of status epilepticus within 6 months before Day 1 in the Treatment Phase 
3. Are unsuitable for venipuncture and intravenous administration 
4. Require medical intervention due to safety issues related to the concomitant 
administration of 1 to 3 AEDs 
5. Have a history of suicidal ideation/attempt within 2 years before Day 1 in the Treatment 
Phase 
6. Have clinically problematic psychological or neurological disorder(s) 
7. Clinical symptoms or imaging suggest a progressive central nervous system (CNS) 
abnormality, disorder, or brain tumor 
8. Current evidence of a clinically significant disease (eg, cardiac, respiratory, 
gastrointestinal, or renal disease) that in the opinion of the investigator(s) could affect the 
subject’s safety, interfere with the study assessments, or require prohibited medications as 
specified in the study protocol 
9. Clinically significant abnormal laboratory values 
10. Concomitant use of the following drugs except for carbamazepine and phenytoin or foods 
known to induce CYP3A (not limited to these drugs or foods) within 14 days before Day 
1 in the Treatment Phase: 


 
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enzalutamide, mitotane, phenobarbital (except for use as an AED), amobarbital, 
secobarbital, rifabutin, rifampicin, food containing St. John’s Wort (hypericum 
perforatum), bosentan, efavirenz, etravirine, modafinil, aprepitant, echinacea, 
pioglitazone, vemurafenib, nevirapine, and glucocorticoid (except for topical use) 
11. Hypersensitivity to the study drug or any of its excipients 
12. A history of multiple drug allergies or a severe drug reaction to an AED(s), including 
dermatological (eg, Stevens-Johnson syndrome), hematological, or organ toxicity 
reactions 
13. Females of childbearing potential who: 
• 
In the Pretreatment Phase, are breastfeeding or pregnant (as documented by a positive 
beta-human chorionic gonadotropin [β-hCG] test). 
• 
Within 28 days before Visit 1, did not use a highly effective method of contraception, 
which includes any of the following: 
˗ total abstinence (if it is their preferred and usual lifestyle) 
˗ an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) 
˗ a contraceptive implant 
˗ an oral contraceptive (with additional barrier method) 
(Subject must be on a stable dose of the same oral contraceptive product for at least 
28 days before Day 1 in the Treatment Phase and throughout the entire study period, 
and for 28 days after the last dose of the study drug) 
˗ have a vasectomized partner with confirmed azoospermia. 
• 
Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after the last dose of the study drug. 
It is permissible that if a highly effective method of contraception is not appropriate or 
acceptable to the subject, then the subject must agree to use a medically acceptable 
method of contraception, ie, double-barrier methods of contraception such as latex or 
synthetic condom plus diaphragm or cervical/vault cap with spermicide. 
NOTE: All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause) or have been sterilized surgically (ie, 
bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at 
least 1 month before dosing). 
14. Be considered inappropriate for evaluation in the investigator’s judgment 
15. Have participated in a study involving administration of an investigational drug or device 
within 28 days before Visit 1, or within approximately 5 half-lives of the previous 
investigational drug, whichever is longer 
16. Have a prolonged QTcF interval (>450 ms) 2 or more times as demonstrated by a 
repeated electrocardiogram (ECG) 


 
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17. Have a vagal nerve stimulation (VNS) device implanted less than 5 months before Visit 1 
or changes in stimulation parameters less than 28 days before Visit 1 
9.3.3  Removal of Subjects From Therapy or Assessment 
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  The subject may stop the study drug or withdraw from the study at 
any time for any reason. 
Further details are provided in Section 9.5.5 . 
9.4  Treatment 
9.4.1  Treatment Administered 
The study drug, perampanel intravenous formulation, is a lyophilized powder for injection 
containing 8 mg of perampanel (anhydrate) in a vial. 
Subjects will be switched from oral perampanel (8 to 12 mg/day; stable-dosage treatment 
during the Pretreatment Phase) on Day 1 to intravenous infusion of perampanel at a dose 
equivalent to the oral perampanel dose.  Subjects will receive 30-minute intravenous 
infusions of perampanel once a day in a supine position for 4 days under inpatient conditions 
(Days 1 through 4). 
The start time of intravenous infusions of perampanel from Day 1 to Day 4 will be designated 
as the same time as the administration time of oral perampanel on Day –1 (allowance window: 
±1 hour). 
As for the procedure for preparation of the intravenous infusion of perampanel, refer to the 
Instructions for Handling of Investigational Products provided by the sponsor. 
Recording of Information Regarding the Study Treatment (Perampanel Intravenous Infusion) 
The following information will be recorded in the CRF:  Dose of perampanel; timing of dose 
(before/after a meal); planned intravenous-perampanel-infusion dose (mg); planned 
intravenous-perampanel-infusion volume (mL); actual intravenous-perampanel-infusion 
volume (mL); start date and time of infusion; end date and time of infusion; as well as date and 
time of both stopping infusion and resuming infusion, if applicable.  In addition, if the 
intravenous-perampanel infusion is not performed as planned, the reason(s) will also be 
recorded on the CRF. 
Recording of Information Regarding Oral Perampanel 
Information regarding the oral perampanel will be obtained for the CRF.  In addition, as for 
the administration time of the oral perampanel on Day –1, the day and time of the dose, as well 
as the timing of the dose (before/after a meal), will be recorded on the CRF. 


 
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9.4.2  Identity of Investigational Product 
The study drug will be supplied by the sponsor in labeled containers. 
9.4.2.1  Chemical Name of E2007 
• 
Test drug code:  E2007 
• 
Generic name:  Perampanel Hydrate 
• 
Chemical name:  2-(2-Oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) 
benzonitrile hydrate (4:3) 
• 
Molecular formula:  C23H15N3O∙3/4H2O 
• 
Molecular weight:  362.90 (3/4 hydrate); 349.38 (anhydrous) 
9.4.2.2  Comparator Drug 
Not applicable. 
9.4.2.3  Labeling for Study Drug 
The following information has to be provided: 
• 
For clinical study use only 
• 
Name and address of the sponsor 
• 
Study drug code 
• 
Drug identifier 
• 
Lot number 
• 
Storage conditions 
9.4.2.4  Storage Conditions 
The study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained within 
an established temperature range.  The head of the medical institution is responsible for 
ensuring that the temperature is monitored throughout the total duration of the study and that 
records are maintained.  The temperature should be monitored continuously using either an 
in-house validated data acquisition system, a mechanical recording device such as a calibrated 
chart recorder, or by manual means, such that minimum and maximum thermometric values 
over a specific time period can be recorded and retrieved as required. 
9.4.3  Method of Assigning Subjects to Treatment Groups 
There is no randomization in this study. 
9.4.4  Selection of Doses in the Study 
See Section 9.2 . 


 
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9.4.5  Selection and Timing of Dose for Each Subject 
See Section 9.4.1 . 
9.4.6  Blinding 
The study will not be blinded. 
9.4.7  Prior and Concomitant Therapy 
All medications (including over-the-counter medications) and non-pharmacological 
procedures administered to the subject during the study (or until the visit at the time of early 
discontinuation for discontinued subjects) will be recorded on the CRF. 
9.4.7.1  Antiepileptic Drugs Other Than Perampanel 
For at least 28 days before Day 1 in the Treatment Phase and throughout the study (or until the 
visit at the time of early discontinuation for discontinued subjects), subjects must be on a stable 
dosage of 1 to a maximum of 3 marketed concomitant AEDs. 
9.4.7.2  Prohibitions and Restrictions During Study Period 
9.4.7.2.1  PROHIBITED CONCOMITANT MEDICATIONS AND FOODS 
For 14 days before Day 1 in the Treatment Phase and throughout the study (or until the visit at 
the time of early discontinuation for discontinued subjects), concomitant use of the following 
drugs and foods is prohibited. 
• 
Other than carbamazepine and phenytoin, concomitant use of the following drugs or 
foods known to induce CYP3A (not limited to these): 
enzalutamide, mitotane, phenobarbital (except for use as an AED), amobarbital, 
secobarbital, rifabutin, rifampicin, food containing St. John’s Wort (hypericum 
perforatum), bosentan, efavirenz, etravirine, modafinil, aprepitant, echinacea, 
pioglitazone, vemurafenib, nevirapine, and glucocorticoids (except for topical use) 
The use of the following drugs is prohibited within 28 days or approximately 5 half-lives of 
the previous investigational drug (whichever is longer) before Visit 1, as well as during the 
study (or until the visit at the time of early discontinuation for discontinued subjects). 
• 
Other investigational drugs 
The use of the following drug is prohibited during the Treatment Phase: 
• 
Oral perampanel 
9.4.7.2.2  PROHIBITED CONCOMITANT THERAPIES 
The following therapies must not be implemented during the study (or until the visit at the time 
of early discontinuation for discontinued subjects). 


 
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• 
Brain surgery 
• 
Neuromodulation therapy except for VNS (transcranial magnetic stimulation, etc.) 
The following therapies must not be implemented within 28 days before Visit 1, as well as 
throughout the study (or until the visit at the time of early discontinuation for discontinued 
subjects). 
• 
Therapies with a medical device under clinical study 
9.4.7.2.3  RESTRICTED CONCOMITANT DRUGS 
The dosing regimens of the following drugs must not be altered, newly introduced, or 
discontinued during the study (or until the visit at the time of early discontinuation for 
discontinued subjects). 
• 
Antidepressants 
• 
Antipsychotics 
• 
Antianxiety drugs 
• 
Benzodiazepine hypnotics 
9.4.7.2.4  RESTRICTED CONCOMITANT THERAPIES 
• 
A ketogenic diet must not be changed, initiated, or discontinued during the study (or until 
the visit at the time of early discontinuation for discontinued subjects). 
• 
A VNS is allowed, however, stimulation parameters cannot be changed for 28 days 
before Visit 1 and throughout the study (or until the visit at the time of early 
discontinuation for discontinued subjects). 
9.4.8  Treatment Compliance 
Records of treatment compliance for each subject will be kept during the study.  CRAs will 
review treatment compliance during site visits and at the completion of the study. 
9.4.9  Drug Supplies and Accountability 
The designated pharmacist (or designee) will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions 
(Instructions for Handling of Investigational Products) and adherence to J-GCP guidelines as 
well as other requirements. 
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study. 
The designated pharmacist (or designee) must maintain an accurate and timely record of the 
following: receipt of all study drugs, dispensing of study drugs to the subject, unused study 
drugs that are returned by the subjects (unused study drug-1), unused study drugs that are 


 
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shipped to the site but not dispensed to subjects (unused study drug-2), and return of reconciled 
study drugs to the sponsor (sum of unused study drugs 1 and 2), or destruction of reconciled 
study drugs at the site (if applicable).  This includes, but may not be limited to: (a) 
documentation of the receipt of study drugs, (b) a study drug dispensing/return reconciliation 
log, (c) a study drug accountability log, and (d) documentation of returns to the sponsor. 
The study drugs and inventory records must be made available, upon request, for inspection by 
a designated representative of the sponsor or a representative of a health authority.  Upon 
completion of unused drug accountability and reconciliation procedures by the designated 
pharmacist (or designee) and documentation procedures by the designated pharmacist (or 
designee) and the sponsor’s personnel, unused study drugs must be returned to the sponsor by 
the designated pharmacist (or designee).  Unused study drugs will be removed from the site 
and hand-delivered to the sponsor’s designated depot by sponsor representatives (ie, CRA). 
Drug accountability will be reviewed during site visits and at the completion of the study. 
9.5  Study Assessments 
9.5.1  Assessments 
9.5.1.1  Demography 
Subject demography information will be recorded in the CRF at Visit 1.  Demography 
information includes date of birth, age, sex, race, and ethnicity. 
9.5.1.2  Pretreatment Assessments 
9.5.1.2.1  EPILEPSY HISTORY 
Epilepsy history (date of diagnosis, etiology, epileptic syndrome, suspected localization of the 
epileptogenic region, and seizure types) will be recorded in the CRF at Visit 1. 
9.5.1.2.2  MEDICAL HISTORY OTHER THAN EPILEPSY 
Medical history (other than epilepsy) within 1 year before Visit 1, and current medical 
conditions will be noted in the CRF at Visit 1. 
9.5.1.2.3  HEIGHT MEASUREMENT 
Height at Visit 1 will be recorded in the CRF. 
9.5.1.2.4  URINE DRUG SCREEN 
At each investigational site, a urine sample will be collected at Visit 1.  This sample will be 
tested for common drugs of use/abuse: eg, PCP (phencyclidine), benzodiazepines, cocaine, 
amphetamines, cannabinoids, opioids (as a group), barbiturates, and tricyclic antidepressants. 


 
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9.5.1.3  Efficacy Assessments 
Efficacy will be assessed by seizure counts and types as recorded in the diary.  Diaries will be 
dispensed to all subjects and returned from all subjects at the visits designated in the Schedule 
of Procedures/Assessments (Table 2). 
The diary is to be completed by the subject, the designated subject’s caregiver, clinical nurses, 
or other site staff.  In the diary, all seizure counts and types will be recorded.  At each visit, 
the subject or the caregiver will be instructed by the investigator or the designated 
investigator’s staff as to how to complete the diary and reminded that they must bring the diary 
to their next scheduled visits including the Early Discontinuation Visit and the Follow-up Visit.  
Based on the diary, seizure counts and types will be recorded on the CRF. 
The investigator should review the diary for each subject at the visits designated in the 
Schedule of Procedures/Assessments (Table 2).  Subjects or caregivers must be counseled if 
diary compliance is not satisfactory. 
The retrieved diaries for each subject will be maintained appropriately at each investigational 
site throughout the required retention period (See Section 11.6 ). 
9.5.1.4  Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments 
9.5.1.4.1  PHARMACOKINETIC ASSESSMENTS 
Blood samples will be collected as specified in Table 2.  For procedures to collect, handle, 
and ship samples, see the separately specified written procedure.  The sampling date and time 
will be recorded in the CRF. 
Plasma concentration of perampanel will be measured by a validated liquid chromatography 
with tandem mass spectrometry (LC/MS/MS) assay. 
9.5.1.4.2  PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS 
Not applicable. 
9.5.1.5  Safety Assessments 
Safety assessments will consist of monitoring and recording all AEs and SAEs; laboratory 
evaluations for biochemistry, hematology, and urine values; periodic measurements of vital 
signs, weight, and 12-lead ECG; and the performance of physical examinations as detailed in 
Table 2. 
9.5.1.5.1  ADVERSE EVENTS 
An AE is any untoward medical occurrence in a clinical investigation subject administered an 
investigational product.  An AE does not necessarily have a causal relationship with the 


 
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medicinal product.  For this study, the study drug is perampanel intravenous formulation. 
The criteria for identifying AEs in this study are: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE) 
• 
Any new disease or exacerbation of an existing disease 
• 
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of the study drug 
• 
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
• 
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of the study drug, or 
withholding of the study drug, whether prescribed in the protocol or not. 
All AEs, regardless of relationship to the study drug or procedure, should be recorded in the 
CRF beginning from the time the subject signs the study ICF through the last visit and for 21 
days after the subject’s last dose of the study drug.  Serious AEs will be collected for 28 days 
after the last dose of the study drug.  In addition, the start date and time of an adverse event, 
and the end date and time of the adverse event will be recorded in the CRF. 
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute an 
AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality considered 
to constitute an AE should be reported on the CRF. 
All events associated with suicidal ideation/attempt, regardless of severity, must be recorded 
as an AE in the CRF. 
All AEs must be followed for 28 days after the subject’s last dose of the study drug, or until 
resolution, whichever comes first.  All SAEs and AEs of special interest (see Section 
9.5.1.5.3 ) must be followed to resolution or, if resolution is unlikely, to stabilization. 
Every effort must be made by the investigator to categorize each AE according to its severity 
and its relationship to the study treatment. 
Assessing Severity of Adverse Events 
AEs will be graded on a 3-point scale (mild, moderate, or severe) and reported in the detail 
indicated on the CRF.  The definitions are as follows: 


 
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Mild 
Discomfort noticed, but no disruption of normal daily activities 
Moderate 
Discomfort sufficient to reduce or affect normal daily activities 
Severe 
 
Incapacitating, with inability to work or perform normal daily activities 
The criteria for assessing severity are different than those used for seriousness (see Section 
9.5.1.5.2 for the definition of an SAE). 
Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
• 
Temporal relationship of the onset of the event to the initiation of the study treatment 
• 
The course of the event, especially the effect of discontinuation of the study treatment, as 
applicable 
• 
Whether the event is known to be associated with the study treatment or with other 
similar treatments 
• 
The presence of risk factors in the study subject that are known to increase the occurrence 
of the event 
• 
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event 
Classification of Causality 
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question: 
Is there a reasonable possibility that the study drug caused the AE? 
Yes (related) 
A causal relationship between the study drug and the AE is a reasonable 
possibility. 
No (not related) A causal relationship between the study drug and the AE is not a reasonable 
possibility. 
9.5.1.5.2  SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (ie, the subject was at an immediate risk of death from the adverse 
event as it occurred; this does not include an event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 


 
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• 
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) 
Other important medical events that may not be immediately life-threatening or result in death 
or hospitalization but, when based on appropriate medical judgment, may jeopardize the 
subject or may require intervention to prevent one of the outcomes in the definition of SAE 
listed above should also be considered SAEs.  Medical and scientific judgment should be 
exercised in deciding whether expedited reporting is appropriate in such situations.  
In addition to the above, other events associated with special situations include: pregnancy or 
exposure to the study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, and medication errors (See Sections 9.5.4.2  and 9.5.4.3 ).  These events 
associated with special situations are to be captured using the SAE procedures but are to be 
considered as SAEs only if they meet one of the above criteria.  All AEs associated with 
special situations are to be reported on the CRF whether or not they meet the criteria for SAEs. 
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization. 
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization: 
• 
Hospitalizations for respite care 
• 
Planned hospitalizations required by the protocol 
• 
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
• 
Hospitalization for administration of the study drug or insertion of access for 
administration of the study drug 
• 
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry 
9.5.1.5.3  STUDY-SPECIFIC ADVERSE EVENTS 
In a non-clinical toxicity study of sodium sulphobutylether-beta-cyclodextrin (hereinafter 
“SBECD”), which is one of the additives in this study drug, vacuolation was observed in 
tubular epithelial cells, suggesting that patients with impaired renal function have a risk of 
SBECD accumulation (Luke, et al., 2010).  In addition, there have been reports of anaphylaxis, 
possibly due to SBECD, with other formulations containing SBECD. 
In this study, based on the above findings, adverse events associated with renal dysfunction, 
and adverse events associated with anaphylaxis will be handled as “adverse events of special 
interest (AESIs)” and recorded in the CRF. 
For the procedures for reporting adverse events of special interest, see Section 9.5.4.3.2  
 


 
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1. Adverse Events Associated With Renal Dysfunction 
If an adverse event associated with renal dysfunction occurs, and does not resolve at the time 
point when the Follow-up Phase is completed, the investigator will monitor the subject for 14 
days from the follow-up visit, regardless of severity, and will continue following up the subject 
as needed until resolution of the event or, if resolution is unlikely, until stabilization of the 
symptom or sign.  During this period, the subject will be followed up continuously by renal 
function monitoring at unscheduled visits (eg, once weekly, or at a frequency deemed necessary 
by the investigator). 
2. Adverse Events Associated With Anaphylaxis 
In the event of an adverse event associated with anaphylaxis, the investigator will take the 
following responsive actions: 
• 
Take the first response, for example, by immediately referring the subject to an 
appropriate clinical department; 
• 
Make a decision regarding whether or not to continue administration of the study drug to 
the subject, based on advice from the physician in the above-mentioned department; 
• 
In the event of an adverse event associated with anaphylaxis while continuing intravenous 
administration of the study drug, discontinue the administration. In the event of any 
symptom or sign that is suspected of anaphylaxis while continuing intravenous 
administration of the study drug, careful judgment will be exercised in determining 
whether or not to continue the administration. 
The follow-up of anaphylaxis will be continued until resolution of the event or, if resolution is 
unlikely, until stabilization of the symptom or sign. 
9.5.1.5.4  LABORATORY MEASUREMENTS 
The clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 1.  The Schedule of Procedures/Assessments (Table 2) shows the 
visits and time points at which blood for clinical laboratory tests and urine for urinalysis will 
be collected in the study.  The sampling date will be recorded in the CRF. 


 
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Table 1 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils) 
Chemistry 
 
 
Electrolytes 
Sodium, potassium, chloride, calcium 
 
Liver function tests 
Alanine aminotransferase, aspartate aminotransferase,  
alkaline phosphatase, gamma glutamyl transpeptidase,  
total bilirubin 
 
Renal function tests 
Blood urea/blood urea nitrogen, creatinine 
 
Other 
Albumin, cholesterol, glucose, lactate dehydrogenase, phosphorus, 
total protein, triglycerides, uric acid 
Urinalysis 
glucose, ketones, occult blood, pH, protein, specific gravity 
RBC = red blood cell, WBC = white blood cell 
 
The clinical laboratory tests indicated above will be performed by the central laboratory. 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this protocol 
(see Section 9.5.1.5.1 ).  In these instances, the AE corresponding to the laboratory 
abnormality will be recorded on the Adverse Event CRF. 
9.5.1.5.5  VITAL SIGNS AND WEIGHT MEASUREMENTS 
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute], and body temperature [in centigrade]), and weight 
(kg) will be recorded on the CRF at the visits designated in the Schedule of 
Procedures/Assessments (Table 2) by a validated method.  Blood pressure and pulse will be 
measured after the subject has been resting for 5 minutes.  All BP measurements should be 
performed on the same arm, and preferably by the same person. 
9.5.1.5.6  PHYSICAL EXAMINATIONS 
Physical 
examinations 
will 
be 
performed 
as 
designated 
in 
the 
Schedule 
of 
Procedures/Assessments (Table 2).  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from the screening physical 
examination findings that meet the definition of an AE will be recorded on the Adverse Events 
CRF. 
9.5.1.5.7  ELECTROCARDIOGRAMS 
Twelve-lead electrocardiograms will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 2) after the subject has been resting for 5 minutes.  The 


 
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investigator will record the presence or absence of any ECG abnormalities (Normal/Abnormal, 
Not Clinically Significant/Abnormal Clinically Significant) based on the relevant ECG 
findings in the CRF. 
In the Pretreatment Phase, only if the QTcF interval is more than 450 ms, an additional 2 
consecutive ECGs separated by 5 or more minutes will be recorded. 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see Section 
9.5.1.5.1 ).  In these instances, the AE corresponding to the ECG abnormality will be recorded 
on the Adverse Events CRF. 
9.5.1.5.8  OTHER SAFETY ASSESSMENTS 
Not applicable. 
9.5.1.6  Other Assessments 
9.5.1.6.1  PREGNANCY TEST 
At Visit 1, all females of childbearing potential will undergo the serum β-hCG pregnancy test 
(the measurements will be performed by the central laboratory).  At Visit 2 and thereafter, all 
females of childbearing potential will undergo the urine β-hCG pregnancy test (the 
measurements will be performed by each investigational site). 
9.5.2  Schedule of Procedures/Assessments 
9.5.2.1  Schedule of Procedures/Assessments 
Table 2 presents the schedule of procedures/assessments. 


 
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Table 2 
Schedule of Procedures / Assessments in Study E2007-J081-240 
Phase 
Pretreatment 
Phase 
Treatment Phase a 
Follow-up Phase b, c 
 
 
Study Day(s) (from Day 1 of Treatment Phase) 
Day 
–28 to –7 
(Screening) 
Day 
–1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
7 days after the last 
intravenous infusion 
 
 
Visit 
1 
2 
3a 
3b 
3c 
3d 
4 
Unscheduled 
Visit k 
Early 
Discontinuation 
Visit 
Procedure/Assessment 
 
 
 
 
 
 
 
 
 
Informed consent/assent d 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
Physical examinations 
X 
X 
Xm 
Xm 
Xm 
Xm 
X 
X 
X 
Medical history 
X 
 
 
 
 
 
 
 
 
Concomitant medications/therapies 
Xe 
Xe 
Xe 
X 
X 
X 
X 
X 
X 
Hospitalization 
 
X 
X 
X 
X 
Xl 
 
 
 
Intravenous administration of the study drug  
(intravenous infusion of perampanel) 
 
 
X 
Xn 
Xn 
Xn 
 
 
 
Oral perampanel administration at the hospital 
 
Xn 
 
 
 
 
 
 
 
Adverse events f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Oral perampanel/study drug compliance 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dispense subject diary 
X 
 
X 
 
 
X 
 
 
X 
Return and review subject diary 
 
 
X 
 
 
X 
Xo 
 
X 
Discontinuation/continuation judgment g 
 
X 
X 
X 
X 
X 
 
 
 
Vital signs and weight/height h 
X 
X 
Xm 
Xm 
Xm 
Xm 
X 
X 
X 
Clinical laboratory evaluations 
X 
X 
 
 
 
Xm 
X 
X 
X 
PK blood sampling for perampanel i 
 
X 
X 
X 
X 
X 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
Urine pregnancy test j 
 
X 
 
 
 
 
X 
X 
X 
Serum pregnancy test j 
X 
 
 
 
 
 
 
X 
 
12-lead ECG 
X 
X 
 
 
 
Xm 
X 
X 
X 


 
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a: 
The date of each visit to be specified based on the date of Visit 3a.  The Treatment Phase is defined as the period beginning at the start of the study 
treatment (intravenous infusion of perampanel) on Day 1 to immediately before the oral perampanel administration on Day 5. 
b: 
Visit to be performed within +7 days of the schedule.  The visit is to be specified based on the date of the last intravenous infusion of perampanel. 
c: 
To be completed by subjects who received at least 1 intravenous infusion of perampanel, in principle. 
d: 
Informed consent must be obtained before any study-related procedure. 
e: 
Prior and concomitant medication(s)/therapies(s). 
f: 
Adverse events will be collected from the time the subject signs the informed consent form through the 21 days after the subject’s last intravenous infusion 
of perampanel.  Serious adverse events will be collected for 28 days after the subject’s last intravenous infusion of perampanel. 
g: 
During the period from Visit 3a to Visit 3d, if a subject experiences seizures or has safety issue, the investigator will make as judgment regarding study 
continuation/discontinuation based on the subject’s tolerability and efficacy. 
h: 
Height is to be measured only at Visit 1. 
i: 
Blood samples for the plasma perampanel concentration will be collected at predose and at 0.5, 1, and 1.5 hours after the oral administration of perampanel 
on Visit 2 (Day –1), predose and at 0.5 hours after the start of intravenous infusions of perampanel on Visits 3a, 3b, 3c, and 3d (Days 1, 2, 3, and 4).  In 
addition, for the blood samplings at 0.5 hours after the start of intravenous infusions of perampanel on Days 1 through 4, they should be performed 
immediately after completion of the intravenous perampanel infusions (ie, within 5 minutes after completion). 
j: 
All females of childbearing potential will undergo the serum β-hCG pregnancy test at Visit 1.  At Visit 2 and thereafter, all females of childbearing 
potential will undergo the urine β-hCG pregnancy test. 
k: 
At an Unscheduled Visit, only the procedures/assessments that the investigator has judged as necessary according to the subject’s condition will be 
performed. 
l: 
Subjects will be discharged from the hospital the next day following Day 4 (ie, on Day 5). 
m: The examinations will be conducted predose. 
n: 
The start time of intravenous infusions of perampanel from Day 1 to Day 4 will be designated as the same time as the administration time of oral 
perampanel on Day –1 (allowance window: ±1 hour). 
o: 
As for subjects who have been withdrawn from the study, recording in the diary after discontinuation will continue as far as possible.  Further, the 
investigator or the designated investigator’s staff should record seizure counts and types on the CRF for up to 14 days after the subject’s last intravenous 
infusion of perampanel. 
 


 
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9.5.3  Appropriateness of Measurements 
The safety assessments in this study are standard evaluations to ensure subject safety. 
The efficacy assessment (ie, seizure counts and types) comprises standard measurements 
commonly used in studies evaluating the effect of AEDs. 
9.5.4  Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated With Special Situations 
9.5.4.1  Reporting of Serious Adverse Events 
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study 
treatment, must be reported on a completed SAE form as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the event. 
Serious adverse events, regardless of causality assessment, must be collected through the 
last visit and for 28 days after the subject’s last dose of study drug.  All SAEs must be 
followed to resolution or, if resolution is unlikely, to stabilization. Any SAE judged by the 
investigator to be related to the study treatment or any protocol-required procedure should 
be reported to the sponsor regardless of the length of time that has passed since study 
completion. 
The detailed contact information for reporting of SAEs is provided in Attachment 1. 
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report. This includes the investigator’s assessment of causality. 
Any follow-up information received on SAEs should be forwarded within 1 business day 
of its receipt. If the follow-up information changes the investigator’s assessment of 
causality, this should also be noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested 
by the sponsor. 
9.5.4.2  Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding 
Any pregnancy in a female subject in which the estimated date of conception is either 
before the last visit or within 28 days of the last study treatment or any exposure to the 
study drug through breastfeeding during study treatment or within 28 days of the last study 
treatment must be reported. 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, 
this should be reported regardless of the length of time that has passed since the exposure 
to study treatment. 


 
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A congenital anomaly, death during the perinatal period, an induced abortion, or a 
spontaneous abortion is considered to be an SAE and should be reported in the same time 
frame and in the same format as all other SAEs (see Section 9.5.4.1 ). 
Pregnancies or exposure to the study drug through breastfeeding must be reported by fax 
or email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy. The contact information for the reporting of pregnancies 
and exposure to the study drug through breastfeeding is provided in Attachment 1. The 
Pregnancy Report Form (Attachment 4) must be used for reporting. All pregnancies must 
be followed to outcome. The outcome of the pregnancy must be reported using the 
Pregnancy Outcome Report Form (Attachment 5) as soon as possible but no later than 1 
business day from the date the investigator becomes aware of the outcome. 
A subject who becomes pregnant must be withdrawn from the study. 
9.5.4.3  Reporting of Events Associated With Special Situations 
9.5.4.3.1  REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE, 
MISUSE, ABUSE, OR MEDICATION ERROR 
Adverse events associated with study drug overdose, misuse, abuse, and medication errors 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication errors are defined as follows: 
Overdose 
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose 
Misuse 
Intentional and inappropriate use of the study drug not in 
accordance with the protocol 
Abuse 
Sporadic or persistent intentional excessive use of the study drug 
accompanied by harmful physical or psychological effects 
Medication error 
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of 
site personnel 
All AEs associated with overdose, misuse, abuse, or medication errors should be captured 
on the Adverse Event CRF and also reported using the procedures detailed in Section 
9.5.4.1  even if the AEs do not meet serious criteria.  Abuse is always to be captured as 
an AE. If the AE associated with an overdose, misuse, abuse, or medication error does not 
meet serious criteria, it must still be reported using the SAE form and in an expedited 
manner but should be noted as nonserious on the SAE form and the Adverse Event CRF. 
9.5.4.3.2  REPORTING OF STUDY-SPECIFIC EVENTS 
In this study, adverse events associated with renal dysfunction and adverse events 
associated with anaphylaxis will be handled as “adverse events of special interest (AESIs)” 


 
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(see Section 9.5.1.5.3 ). 
If an adverse event of special interest associated with renal dysfunction, with an elevated 
creatinine level >3× the upper limit of normal (ULN), or an adverse event associated with 
anaphylaxis (regardless of severity) is observed, it will be reported according to the 
procedures specified in “Reporting of Serious Adverse Events” (Section 9.5.4.1 ) even if 
the AEs do not meet serious criteria.  If the event does not meet the definition of a SAE, 
it must still be reported using the SAE form and in an expedited manner but should be 
noted as nonserious on the SAE form and the Adverse Event CRF. 
9.5.4.4  Expedited Reporting 
The sponsor must inform the investigator, the head of the medical institution, and 
regulatory authorities of reportable events, in compliance with applicable regulatory 
requirements.  For this reason, it is imperative that the investigator provides complete 
SAE information in the manner described in Section 9.5.4.1 . 
9.5.4.5  Breaking the Blind 
Not applicable. 
9.5.4.6  Regulatory Reporting of Adverse Events 
Adverse events will be reported by the sponsor to the regulatory authorities in compliance 
with regulatory requirements and established guidance.  The format of these reports will 
be dictated by the regulatory requirements. 
9.5.5  Completion/Discontinuation of Subjects 
A subject may elect to discontinue the study at any time for any reason.  The investigator 
will promptly explain to the subject involved that the study will be discontinued for that 
subject and provide appropriate medical treatment and other necessary measures for the 
subject. 
All subjects who discontinue the study between the start of the first study treatment (Day 
1) and Day 4 are to complete the procedures/assessments at the Early Discontinuation Visit 
indicated in the Schedule of Procedures/Assessments (Table 2).  In addition, when the 
discontinuation has occurred before the start of the study treatment on Day 2, Day 3, or 
Day 4, the procedures/assessments that had been performed on that day of discontinuation 
can be deemed to be those at the Early Discontinuation Visit. 
Even if the procedures/assessments at the Early Discontinuation Visit have been conducted, 
the procedures/assessments at the Follow-up Visit designated in the Schedule of 
Procedures/Assessments (Table 2) will be performed 7 days (allowance window: +7 days) 
after the last dose of study drug, as far as possible.  In addition, between the Early 
Discontinuation Visit and the Follow-up Visit, the study treatment will be switched back 
to the original dose of oral perampanel used in the Pretreatment Phase, and a stable dosage 
of another AED(s) as an adjunctive therapy as well as recording of seizures (recording by 


 
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the subjects’ caregiver is also acceptable) will be continued, as far as possible.  The results 
of these procedures/assessments and the relevant drug information regarding oral 
perampanel and the other AED(s) will be recorded in the CRF. 
If by any chance the procedures/assessments at the Early Discontinuation Visit cannot be 
conducted before the Follow-up Visit which is to occur 7 days (allowance window: +7 
days) after the last dose of study drug, the procedures/assessments at the Follow-up Visit 
can be omitted. 
A subject who has ceased to return for visits will be followed up by mail, phone, or other 
means to gather information such as the reason for failure to return, the status of treatment 
compliance, the presence or absence of AEs, and clinical courses of signs and symptoms. 
Subjects who discontinue early from the study will be discontinued for 1 primary reason.  
In addition to the primary reason, the subject may indicate 1 or more secondary reason(s) 
for discontinuation.  Study disposition information will be collected on the Subject 
Disposition CRF. 
If subjects cannot continue the study drug for any reason(s), they must discontinue the 
study.  In addition, a subject who becomes pregnant must be withdrawn from the study. 
9.5.6  Abuse or Diversion of Study Drug 
Not applicable. 
9.5.7  Confirmation of Medical Care by Another Physician 
The investigator or the designated investigator’s staff will instruct the subjects and the 
subjects’ legally acceptable representatives (if applicable) to inform site personnel when 
the subjects are planning to receive medical care from another physician.  At each visit, 
the investigator or the designated investigator’s staff will ask the subject and the subject’s 
legally acceptable representative (if applicable) whether the subject has received medical 
care by another physician since the last visit or is planning to do so in the future.  When 
the subject is going to receive medical care by another physician, the investigator, with the 
consent(s) of the subject and the subject’s legally acceptable representative (if applicable), 
will inform the other physician that the subject is participating in the clinical study. 
9.6  Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines. 
9.6.1  Data Collection 
Data required by the protocol will be collected on the CRFs and entered into a validated 
data management system that is compliant with all regulatory requirements.  As defined 
by J-GCP guidelines, the CRF is a printed, optical, or electronic document designed to 
record all of the protocol-required information to be reported to the sponsor on each study 


 
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subject. 
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting 
of all clinical data entered on the CRF.  The investigator must sign the completed CRF to 
attest to its accuracy, authenticity, and completeness. 
Completed, original CRFs are the sole property of Eisai and should not be made available 
in any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities. 
9.6.2  Clinical Data Management 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  
All data, both CRF and external data (eg, laboratory data), will be entered into a clinical 
system. 
9.7  Statistical Methods 
All statistical analyses will be performed after the study is completed and the database is 
locked.  Statistical analyses will be performed using SAS software or other validated 
statistical software as required. 
9.7.1  Statistical and Analytical Plans 
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the statistical analysis plan (SAP), which will be 
finalized before database lock. 
9.7.1.1  Study Endpoints 
The safety endpoints are AEs, clinical laboratory tests (biochemistry, hematology, and 
urinalysis), vital signs, weight, and 12-lead ECG. 
The efficacy endpoint is the seizure frequency per day in each of the 3 phases (Pretreatment 
Phase, Treatment Phase, and Follow-up Phase).  Seizure frequency per day will be 
derived from the information recorded in the subject diaries. 
The pharmacokinetic endpoint is the plasma concentration of perampanel. 
All observed data will be reported with no adjustments for missing data. 
9.7.1.2  Definitions of Analysis Sets 
The Safety Analysis Set is the group of subjects who received at least 1 intravenous 
infusion of perampanel. 
The Efficacy Analysis Set is the group of subjects who received at least 1 intravenous 


 
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infusion of perampanel and had at least 1 postdose efficacy measurement. 
The Pharmacokinetic Analysis Set is the group of subjects who received at least 1 
intravenous infusion of perampanel and had at least 1 evaluable measurement of plasma 
perampanel concentration. 
9.7.1.3  Subject Disposition 
The number (percentage) of subjects who discontinued the Pretreatment Phase will be 
summarized for those who gave informed consent. 
The number (percentage) of subjects who completed and discontinued the study will be 
summarized for those who received study drug. 
In addition, the number of subjects who discontinued the study will be described according 
to the reason(s) for discontinuation. 
9.7.1.4  Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the Safety Analysis Set will be 
summarized using descriptive statistics.  Continuous demographic and baseline variables 
include age, height, weight, and others (if necessary); categorical variables include sex, 
age group, and others (if necessary). 
9.7.1.5  Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded to an 11-digit 
code using the World Health Organization Drug Dictionary (WHO DD).  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized 
in the Safety Analysis Set by Anatomical Therapeutic Chemical (ATC) class (ie, 
anatomical class, therapeutic class, pharmacologic class, and chemical class) and WHO 
DD preferred term. 
Prior medications/non-pharmacological procedures will be defined as medications/non-
pharmacological procedures that stopped before the start of doses of the study drug.  
Concomitant 
medications/non-pharmacological 
procedures 
will 
be 
defined 
as 
medications/non-pharmacological procedures that were used on or after the start of doses 
of the study drug.  All medications/non-pharmacological procedures will be presented in 
subject data listings. 
9.7.1.6  Efficacy Analyses 
The efficacy analyses will be performed on the Efficacy Analysis Set. 
The seizure frequency per day for each of the 3 phases (Pretreatment Phase, Treatment 
Phase, and Follow-up Phase) will be summarized using descriptive statistics (eg, mean, 
SD, median, minimum, and maximum).  The seizure frequency per day from the 
Pretreatment Phase to the Follow-up Phase for each subject will be displayed using a 


 
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spaghetti-plot. 
9.7.1.7  Pharmacokinetic, 
Pharmacodynamic, 
Pharmacogenomic, 
and 
Other 
Biomarker Analyses 
9.7.1.7.1  PHARMACOKINETIC ANALYSES 
The PK analyses will be performed on the Pharmacokinetic Analysis Set using the plasma 
concentrations of perampanel.  Summary statistics for the plasma concentrations will be 
obtained by sampling time point and dose.  The plasma concentrations of perampanel 
before and after switching from oral tablet to intravenous infusion will be plotted.  A 
similar analysis may be conducted using dose-normalized plasma concentration data. 
9.7.1.7.2  PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES 
Not applicable. 
9.7.1.8  Safety Analyses 
The safety analyses will be performed on the Safety Analysis Set. 
Safety data will be summarized using descriptive statistics (eg, n, mean, SD, median, 
minimum, and maximum for continuous variables; n [%] for categorical variables).  
Safety variables include AEs, clinical laboratory parameters (biochemistry, hematology, 
and urinalysis), vital signs, weight, and 12-lead ECG results. 
9.7.1.8.1  EXTENT OF EXPOSURE 
The extent of exposure to the study drug will be summarized using descriptive statistics. 
9.7.1.8.2  ADVERSE EVENTS 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse events will be coded to the MedDRA (Version 21.0 or higher) lowest 
level term (LLT) closest to the verbatim term. The linked MedDRA preferred term (PT) 
and primary system organ class (SOC) are also captured in the database. 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges on or after 
the start of the study treatment, having been absent at pretreatment or 
• 
Reemerges on or after the start of the study treatment, having been present at 
pretreatment but stopped before the start of the study treatment, or 
• 
Worsens in severity on or after the start of the study treatment relative to the 
pretreatment state, when the AE is continuous. 
All AEs, treatment-emergent or otherwise, will be presented in the subject data listings. 
The incidences of TEAEs will be reported as the number (percentage) of subjects with 
TEAEs by SOC and PT.  A subject will be counted only once within an SOC and PT, 


 
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even if the subject experienced more than 1 TEAE within a specific SOC and PT.  The 
number (percentage) of subjects with TEAEs will also be summarized by maximum 
severity (mild, moderate, or severe). 
The number (percentage) of subjects with treatment-related TEAEs will be summarized 
by SOC and PT.  Treatment-related TEAEs include those events considered by the 
investigator to be related to the study treatment.  The number (percentage) of subjects 
with treatment-related TEAEs will also be summarized by maximum severity (mild, 
moderate, or severe). 
The number (percentage) of subjects with AEs by SOC and PT will be summarized by 
Phase (Pretreatment Phase, Treatment Phase, and Follow-up Phase) of onset. 
Subject data listings of all AEs leading to death, all SAEs, and all AEs leading to 
discontinuation from the study will be provided. 
9.7.1.8.3  LABORATORY VALUES 
Laboratory results will be summarized using Système International (SI) units, as 
appropriate.  For all quantitative parameters, the actual value at each visit and the change 
from baseline to each postbaseline visit will be summarized using descriptive statistics.  
Qualitative parameters will be summarized using frequencies (number and percentage of 
subjects), and changes from baseline to each postbaseline visit will be reported using shift 
tables.  Percentages will be based on the number of subjects with both nonmissing 
baseline and relevant postbaseline results. 
Laboratory test results will be assigned a low/normal/high (LNH) classification according 
to whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be 
based on shift tables that compare the baseline LNH classification to the LNH 
classification at each postbaseline visit. 
Appendix 1 (Sponsor’s Grading for Laboratory Values) presents the criteria that will be 
used to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAVs).  Except for phosphate, a TEMAV is defined as a postbaseline value with an 
increase from baseline to a grade of 2 or higher.  For phosphate, a TEMAV is defined as 
a postbaseline value with an increase from baseline to a grade of 3 or higher.  The 
definition of TEMAV will be detailed in the SAP.  When displaying the incidence of 
TEMAVs, each subject may be counted once in the laboratory parameter high and in the 
laboratory parameter low categories, as applicable. 
9.7.1.8.4  VITAL SIGNS AND WEIGHT 
Descriptive statistics for vital sign parameters (ie, systolic and diastolic blood pressure, 
pulse, respiratory rate, temperature) and weight; and changes from baseline will be 
presented by visit. 


 
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9.7.1.8.5  ELECTROCARDIOGRAMS 
Shift tables will present changes from baseline in ECG interpretation (categorized as 
normal; abnormal, not clinically significant; and, abnormal, clinically significant) by visit. 
9.7.1.8.6  OTHER SAFETY ANALYSES 
Not applicable. 
9.7.2  Determination of Sample Size 
This is an uncontrolled, open-label study for the safety evaluation of intravenous infusion 
of perampanel and the sample size (20 subjects) is not based on statistical power 
considerations, but rather on feasibility.  It is considered that a sufficient number of 
subjects will be obtained for the safety evaluation of intravenous infusion of perampanel 
if the sample size is 20. 
9.7.3  Interim Analysis 
No interim analysis is planned for this study. 
9.7.4  Other Statistical/Analytical Issues 
Not applicable. 
9.7.5  Procedure for Revising the Statistical Analysis Plan 
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of 
the revision will be documented and described in the clinical study report. 


 
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10. REFERENCE LIST 
Inoue Y, Suzuki A, Yoshida K, Yamamoto K. An open-label, multicenter study to evaluate 
the safety of adjunctive treatment with intravenous infusion of levetiracetam in adult 
epilepsy patients with partial seizures. Jpn J Clin Psychopharmacol. 2014; 17 (3): 413-22. 
Luke DR, Tomaszewski K, Damle B, Schlamm HT.  Review of the basic and clinical 
pharmacology of sulfobutylether-beta-cyclodextrin (SBECD). J Pharm Sci. 2010; 99 (8): 
3291-301. 


 
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11. PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES) 
11.1  Changes to the Protocol 
Any change to the protocol requires a written protocol amendment or administrative 
change that must be approved by the sponsor before implementation. 
Amendments specifically affecting the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study require additional approval by the applicable IRBs.  
These requirements should in no way prevent any immediate action from being taken by 
the investigator, or by the sponsor, in the interest of preserving the safety of all subjects 
included in the study.  If the investigator determines that an immediate change to or 
deviation from the protocol is necessary for safety reasons to eliminate an immediate 
hazard to the subjects, the sponsor and the IRB for the site must be notified immediately.  
The sponsor must notify the health or regulatory authority as required per regulations. 
Protocol amendments that affect only administrative aspects of the study may not require 
submission to the IRB.  In these cases, the sponsor may be required to send a letter to the 
head of the medical institution detailing such changes. 
11.2  Adherence to the Protocol 
The investigator will conduct the study in strict accordance with the protocol. 
11.3  Monitoring Procedures 
The sponsor’s CRA will maintain contact with the investigator and designated staff by 
telephone, letter, or email between study visits.  Monitoring visits to the site will be 
conducted by the assigned CRA as described in the monitoring plan.  The head of the 
medical institution will allow the CRA to inspect the clinical, laboratory, and pharmacy 
facilities to assure compliance with J-GCP and other regulatory requirements.  The CRFs 
and subject’s corresponding original medical records (source documents) are to be fully 
available for review by the sponsor’s representatives at regular intervals.  These reviews 
verify adherence to the study protocol and data accuracy in accordance with J-GCP.  All 
records at the site are subject to inspection by the auditing agency and to IRB review. 
In accordance with J-GCP, source documents include, but are not limited to the following: 
• 
Clinic, office, or hospital charts 
• 
Copies or transcribed health care provider notes which have been certified for 
accuracy after production 
• 
Recorded data from automated instruments 
• 
Medical history questionnaires completed by subjects 
• 
Records of telephone contacts 
• 
Diaries or evaluation checklists 


 
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• 
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
• 
Laboratory results and other laboratory test outputs 
• 
Correspondence regarding a study subject’s treatment between physicians or 
memoranda sent to the IRB 
11.4  Recording of Data 
A CRF is required and must be completed for each subject who has consented/assented to 
participate in the study by qualified and authorized personnel.  All data on the CRF must 
reflect the corresponding source document, except when a section of the CRF is itself used 
as the source document.  Any correction to entries made on the CRF must be documented 
in a valid audit trail where the correction is dated, the individual making the correct is 
identified, the reason for the change is stated, and the original data are not obscured.  Only 
data required by the protocol for the purposes of the study should be collected. 
The investigator must sign each CRF.  The investigator will report the CRFs to the 
sponsor and retain copies of the CRFs. 
11.5  Identification of Source Data 
All data to be recorded on the CRF must reflect the corresponding source documents. 
The data collected directly on the CRF are considered source data.  For instance, the 
following data recorded directly on the CRF are to be considered source data: 
• 
Status of the study treatment (eg, reasons for discontinuation of the study treatment) 
• 
Indication for prior or concomitant therapy 
• 
Information on withdrawal from the study, for example, in the case of being lost to 
follow-up 
• 
Sampling date and time for drug concentrations and clinical laboratory tests 
• 
Information on AEs (eg, severity, relationship to the study drug, and outcome) 
11.6  Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the head of 
the medical institution (or the designated representative) is responsible for retaining all 
study documents, including but not limited to the protocol, copies of the CRFs, the 
Investigator's Brochure, and regulatory agency registration documents (eg, ICFs, and IRB 
correspondence).  The site should retain study documents until the approval date of a 
marketing application, at least 3 years have elapsed since the formal discontinuation of 
clinical development of the investigational product, at least 3 years have elapsed since 
receipt of a notice that the registration application should not include the results of the 
study, or at least 3 years have elapsed since the formal discontinuation or termination of 
the study, whichever comes last. 
It is requested that at the completion of the required retention period, the site contact the 


 
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sponsor, allowing the sponsor the option of permanently retaining the study records. 
11.7  Auditing Procedures and Inspection 
In addition to the routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of J-GCP and other applicable regulations.  
In addition, there is the possibility that a government regulatory authority will conduct an 
inspection. 
11.8  Handling of Study Drug 
All study drug will be supplied to the designated pharmacist or the designee by the sponsor.  
Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored 
according to the conditions specified on the drug labels.  The designated pharmacist or 
the designee must maintain an accurate record of the shipment and dispensing of the study 
drug in a drug accountability ledger.  An accurate record of the date and amount of study 
drug dispensed to each subject must be available for inspection at any time.  The CRA 
will visit the site and review these documents along with all other study conduct documents 
at appropriate intervals once the study drug has been received by the site. 
All drug supplies are to be used only for this study and not for any other purpose.  The 
designated pharmacist or the designee must not destroy any drug labels or any partly used 
or unused drug supply before approval to do so by the sponsor.  At the conclusion of the 
study and as appropriate during the study, the designated pharmacist or the designee will 
return all unused study drug to the sponsor. 
11.9  Publication of Results 
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the head of the medical institution and the sponsor.  The review is aimed at 
protecting the sponsor's proprietary information existing either at the date of the 
commencement of the study or generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the Clinical 
Trial Agreement executed between the head of the medical institution and the sponsor, as 
appropriate. 
11.10  Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the investigator’s staff, and the IRB and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 


 
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collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-
use shall in no way diminish such obligations as set forth in the Clinical Trial Agreement 
executed between the head of the medical institution and the sponsor. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in the Clinical Trial Agreement executed between the 
head of the medical institution and the sponsor. 
11.11  Discontinuation of Study 
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/head of the medical institution and the regulatory 
authorities of the termination or suspension and the reason(s) for the termination or 
suspension.  The IRB will also be informed promptly and provided the reason(s) for the 
termination or suspension by the sponsor or by the investigator/head of the medical 
institution, as specified by the applicable regulatory requirement(s). 
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without the prior agreement of 
the sponsor, the investigator should inform the head of the medical institution where 
applicable, and the investigator/head of the medical institution should promptly inform the 
sponsor and the IRB and provide the sponsor and the IRB with a detailed written 
explanation of the termination or suspension.  Study records must be retained as noted 
above. 
11.12  Subject Insurance and Indemnity 
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations. 


 
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12. APPENDICES 
 


 
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Appendix 1 
Sponsor’s Grading for Laboratory Values 
Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
BLOOD/BONE MARROW 
 
 
 
 
Hemoglobin   
<LLN – 10.0 g/dL 
<LLN – 100 g/L 
<LLN – 6.2 mmol/L 
<10.0 – 8.0 g/dL 
<100 – 80 g/L 
<6.2 – 4.9 mmol/L  
<8.0 g/dL 
<80 g/L 
<4.9 mmol/L; 
transfusion indicated 
life-threatening 
consequences; urgent 
intervention indicated 
Leukocytes (total WBC) 
<LLN – 3.0×109/L 
<LLN – 3000/mm3  
<3.0 – 2.0×109/L 
<3000 – 2000/mm3  
<2.0 – 1.0×109/L 
<2000 – 1000/mm3  
<1.0×109/L 
<1000/mm3  
Lymphocytes  
<LLN – 800/mm3  
<LLN – 0.8×109/L 
<800 – 500/mm3 
<0.8 – 0.5×109/L 
<500 – 200/mm3  
<0.5 – 0.2×109/L 
<200/mm3 
<0.2×109/L 
Neutrophils  
<LLN – 1.5×109/L 
<LLN – 1500/mm3  
<1.5 – 1.0×109/L 
<1500 – 1000/mm3 
<1.0 – 0.5×109/L 
<1000 – 500/mm3  
<0.5×109/L 
<500/mm3  
Platelets 
<LLN – 75.0×109/L 
<LLN – 75,000/mm3  
<75.0 – 50.0×109/L 
<75,000 – 50,000/mm3  
<50.0 – 25.0×109/L 
<50,000 – 25,000/mm3 
<25.0×109/L 
<25,000/mm3  
METABOLIC/LABORATORY 
 
 
 
 
Albumin, serum- low 
(hypoalbuminemia)  
<LLN – 3 g/dL 
<LLN – 30 g/L 
<3 – 2 g/dL 
<30 – 20 g/L 
<2 g/dL 
<20 g/L 
life-threatening 
consequences; urgent 
intervention indicated 
Alkaline phosphatase  
>ULN – 3.0×ULN 
>3.0 – 5.0×ULN 
>5.0 – 20.0×ULN 
>20.0×ULN 
ALT 
>ULN – 3.0×ULN 
>3.0 – 5.0×ULN 
>5.0 – 20.0×ULN 
>20.0×ULN 
AST 
>ULN – 3.0×ULN 
>3.0 – 5.0×ULN 
>5.0 – 20.0×ULN 
>20.0×ULN 
Bilirubin (hyperbilirubinemia) 
>ULN – 1.5×ULN  
>1.5 – 3.0×ULN 
>3.0 – 10.0×ULN  
>10.0×ULN 
Calcium, serum-low (hypocalcemia)  
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
<6.0 mg/dL 
<1.5 mmol/L 
Calcium, serum-high (hypercalcemia) 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
>13.5 mg/dL 
>3.4 mmol/L 
Cholesterol, serum-high 
(hypercholesterolemia) 
>ULN – 300 mg/dL 
>ULN – 7.75 mmol/L  
>300 – 400 mg/dL 
>7.75 – 10.34 mmol/L  
>400 – 500 mg/dL 
>10.34 – 12.92 mmol/L  
>500 mg/dL 
>12.92 mmol/L  
Creatinine 
>ULN – 1.5×ULN 
>1.5 – 3.0×ULN 
>3.0 – 6.0×ULN 
>6.0×ULN 
GGT (γ-glutamyl transpeptidase)  
>ULN – 3.0×ULN 
>3.0 – 5.0×ULN 
>5.0 – 20.0×ULN 
>20.0×ULN 
Glucose, serum-high (hyperglycemia) 
Fasting glucose value: 
>ULN – 160 mg/dL 
>ULN – 8.9 mmol/L  
Fasting glucose value: 
>160 – 250 mg/dL 
>8.9 – 13.9 mmol/L  
>250 – 500 mg/dL; 
>13.9 – 27.8 mmol/L; 
hospitalization indicated 
>500 mg/dL; 
>27.8 mmol/L; 
life-threatening 
consequences  
Glucose, serum-low (hypoglycemia) 
<LLN – 55 mg/dL 
<LLN – 3.0 mmol/L 
<55 – 40 mg/dL 
<3.0 – 2.2 mmol/L 
<40 – 30 mg/dL 
<2.2 – 1.7 mmol/L 
<30 mg/dL 
<1.7 mmol/L 
life-threatening 
consequences; 
seizures 
Phosphate, serum-low 
(hypophosphatemia,  
a low concentration of phosphates in 
the blood) 
<LLN – 2.5 mg/dL 
<LLN – 0.8 mmol/L 
<2.5 – 2.0 mg/dL 
<0.8 – 0.6 mmol/L 
<2.0 – 1.0 mg/dL 
<0.6 – 0.3 mmol/L 
<1.0 mg/dL 
<0.3 mmol/L 
life-threatening 
consequences 


 
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Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Potassium, serum-high (hyperkalemia) >ULN – 5.5 mmol/L  
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
hospitalization indicated 
>7.0 mmol/L 
life-threatening 
consequences 
Potassium, serum-low (hypokalemia)  
<LLN – 3.0 mmol/L 
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated 
<3.0 – 2.5 mmol/L 
hospitalization indicated 
<2.5 mmol/L 
life-threatening 
consequences 
Sodium, serum-high (hypernatremia) 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
hospitalization indicated 
>160 mmol/L 
life-threatening 
consequences 
Sodium, serum-low (hyponatremia) 
<LLN – 130 mmol/L 
N/A 
<130 – 120 mmol/L 
<120 mmol/L 
life-threatening 
consequences 
Triglyceride, serum-high 
(hypertriglyceridemia)  
150 – 300 mg/dL 
1.71 – 3.42 mmol/L 
>300 – 500 mg/dL 
>3.42 – 5.7 mmol/L  
>500 – 1000 mg/dL 
>5.7 – 11.4 mmol/L 
>1000 mg/dL 
>11.4 mmol/L 
life-threatening 
consequences  
Uric acid, serum-high (hyperuricemia) 
>ULN – 10 mg/dL  
(>ULN – 
≤0.59 mmol/L)  
without physiologic 
consequences  
N/A 
>ULN – 10 mg/dL  
(>ULN – 
≤0.59 mmol/L)  
with physiologic 
consequences  
>10 mg/dL 
(>0.59 mmol/L)  
life-threatening 
consequences 
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = 
white blood cell. 
Based on Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010). 
 
 


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List of Changes of Protocol (from Version 1 to Version 2) 
Title: A multicenter, uncontrolled, open-label study to evaluate the safety and tolerability of intravenous perampanel as substitute for 
oral tablet in subjects with partial onset seizures (including secondarily generalized seizures) or primary generalized tonic-
clonic seizures 
 
Protocol Sections 
Before (Version 1 dated 07 Sep 2018) 
After (Version 2 dated 09 Oct 2018) 
Rationale 
9.5.1.5.1 
ADVERSE EVENTS 
Abnormal laboratory values should not be listed as 
separate AEs if they are considered to be part of 
the clinical syndrome that is being reported as an 
AE.  It is the responsibility of the investigator to 
review all laboratory findings in all subjects and 
determine if they constitute an AE.  Medical and 
scientific judgment should be exercised in 
deciding whether an isolated laboratory 
abnormality should be classified as an AE.  Any 
laboratory abnormality considered to constitute an 
AE should be reported on the CRF. 
All AEs must be followed for 28 days after the 
subject’s last dose of the study drug, or until 
resolution, whichever comes first.  All SAEs and 
AEs of special interest (see Section 9.5.1.5.3 ) 
must be followed to resolution or, if resolution is 
unlikely, to stabilization. 
Abnormal laboratory values should not be listed as 
separate AEs if they are considered to be part of 
the clinical syndrome that is being reported as an 
AE.  It is the responsibility of the investigator to 
review all laboratory findings in all subjects and 
determine if they constitute an AE.  Medical and 
scientific judgment should be exercised in 
deciding whether an isolated laboratory 
abnormality should be classified as an AE.  Any 
laboratory abnormality considered to constitute an 
AE should be reported on the CRF. 
All events associated with suicidal 
ideation/attempt, regardless of severity, must be 
recorded as an AE in the CRF. 
All AEs must be followed for 28 days after the 
subject’s last dose of the study drug, or until 
resolution, whichever comes first.  All SAEs and 
AEs of special interest (see Section 9.5.1.5.3 ) 
must be followed to resolution or, if resolution is 
unlikely, to stabilization. 
Added the handling of 
events associated with 
suicidal ideation/attempt 
based on the sponsor’s 
response to PMDA’s 
inquiry issued after the first 
Clinical Trial Notification 
(CTN) for perampanel 
intravenous formulation. 
 

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STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E2007-J081-240
Study Protocol 
Title:
A multicenter, uncontrolled, open-label study to evaluate the safety 
and tolerability of intravenous perampanel as substitute for oral tablet 
in subjects with partial onset seizures (including secondarily 
generalized seizures) or primary generalized tonic-clonic seizures
Date:
14th Feb 2020
Version:
2.0


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TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................6
1
INTRODUCTION.........................................................................................................8
1.1
Study Objectives..................................................................................................8
1.1.1
Primary Objective ......................................................................................8
1.1.2
Secondary Objectives .................................................................................8
1.2
Overall Study Design and Plan.............................................................................8
2
DETERMINATION OF SAMPLE SIZE.......................................................................9
3
STATISTICAL METHODS........................................................................................10
3.1
Study Endpoints.................................................................................................10
3.2
Study Subjects ...................................................................................................10
3.2.1
Definitions of Analysis Sets......................................................................10
3.2.2
Subject Disposition...................................................................................11
3.2.3
Protocol Deviations ..................................................................................11
3.2.4
Demographic and Other Baseline Characteristics......................................11
3.2.5
Prior and Concomitant Therapy................................................................13
3.3
Data Analysis General Considerations................................................................13
3.3.1
Pooling of Centers....................................................................................13
3.3.2
Adjustments for Covariates ......................................................................13
3.3.3
Multiple Comparisons/Multiplicity...........................................................13
3.3.4
Examination of Subgroups........................................................................13
3.3.5
Handling of Missing Data, Dropouts, and Outliers....................................14
3.3.6
Other Considerations................................................................................14
3.4
Efficacy Analyses ..............................................................................................14
3.4.1
Primary Efficacy Analyses .......................................................................14
3.4.2
Secondary Efficacy Analyses ...................................................................14
3.4.3
Other Efficacy Analyses...........................................................................15
3.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses...........................................................................................15


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3.5.1
Pharmacokinetic Analyses........................................................................15
3.5.1.1
Plasma Concentration Analysis.......................................................15
3.5.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses....16
3.6
Safety Analyses..................................................................................................16
3.6.1
Extent of Exposure...................................................................................16
3.6.2
Adverse Events.........................................................................................17
3.6.3
Laboratory Values ....................................................................................18
3.6.4
Vital Signs................................................................................................19
3.6.5
Electrocardiograms...................................................................................20
3.6.6
Other Safety Analyses ..............................................................................20
3.7
Other Analyses...................................................................................................20
4
INTERIM ANALYSES...............................................................................................20
5
CHANGES IN THE PLANNED ANALYSES ............................................................21
6
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .............................21
6.1
General Data Handling.......................................................................................21
6.2
Efficacy Data Handling......................................................................................22
6.3
Safety Data Handling .........................................................................................23
6.4
Pharmacokinetic Data Handling .........................................................................24
6.4.1
Lower Limit of Quantification of Perampanel Plasma Concentration........24
6.4.2
BLQ Handling for Calculation of PK Parameters......................................24
6.4.3
BLQ Handling for Developing Concentration-Time Profiles ....................24
6.4.4
Handling of Anomalous Concentration Values .........................................24
6.4.5
General Rules for Presentation of Drug Concentrations and PK 
Parameters................................................................................................25
7
PROGRAMMING SPECIFICATIONS .......................................................................25
8
STATISTICAL SOFTWARE......................................................................................25
9
MOCK TABLES, LISTINGS, AND GRAPHS............................................................25


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LIST OF IN-TEXT TABLES
Table 1.
Vital Sign Criteria ..................................................................................19
LIST OF IN-TEXT FIGURES
Figure 1.
Study Design............................................................................................9
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................26


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SIGNATURE PAGE
Authors: 
Kohei 
C
Date
K
C
 
D
Date
Approval:
H
C
 
C
Date
K
Ja
Clinical, Medicine Creation, Neurology Business Group
Date
J
lopment Department,
Clinical, Medicine Creation, Neurology Business Group
Date
PPD
PPD
PPD
PPD
PPD
PPD


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AED
antiepileptic drug
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
AST
aspartate aminotransferase
ATC
anatomical therapeutic chemical
β-hCG
beta-human chorionic gonadotropin
BMI
Body mass index
BUN
blood urea nitrogen
CoA
certificate(s) of analysis
CI
confidence interval
CNS
central nervous system
CPK
creatine phosphokinase
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CT
computed tomography
CYP
cytochrome P450
EAID
enzyme inducing antiepileptic drug
ECG
electrocardiogram
EEG
electroencephalogram
EIAED
enzyme inducing antiepileptic drug
EQ-5D-5L
EuroQol 5 Dimensions 5 Levels
EU
European Union
GABA
gamma-aminobutylic acid
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
ILAE
International League Against Epilepsy
IRB
institutional review board


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Abbreviation
Term
ITT
intent-to-treat
IUPAC
International Union of Pure and Applied Chemistry
IUS
intrauterine hormone-releasing system
LC-MS/MS
liquid chromatography with tandem mass spectrometry
LLT
lowest level term
LNH
low/normal/high
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
MRI
magnetic resonance imaging
POS
partial onset seizure
PT
preferred term
QD
once daily
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System
SOC
system organ class
SOP
standard operating procedure
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
ULN
upper limit of normal
VNS
vagal nerve stimulation
WHO DD
World Health Organization Drug Dictionary


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1
INTRODUCTION
The purpose of this statistical analysis plan (SAP) is to describe the procedures and statistical 
methods in detail that will be used to analyze and report results Eisai Protocol E2007-J081-
240.
1.1
Study Objectives
1.1.1
Primary Objective
To evaluate the safety and tolerability of perampanel administered as a 30-minute intravenous 
(IV) infusion after switching from oral tablets (8 to 12 mg/day) as an adjunctive therapy in 
subjects with epilepsy with partial onset seizures (including secondarily generalized seizures) 
or primary generalized tonic-clonic seizures.
1.1.2
Secondary Objectives
・To evaluate the plasma concentration of perampanel before and after switching from oral 
tablets to 30-minute IV infusion
・To evaluate the seizure frequency before and after switching from oral tablets to 30-minute 
IV infusion
1.2
Overall Study Design and Plan
This study is a multicenter, uncontrolled, open-label study in subjects with partial onset 
seizures (including secondarily generalized seizures) or primary generalized tonic-clonic 
seizures. This study will consist of 3 phases (Pretreatment Phase, Treatment Phase, Follow-up 
Phase).
Pretreatment Phase
During the Pretreatment Phase, subjects will be screened and be assessed for their eligibility 
to participate in the study. Subject informed consent/assent will be obtained prior to the 
screening (Day –28 to Day –7), and subsequently protocol eligibility will be established.  
Eligible subjects must be on a stable dosage (8 to 12 mg/day) of oral perampanel as an 
adjunctive therapy with up to 3 marketed concomitant antiepileptic drugs (AEDs) for at least 


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28 days prior to the Treatment Phase. Enrolled subjects will be hospitalized 1 day prior to 
switching to IV perampanel (Day –1 [Visit 2]).
Treatment Phase
During the Treatment Phase, subjects will be hospitalized, and oral perampanel must be 
switched to equivalent dose of IV perampanel infusion. Subjects will receive 30-minute IV 
infusion (once a day) for 4 days.  Then, the subject must be switched to oral perampanel at 
the equivalent daily dose of the IV infusion.
Follow-up Phase
The assessments at the Follow-up Visit will be performed 7 days (+7 days) after the last IV 
infusion.
The study design is shown in Figure 1.
Figure 1.
Study Design
2
DETERMINATION OF SAMPLE SIZE
This study is an open label study for safety evaluation of IV perampanel infusion and the 
sample size (20 subjects) is not based on statistical power considerations, but rather on 
feasibility. It is considered that it will be a sufficient number of subjects for the safety 
evaluation of IV perampanel infusion if the sample size is 20.
phase
Pretreatment
Treatment
Follow-up
Oral tablets
stable dose (8~12 mg/day)
IV infusion
8~12 mg/day
Oral tablets
8~12 mg/day
Day 1
Day-1
Day 4
In-Hospital
Day 5
Perampanel
treatment
Out-of-Hospital
Out-of-Hospital
Day 11
Day-28 
Visit
V1 (Screening)
Day-7
V2
V3a-d
V4


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3
STATISTICAL METHODS
All descriptive statistics for continuous variables will be reported using mean, standard 
deviation (SD), median, minimum and maximum. Categorical variables will be summarized 
as number (percentage) of subjects.
3.1
Study Endpoints
The safety endpoints are AEs, clinical laboratory tests (biochemistry, hematology, and 
urinalysis), vital signs, weight, and 12-lead ECG.
The efficacy endpoint is the seizure frequency per day in each of 3 phases (Pretreatment Phase, 
Treatment Phase, Follow-up Phase). Seizure frequency per day will be derived from the 
information recorded in the subject diaries.
The pharmacokinetic endpoint is plasma concentration of perampanel.
3.2
Study Subjects
3.2.1
Definitions of Analysis Sets
Safety Analysis Set
The Safety Analysis Set is the group of subjects who received at least 1 IV perampanel infusion.
Efficacy Analysis Set
The Efficacy Analysis Set is the group of subjects who received at least 1 IV perampanel 
infusion and had at least 1 postdose efficacy measurement.
Pharmacokinetic Analysis Set
The Pharmacokinetic Analysis Set is the group of subjects who received at least 1 IV 
perampanel infusion and had at least 1 evaluable measurement of plasma perampanel 
concentration.


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3.2.2
Subject Disposition
The number (percentage) of subjects who completed/discontinued the Pretreatment Phase and 
the number of the reason(s) for the discontinuation will be presented.
For the summary of the subject disposition, the following items will be presented;
・the number of subjects who were treated
・the number (percentage) of subjects who completed/discontinued the Treatment Phase and 
the number of the primary reason and other reason(s) for the discontinuation
・the number (percentage) of subjects who discontinued the Treatment Phase and assessed 
at the Follow-up Visit
・the number (percentage) of subjects who completed/discontinued the Follow-up Phase and 
the number of the primary reason and other reason(s) for the discontinuation
・the number (percentage) of subjects who completed/discontinued the study and the 
number of the primary reason and other reason(s) for the discontinuation
Subject data listings will be provided.
3.2.3
Protocol Deviations
Major protocol deviation criteria will be established and subjects with major protocol 
deviations will be identified and documented before the database lock. A subject data listing 
of major protocol deviations will be provided.
3.2.4
Demographic and Other Baseline Characteristics
This summary table will be generated on the Safety Analysis Set, Efficacy Analysis Set and 
Pharmacokinetic Analysis Set (for instance, this will be summarized as “ Safety Analysis Set” 
if all the analysis set will be the same.).
Continuous demographic and baseline variables include
・Age


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・Height
・Weight
・BMI
Categorical demographic and baseline variables include
・Age group (< 18 years, 18 - < 65 years, 65years ≤)
・Sex
・Race
・Ethnicity
・Daily dose of oral Perampanel (8 mg, 10 mg, 12 mg)
Epilepsy specific history and characteristics at study entry will also be summarized by:
・Time since latest diagnosis of epilepsy (months)
・Etiology
・Epileptic syndrome
・Suspected localization of the epileptogenic region
・Seizure type
・Inducer / Non-Inducer
・Number of concomitant AEDs at the Screening (ie., Visit 1)
When summarizing the number of concomitant AEDs at the Screening, Oral Perampanel will 
not be included.
Subject data listings for demographic and other baseline characteristics will be provided.
Medical History


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A subject data listing of medical history and current medical condition will be provided.
3.2.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) drug codes.
Prior medications will be defined as medications that stopped before the first dose of study 
drug. Concomitant medications will be defined as medications that (1) started before the first 
dose of study drug and were continuing at the time of the first dose of study drug, or (2) started 
on or after the date of the first dose of study drug. If there are medications started after the last 
dose of study drug, those will be defined as post medications. In addition, prior and 
concomitant non-pharmacological procedures will be defined similarly to prior, concomitant
and post medications.
All medications and non-pharmacological procedures will be presented in subject data listings.
3.3
Data Analysis General Considerations
3.3.1
Pooling of Centers 
Subjects from all centers will be pooled for all analyses.
3.3.2
Adjustments for Covariates
No adjustment for covariates will be performed.
3.3.3
Multiple Comparisons/Multiplicity
No statistical comparison is planned in this study.
3.3.4
Examination of Subgroups
The following subgroup will be used for the efficacy and the safety (ie., AE) analyses. See 
section 3.4.1 and 3.6.2.
・Concomitant AED (Inducer/ Non-Inducer) 


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3.3.5
Handling of Missing Data, Dropouts, and Outliers
The details of handling of missing data will be described in section 6.
3.3.6
Other Considerations
Not applicable.
3.4
Efficacy Analyses
All efficacy analyses will be performed based on the Efficacy Analysis Set. Efficacy data will 
be summarized using descriptive statistics (e.g., n, mean, standard deviation, median,
minimum, Q1, Q3, maximum for continuous variables; number [percentage] for categorical 
variables). In the summary table, the following seizure type will be presented separately.
・For subjects who had POS(s) as an epilepsy history, POS total seizures (i.e., sum of the 
Simple partial seizures without motor signs, Simple partial seizures with motor signs, 
Complex partial seizures and Complex partial seizures with secondary generalization)
・For subjects who had generalized seizures as an epilepsy history, Tonic-clonic seizures
3.4.1
Primary Efficacy Analyses
The seizure frequency per day in each of the corresponding phases (ie., Pretreatment Phase, 
Treatment Phase, Follow-up Phase) will be summarized using descriptive statistics. The 
derivation of seizure frequency will be defined in the section 6.2.
The seizure frequency per day from the Pretreatment Phase to the Follow-up Phase for each 
subject will be displayed using a spaghetti-plot by seizure types (ie., POS total seizures and 
Tonic-clonic seizures). The plot will also be produced by concomitant AED (Inducer, Non-
Inducer). Furthermore, the number of seizures from the Pretreatment Phase to the Follow-up 
Phase for each subject will be displayed using a spaghetti-plot by POS total seizures and Tonic-
clonic seizures.
3.4.2
Secondary Efficacy Analyses
No secondary efficacy analyses are planned for this study.


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3.4.3
Other Efficacy Analyses
No other efficacy analyses are planned for this study.
3.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses
3.5.1
Pharmacokinetic Analyses
The Pharmacokinetic Analysis Set will be used for summaries of perampanel plasma 
concentrations. 
3.5.1.1
Plasma Concentration Analysis
Plasma concentrations of perampanel will be summarized using summary statistics (n, mean, 
SD, median, min and max) by nominal sampling time points and dose.  Maximum plasma 
concentrations among 0.5, 1, 1.5 hours after oral administration in each individual subject is 
defined as Cmax, po.  Summary statistics of Cmax, po will be also derived.
Plasma concentrations of perampanel which are normalized to dose 8 mg, hereinafter called to 
as dose-normalized plasma concentrations, will be summarized using summary statistics (n, 
mean, SD, median, min and max) by nominal sampling time points.  Summary statistics of 
Cmax, po which are normalized to dose 8 mg, hereinafter called to as dose-normalized Cmax, po, 
will be also derived.
Ratio of plasma concentrations at 0.5 hours after start of intravenous administration on Days 
1, 2, 3, 4 to Cmax, po will be calculated and summarized using summary statistics (n, mean, SD, 
median, min and max).
Spaghetti plot will be developed using individual plasma concentrations of perampanel for Y 
and time points for X; each for pre-dose (pre-dose concentrations on Day –1 to Day 4) and 
post-dose (0.5, 1, 1.5 hours after dosing on Day –1 and 0.5 hours after start of intravenous 
administration on Days 1, 2, 3, 4).  The plasma concentrations of 8 mg, 10 mg and 12 mg will 
be shown in different type of lines.
Spaghetti plot will be developed using individual dose-normalized plasma concentrations of 
perampanel for Y and time points for X ; each for pre-dose (pre-dose concentrations on Day –


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1 to Day 4) and post-dose (0.5, 1, 1.5 hours after dosing on Day –1 and 0.5 hours after start of 
intravenous administration on Days 1, 2, 3, 4).
Following box plots will be developed; 
・Pre-dose concentrations on Day –1 to Day 4 each for 8 mg, 10 mg and 12 mg
・Cmax, po and plasma concentrations at 0.5 hours after start of intravenous administration 
on Days 1, 2, 3, 4 each for 8 mg, 10 mg and 12 mg
・Dose-normalized pre-dose concentrations on Day –1 to Day 4
・Dose-normalized Cmax, po and dose-normalized plasma concentrations at 0.5 hours after 
start of intravenous administration on Days 1, 2, 3, 4 
Plasma concentrations of perampanel will be listed for each subject belonging to Safety 
Analysis Set by actual sampling time.
3.5.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Not applicable
3.6
Safety Analyses
All safety analysis will be performed based on the Safety Analysis Set. Safety data will be 
summarized using descriptive statistics (e.g., n, mean, standard deviation, median, minimum, 
maximum for continuous variables; number [percentage] for categorical variables).
3.6.1
Extent of Exposure
The parameters for extent of exposure defined as follows will be summarized by study phase 
(ie., Pre-treatment, Treatment, Follow-up) accordingly.
1. Duration of exposure (days)
-
the date of last study drug dosing – the date of first study drug dosing + 1 
-
the date of last oral perampanel dosing – the date of first oral perampanel dosing + 1 
(for Pretreatment Phase and the Follow-up Phase, respectively)


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2. Oral-perampanel mean daily dose (8 to 12 mg) (for Pretreatment Phase and Follow-up 
Phase, respectively)
-
Sum of daily dose / duration of exposure (days)
3. IV-perampanel-infusion mean daily dose (mg)
-
Sum of daily dose* / duration of exposure (days)
*: Daily dose: the planned concentration of IV-perampanel (mg/mL) * the actual IV-
perampanel-infusion volume (mL)
Subject data listings will be provided.
3.6.2
Adverse Events
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA version 21.1 or later).  Adverse events will be coded to the MedDRA lower level 
term (LLT) closest to the verbatim term. The linked MedDRA preferred term (PT) and primary 
system organ class (SOC) will also be captured in the database.
A treatment-emergent adverse event (TEAE), defined in section 6.3, will be included in 
summary tables.
A subject will be counted only once within a SOC and PT, even if the subject experienced 
more than 1 TEAE within a specific SOC and PT.
An overview table, including the incidence of and the number of subjects with TEAEs,
Treatment-related TEAEs, severe TEAEs, serious TEAEs , deaths, other serious TEAEs, and 
TEAEs that led to treatment discontinuation and interruption will be provided.
All analysis of TEAEs by SOC and PT will also be performed. The incidence of following 
events will be reported as the number (percentage) of subjects with TEAEs by MedDRA SOC 
and PT.
・TEAEs
・TEAEs by maximum severity
・Treatment-related TEAEs


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・Treatment-related TEAEs by maximum severity
In addition, the incidence of following events will be reported as the number (percentage) of 
subjects with AEs by MedDRA SOC and PT. If a subject experienced at least 1 AE within a 
specific SOC and PT in the multiple phases, the subject will be counted once in each phase.
Furthermore, the overview table and AE tables by SOC and PT will also be provided for each 
study phase in one table.
・AEs (non-TEAEs) that occurred during the Pretreatment Phase
・TEAEs that occurred during the Treatment Phase
・TEAEs that occurred during the Follow-up Phase
The following tables will be produced by concomitant AEDs (ie., Inducer, Non-Inducer) and 
planned perampanel dose.
・TEAEs by SOC and PT
・Treatment-related TEAEs by SOC and PT
Subject data listings of all deaths, serious adverse events (SAEs), AE leading to study 
treatmentdiscontinuation. All AE regardless of treatment-emergent or not will be included in 
the subject data listings.
AEs of special Interest
TEAEs which were reported as an event associated with renal dysfunction or an event 
associated with anaphylaxis on the CRF will be summarized by PT.
3.6.3
Laboratory Values
Laboratory results will be summarized using Système International (SI) units. For all 
quantitative parameters, the actual value and the change from baseline to each postbaseline 
visit will be summarized using summary statistics. Qualitative parameters will be summarized 
by number and percentage of subjects, and changes from baseline to each postbaseline visit 
will be reported using shift tables. Percentages will be based on the number of subjects with 
both nonmissing baseline and relevant postbaseline results.


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Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value is below (L), within (N), or above (H) the laboratory parameter’s reference 
range. The changes from baseline to each postbaseline visit will be reported using shift tables. 
The result of LNH classification will be provided in a subject data listing. 
Sponsor’s Grading for Laboratory Values (see Appendix 1) will be used to identify subjects 
with Treatment-emergent markedly abnormal laboratory value (TEMAV). The number 
(percentage) of subjects with TEMAV (markedly abnormal high/low) will be summarized 
separately for the Treatment Phase and the Follow-up Phase.  The TEMAV will be defined 
in the section 6.3. 
The baseline to each postbaseline values for quantitative data will be displayed using Box plot.
Subject data listings will be provided.
3.6.4
Vital Signs
Summary statistics for vital signs parameters (diastolic and systolic blood pressure, pulse, 
respiratory rate, and temperature) and weight, and changes from baseline to each postbaseline 
visit will be presented.
In addition, clinically notable vital sign values will be identified using the criteria in Table 1. 
The clinically notable vital sign values will be summarized using frequency count (percentage) 
separately for the Treatment Phase and the Follow-up Phase.
Table 1.
Vital Sign Criteria
Variable
Criterion value a
Change relative to baseline a
Clinically notable range
Pulse
>120 bpm
Increase of  ≥15 bpm
H
<50 bpm
Decrease of  ≥15 bpm
L
Systolic BP
>180 mmHg
Increase of  ≥20 mmHg
H
<90 mmHg
Decrease of  ≥20 mmHg
L
Diastolic BP
>105 mmHg
Increase of  ≥15 mmHg
H
<50 mmHg
Decrease of  ≥15 mmHg
L


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Table 1.
Vital Sign Criteria
Variable
Criterion value a
Change relative to baseline a
Clinically notable range
Weight
--
Increase of  ≥7% 
H
--
Decrease of  ≥7%
L
Respiratory Rate
>30 bpm
Increase of  ≥10 bpm
H
< 8 bpm
Decrease of  ≥4 bpm
L
BP = blood pressure, H = high, L = low.
a: Clinically notable means that a value must meet the criterion value and must attain the specified magnitude 
of change relative to baseline.
The baseline to each postbaseline visit values will be displayed using Box plot.
Subject data listings will be provided.
3.6.5
Electrocardiograms
Shift tables will present changes from baseline to each postbaseline visit in ECG interpretation 
(categorized as normal; abnormal, not clinically significant; and abnormal, clinically 
significant). 
Subject data listings will be provided.
3.6.6
Other Safety Analyses
No other safety analyses are planned for this study. 
3.7
Other Analyses
No other analyses are planned for this study.
4
INTERIM ANALYSES
No interim analyses are planned for this study.


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5
CHANGES IN THE PLANNED ANALYSES
A summary of all major additions, changes and deletions in the planned analyses described in 
the protocol will be provided in this section.
・The analysis for AE of special interest was added (section 3.6.2).
・The analysis for TEAE and Treatment-related TEAE by concomitant AED (Inducer, Non-
Inducer) was added (section 3.6.2).
・The plot for seizure frequency by concomitant AED (Inducer, Non-Inducer) was added 
(section 3.4.1). 
・The analysis for clinically notable vital sign values was added (section 3.6.4).
6
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
The data will be handled as follows. The sponsor will determine how to handle all data prior 
to data base lock.
6.1
General Data Handling
Definition of Baseline data
Baseline is defined as the last non-missing value observed on or prior to the first study drug
dispensing date.
Definition of Change from Baseline, Percent Change from Baseline
・Change from baseline = Post-baseline value - Baseline value
・% Change from baseline = (Change from baseline / Baseline value) * 100
For any baseline value of 0, the subject’s corresponding percent change from baseline will not 
be included in the summary statistics table.
Handling of data within the follow-up period after discontinuation
Data in the Follow-up Phase obtained after discontinuation will be included in the summary 
tables. These data will be presented in the subject data listing.


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6.2
Efficacy Data Handling
Handling of seizure frequency
・Baseline (ie., Pretreatment Phase)
Baseline seizure frequency will be composed of the dispensed diary.
Baseline seizure 
frequency will be calculated as the number of seizures per day (see below). All diary data 
collected during the Pretreatment Phase (ie., the date of first diary entry to the first dose date 
of Perampanel IV infusion) will be used in the computation of baseline seizure frequency per 
day.
Sum of seizures during the Pretreatment Phase
Number of study days during the Pretreatment Phase
Study days during the Pretreatment Phase will be the period between visit 1 and visit 2.
・Treatment Phase
Treatment Phase seizure frequency will be composed of the dispensed diary. Treatment Phase 
seizure frequency will be calculated as the number of seizures per day (see below). All diary 
data collected during the Treatment Phase (ie., the first dose date of Perampanel IV infusion to 
the first dose date of oral Perampanel) will be used in the computation of baseline seizure 
frequency per day.
Sum of seizures during the Treatment Phase
Number of study days during the Treatment Phase
Study days during the Treatment Phase will be the period between visit 3a and the day after
visit 3d.
・Follow-up Phase
Follow-up Phase seizure frequency will be composed of the dispensed diary.  Follow-up 
Phase seizure frequency will be calculated as the number of seizures per day (see below).
All 
diary data collected during the Follow-up Phase (ie., the first dose date of oral Perampanel to 
the date of last diary entry) will be used in the computation of baseline seizure frequency per 
day.


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Sum of seizures during the Follow −up Phase
Number of study days during the Follow −up Phase
Study days during the Follow-up Phase will be the period between the day after visit 3d and 
visit 4.
Handling of missing data
Seizure frequency
If subjects have a missing seizure count in any of each seizure type (ie, simple partial seizure 
with motor signs, simple partial seizure without motor signs, complex partial seizure, and 
complex partial seizure with secondarily generalized seizure) for each unique diary record, the 
overall seizure frequency for that record will be handled as missing data.  Similarly, if 
complex partial seizure and/or complex partial seizure with secondarily generalized seizure are 
missing for each unique diary record, then complex partial seizure plus secondary generalized 
seizure frequency will be handled as a missing data.
6.3
Safety Data Handling
Definition of derived variables for extent of exposure
The derivation rule will be presented in the section 3.6.1.
Treatment-emergent adverse event
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during time 
from the first dose of study drug to 28 days after the subject’s last dose, having been absent at 
pretreatment (Baseline) or 
・Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 
・Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
TEMAV (Treatment-Emergent Markedly Abnormal Value)
A TEMAV is defined as follows: 


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・For a phosphate, if the post baseline grade increases from baseline and the post baseline 
grade is greater than or equal to 3 then a value will be determined to be a TEMAV. 
・For all other parameters presented in the section 12, if the post baseline grade increases 
from baseline and the post baseline grade is greater than or equal to 2 then a value will be 
determined to be a TEMAV.
If the grade of baseline value is missing, then, if the grade of post-baseline value fall within 
the above TEMAV definition , the laboratory values will be classified into treatment emergent 
markedly abnormal. When displaying the incidence of TEMAVs, each subject may be counted 
once in the laboratory parameter high and in the laboratory parameter low categories, as 
applicable. 
Handling of below lower quantification values in laboratory results
・In the cases where laboratory result contains below lower quantification (BLQ) value, it 
will be replaced to the lower limit value of quantification (LLOQ) for summary tables.
6.4
Pharmacokinetic Data Handling
6.4.1
Lower Limit of Quantification of Perampanel Plasma Concentration
The LLOQ of perampanel plasma concentrations is 0.250 ng/mL.
6.4.2
BLQ Handling for Calculation of PK Parameters
Not applicable
6.4.3
BLQ Handling for Developing Concentration-Time Profiles
Not applicable
6.4.4
Handling of Anomalous Concentration Values
The handling of anomalous concentration values will follow the guidance in the Eisai manual 
302-104.00-MNL for non compartmental PK analysis (Version Date: 08 Jun 2016).


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6.4.5
General Rules for Presentation of Drug Concentrations and PK Parameters
When presenting individual/raw (raw, hereafter) values and summary statistics, the following 
rule will be applied:  for drug concentrations, all summary statistics (mean, median, and 
standard deviation [SD]) will have 3 significant digits. 
Variable
Unit
N
Digit rule
Raw/
Minimum/
Maximum
Mean
Media
n
SD
Geomet
ric  
Mean
CV
(%)
Perampanel
concentration
ng/mL
X
Significant 
digits
3
3
3
-
-
7
PROGRAMMING SPECIFICATIONS
The rules for programming derivations and dataset specifications are provided in separate 
documents.
8
STATISTICAL SOFTWARE
All statistical analyses will be conducted by the designee, using validated standard programs 
or double programming.  For analyses needed in data review, single programming will be 
used.
All statistical analyses will be performed using SAS (version 9.2 or later).  As necessary, 
other validated statistical software will also be used.
9
MOCK TABLES, LISTINGS, AND GRAPHS
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail.


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Appendix 1
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L
N/A
Leukocytes (total WBC)
<LLN – 3.0×109/L
<LLN – 3000/mm3
<3.0 – 2.0×109/L
<3000 – 2000/mm3
<2.0 – 1.0×109/L
<2000 – 1000/mm3
<1.0×109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8×109/L
<800 – 500/mm3
<0.8 – 0.5×109/L
<500 – 200/mm3
<0.5 – 0.2×109/L
<200/mm3
<0.2×109/L
Neutrophils 
<LLN – 1.5×109/L
<LLN – 1500/mm3
<1.5 – 1.0×109/L
<1500 – 1000/mm3
<1.0 – 0.5×109/L
<1000 – 500/mm3
<0.5×109/L
<500/mm3
Platelets
<LLN – 75.0×109/L
<LLN – 75,000/mm3
<75.0 – 50.0×109/L
<75,000 – 50,000/mm3
<50.0 – 25.0×109/L
<50,000 – 25,000/mm3
<25.0×109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, 
serum-
low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
N/A
ALP
>ULN – 3.0×ULN
>3.0 – 5.0×ULN
>5.0 – 20.0×ULN
>20.0×ULN
ALT
>ULN – 3.0×ULN
>3.0 – 5.0×ULN
>5.0 – 20.0×ULN
>20.0×ULN


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Grade 1
Grade 2
Grade 3
Grade 4
AST
>ULN – 3.0×ULN
>3.0 – 5.0×ULN
>5.0 – 20.0×ULN
>20.0×ULN
Bicarbonate, serum-low
<LLN – 16 mmol/L
11 – 15 mmol/L
8 – 10 mmol/L
<8 mmol/L
Bilirubin (hyperbilirubinemia)
>ULN – 1.5×ULN 
>1.5 – 3.0×ULN
>3.0 – 10.0×ULN 
>10.0×ULN
Calcium
corrected, 
serum-low 
(hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium
corrected, 
serum-high 
(hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, 
serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5×ULN
>1.5 – 3.0×ULN
>3.0 – 6.0×ULN
>6.0×ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 3.0×ULN
>3.0 – 5.0×ULN
>5.0 – 20.0×ULN
>20.0×ULN
Glucose, serum-high (hyperglycemia)
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L
>500 mg/dL;
>27.8 mmol/L 
Glucose, seruypoglycemiam-low (h)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
Phosphate, 
serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L


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Grade 1
Grade 2
Grade 3
Grade 4
Potassium, 
serum-high 
(hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
>7.0 mmol/L
Potassium, serum-low (hypokalemia) <LLN – 3.0 mmol/L
N/A
<3.0 – 2.5 mmol/L
<2.5 mmol/L
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
>160 mmol/L
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
Triglyceride, 
serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L 
Uric 
acid, 
serum-high 
(hyperuricemia)
>ULN - 10 mg/dL 
≤ULN – 0.59 mmol/L 
N/A
N/A 
>10 mg/dL
>0.59 mmol/L 
ALP = alkaline phosphatase, ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = 
aspartate aminotransferase (serum glutamic oxaloacetic transaminase), GGT = γ-glutamyl transpeptidase, N/A = 
not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 
(v4.03: June 14, 2010).