Conditions: Restless Legs Syndrome (RLS)
Keywords: Restless Legs Syndrome ASP8825 Gabapentin enacarbil
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 375
Healthy volunteers: no

Brief summary:
The objective of this study was to assess the efficacy of once-daily oral administration of gabapentin enacarbil versus placebo, based on the change in International Restless Legs Syndrome Rating Scale (IRLS) score in participants with moderate-to-severe idiopathic restless legs syndrome. This study also assessed the safety of Gabapentin enacarbil.

Detailed description:
After 1 week run in period with single-blind placebo, participants meeting the inclusion and none of the exclusion criteria were randomized to receive double-blind treatment with either gabapentin enacarbil 600 mg or placebo for 12 weeks treatment period. After then, single-blind placebo was given for 1 week for follow-up observation.

Arms:
arm 1: Placebo was administered orally once daily after the evening meal. arm 2: Gabapentin enacarbil was administered orally once daily after the evening meal. Participants with an estimated creatinine clearance of ≥ 60 mL/min to \< 90 mL/min at the start of the run-in period were administrated gabapentin enacarbil 300 mg for 1 week followed by gabapentin enacarbil 600 mg for 11 weeks.

Interventions: intervention 1: Placebo intervention 2: Gabapentin enacarbil
Intervention descriptions: intervention 1: Oral administration intervention 2: Oral administration

Protocol document:
Prot_000.pdf: 
Sponsor: API
ISN/Protocol <8825-CL-0101>
‐ CONFIDENTIAL ‐
13 January 2017
Astellas
Page 1 of 105
Gabapentin Enacarbil Post-marketing Clinical Study Protocol
- A Randomized, Double-blind, Placebo-controlled, Parallel-group 
Study in Subjects With Restless Legs Syndrome -
ISN/Protocol 8825-CL-0101
Version 3.0
13 January 2017
(Translation from Japanese)
Sponsor:
Astellas Pharma Inc.(API)
2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo
This document is the property of the Sponsor. Unpublished information in this document 
must not be disclosed without prior written agreement of the Sponsor.


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Table of Contents
I
SIGNATURE ······················································································· 8
II
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL ···························· 9
III
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERM ··················· 10
IV
SYNOPSIS·························································································· 13
V
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································20
1
INTRODUCTION ················································································ 24
1.1
Background····················································································24
1.2
Nonclinical and Clinical Data ·······························································25
1.2.1
Nonclinical Data ········································································25
1.2.2
Clinical Data·············································································26
1.3
Summary of Key Safety Information for the Study Drug································34
1.4
Risk Benefit Assessment·····································································34
1.4.1
Risk Assessment ········································································34
1.4.2
Benefit Assessment ·····································································35
2
STUDY OBJECTIVES, DESIGN, AND ENDPOINTS····································35
2.1
Study Objectives··············································································35
2.2
Study Design and Dose Rationale ··························································36
2.2.1
Study Design ············································································36
2.2.2
Dose Rationale ··········································································36
2.3
Endpoints ······················································································37
2.3.1
Primary Endpoint ·······································································37
2.3.2
Secondary Endpoints ···································································37
2.3.3
Safety Endpoints ········································································37
3
STUDY POPULATION ········································································· 38
3.1
Selection of Study Population·······························································38
3.2
Inclusion Criteria ·············································································38
3.3
Exclusion Criteria·············································································40
4
TREATMENT····················································································· 42
4.1
Identification of Study Drug·································································42
4.1.1
Test Drug·················································································42


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4.1.2
Comparative Drug ······································································42
4.1.3
Study drug for the run-in period and study drug for the follow-up period ·······42
4.2
Packaging and Labeling······································································43
4.3
Study Drug Handling·········································································48
4.4
Blinding························································································48
4.4.1
Blinding Method ········································································48
4.4.2
Confirmation of the Indistinguishability of the Study Drugs ······················48
4.4.3
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking··················································································48
4.4.4
Breaking the Treatment Code for Emergency ·······································49
4.4.5
Breaking the Treatment Code by the Sponsor ·······································49
4.5
Assignment and Allocation··································································50
5
TREATMENTS AND EVALUATION ······················································· 50
5.1
Dosing and Administration of Study Drug and Other Medications·····················50
5.1.1
Dose, Dosage Regimen, and Administration Period································50
5.1.2
Increase or Reduction in Dose of the Study Drug···································51
5.1.3
Previous and Concomitant Treatment (Medication and Non-medication 
Therapy)··················································································51
5.1.3.1
Previous Treatment (Medications and Non-medication Therapies)·········51
5.1.3.2
Concomitant Treatment (Medication and Non-medication Therapy)·······52
5.1.4
Treatment Compliance ·································································53
5.1.5
Emergency Procedures and Management of Overdose·····························53
5.1.6
Criteria for Continuation of Treatment ···············································53
5.1.7
Restrictions During the Study ·························································53
5.2
Demographics and Baseline Characteristics···············································55
5.2.1
Demographics ···········································································55
5.2.2
Medical History ·········································································55
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease ·············55
5.3
Efficacy Assessment··········································································55
5.4
Safety Assessment ············································································56
5.4.1
Vital Signs ···············································································56
5.4.2
Adverse Events··········································································56
5.4.3
Laboratory Assessments································································56
5.4.4
Physical Examination···································································57


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5.4.5
Imaging···················································································57
5.4.6
Other······················································································57
5.5
Adverse Events and Other Safety Aspects·················································57
5.5.1
Definition of Adverse Events (AEs)··················································57
5.5.2
Definition of Serious Adverse Events (SAEs)·······································58
5.5.3
Criteria for Causal Relationship to the Study Drug·································59
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························60
5.5.5
Reporting of Serious Adverse Events (SAEs) ·······································60
5.5.6
Follow-up of Adverse Events··························································61
5.5.7
Monitoring of Common Serious Adverse Events ···································61
5.5.8
Procedure in Case of Pregnancy·······················································61
5.5.9
Emergency Procedures and Management of Overdose·····························62
5.5.10
Supply of New Information Affecting the Conduct of the Study ·················62
5.5.11
Deviations from the Protocol and Other Actions Taken to Avoid Life-
Threatening Risks to Subjects ·························································62
5.6
Test Drug Concentration·····································································63
5.7
Other Measurements, Assessments or Methods···········································63
5.8
Total Amount of Blood Collected ··························································63
6
DISCONTINUATION ··········································································· 64
6.1
Discontinuation of Individual Subjects·····················································64
6.2
Discontinuation of the Site ··································································66
6.3
Discontinuation of the Study ································································66
7
STATISTICAL METHODOLOGY··························································· 66
7.1
Sample Size····················································································66
7.2
Analysis Sets ··················································································67
7.2.1
Full Analysis Set (FAS) ································································67
7.2.2
Per Protocol Set (PPS)··································································67
7.2.3
Safety Analysis Set (SAF) ·····························································67
7.3
Demographic and Baseline Characteristics················································67
7.4
Analysis of Efficacy··········································································68
7.4.1
Analysis of Primary Endpoint ·························································68
7.4.1.1
Primary Analysis ··································································68
7.4.1.2
Secondary Analysis ·······························································68


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7.4.2
Analysis of Secondary Endpoints ·····················································68
7.5
Analysis of Safety ············································································70
7.5.1
Adverse Events··········································································70
7.5.2
Laboratory Assessments································································70
7.5.3
Vital Signs ···············································································70
7.5.4
Body Weight·············································································70
7.5.5
Epworth Sleepiness Scale······························································70
7.6
Analysis of Pharmacokinetics·······························································70
7.7
Other Analyses················································································70
7.8
Interim Analysis (and Early Discontinuation of the Study)······························70
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········70
7.9.1
IRLS score and RLS Pain score·······················································71
7.9.2
ICGI and PCGI··········································································71
7.9.3
Pittsburgh Sleep Quality Index, Athens Insomnia Scale, and EQ-5D-5L········72
7.9.4
Laboratory Tests ········································································72
7.9.5
Vital Signs ···············································································72
7.9.6
Body Weight·············································································73
7.9.7
Epworth Sleepiness Scale······························································73
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS···················· 74
8.1
Procedure for Clinical Study Quality Control·············································74
8.1.1
Data Collection··········································································74
8.1.2
Specification of Source Documents···················································75
8.1.3
Clinical Study Monitoring ·····························································75
8.1.4
Direct Access to Source Data/Documents ···········································76
8.1.5
Data Management·······································································76
8.2
Ethics and Protection of Subject Confidentiality··········································76
8.2.1
Institutional Review Board (IRB)·····················································76
8.2.2
Ethical Conduct of the Study ··························································76
8.2.3
Informed Consent of Subjects ·························································76
8.2.3.1
Subject Information and Consent················································76
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent, and Revision of the Written Information····························77
8.2.4
Subject Confidentiality and Privacy ··················································77
8.3
Administrative Matters·······································································78


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8.3.1
Arrangement for Use of Information and Publication of the Clinical Study·····78
8.3.2
Documents and Records Related to the Clinical Study·····························78
8.3.3
Protocol Amendment and/or Revision················································80
8.3.4
Insurance of Subjects and Others ·····················································80
8.3.5
Signatory Investigator for Clinical Study Report ···································80
9
QUALITY ASSURANCE ·······································································80
10
STUDY ORGANIZATION ·····································································81
10.1
Independent Data-Monitoring Committee (IDMC) | Data and Safety Monitoring 
Board (DSMB) | Monitoring Committee | Other Evaluation Committee(s) ···········81
10.2
Other Study Organizations···································································81
10.3
Registration of Subjects······································································82
11
REFERENCES ···················································································· 83
12
APPENDICES ····················································································· 84
12.1
List of Excluded Concomitant Medications ···············································84
12.2
Laboratory Tests ··············································································85
12.3
Common Serious Adverse Events ··························································86
12.4
Events Handled as Serious···································································86
12.5
Criteria for Seriousness/Severity Grading of Adverse Drug Reactions 
(Notification No. 80 of the Safety Division, Pharmaceutical Affairs Bureau, 
dated June 29, 1992)··········································································87
12.6
International Restless Legs Syndrome Study Group Rating Scale (IRLS) 
(Investigator Version 2.2)·································································· 103
List of Tables
Table 1:
Schedule of Assessments ····································································22
Table 2:
Change in IRLS score at final observation in the treatment period: FAS··············27
Table 3:
ICGI and PCGI at final observation in the treatment period: FAS······················27
Table 4:
Change from baseline in IRLS score at Week 12 using LOCF (MITT analysis 
set) ······························································································29
Table 5:
Change from baseline in IRLS score at Week 12 using LOCF (MITT analysis 
set) ······························································································30
Table 6:
Change from baseline in IRLS score at Week 12 using LOCF (MITT analysis 
set) ······························································································32
Table 7:
Change in IRLS score at each time point of evaluation: FAS···························33


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Table 8:
Change in IRLS score (mean and standard deviation) at the end of treatment 
period (i.e., Week 12 of study treatment) in the Japanese phase II/III study [CL-
0003]: FAS ····················································································66


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I
SIGNATURE
AGREEMENT BETWEEN THE SPONSOR’S RESPONSIBLE PERSON AND THE 
INVESTIGATOR
This clinical study will be conducted in adherence to GCP, GPSP, ICH Guidelines and applicable laws 
and regulatory requirements, as well as this study protocol.  As the evidence of the agreement, the 
investigator and responsible person of the Sponsor inscribe in the bipartite agreement by signature or 
“printed name and seal.”


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II
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL
Contact Information for the Sponsor
Corporate Name: Astellas Pharma Inc.
Location: 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo
Phone No.: 
Fax: 
Sponsor’s personnel: 
, 
, 
, 
, 
[Contact numbers during non-business hours and for emergency]
Sponsor contact personnel: 
Contact Information for the Contract Research Organization (CRO)
Corporate name: 
Location: 
Phone No.: 
Fax: 
CRO’s person:
[Contact numbers during non-business hours and for emergency]
CRO contact personnel: 


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III
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERM
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase (GPT)
AST
Aspartate Aminotransferase (GOT)
AUCinf
AUC from the time of dosing up to infinity with extrapolation of the 
terminal phase
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
Cmax
Maximum plasma concentration
CPK
Creatine Phosphokinase
CRF
Case Report Form
CRO
Contract Research Organization
DSM-V
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EDTA-2K
Ethylenediaminetetraacetic acid dipotassium salt
EQ-5D-5L
EuroQol-5Dimension-5 Level
FAS
Full Analysis Set
Free T4
Free thyroxine
GABA
gamma-aminobutyric acid
GCP
Good Clinical Practice
GMP
Good Manufacturing Practices
GPSP
Good Post-marketing Study Practice
γ-GTP
γ-glutamyltranspeptidase
ICGI
Investigator-rated Clinical Global Impression
ICH
International 
Conference 
on 
Harmonization 
of 
Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IDF
Iyakuhinmei Data File
IRB
Institutional Review Board
IRLS
International Restless Legs Syndrome Rating Scale
IRT
Interactive Response Technology (used for subject registration) 
ISN
International Study Number
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Regulatory Activities
MedDRA/J
Medical Dictionary for Regulatory Activities/Japanese version
MITT
Modified Intention-to-Treat
NGSP
National 
Glycohemoglobin 
Standardization 
Program 
(HbA1c 
reporting units)
PCGI
Patient-rated Clinical Global Impression: Patient-rated Clinical Global 
Impression
PPS
Per Protocol Set


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Abbreviations
Description of abbreviations
PT
Preferred Term
QOL
Quality Of Life
RBC
Red Blood Cell
RLS
Restless Legs Syndrome
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SDV
Source Document Verification
SMO
Site Management Organization
SOC
System Organ Class
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
Total Bilirubin
TSH
Thyroid Stimulating Hormone
WBC
White Blood Cell


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Definition of Key Study Terms
Term
Definition of terms
Follow-up period
The period from the start of administration of the study drug for the 
follow-up period to the final observation
Gabapentin
An antiepileptic drug synthesized in Germany in 1973; the active 
metabolite of gabapentin enacarbil
Gabapentin 
enacarbil
The active substance of Regnite Tablets; nonproprietary name of the 
drug
Registration failure
A subject who provided informed consent but did not fulfill the 
inclusion/exclusion criteria for formal registration and thus was not 
randomized or did not receive open-label study drug, or who withdrew 
consent during the run-in period.
Study period
The period from informed consent of the subject to completion of 
protocol-specified last evaluation/observation in the subject
Screening
A process of active consideration of potential subjects for enrollment 
in the study, conducted during the run-in period to determine the 
eligibility for the study
Enroll
To register or enter a patient into a clinical trial as a subject; NOTE: 
Once a subject is enrolled into the study, the clinical study protocol 
applies to the subject.
Subject
Study participant
Subject ID number
A number assigned to a subject who provided consent to participate in 
the study by signing the consent form
Endpoint
An attribute, phenomenon, or event that varies in quality or quantity 
and serves as a variable
Baseline
Measurement or finding obtained at a time point judged to be initiation
of observation for comparison
Run-in period
The period from the start of administration of the study drug for the
run-in period to before the start of administration of the study drug for 
the treatment period
Randomization
A process of assigning study subjects to treatment or control groups in 
which an element of chance is used in the determination of 
assignments to reduce bias
Regnite® Tablets
Alternative name for the study drug gabapentin enacarbil; brand name 
of the drug product approved for marketing in January 2012 
ASP8825
Alternative name for the study drug gabapentin enacarbil; a drug 
substance code used by Astellas Pharma Inc.
GSK1838262
Alternative name for the study drug gabapentin enacarbil; a drug 
substance code used by GlaxoSmithKline K.K.
XP13512
Alternative name for the study drug gabapentin enacarbil; a Drug 
substance code used by XenoPort, Inc.


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IV
SYNOPSIS
Date and Version No of Protocol Synopsis: Version 3.0, 
dated 13 January 2017
Sponsor:
Astellas Pharma Inc.(API)
Protocol Number:
8825-CL-0101
Name of Study Drug:
Gabapentin enacarbil
Phase of Development:
Post-marketing clinical study
Title of Study:
Gabapentin enacarbil post-marketing clinical study
- A Randomized, Double-blind, Placebo-controlled, Parallel-group Study in Subjects With Restless Legs 
Syndrome -
Planned Study Period:
December 2016 to November 2018
Study Objectives:
- To verify the efficacy of oral gabapentin enacarbil 600 mg once daily compared with placebo on the basis 
of the change from baseline in IRLS score in patients with moderate to severe idiopathic restless legs 
syndrome (RLS), using a multicenter, randomized, double-blind, parallel-group, comparative design
- To evaluate the safety of gabapentin enacarbil 600 mg
Planned Total Number of Study Centers and Location:
Approximately 50 centers
Japan
Study Population:
Patients with moderate to severe idiopathic RLS
Number of Subjects to be Enrolled/Randomized:
360 subjects as participants in the treatment period (180 subjects per group × 2)
Study Design Overview:
Gabapentin enacarbil 600 mg or placebo will be administered orally once daily after the evening meal. 
Patients meeting the inclusion and exclusion criteria at provisional registration will receive single-blind 
placebo for 1 week (run-in period). Of these, patients meeting the inclusion and exclusion criteria at 
formal registration will be randomized to recieve double-blind treatment with either gabapentin enacarbil 
600 mg or placebo for 12 weeks (treatment period). After the end of the 12-week treatment period, 
single-blind placebo will be given for 1 week (follow-up period) for follow-up observation.
However, of the patients meeting the inclusion and exclusion criteria at formal registration, those with an 
estimated creatinine clearance of ≥60 to < 90 mL/min at the start of the run-in period will receive 
randomized double-blind treatment initially with either gabapentin enacarbil 300 mg or placebo for 1 week 
(upward titration period) followed by gabapentin enacarbil 600 mg or placebo for 11 weeks, totaling 12 
weeks (treatment period including the upward titration period).
[Randomiation method]
Stratified allocation will be performed with stratification factors of age (< 50 years and ≥50 years) at the 
start of the run-in period and estimated creatinine clearance (≥60 to < 90 mL/min and ≥90 mL/min) at the 
start of the run-in period.
Inclusion/Exclusion Criteria:


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Inclusion:
Subject is eligible for the study if all of the following apply:
At provisional registration:
1.
Provided written informed consent using the informed consent form approved by the Institutional 
Review Board (IRB) prior to any study-related procedures (including discontinuation of excluded 
concomitant medications)
2.
Male or female outpatient aged between ≥20 and ≤80 years years at the time of consent
3.
Patient with a diagnosis of RLS according to the International RLS Study Group diagnostic criteria for 
RLS (2014 update)
4.
Had RLS symtoms for ≥15 days during the month prior to the start of the run-in period, or if on 
treatment for RLS, during the month prior to the start of that treatment
5.
Has an International Restless Legs Syndrome Rating Scale (IRLS) score of ≥15 at the start of the run-
in period
6.
Has not taken dopamine agonists, dopamine preparations, gabapentin, gabapentin enacarbil, or 
pregabalin during at least one week before the first day of the run-in period
7.
Has not received other treatments for RLS (opioids, benzodiazepines, long-acting dopamine agonists) 
during at least 2 weeks before the first day of the run-in period
8.
Female subject must either:
Be of nonchildbearing potential:

Postmenopausal (defined as at least 1 year without any menses) at the start of the run-in 
period, or

Documented surgically sterile
Or, if of childbearing potential,

Agree not to become pregnant during the study and for 28 days after the final study drug 
administration,

And have a negative pregnancy test at the start of the run-in period

And if heterosexually active, agree to consistently use two (one or both of which must be 
the barrier method) of the established forms of birth control* specified below, during the 
study period and for 28 days after the final study drug administration
*Established forms of birth control include:
- Correct usage of approved oral contraceptives
- Intrauterine device (IUD), intrauterine system (IUS), and other intrauterine instruments
- Barrier method with male condoms or female condoms
- Rhythm method (Knaus-Ogino method)
9.
Female subject must agree not to breastfeed throughout the study period and for 28 days after the final 
study drug administration.
10. Female subject must not donate ova throughout the study period and for 28 days after the final study 
drug administration.
11. Agrees not to participate in another interventional study during the study period
12. Has a body mass index (BMI) range of 18.5 to < 30 (BMI = Body weight (kg)/Height (m)2)
At formal registration:
13. Has an IRLS score of ≥15 at the start of the treatment period
14. Has RLS symtoms (evenings and nights) for at least 4 days during the 1-week run-in period
15. Has an estimated creatinine clearance value* of ≥60 mL/min as calculated using the Cockcroft-Gault 
equation at the start of the run-in period
*For calculation of the estimated creatinine clearance, refer to Section 5.7 Other Measurements, 
Assessments or Methods.
Waivers to the inclusion criteria will NOT be allowed.
Exclusion:
Subject will be excluded from participation if any of the following apply:


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At provisional registration:
1.
A sleep disorder (e.g., sleep apnea) that may affect the assessment of RLS
2.
A history of RLS symptom augmentation or post-therapy rebound with previous dopamine agonist 
treatment
3.
Neurologic disease or movement disorder (e.g., neurologic disease, Parkinson’s disease, multiple 
sclerosis, dyskinesia, dystonia, rheumatoid arthritis)
4.
Poorly controlled diabetes mellitus (i.e., HbA1c > 7.5% [NGSP-value] on a test during the past 6 
months), iron deficiency anemia, or current use of oral sedative-hypnotics
5.
Has a history of suicide attempt within 6 months before consent, or judged by the investigator/sub-
investigator to be at risk for suicide
6.
Has elevated ALT or AST (based on laboratory data within the past 6 months) (For reference, grade 
≥2 according to the “Criteria for Seriousness/Severiy Grading of Adverse Drug Reactions,” 
[Notification No. 80 of the Safety Division, Pharmaceutical Affairs Bureau, dated June 29, 1992] will 
be used.)
7.
Moderate or severe depression (DSM-V)
8.
Previously had alcohol dependence or drug poisoning, or within the past year had substance abuse or 
dependence.
9.
Shift worker (including night-work), professional driver, or dangerous machinery operater
10. Clinically significant or unstable medical conditions (e.g., current or past history of cancer, 
complication of serious cardiac disease*, hepatic disease*, renal disease*, hematological disease*, 
immunodeficiency, psychiatric disease).
*For reference, Grade 3 of the “Criteria for Seriousness/Severiy Grading of Adverse Drug Reactions,” 
(Notification No. 80 of the Safety Division, Pharmaceutical Affairs Bureau, dated June 29, 1992) will 
be used.
11. History of hypersensitivity to gabapentin
12. Had previously taken pregabalin, gabapentin enacarbil, or ASP8825 (including GSK1838262 and 
XP13512) as an investigational drug
13. Participated within 12 weeks (84 days) before the first day of the run-in period, or currently 
participating, in a clinical trial or post-marketing clinical study of another drug or a medical device
14. Is employed by the Sponsor or the CRO, SMO or study site involved in this study
15. Other subjects for whom participation in this study is judged to be inappropriate in the opinion of the 
investigator/sub-investigator
At formal registration:
16. Has a decrease in IRLS score at the start of the treatment period by 10 or more points from the start of 
the run-in period
17. Has clinically relevant abnormalities on laboratory tests* in the opinion of the investigator/sub-
investigator
*For reference, Grade 3 of the “Criteria for Seriousness/Severiy Grading of Adverse Drug Reactions,” 
(Notification No. 80 of the Safety Division, Pharmaceutical Affairs Bureau, dated June 29, 1992) will 
be used.
18. Poorly controlled diabetes mellitus (i.e., HbA1c > 7.5% [NGSP-value] on a laboratory test in the run-
in period)
19. Serum ferritin < 12 ng/mL on a laboratory test at the start of the run-in period
20. Elevated ALT or AST on laboratory tests at the start of the run-in period (For reference, grade ≥2 
according to the “Criteria for Seriousness/Severiy Grading of Adverse Drug Reactions,” [Notification 
No. 80 of the Safety Division, Pharmaceutical Affairs Bureau, dated June 29, 1992] will be used.)
21. Female other than female of nonchildbearing potential judged to be pregnant based on the pregnancy 
test in the run-in period (in line with inclusion criterion 8)
22. Subjects for whom participation in this study is judged to be inappropriate in the opinion of the 
investigator/sub-investigator
Waivers to the exclusion criteria will NOT be allowed.


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Test Drug:
Gabapentin enacarbil tablets 300 mg
Dose:
Gabapentin enacarbil 600 mg group: 600 mg/day of gabapentin enacarbil
Mode of Administration:
Orally once daily after the evening meal
●: Gabapentin enacarbil tablets 300 mg. ○: Placebo matching gabapentin enacarbil tablets.
Treatment group
Run-in 
period 
(1 week)
Treatment period 
(12 weeks)
Follow-
up period 
(1 week)
Upward 
titration period
(1 week)
(11 weeks)
Placebo group (0 mg/day)
○○
○○
○○
○○
600 mg group (600 mg/day)
(Subjects with an estimated creatinine 
clearance of ≥90 mL/min at the start of 
the run-in period)
●●
●●
600 mg group (600 mg/day)
(Subjects with an estimated creatinine 
clearance of ≥60 to < 90 mL/min at the 
start of the run-in period)
○●
●●
Comparative Drug:
Placebo matching gabapentin enacarbil tablets
Dose:
Placebo group: 0 mg/day of gabapentin enacarbil
Mode of Administration:
See the “Test Drug” section.
Concomitant Medication Restrictions or Requirements:
Excluded concomitant medications
1.
Concomitant use of the following drugs will be prohibited from 14 days before the first day of the run-
in period through the end of the study period:
Benzodiazepines (for only if used to treat RLS): clonazepam, etc.
Opioids: codeine, oxycodone, morphine, etc.
Long-acting dopamine agonists: cabergoline, etc.
2.
Concomitant use of the following drugs will be prohibited from 7 days before the first day of the 
run-in period through the end of the study period:
Dopamine agonists: pramipexole (BI-Sifrol®), talipexole, rotigotine (Neupro Patch®), ropinirole, 
etc.
Dopamine preparations: levodopa/carbidopa combined drug, etc.
Gabapentin: Gabapen®
Gabapentin enacarbil: Regnite®
Pregabalin: Lyrica®
3.
Concomitant use of the following drugs will be prohibited from the first day of the run-in period 
through the end of the study period:
Dopamine receptor inhibitors: Primperan (metoclopramide), Nauzelin (domperidone), etc.


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Central depressants (hypnotics, antianxiety drugs, antipsychotic druga, antidepressants, antimanic 
drugs, antiepileptic drugs)
Magnesium preprations*1, iron preparations*1, folic acid*1, vitamin B12 preparations*1
Other investigational products or post-marketing clinical studys
*1 These apply to prescription drugs
4.
The following drugs are prohibited for concomitant use from 7 days before a visit (day of IRLS score 
assessment) until the time of the IRLS score assessment at the visit, between the first day of the run-in 
period and the end of the study period:
Antihistamines
Duration of treatment:
See the “Test Drug” section.
Discontinuation Criteria
1.
Adverse events (AEs)

Subject experiences an AE, and further participation in the study is judged to be 
difficult.
2.
Lack of efficacy (Worsening of the target disease)

Subject has insufficient improvement with the study drug, and is judged to require 
change of treatment.

Subject has worsening of the target disease, and further participation in the study is 
judged to be difficult.
3.
Withdrawal of consent

Subject requests to withdraw from the study.
4.
Lost to follow-up

Subject changed residence or is referred to another clinic/hospital or has other 
personal reasons such as busy schedule, which prevents further participation in the 
study.

Subject does not return to the study site (or lost contact with the study site).
5.
Ineligibility (i.e., not fulfilling the inclusion criteria or meeting any of the exclusion 
criteria)

Subject is noted not to fulfill the inclusion criteria or to meet any of the exclusion 
criteria, on the basis of the results of tests or observations performed after the 
informed consent and before formal registration.
6.
Protocol deviation

Subject is found not to have met the inclusion/exclusion criteria, after formal 
registration as an eligible subject.

Subject is found to have any other major deviation from the protocol.
7.
Suicide

Subject attempted suicide, or is judged by the investigator/sub-investigator to be at 
high risk for suicide.
8.
Death

Subject died (from any cause).
9.
Pregnancy

Female subject is found to be pregnant during the study period.
10. Other

The investigator/sub-investigator judges that further study treatment is inappropriate 


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in the subject, or the Sponsor requests to discontinue study treatment in the subject 
because of safety issues.
Endpoints for Evaluation:
Efficacy Endpoints
Primary:

Change from baseline in IRLS score at the end of treatment period (Week 12)
Secondary:

Change from baseline in IRLS score at each time point

Investigator-rated Clinical Global Impression (ICGI) responder rate

Patient-rated Clinical Global Impression (PCGI) responder rate

Change from baseline in Pittsburgh Sleep Quality Index

Change from baseline in Athens Insomnia Scale

Change from baseline in RLS Pain score

Change from baseline in EQ-5D-5L
Safety endpoints

Vital signs

Adverse events

Laboratory tests

Body weight

Epworth Sleepiness Scale
Statistical Methods:
Sample size justification:
On the basis of Japanese phase II/III study [CL-0003] results, the difference between treatment groups in 
the primary endpoint of this study, i.e., the change from baseline in IRLS score at the end of treatment 
period (Week 12), was assumed to be −2.56, with a standard deviation of 8.000 in both groups. Under
these assumptions, to detect a statistically significant difference between gabapentin enacarbil and placebo 
using a 2-sample t-test with a two-sided significance level of 0.05 and a power of 80%, 155 subjects per 
group would be required. Assuming the discontinuation rate during the treatment period was
approximately 15.0% in each group, the sample size has been set to 180 per group.


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Efficacy:
The primary analysis set will be FAS (which will consist of all subjects who received the study drug for the 
reatment period and were evaluated for at least one efficacy endpoint during the treatment period).
< Anlaysis of the primary efficacy endpoint >
The primary efficacy endpoint is the change from baseline in IRLS score at the end of treatment period.
Using a repeated measures analysis of variance model having the following average structure, the adjusted 
mean in each treatment group and its difference (gabapentin enacarbil group − placebo group) at the end of 
treatment period (Week 12) will be calculated, with comparison between the placebo group and the 
gabapentin enacarbil group:
Change in IRLS score at each time point
= IRLS score at baseline + Age category*1) + Estimated creatinine clearance category *2) + Treatment group + 
Time point + Treatment group × Time point
*1)Age category: < 50 years and ≥50 years
*2)Estimated creatinine clearance category: ≥60 to < 90 mL/min and ≥90 mL/min
Compound symmetry will be used as the covariance structure for repeated measures of the response 
variable. A two-sided significance level of 0.05 will be used for statistical tests.
Pharmacokinetics:
No pharmacokinetic evaluation will be performed.
Pharmacodynamics:
No pharmacodynamic evaluation will be performed.
Safety:
Using safety analysis set, the following analyses will be performed by treatment group:

Adverse events
The frequency of AEs will be tabulated. In addition, AEs will be summarized by System Organ Class 
(SOC) and Preferred Term (PT) of the the Medical Dictionary for Regulatory Activities (MedDRA).

Vital signs, laboratory test values, body weight, and Epworth Sleepiness Scale
The measured value and its change from baseline at each time point will be summarized using descriptive 
statistics. The frequency will be tabulated as needed.
Interim analysis:
Not applicable.


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V
FLOW CHART AND SCHEDULE OF ASSESSMENTS
Flow Chart
< Gabapentin enacarbil 600 mg group >
Estimated creatinine clearance at 
the start of the run-in period: 
≥90 mL/min
Estimated creatinine clearance at 
the start of the run-in period: 
≥60 to < 90 mL/min
Treatment period (12 weeks) 
(double-blind)
Gabapentin enacarbil
300 mg 2 tablets
Treatment period (upward 
titration period, 1 week)
(double-blind)
Gabapentin enacarbil
300 mg 1 tablet
+
Placebo 1 tablet
↓
Treatment period (11 weeks) 
(double-blind)
Gabapentin enacarbil 
300 mg 2 tablets
< Placebo group >
Treatment period (12 weeks) 
(double-blind)
Placebo 2 tablets
Formal registration
Provisional registration
Run-in period (1 week) (single-blind)
Placebo 2 tablets
Assessment against inclusion/exclusion
criteria (Formal registration)
Assessment against inclusion/exclusion criteria 
(Provisional registration)
Washout period*
Informed consent
Follow-up period (1 week)** (single-blind)
Placebo 2 tablets


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*
Subjects using the following drugs before the start of the run-in period will require the specified washout 
period:
1. Dopamine agonists, dopamine preparations, gabapentin, pregabalin: ≥7 days
2. Opioids, benzodiazepines (for only if used to treat RLS), long-acting dopamine agonists: ≥14 days
** For the subjects discontinued during the treatment period, the tests/observations required at discontinuation 
will be performed and then post-treatment follow-up will be performed as far as possible, but this does not 
require the use of placebo during the follow-up period.
< Start and end of the post-marketing clinical study >
The time of the start of this post-marketing clinical study is defined as the time at which 
informed consent is obtained from the first subject. The time of the end of this post-
marketing clinical study is defined as the time at which protocol-specified final assessment is 
implemented in the last subject.


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Table 1:
Schedule of Assessments
Run-in 
period
Treatment period 
Follow-up period Discontinuation*5
W-1
W0
W1
W2
W4
W6
W8
W10
W12
W13
Day of observation
−7
1
8
15
29
43
57
71
85
Last dosing of the 
study drug for the 
treatment period 
+ 8 days*4
Allowed visit 
window
−10 to −7
1
5 to 
11
12 to 
18
26 to 
32
40 to 
46
54 to
60
68 to 
74
82 to 
88
Last dosing of the 
study drug for the 
treatment period
+ 5 to 11 days*4
Visit











Informed consent 

Subject 
characteristics

Assessment against 
inclusion/
exclusion criteria


Patient registration

Provisional

Formal

Discontinuation
Prescription of the 
study drug


*3






Compliance status










Concomitant 
medication 
monitoring











IRLS score











ICGI







PCGI







Pittsburgh Sleep 
Quality Index





Athens Insomnia 
Scale 





EQ-5D-5L





RLS Pain score 











Epworth Sleepiness 
Scale










Laboratory tests







Thyroid function 
tests
(TSH, Free T4)



HbA1c

Ferritin

Estimated creatinine 
clearance

Pregnancy test*1



Height

Body weight






Vital signs










Adverse event 
monitoring*2


*3








Central measurements


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*1 Not required in men, postmenopausal women (no menstruation for at least 1 year), or other women with a 
history of hysterectomy, bilateral oophorectomy, etc. in whom a possibility of pregnancy is clearly excluded.
*2 A medical interview should determine any occurrence of eye disorders such as blurred vision or 
accommodation disorder.
*3 In subjects with an estimated creatinine clearance of ≥60 to < 90 mL/min at the start of the run-in period 
randomized to the gabapentin enacarbil group, in whom the dose is titrated from 300 mg to 600 mg, any 
occurrence of AEs should be carefully assessed and the subject’s condition should be adequately observed, 
based on which whether the subject can continue with the study should be carefully determined.
*4 Follow-up observation will occur on the day of “last dosing of the study drug for the treatment period +8 days,” 
which will be Day 92 in subjects who take the study drug for the treatment period up to Day 84 per protocol.
*5 For the subjects discontinued during the run-in period, the compliance status and any AEs will be investigated.
For the subjects discontinued during the treatment period, the tests/observations required at discontinuation 
will be performed, and then post-treatment follow-up (i.e., the Week 13 procedure) will be performed as far 
as possible, but this does not require the use of placebo during the follow-up period.
For the subjects discontinued during the follow-up period, the Week 13 procedure will be performed as the 
tests/observations at discontinuation.


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1
INTRODUCTION
1.1
Background
Restless legs syndrome (RLS) is believed to be caused by a central nervous system disorder, 
and manifests as an overwhelming urge to move the legs, usually due to uncomfortable 
sensations in the limbs (primarily in the legs). Associated symptoms include unusual 
sensations that can vary among patients, such as periodic limb movements or involuntary 
movements during sleep, hot flashes, or pain.  Because of nocturnal worsening of the urge to 
move the legs and uncomfortable unusual sensations, with resultant disturbance of sleep 
initiation and maintenance, many patients complain of chronic fatigue or insomnia. RLS is 
thus classified as a sleep abnormality in the International Classification of Sleep Disorders, 
established in 1990 mainly by the American Sleep Disorders Association.  Also in Japan, RLS 
is handled as a sleep disorder in the Guidelines for Measures and Treatment for Sleep 
Disorders, established in 2002.
The prevalence of RLS in the U.S. and Europe, where RLS is a common sensorimotor 
disorder, has been reported to be 5.5%–11.6% of the population [Rinaldi et al., 2016].  In 
Japan, the reported prevalence of RLS is 1.0%–4.0%, which is lower than that in the Western 
countries and similar to that in other Asian countries [Nomura et al., 2012].  Despite 
increasing recognition of this disease year by year owing to public enlightenment through 
media such as television and newspapers, the proportion of patients who visited medical 
institutions and are treated remains limited.
In the Treatment Algorithm for RLS published in 2004 by the Restless Legs Syndrome 
Foundation in the U.S., RLS was classified into intermittent, daily, and refractory types, with 
recommendations on pharmacological therapies appropriate for the symptoms and conditions 
of each type [Silber et al., 2004].  In the 2013 update version of the algorithm, non-
pharmacologic approaches to prevent exacerbation were introduced, while treatment with a 
non-ergot dopamine agonist or a calcium channel α2δ receptor ligand is recommended for 
daily RLS [Rinaldi et al., 2016; Silber et al., 2013].
Gabapentin is an α2δ receptor ligand created by Pfizer, Inc. in the U.S.  In Japan, gabapentin 
was approved in July 2006 for marketing with the indication of “adjunctive therapy for the 
treatment of partial seizures with and without secondary generalization in patients with 
epilepsy that did not sufficiently respond to other antiepileptic agents.” While various reports 
described the pharmacokinetics of gabapentin, marked variability in absorption following oral 
administration is well known [Gidal et al., 2000; Boyd et al., 1999; Gidal et al., 1998; 
Beydoun et al., 1995].  Another known drawback of gabapentin is that, despite an established 
dose-dependent effect with oral administration, the drug absorption is saturated around the 
clinical dose because of saturation of transporters responsible for the absorption, and thus 
some patients do not have expected clinical response even with a dose increase.  On the other 
hand, off-label use of gabapentin for RLS in overseas clinical studies demonstrated 
therapeutic effects [Garcia-Borreguero et al., 2002; Happe et al., 2001; Thorp et al., 2001; 
Adler, 1997; Mellick et al., 1996].  Gabapentin is positioned as one of the first-line agents 


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along with dopamine agonists in the RLS Treatment Algorithm as stated above [Rinaldi et al., 
2016; Silber et al., 2013].
Gabapentin enacarbil is a new prodrug of gabapentin with improved absorption, created by 
XenoPort, Inc. in the U.S. to overcome the pharmacokinetic drawbacks of gabapentin.  
Gabapentin enacarbil is designed to be stable in the gastrointestinal tract, actively absorbed by 
the high-capacity transport mechanisms present throughout the intestine, and rapidly 
converted to gabapentin in the body by hydrolysis.  The blood concentrations of gabapentin 
following the oral administration of gabapentin enacarbil have been demonstrated to be dose-
dependent.  In summary of the above, gabapentin enacarbil, a prodrug of gabapentin, has 
improved pharmacokinetics and thus is expected to exert stable clinical efficacy, and is 
currently positioned as one of the first-line agents in the RLS treatment algorithm [Rinaldi et 
al., 2016; Silber et al., 2013].
In Japan, the new drug approval application for gabapentin enacarbil was filed in 19 
November 2009.  Subsequently, on 02 December 2011, the First Committee on Drugs 
concluded that Regnite Tablets 300 mg may be approved (Dosage and Administration: The 
usual adult dose for oral use is 600 mg as gabapentin enacarbil once daily after dinner).  
However, the efficacy of gabapentin enacarbil 600 mg was not verified by the primary 
analysis of the Japanese phase II/III study [CL-0003], and “implementation of a clinical study 
to verify the efficacy of gabapentin enacarbil 600 mg” was included in the advice based on 
the deliberation results of the First Committee on Drugs.  Thus, this post-marketing clinical 
study has been planned to verify the efficacy of gabapentin enacarbil 600 mg.
1.2
Nonclinical and Clinical Data
1.2.1
Nonclinical Data
Gabapentin enacarbil is a prodrug of gabapentin, and is converted to gabapentin in the body 
rapidly after absorption following oral administration.  Although no detailed mechanism of 
the action of gabapentin in the treatment of RLS has been elucidated, a suggested contributing 
mechanism is that gabapentin binds to the α2δ subunit of voltage-gated calcium channels 
[Marais et al., 2001], thereby preventing presynaptic influx of calcium ions, which results in a 
reduction in the release of excitatory neurotransmitters [Fink et al., 2000].
There have been no established animal models appropriately reflecting the disease condition 
of RLS, and thus no pharmacological studies to support the efficacy of gabapentin enacarbil 
have been conducted.  However, since gabapentin enacarbil is rapidly hydrolyzed to 
gabapentin in the body, the maximum blood concentration of the unchanged drug in humans 
is very low, compared to that of gabapentin.  In addition, given that gabapentin enacarbil does 
not bind to the α2δ subunit of voltage-gated calcium channels, unlike gabapentin, and has very 
low affinity for dopamine and other receptors, ion channels, and transporters, the therapeutic 
efficacy of gabapentin enacarbil is exerted based on gabapentin produced in the living body
[Kaneko, 2012].
Gabapentin has been reported to improve excessive signal transmission by the following 
mechanisms [Kaneko, 2012]:


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1.
It binds to the α2δ subunit of voltage-gated calcium channels in the excitatory nerve 
ending, and suppresses the release of excitatory neurotransmitters (e.g., glutamate). 
2.
It increases the amount of GABA in the brain and activates GABA transporters, thereby 
promoting intracellular uptake of GABA, leading to activation of GABA neurons.
1.2.2
Clinical Data
1) Japanese phase II/III study [CL-0003]
This was a placebo-controlled, randomized, double-blind, parallel-group, comparative study 
to evaluate the efficacy, safety, and pharmacokinetics of gabapentin enacarbil in Japanese 
patients (target sample size, 400 patients; 100 patients per group) with RLS diagnosed 
according to the diagnostic criteria established by the International RLS Study Group.
As for the dosage regimen, during the run-in period placebo was to be administered in a 
single-blind manner orally for 1 week, and during the treatment period gabapentin enacarbil 
600, 900, 1200 mg or placebo was to be administered orally after evening meals.  In the 
gabapentin enacarbil group, the starting dose was 600 mg, and 3 days later the dose was 
increased to 600, 900 or 1200 mg (or unchanged in the 600 mg group), with the duration of 
treatment set to 12 weeks.
All of the 469 treated subjects (116 subjects in the placebo group, 120 subjects in the 600 mg 
group, 119 subjects in the 900 mg group, 114 subjects in the 1200 mg group) were included in 
the safety analysis set.  Of these, after 1 subject with missing efficacy endpoint data was 
excluded, the remaining 468 subjects (116 subjects in the placebo group, 120 subjects in the 
600 mg group, 119 subjects in the 900 mg group, 113 subjects in the 1200 mg group) were 
included in the FAS and analyzed for efficacy.
The change from baseline in IRLS score [International Restless Legs Syndrome Study Group, 
2003] at final evaluation in the FAS, which was the primary endpoint of the study, is shown in 
Table 2.  Compared with the placebo group, the 1200 mg group showed a statistically 
significant difference (P = 0.011, Williams’ multiple comparison test).  On the other hand, the 
900 mg group and the 600 mg group did not show superiority to the placebo group.


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Table 2:
Change in IRLS score at final observation in the treatment period: FAS
Variable
Treatment 
group
N
Mean Standard 
deviation 
Gabapentin 
enacarbil 
group-
Placebo 
group
95% confidence 
interval for 
Gabapentin
enacarbil group-
Placebo group
Statistical 
test†
IRLS score
Placebo 
116
−8.96
7.286
-
-
-
600 mg
120
−11.10
7.921
−2.14
−4.097 to −0.189
-‡
900 mg
119
−10.28
7.750
−1.32
−3.255 to 0.614
P = 0.052
1200 mg
113
−11.38
8.297
−2.42
−4.455 to −0.392
P = 0.011
†Williams’ multiple comparison test (lower limit) [significance level: one-sided, 0.025]
‡ Not applicable for Williams’ multiple comparison test
Table 3 summarizes the Investigator-rated Clinical Global Impression (ICGI) and Patient-
rated Clinical Global Impression (PCGI) results at final observation in the treatment period 
from baseline.  Subjects who were “Very much improved” or “Much improved” were defined 
as “Responders,” and others were defined as “Non-responders.” The proportion of responders 
was defined as the responder rate.
The ICGI responder rate at final observation in the treatment period was 44.8% in the placebo 
group, 65.8% in the 600 mg group, 52.9% in the 900 mg group, and 62.8% in the 1200 mg 
group, showing superiority of all gabapentin enacarbil groups to the placebo group (P < 0.001 
for the 600 mg group, P = 0.014 for the 900 mg group, P = 0.003 for the 1200 mg group).  In 
addition, the PCGI responder rate at final observation in the treatment period was 44.0% in 
the placebo group, 65.8% in the 600 mg group, 52.1% in the 900 mg group, and 61.9% in the 
1200 mg group, showing superiority of all gabapentin enacarbil groups to the placebo group 
(P < 0.001 for the 600 mg group, P = 0.012 for the 900 mg group, P = 0.003 for the 1200 mg 
group).
Table 3:
ICGI and PCGI at final observation in the treatment period: FAS
Variable Treatment 
group
N
Responders
Response 
rate
95% 
confidence 
interval for the 
response rate
Difference in the responder rate
Statistical 
test†
Gabapentin 
enacarbil 
group-
Placebo 
group
95% confidence 
interval for 
Gabapentin 
Enacarbil group-
Placebo group
ICGI
Placebo 116
52
44.8%
35.59 to 54.34
-
-
-
600 mg
120
79
65.8%
56.62 to 74.24
21.01
8.60 to 33.41
P < 0.001
900 mg
119
63
52.9%
43.58 to 62.15
8.11
−4.63 to 20.85
P = 0.014
1200 mg
113
71
62.8%
53.24 to 71.74
18.00
5.30 to 30.70
P = 0.003
Total
468
265
56.6%
52.00 to 61.17
-
-
-
PCGI
Placebo 116
51
44.0%
34.76 to 53.48
-
-
-
600 mg
120
79
65.8%
56.62 to 74.24
21.87
9.47 to 34.26
P < 0.001
900 mg
119
62
52.1%
42.75 to 61.34
8.14
−4.60 to 20.87
P = 0.012
1200 mg
113
70
61.9%
52.33 to 70.92
17.98
5.26 to 30.70
P = 0.003
Total
468
262
56.0%
51.35 to 60.54
-
-
-
†Shirley-Williams’ multiple comparison test (upper limit) [significance level: one-sided, 0.025]


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AEs (including abnormal laboratory test values) were reported in 71.6% (83/116 subjects) in 
the placebo group, 76.7% (92/120 subjects) in the 600 mg group, 84.0% (100/119 subjects) in 
the 900 mg group, and 85.1% (97/114 subjects) in the 1200 mg group.  There were no deaths 
or other serious adverse events (SAEs).
AEs (including abnormal laboratory test values) for which a causal relationship to the study 
drug was not ruled out were reported in 50.9% (59/116 subjects) in the placebo group, 56.7% 
(68/120 subjects) in the 600 mg group, 69.7% (83/119 subjects) in the 900 mg group, and 
72.8% (83/114 subjects) in the 1200 mg group.  Common events included dizziness (8 
subjects in the placebo group, 30 subjects in the 600 mg group, 30 subjects in the 900 mg 
group, and 33 subjects in the 1200 mg group), somnolence (19 subjects in the placebo group, 
23 subjects in the 600 mg group, 32 subjects in the 900 mg group, and 37 subjects in the 
1200 mg group), headache (6 subjects in the placebo group, 5 subjects in the 600 mg group, 9 
subjects in the 900 mg group, and 5 subjects in the 1200 mg group), nausea (0 subjects in the 
placebo group, 6 subjects in the 600 mg group, 5 subjects in the 900 mg group, and 4 subjects 
in the 1200 mg group).
Vital signs (blood pressure and pulse rate) showed no clinically relevant changes. 
As electrocardiogram (ECG)-related AEs, aortic dilatation and arrhythmia (each in 1 subject) 
were reported in 2 subjects in the 600 mg group.
In summary of the above, the study demonstrated the superiority of gabapentin enacarbil 
1200 mg to placebo in Japanese patients with RLS, and did not raise any major concerns 
about the safety of gabapentin enacarbil up to 1200 mg.
2) Overseas phase III study [XP052]
This was a placebo-controlled, randomized, double-blind, parallel-group, comparative study 
to evaluate the efficacy and safety of gabapentin enacarbil in non-Japanese patients (target 
sample size 210 subjects; 105 subjects per group) with RLS diagnosed according to the 
diagnostic criteria established by the International RLS Study Group.
As for the dosage regimen, gabapentin enacarbil 1200 mg or placebo was administered orally 
once daily at 17:00 with a meal (in the gabapentin enacarbil group, the starting dose was 
600 mg, and 3 days later the dose was increased to 1200 mg), with the duration of treatment 
set to 12 weeks.
All of the 221 treated subjects (108 subjects in the placebo group, 113 subjects in the 
gabapentin enacarbil group) were included in the safety analysis set.  Of these, after 1 subject 
without efficacy evaluation was excluded, the remaining 220 subjects (108 subjects in the 
placebo group, 112 subjects in the gabapentin enacarbil group) were included in the MITT 
analysis set and analyzed for efficacy.


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The change from baseline in IRLS score at final evaluation in the MITT analysis set, which 
was a primary endpoint of the study, is shown in Table 4.  A paired comparison between the 
placebo group and the gabapentin enacarbil group showed a statistically significant difference 
(P = 0.0003; analysis of covariance adjusted for pooled study site and baseline).
Table 4:
Change from baseline in IRLS score at Week 12 using LOCF (MITT 
analysis set)
Placebo
XP13512*
Mean difference
(XP13512 group − placebo 
group)
95% CI
n = 108
n = 112
Mean (SD)
Mean (SD)
Baseline
22.6 (4.91)
23.1 (4.86)
Week 12
13.8 (7.47)
9.8 (8.70)
Change from 
baseline
−8.8 (8.63)
−13.2 (9.21)
−4.0
−6.2, −1.9
*Gabapentin enacarbil
The ICGI responder rate at final evaluation, which was another primary endpoint of the study, 
was 38.9% (42/108 subjects) in the placebo group and 76.1% (83/109 subjects) in the 
gabapentin enacarbil group with an odds ratio [95% confidence interval] of 5.1 [2.8, 9.2], 
showing a statistically significant difference between the placebo group and the gabapentin 
enacarbil group (P < 0.0001; logistic regression analysis model with treatment group and 
pooled study site as explanatory variables).
AEs (including abnormal laboratory test values) were reported in 74.1% (80/108 subjects) in 
the placebo group and 82.3% (93/113 subjects) in the gabapentin enacarbil group.  There were 
no deaths.  An SAE other than deaths was reported in 1 subject in the placebo group 
(appendicitis), for which a causal relationship to the study drug was ruled out.
AEs for which a causal relationship to the study drug was not ruled out were reported in 
40.7% (44/108 subjects) in the placebo group and 70.8% (80/113 subjects) in the gabapentin 
enacarbil group.  Common events included somnolence (8 subjects in the placebo group, 29 
subjects in the gabapentin enacarbil group), dizziness (3 subjects in the placebo group, 20 
subjects in the gabapentin enacarbil group), headache (8 subjects in the placebo group, 14 
subjects in the gabapentin enacarbil group), fatigue (2 subjects in the placebo group, 11 
subjects in the gabapentin enacarbil group), and nausea (2 subjects in the placebo group, 9 
subjects in the gabapentin enacarbil group).
As an AE related to vital signs (blood pressure, pulse rate, respiratory rate, and body 
temperature), orthostatic hypotension was reported in 1 subject in the gabapentin enacarbil 
group.
ECG showed no clinically relevant abnormal findings.


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In summary of the above, the study demonstrated the efficacy of gabapentin enacarbil 1200 
mg for 12 weeks in non-Japanese patients with RLS, and raised no particular major concerns 
about the safety.
3) Overseas phase III study [XP053]
This was a placebo-controlled, randomized, double-blind, parallel-group, comparative study 
to evaluate the efficacy and safety of gabapentin enacarbil in non-Japanese patients (target 
sample size 315 subjects; 105 subjects per group) with RLS diagnosed according to the 
diagnostic criteria established by the International RLS Study Group.
As for the dosage regimen, gabapentin enacarbil 600 or 1200 mg or placebo was administered 
orally once daily at 17:00 with a meal (in the 1200 mg group, the starting dose was 600 mg, 
and 3 days later the dose was increased to 1200 mg), with the duration of treatment set to 12 
weeks.
All of the 322 treated subjects (96 subjects in the placebo group, 115 subjects in the 600 mg 
group, and 111 subjects in the 1200 mg group) were included in the safety analysis set.  Of 
these, after 1 subject without efficacy evaluation, the remaining 321 subjects (96 subjects in 
the placebo group, 114 subjects in the 600 mg group, and 111 subjects in the 1200 mg group) 
were included in the MITT analysis set and analyzed for efficacy.
The change from baseline in IRLS score at final evaluation in the MITT analysis set, which 
was a primary endpoint of the study, is shown in Table 5.  The gabapentin enacarbil 1200 mg 
group showed a statistically significant difference compared with the placebo group (P = 
0.0015; analysis of covariance adjusted for study site and baseline).
Table 5:
Change from baseline in IRLS score at Week 12 using LOCF
(MITT analysis set)
Placebo 
XP13512 1200 mg
Mean 
difference1)
95% CI
n = 96
n = 111
Mean
SD
Mean
SD
Baseline
23.8
4.58
23.2
5.32
Week 12
14.0
7.87
10.2
8.03
Change from 
baseline
−9.8
7.69
−13.0
9.12
−3.5
−5.6, −1.3
1) Calculated as “XP13512 1200 mg group −Placebo group”
The ICGI responder rate at final evaluation, which was another primary endpoint of the study, 
was 44.8% (43/96 subjects) in the placebo group and 77.5% (86/111 subjects) in the 1200 mg 
group with an odds ratio [95% confidence interval] of 4.3 [2.3, 7.9], showing a statistically 
significant difference between the placebo group and the gabapentin enacarbil 1200 mg group 


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(p < 0.0001; logistic regression model with treatment group and pooled study site as 
explanatory variables).
AEs (including abnormal laboratory test values) were reported in 79.2% (76/96 subjects) in 
the placebo group, 87.0% (100/115 subjects) in the 600 mg group, and 84.7% (94/111 
subjects) in the 1200 mg group.  There were no deaths.  Other SAEs were reported in 1 
subject in the placebo group (cholelithiasis) and 2 subjects in the 600 mg group (cellulitis and 
intervertebral disc protrusion, each in 1 subject), for all of which a causal relationship to the 
study drug was ruled out.
AEs (including abnormal laboratory test values) for which a causal relationship to the study 
drug was not ruled out were reported in 41.7% (40/96 subjects) in the placebo group, 54.8% 
(63/115 subjects) in the 600 mg group, and 61.3% (68/111 subjects) in the 1200 mg group.  
Common events included somnolence (2 subjects in the placebo group, 23 subjects in the 600 
mg group, and 18 subjects in the 1200 mg group), dizziness (4 subjects in the placebo group, 
11 subjects in the 600 mg group, and 26 subjects in the 1200 mg group), and headache (4 
subjects in the placebo group, 11 subjects in the 600 mg group, and 12 subjects in the 1200 
mg group).
AEs related to vital signs (blood pressure, pulse rate, body temperature, and respiratory rate) 
were reported in 3 subjects in the placebo group (hypertension); 1 subject in the 600 mg group 
(hypertension); and 3 subjects in the 1200 mg group (hypotension, blood pressure increased, 
and hypertension, each in 1 subject).
As an ECG-related AE, bundle branch block was reported in 1 subject in the 1200 mg group. 
In summary of the above, the study demonstrated the efficacy of gabapentin enacarbil 
1200 mg given repeatedly for 12 weeks in non-Japanese patients with RLS, and raised no 
particular major concerns about the safety.
4) Overseas phase IV study [RXP114025]
This was a placebo-controlled, randomized, double-blind, parallel-group, comparative study 
to evaluate the efficacy and safety of gabapentin enacarbil in non-Japanese patients (target 
sample size 428 subjects; 107 subjects per group) with RLS diagnosed according to the 
diagnostic criteria established by the International RLS Study Group.
As for the dosage regimen, gabapentin enacarbil 300, 450, or 600 mg or placebo was 
administered orally once daily at 17:00 with a meal, with the duration of treatment set to 12 
weeks.
Of the total of 501 subjects (125 subjects in the placebo group, 125 subjects in the 300 mg 
group, 125 subjects in the 450 mg group, and 126 subjects in the 600 mg group), the safety 
analysis set consisted of 487 subjects (121 subjects in the placebo group, 121 subjects in the 
300 mg group, 123 subjects in the 450 mg group, and 122 subjects in the 600 mg group).  The 


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efficacy analysis set consisted of 459 subjects (117 subjects in the placebo group, 111 subjects 
in the 300 mg group, 112 subjects in the 450 mg group, and 119 subjects in the 600 mg group).
The change from baseline in IRLS score at final evaluation in the MITT analysis set, which 
was a primary endpoint of the study, is shown in Table 6.  The gabapentin enacarbil 450 mg 
and 600 mg groups showed statistically significant differences compared with the placebo 
group (P = 0.014 and P = 0.014, respectively; analysis of covariance adjusted for study site 
and baseline).  The gabapentin enacarbil 300 mg group showed no statistically significant 
difference compared with the placebo group.
Table 6:
Change from baseline in IRLS score at Week 12 using LOCF
(MITT analysis set)
Placebo
GEn1) 300 mg
GEn 450 mg
GEn 600 mg
n = 117
n = 111
n = 112
n = 119
Adjusted mean (SE)
−9.93 (0.753)
−11.48 (0.767)
−12.54 (0.764)
−12.50 (0.745)
Mean difference 2)
−1.55
−2.61
−2.57
95% Cl
(−3.63, 0.53)
(−4.68, −0.54)
(−4.62, −0.52)
P-value†
0.144
0.014
0.014
1) Gabapentin enacarbil
2) Calculated as “GEn group −Placebo group”
† Analysis of covariance adjusted for study site and baseline
AEs were reported in 55% (66/121 subjects) in the placebo group, 53% (64/121 subjects) in 
the 300 mg group, 59% (73/123 subjects) in the 450 mg group, and 56% (68/122 subjects) in 
the 600 mg group.  SAEs were reported in 1 subject in the placebo group, 2 subjects in the 
300 mg group, and 1 subject in the 600 mg group, but there were no deaths.
Common AEs included somnolence (8 subjects in the placebo group, 12 subjects in the 
300 mg group, 20 subjects in the 450 mg group, and 13 subjects in the 600 mg group), 
headache (12 subjects in the placebo group, 10 subjects in the 300 mg group, 9 subjects in the 
450 mg group, and 11 subjects in the 600 mg group), and dizziness (5 subjects in the placebo 
group, 5 subjects in the 300 mg group, 8 subjects in the 450 mg group, and 15 subjects in the 
600 mg group).  In summary of the above, the study demonstrated the efficacy, safety, and 
tolerability of gabapentin enacarbil 600 mg.  The clinical effectiveness of gabapentin 
enacarbil 450 mg did not appear to exceed that of gabapentin enacarbil 600 mg.
5) Japanese post-marketing study in RLS patients with moderate renal impairment [CL-0103]
This was a multicenter, open-label, uncontrolled study (using a centralized registration 
method) in patients (target sample size, 50 subjects) who had moderate to severe idiopathic 
RLS diagnosed according to the diagnostic criteria established by the International RLS Study 
Group and who had moderate renal impairment, conducted to evaluate the safety, efficacy, 
and pharmacokinetics of gabapentin enacarbil and to determine the dosage regimen for 


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patients with renal impairment.  The study consisted of a 1-week run-in period for 
observation, a 4-week treatment period for oral administration of gabapentin enacarbil tablets 
300 mg once daily after the evening meal, and a 1-week follow-up period for post-treatment 
observation.
Although the planned sample size was not reached, the study was terminated at the planned 
end time of the study period, at which time informed consent had been obtained from 40 
subjects.  Of these 40 subjects who provided consent, 21 subjects were not enrolled for 
reasons such as not fulfilling the inclusion criteria or meeting any exclusion criteria, and the 
remaining 19 subjects were treated with gabapentin enacarbil.  Of these 19 subjects treated 
with gabapentin enacarbil, 17 subjects completed the study, while 2 subjects were 
discontinued from the study.  The reason for discontinuation was AE in 1 subject and 
subject’s request in the other subject.
The change in IRLS score at each point of evaluation in the FAS, which was the primary 
endpoint of the study, is shown in Table 7.  The mean (standard deviation) change in IRLS 
score at the end of treatment period was −9.1 (5.7), showing improvement in IRLS score.  In 
terms of the secondary endpoints, the ICGI and PCGI responder rates increased over time, 
and at the responder rate at the end of treatment period, the ICGI responder rate was 68.4% 
and the PCGI responder rate was 78.9%.
In moderate to severe idiopathic RLS patients with moderate renal impairment, gabapentin 
enacarbil once daily 300 mg demonstrated symptomatic improvement of RLS.
Table 7:
Change in IRLS score at each time point of evaluation: FAS
Week 1
Week 2
Week 4
End of 
treatment 
period
Follow-up 
period
n
19
18
18
19
19
Mean
−4.4
−8.1
−9.4
−9.1
−7.4
standard 
deviation
5.8
5.9
5.6
5.7
7.1
Minimum
−14
−22
−22
−22
−24
Q1
−9.0
−11.0
−12.0
−12.0
−11.0
Median
−4.0
−6.5
−9.0
−9.0
−8.0
Q3
−2.0
−5.0
−7.0
−4.0
0.0
Maximum
8
0
-1
−1
3
The incidence of AEs in this study was 63.2% (12/19 subjects, 19 events).  The incidence of 
AEs for which a causal relationship to the study drug was not ruled out was 36.8% (7/19 
subjects, 11 events).  There were no deaths or SAEs in this study.  AEs leading to 
discontinuation of study treatment were reported in 2 subjects, of which a causal relationship 
to the study drug was not ruled out in 1 subject.  The event severity was moderate for 1 event 
of rash in 1 subject, and all other 18 AEs were mild.


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Relatively common AEs with an incidence of ≥10% were somnolence (15.8%, 3/19 subjects) 
and blood creatine phosphokinase increased (10.5%, 2/19 subjects).  The only relatively 
common AE for which a causal relationship to the study drug was not ruled out was 
somnolence (15.8%, 3/19 subjects).
There were no deaths or SAEs.  Laboratory test values showed no clinically relevant changes.  
In summary of the above, the safety and tolerability of gabapentin enacarbil 300 mg once 
daily in moderate to severe idiopathic RLS patients with moderate renal impairment raised no 
major concerns.
1.3
Summary of Key Safety Information for the Study Drug
Refer to the latest package insert for gabapentin enacarbil.
1.4
Risk Benefit Assessment
1.4.1
Risk Assessment
Gabapentin enacarbil is rapidly metabolized to gabapentin in the body following oral 
administration, and is excreted mostly as gabapentin renally into urine.  Renally impaired 
patients may have delayed excretion of gabapentin.  Severe renal impairment is a 
contraindication to gabapentin enacarbil.  Administration of gabapentin enacarbil may cause 
increased body weight.  Sleepiness, decreased attention, decreased mental concentration, 
decreased motor response, etc. may occur.  Eye disorders such as blurred vision or 
accommodation disorder may occur.
In the Japanese phase II/III comparative study [CL-0003], adverse drug reactions, including 
abnormal laboratory test values, were reported in 68 (56.7%) of 120 subjects evaluated for 
safety.  Common adverse drug reactions were dizziness (30 subjects, 25.0%), somnolence (23 
subjects, 19.2%), and nausea (6 subjects, 5.0%).
In terms of the severity of AEs in Japanese clinical studies, the only severe AE was 
lymphoma in 1 subject who took 1200 mg in the Japanese long-term study [CL-0005].  For 
this AE of lymphoma, a causal relationship to the study drug was not ruled out, and the 
patient died of lymphoma.  The incidence of moderate AEs in the placebo group, 600 mg 
group, 900 mg group, and 1200 mg group of the Japanese phase II/III comparative study [CL-
0003] was 6.0% (7/116 subjects), 13.3% (16/120 subjects), 6.7% (8/119 subjects), and 14.0% 
(16/114 subjects), respectively, and that in the Japanese long-term study [CL-0005] was 
28.0% (51/182 subjects).  The incidence was slightly higher in the 600 mg and 1200 mg 
groups than in the placebo group in the Japanese phase II/III comparative study [CL-0003].  
Moderate AEs reported in 2 or more subjects given gabapentin enacarbil were dizziness, 
somnolence, blood CPK increased, nausea, headache, AST increased, ALT increased, and 
back pain.  Of these, dizziness and somnolence were reported in all gabapentin enacarbil 
groups.  In addition, dizziness, somnolence, nausea, headache, and blood CPK increased were 
more common in the Japanese long-term study [CL-0005] than in the Japanese phase II/III 
comparative study [CL-0003].


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A rat carcinogenicity study (2-year forced oral administration) showed carcinogenicity.  At 
5000 mg/kg/day (i.e., 90 times the human systemic exposure at 600 mg of gabapentin 
enacarbil as the clinical daily dose), occurrence of pancreatic acinar cell tumors (adenoma or 
adenocarcinoma) increased in both males and females, with a higher number of tumors in 
males than in females.  At 2000 mg/kg/day (i.e., 40 times the human systemic exposure at 600 
mg of gabapentin enacarbil as the clinical daily dose), males had increased pancreatic acinar 
cell tumors.  At 500 mg/kg/day (i.e., 10 times the human systemic exposure at 600 mg of 
gabapentin enacarbil as the clinical daily dose), no effects were observed.  In mice, no 
carcinogenicity was observed in males or females.  In clinical studies conducted to date inside 
and outside Japan, and in periodic safety reports, no cases of pancreatic tumors have been 
reported.
With gabapentin, the active metabolite of gabapentin enacarbil, acute renal failure, 
oculomucocutaneous syndrome (Stevens-Johnson syndrome), drug-induced hypersensitivity 
syndrome, hepatitis, hepatic function disorder, jaundice, rhabdomyolysis, and anaphylaxis 
have been reported as clinically significant adverse reactions.  Thus, these events can occur in 
this study as well.  Unexpected AEs may also occur.
In a review of 199 placebo-controlled overseas clinical studies of multiple antiepileptic drugs 
that included gabapentin as the active metabolite of gabapentin enacarbil in patients with 
epilepsy, psychiatric diseases, etc., the risk of suicidal ideation and suicide attempt in the 
antiepileptic medication group was approximately 2-fold higher than that in the placebo group 
(0.43% in the antiepileptic medication group and 0.24% in the placebo group), with the 
incidence higher by 1.9 per 1000 persons (95% confidence interval, 0.6-3.9) in the 
antiepileptic medication group compared with the placebo group, or by 2.4 per 1000 persons 
in a subgroup of patients with epilepsy.
1.4.2
Benefit Assessment
Oral administration of gabapentin enacarbil can improve moderate to severe idiopathic RLS 
symptoms and impaired QOL associated with RLS.
2
STUDY OBJECTIVES, DESIGN, AND ENDPOINTS
2.1
Study Objectives
- To verify the efficacy of oral gabapentin enacarbil 600 mg once daily compared with 
placebo on the basis of the change from baseline in IRLS score in patients with moderate to 
severe idiopathic restless legs syndrome (RLS), using a multicenter, randomized, double-blind, 
parallel-group, comparative design
- To evaluate the safety of gabapentin enacarbil 600 mg


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2.2
Study Design and Dose Rationale
2.2.1
Study Design
Gabapentin enacarbil 600 mg or placebo will be administered orally once daily after the 
evening meal.  Patients meeting the inclusion and exclusion criteria at provisional registration 
will receive single-blind placebo for 1 week (run-in period).  Of these, patients meeting the 
inclusion and exclusion criteria at formal registration will be randomized to receive double-
blind treatment with either gabapentin enacarbil 600 mg or placebo for 12 weeks (treatment 
period).  After the end of the 12-week treatment period, single-blind placebo will be given for 
1 week (follow-up period) for follow-up observation.
However, of the patients meeting the inclusion and exclusion criteria at formal registration, 
those with an estimated creatinine clearance of ≥60 to < 90 mL/min at the start of the run-in 
period will receive randomized double-blind treatment initially with either gabapentin 
enacarbil 300 mg or placebo for 1 week (upward titration period) followed by gabapentin 
enacarbil 600 mg or placebo for 11 weeks, totaling 12 weeks (treatment period including the 
upward titration period).
Stratified allocation will be performed with stratification factors of age (< 50 years and ≥50 
years) at the start of the run-in period and estimated creatinine clearance ( ≥60 to 
< 90 mL/min and ≥90 mL/min) at the start of the run-in period.
2.2.2
Dose Rationale
[Rationale for the dosage]
The dosage and administration stated in the Japanese package insert for Regnite Tablets is 
“The usual adult dose for oral use is 600 mg (as gabapentin enacarbil) once daily after dinner.” 
However, the efficacy of gabapentin enacarbil 600 mg was not verified by the primary 
analysis of the Japanese phase II/III study [CL-0003].  Thus, this study has been planned to 
verify the efficacy of gabapentin enacarbil 600 mg/day and also to evaluate the safety.
The mode and duration of administration have been set to once daily for 12 weeks, as in the 
Japanese phase II/III study [CL-0003].  Gabapentin enacarbil is considered to require dose 
adjustment according to renal function, because it is a renally excreted drug, and Japanese and 
overseas studies in patients with renal impairment showed prolonged elimination half-life and 
increased Cmax and AUCinf of gabapentin (active metabolite of gabapentin enacarbil) in 
plasma in association with impaired renal function.  Thus, for patients with an estimated 
creatinine clearance of ≥60 to < 90 mL/min at the start of the run-in period, a 1-week upward 
titration period for administration at the starting dose of 300 mg has been employed with 
reference to the package insert, aiming to verify the efficacy of 600 mg/day while securing the 
safety of the subjects.  A 1-week run-in period has been set to confirm the eligibility against 
the inclusion and exclusion criteria at formal registration.  A 1-week follow-up period has 
been set to check for withdrawal symptoms after the end of administration of the study drug 
in the treatment period.


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2.3
Endpoints 
2.3.1
Primary Endpoint
●
Change from baseline in IRLS score at the end of treatment period (Week 12)
[Rationale for the primary endpoint]
The IRLS is used because it is generally used for evaluation of drug efficacy for RLS.
2.3.2
Secondary Endpoints
●
Change from baseline in IRLS score at each time point
●
ICGI responder rate
●
PCGI responder rate
●
Change from baseline in Pittsburgh Sleep Quality Index [Yuriko et al., 2000; Doi et al., 
1998; Buysse et al., 1989]
●
Change from baseline in Athens Insomnia Scale [Soldatos et al., 2000]
●
Change from baseline in RLS Pain score [Jensen et al., 1986]
●
Change from baseline in EQ-5D-5L [Herdman et al., 2011]
[Rationale for the secondary endpoints]
These endpoints have been set with reference to the Japanese phase II/III study [CL-0003], for 
evaluation for the marketing approval.
The ICGI and PCGI have been employed to evaluate the clinical significance of the treatment, 
because these are the standardized tools widely used in neuropharmacological studies and are 
the parameters of overall evaluation.
The Pittsburgh Sleep Quality Index has been employed because it is a sleep parameter widely 
used in Japan.
The Athens Insomnia Scale has been employed to evaluate sleep because it is an evaluation 
tool based on the global insomnia assessment criteria issued by the Worldwide Project on 
Sleep and Health, established World Health Organization (WHO) and other organizations. 
The RLS Pain score has been employed to evaluate pain.
The EQ-5D-5L has been employed because it is a QOL assessment tool used widely also for 
health economic evaluation, etc.
2.3.3
Safety Endpoints
●
Vital signs
●
Adverse events
●
Laboratory tests
●
Body weight
●
Epworth Sleepiness Scale [Murray, 1991]


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3
STUDY POPULATION
3.1
Selection of Study Population
Patients with moderate to severe idiopathic restless legs syndrome (RLS)
Patients with RLS diagnosed according to the 2014 updated diagnostic criteria for RLS by the 
International RLS Study Group [Allen et al., 2014]; RLS will be diagnosed when all of the 
following 5 diagnostic criteria are met:
1.
An urge to move the legs usually accompanied by, or felt to be caused by, uncomfortable 
and unpleasant sensations in the legs
2.
The urge to move the legs and any accompanying unpleasant sensations begin or worsen 
during periods of rest or inactivity such as lying down or sitting
3.
The urge to move the legs and any accompanying unpleasant sensations are partially or 
totally relieved by movement, such as walking or stretching, at least as long as the 
activity continues
4.
The urge to move the legs and any accompanying unpleasant sensations during rest or 
inactivity only occur or are worse in the evening or night than during the day
5.
The occurrence of the above features is not solely accounted for as symptoms primary to 
another medical or behavioral condition (e.g., myalgia, venous stasis, leg edema, arthritis, 
leg cramps, positional discomfort, or habitual foot tapping).
In addition, the following four features support the diagnosis:
1.
Presence of periodic leg movements in sleep or at rest
2.
Reduction in discomfort with dopamine receptor agonist treatment
3.
Family history of RLS among first-degree relatives
4.
Lack of profound daytime sleepiness
[Rationale for the target disease]
To verify the efficacy and safety of gabapentin enacarbil compared with placebo in patients 
with RLS
3.2
Inclusion Criteria
Subject is eligible for the study if all of the following apply:
At provisional registration:
1.
Provided written informed consent using the informed consent form approved by the 
Institutional Review Board (IRB) prior to any study-related procedures (including 
discontinuation of excluded concomitant medications)
2.
Male or female outpatient aged between ≥20 and ≤80 years at the time of consent 


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3.
Patient with a diagnosis of RLS according to the International RLS Study Group 
diagnostic criteria for RLS (2014 update)
4.
Had RLS symptoms for ≥15 days during the month prior to the start of the run-in period, 
or if on treatment for RLS, during the month prior to the start of that treatment 
5.
Has an International Restless Legs Syndrome Rating Scale (IRLS) score of ≥15 at the 
start of the run-in period
6.
Has not taken dopamine agonists, dopamine preparations, gabapentin, gabapentin 
enacarbil, or pregabalin during at least one week before the first day of the run-in period 
7.
Has not received other treatments for RLS (opioids, benzodiazepines, long-acting 
dopamine agonists) during at least 2 weeks before the first day of the run-in period
8.
Female subject must either:
Be of nonchildbearing potential:
●
Postmenopausal (defined as no menstruation for at least 1 year) at the start of the 
run-in period, or
●
Documented surgically sterile
Or, if of childbearing potential,
●
Agree not to become pregnant during the study and for 28 days after the final study 
drug administration,
●
And have a negative pregnancy test at the start of the run-in period
●
And if heterosexually active, agree to consistently use two (one or both of which 
must be the barrier method) of the established forms of birth control* specified 
below, during the study period and for 28 days after the final study drug 
administration
*Established forms of birth control include:
-
Correct usage of approved oral contraceptives
-
Intrauterine device (IUD), intrauterine system (IUS), and other intrauterine 
instruments
-
Barrier method with male condoms or female condoms
-
Rhythm method (Knaus-Ogino method)
9.
Female subject must agree not to breastfeed throughout the study period and for 28 days 
after the final study drug administration.
10. Female subject must not donate ova throughout the study period and for 28 days after the 
final study drug administration.
11. Agrees not to participate in another interventional study during the study period.
12. Has a body mass index (BMI) range of 18.5 to < 30 (BMI = Body weight (kg)/Height 
(m)2).
At formal registration:
13. Has an IRLS score of ≥15 at the start of the treatment period


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14. Has RLS symptoms (evenings and nights) for at least 4 days during the 1-week run-in 
period
15. Has an estimated creatinine clearance value* of ≥60 mL/min as calculated using the 
Cockcroft-Gault equation at the start of the run-in period.
*For calculation of the estimated creatinine clearance, refer to Section 5.7 Other 
Measurements, Assessments or Methods.
Waivers to the inclusion criteria will NOT be allowed.
3.3
Exclusion Criteria
Subject will be excluded from participation if any of the following apply:
At provisional registration:
1.
A sleep disorder (e.g., sleep apnea) that may affect the assessment of RLS
2.
A history of RLS symptom augmentation or post-therapy rebound with previous 
dopamine agonist treatment
3.
Neurologic disease or movement disorder (e.g., neurologic disease, Parkinson’s disease, 
multiple sclerosis, dyskinesia, dystonia, rheumatoid arthritis)
4.
Poorly controlled diabetes mellitus (i.e., HbA1c > 7.5% [NGSP-value] on a test during 
the past 6 months), iron deficiency anemia, or current use of oral sedative-hypnotics
5.
Has a history of suicide attempt within 6 months before consent, or judged by the 
investigator/sub-investigator to be at risk for suicide
6.
Has elevated ALT or AST (based on laboratory data within the past 6 months) (For 
reference, grade ≥2 according to the “Criteria for Seriousness/Severity Grading of 
Adverse Drug Reactions,” [Notification No. 80 of the Safety Division, Pharmaceutical 
Affairs Bureau, dated June 29, 1992] will be used.)
7.
Moderate or severe depression (DSM-V)
8.
Previously had alcohol dependence or drug poisoning, or within the past year had 
substance abuse or dependence
9.
Shift worker (including night-work), professional driver, or dangerous machinery 
operator
10. Clinically significant or unstable medical conditions (e.g., current or past history of 
cancer, complication of serious cardiac disease*, hepatic disease*, renal disease*, 
hematological disease*, immunodeficiency, psychiatric disease).
*For reference, Grade 3 of the “Criteria for Seriousness/Severity Grading of Adverse 
Drug Reactions,” (Notification No. 80 of the Safety Division, Pharmaceutical Affairs 
Bureau, dated June 29, 1992) will be used.
11. History of hypersensitivity to gabapentin
12. Had previously taken pregabalin, gabapentin enacarbil, or ASP8825 (including 
GSK1838262 and XP13512) as an investigational drug


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13. Participated within 12 weeks (84 days) before the first day of the run-in period, or 
currently participating, in a clinical trial or post-marketing clinical study of another drug 
or a medical device.
14. Is employed by the Sponsor or the CRO, SMO, or study site involved in this study
15. Other subjects for whom participation in this study is judged to be inappropriate in the 
opinion of the investigator/sub-investigator
At formal registration:
16. Has a decrease in IRLS score at the start of the treatment period by 10 or more points 
from the start of the run-in period
17. Has clinically relevant abnormalities on laboratory tests* in the opinion of the 
investigator/sub-investigator
*For reference, Grade 3 of the “Criteria for Seriousness/Severity Grading of Adverse 
Drug Reactions,” (Notification No. 80 of the Safety Division, Pharmaceutical Affairs 
Bureau, dated June 29, 1992) will be used.
18. Poorly controlled diabetes mellitus (i.e., HbA1c > 7.5% [NGSP-value] on a laboratory 
test in the run-in period)
19. Serum ferritin < 12 ng/mL on a laboratory test at the start of the run-in period
20. Elevated ALT or AST on laboratory tests at the start of the run-in period (For reference, 
grade ≥2 according to the “Criteria for Seriousness/Severity Grading of Adverse Drug 
Reactions,” [Notification No. 80 of the Safety Division, Pharmaceutical Affairs Bureau, 
dated June 29, 1992] will be used.)
21. Female other than female of nonchildbearing potential judged to be pregnant based on the 
pregnancy test in the run-in period (in line with the inclusion criterion 8)
22. Subjects for whom participation in this study is judged to be inappropriate in the opinion 
of the investigator/sub-investigator
Waivers to the exclusion criteria will NOT be allowed.


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4
TREATMENT
4.1
Identification of Study Drug
4.1.1
Test Drug
The test drug (gabapentin enacarbil tablets 300 mg) to be given as a study drug during the 
treatment period is described below:
Substance code
ASP8825
Generic name
Gabapentin enacarbil
Chemical name
(1-{[({(1RS)-1-[(2-
Methylpropanoyl)oxy]ethoxy}carbonyl)amino]
methyl}cyclohexyl)acetic acid
Molecular formula and molecular 
weight
C16H27NO6 (Molecular weight: 329.39)
Strength and dosage form
Plain white tablets, each containing 300 mg of 
gabapentin enacarbil
Manufacturer
Astellas Pharma Inc.
Lot number
See the Procedures for Handling Study Drugs.
Storage conditions
Store at room temperature.
4.1.2
Comparative Drug
The comparative drug (placebo matching gabapentin enacarbil tablets) to be given as a study 
drug during the treatment period is described below:
Strength and dosage 
form
Plain white tablets not containing gabapentin enacarbil, 
indistinguishable in appearance from the gabapentin 
enacarbil tablets 300 mg
Manufacturer
Astellas Pharma Inc.
Lot number
See the Procedures for Handling Study Drugs.
Storage conditions
Store at room temperature.
4.1.3
Study drug for the run-in period and study drug for the follow-up period
The study drug to be given during the run-in period and the follow-up period is described 
below.  The study drug for the run-in period and the follow-up period is the same as the 
comparative drug to be given during the treatment period in terms of the strength and dosage 
form.


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Strength and dosage 
form
Placebo matching gabapentin enacarbil tablets: Plain white 
tablets not containing gabapentin enacarbil, 
indistinguishable in appearance from the gabapentin 
enacarbil tablets 300 mg
Manufacturer
Astellas Pharma Inc.
Lot number
See the Procedures for Handling Study Drugs.
Storage conditions
Store at room temperature.
4.2
Packaging and Labeling
All study drugs used in this study will be prepared, packaged, and labeled under the 
responsibility of qualified staff at Astellas Pharma Inc., in accordance with the standard 
operating procedures (SOPs) of Astellas Pharma Inc., Good Manufacturing Practice (GMP) 
guidelines, GCP, and applicable local laws and regulations.
1.
Packaging
The study drugs for the run-in period and the follow-up period will be packaged in bottles for 
each dose.  Each bottle will contain 2 tablets of the placebo matching gabapentin enacarbil 
tablets, together with a desiccant.  Ten bottles of the study drug for the run-in period or the 
follow-up period will be packaged in one box.
The study drugs for the treatment period (including the upward titration period) will be 
packaged in bottles for each dose.  Each bottle will contain a total of 2 tablets of either or both 
of the test drug (gabapentin enacarbil tablets 300 mg) and/or the comparative drug (placebo 
matching gabapentin enacarbil tablets), together with a desiccant.  Ten bottles of the study 
drug will be packaged in one box for prescription at Week 0 and Week 1 of the treatment 
period, and 17 bottles will be packaged in one box for prescription at the other scheduled 
visits.
The combination of the test drug and the comparative drug in each group is shown below:


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●: Gabapentin enacarbil tablets 300 mg. ○: Placebo matching gabapentin enacarbil tablets.
2.
Box labeling
Each box of the study drugs for the run-in period, treatment period, or follow-up period will 
be labeled as below.
Study drug for the run-in period and the follow-up period and the treatment period (for 
prescription at Week 0 and Week 1) (Sample):
Treatment group
Run-in 
period 
(1 week)
Treatment period 
(12 weeks)
Follow-up 
period 
(1 week)
Upward 
titration 
period
(1 week)
(11 weeks)
Placebo group
○○
○○
○○
○○
600 mg group
(Patients with an estimated 
creatinine clearance of 
≥90 mL/min at the start of the 
run-in period)
○○
●●
●●
○○
600 mg group
(Patients with an estimated 
creatinine clearance of ≥60 to 
< 90 mL/min at the start of the 
run-in period)
○○
○●
●●
○○


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Top surface
Lot No.8825-CL-0101
20 tablets (2 tablets × 10 bottles)
Gabapentin enacarbil post-marketing clinical study
Note: 
1.
This box contains the study drug to be taken once daily after the evening meal 
for 10 days.
2.
The study drug should be opened immediately before administration, and both 
of the two tablets in one bottle should be taken at a time.
3.
Be careful not to take the desiccant, contained in the bottle along with the study 
drug.
4.
Do not take any remaining portions of the study drug, but please make sure to 
bring them along with the bottles and box at the next visit.
Storage conditions: Store at room temperature.
Expiration date: Specified in the Procedures for Handling the Study Drugs.
Astellas Pharma Inc.
2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo
Front surface
Lot No. 8825-CL-0101
Gabapentin enacarbil post-marketing clinical study
For use in post-marketing clinical study only
For use in post-marketing clinical study only


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Study drug for the treatment period (for prescription at Weeks 2–10) (Sample):
Top surface
Lot No.8825-CL-0101
34 tablets (2 tablets × 17 bottles)
Gabapentin enacarbil post-marketing clinical study
Note: 
1.
This box contains the study drug to be taken once daily after the evening meal for 17 days.
2.
The study drug should be opened immediately before administration, and both of the two 
tablets in one bottle should be taken at a time.
3.
Be careful not to take the desiccant, contained in the bottle along with the study drug.
4.
Do not take any remaining portions of the study drug, but please make sure to bring them 
along with the bottles and box at the next visit.
Storage conditions: Store at room temperature.
Expiration date: Specified in the Procedures for Handling the Study Drugs.
Astellas Pharma Inc.
2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo
Front surface
Lot No. 8825-CL-0101
Gabapentin enacarbil post-marketing clinical study
For use in post-marketing clinical study only
For use in post-marketing clinical study only


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Bottle appearance:
       
For use in post-marketing 
study only
8825-CL-0101


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4.3
Study Drug Handling
The head of the study site or the study drug storage manager should take accountability of the 
study drugs as following issues:
●
The study drug storage manager should store and take accountability of the study drugs in 
accordance with the procedures for handling the study drugs written by the Sponsor.
●
The study drug storage manager should prepare and retain records of the study drug's 
receipt, the inventory at the study site, the use by each subject, and the return to the 
Sponsor or alternative disposal of unused study drugs. These records should include 
dates, quantities, lot numbers, expiration dates (if applicable), and the subject numbers.
●
The study drug storage manager should prepare and retain records that document 
adequately that the subjects were provided the doses specified by the protocol, and 
reconcile all the study drugs supplied from the Sponsor.
4.4
Blinding
4.4.1
Blinding Method
This study will compare the gabapentin enacarbil 600 mg group and the placebo group in 
terms of the efficacy and safety in a double-blind manner (except for the run-in period and the 
follow-up period, performed in a single-blind manner).  The gabapentin enacarbil tablet 300 
mg and the placebo matching gabapentin enacarbil tablet will be indistinguishable from one 
another in appearance, and packaging for each treatment group will also be indistinguishable 
in appearance.
Access to the treatment codes will be available only to the person responsible for study drug 
randomization (including his/her assistant) and designated personnel authorized to open the 
code for Suspected Unexpected Serious Adverse Reaction (SUSAR) case reporting.
4.4.2
Confirmation of the Indistinguishability of the Study Drugs
The indistinguishability in appearance of the study drugs and their packages will be checked 
by the trustees for manufacturing and packaging or storing the study drugs at the following 
time points, and will be determined by the Quality Assurance Quality Technology
department:
●
Before delivery to the study site: Checked by the trustee for manufacturing and packaging 
the study drugs
●
Between completion of the study drug administration and treatment code breaking: 
Checked by the trustee for storing the study drugs
4.4.3
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking
1)
Retention of the Treatment Codes
The person responsible for study drug randomization will prepare and separately seal one 
original and one copy of each treatment code.  The person responsible for study drug 
randomization will retain the original, while the Sponsor will retain the copy, of the treatment 


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code until the time of the treatment code breaking.  In addition, the person responsible for 
study drug randomization will prepare the treatment codes for emergency and seal them after 
randomization.  The sealed treatment codes for emergency will be retained by the person 
responsible for treatment codes for emergency.  The treatment codes for emergency will be 
able to be opened individually, and will be controlled by the person responsible for treatment 
codes for emergency via a Web-based system.
2)
Treatment Code Breaking
After completion of administration of the study drugs and after the eCRF data are locked and 
handling of the data is decided, the person responsible for study drug randomization will open 
the original assignment schedule.  The person responsible for study drug randomization will 
then submit the original assignment schedule to the Sponsor and document the submission
record.
4.4.4
Breaking the Treatment Code for Emergency
In any medical emergency where the study drug needs to be identified to be either gabapentin 
enacarbil tablets 300 mg or placebo, the investigator/sub-investigator may request the 
sponsor’s responsible person to break the treatment code for emergency for a given subject.  
The sponsor’s responsible person will judge appropriateness of breaking the treatment code 
for emergency and, if appropriate, open the code in accordance with the “Procedures for 
emergency code breaking for gabapentin enacarbil post-marketing clinical study.” The 
investigator/sub-investigator, sponsor’s responsible person, and the person responsible for 
treatment codes for emergency will communicate with each other to allow for prompt 
breaking of the treatment code for emergency.  The sub-investigator may request for breaking 
the treatment code for emergency, in principle after prior agreement of the investigator.  
However, if prior agreement of the investigator cannot be obtained, the sub-investigator will 
promptly notify the investigator of the request.
4.4.5
Breaking the Treatment Code by the Sponsor
The Sponsor may break the treatment code for subjects who experience an SUSAR, in order 
to determine whether the individual case or a group of cases requires expedited regulatory 
reporting.  Individual Emergency Codes will be provided to the limited staff who are 
responsible to break the codes for all SUSAR cases for reporting purposes.
The treatment code for each randomized subject will be provided by the person managing 
treatment codes for emergency or the Interactive Response Technology (IRT) in the event of a 
medical emergency requiring knowledge of the treatment assigned to the subject.  The time, 
date, subject number, and reason for obtaining any of these codes, and therefore breaking the 
blind, must be documented in the study file.  They must only be requested by the investigator 
or other persons designated as sub-investigators.  The need for expedited regulatory reporting 
of the SUSAR will be judged only by the designated personnel of the safety management 


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department.  No subjects or other study personnel will be made aware of the treatment given 
to any subject unless a medical emergency necessitates such disclosure.
Unblinding of the study medication should only be considered for subject safety or when 
clinical therapeutic decisions are contingent upon knowing the blinded study drug assignment.  
Any unblinding by the study staff must be reported immediately to the Sponsor and must 
include an explanation of why the study medication was unblinded.  If possible, the Sponsor 
should be contacted prior to unblinding of the study medication.
4.5
Assignment and Allocation
The person responsible for study drug randomization will prepare the treatment codes for 
randomization of the study drug for the double-blind period, and retain them under lock and 
key until the time of treatment code breaking.
Stratified allocation will be performed with stratification factors of age (< 50 years and 50 
years ) at the start of the run-in period and estimated creatinine clearance (≥60 to <
90 mL/min and ≥90 mL/min) at the start of the run-in period, to minimize imbalance in 
subject characteristics between the treatment groups to allow for proper comparison. The 
patient registration center will assign the drug numbers to the subjects in accordance with the 
patient registration procedures.
5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Study Drug and Other Medications
5.1.1
Dose, Dosage Regimen, and Administration Period
[Dose]
●
Gabapentin enacarbil 600 mg group: 600 mg/day of gabapentin enacarbil
●
Placebo group: 0 mg/day of gabapentin enacarbil
[Dosage regimen and administration period]
Two tablets will be administered orally once daily after the evening meal.


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Treatment group
Run-in 
period
(1 week)
Treatment period
(12 weeks)
Follow-up 
period
(1 week)
Upward 
titration 
period
(1 week)
(11 weeks)
Placebo group
(0 mg/day)
○○
○○
○○
○○
600 mg group (600 mg/day)
(Patients with an estimated 
creatinine clearance of ≥90 mL/min
at the start of the run-in period)
●●
●●
600 mg group (600 mg/day)
(Patients with an estimated 
creatinine clearance of ≥60 to 
< 90 mL/min at the start of the run-in 
period)
○●
●●
●: Gabapentin enacarbil tablets 300 mg. ○: Placebo matching gabapentin enacarbil tablets
5.1.2
Increase or Reduction in Dose of the Study Drug
No dose reduction will be performed in this study.  For patients in the gabapentin enacarbil 
group with an estimated creatinine clearance of ≥60 to < 90 mL/min at the start of the run-in 
period, the starting dose will be 300 mg given for 1 week, and the dose will be increased to 
600 mg with careful monitoring of the subject’s condition for possible occurrence of AEs.
5.1.3
Previous and Concomitant Treatment (Medication and Non-medication 
Therapy)
5.1.3.1 Previous Treatment (Medications and Non-medication Therapies)
Use of the following drugs before the start of the run-in period will require the specified 
washout period:
1)
Dopamine agonists, dopamine preparations, gabapentin: ≥7 days
2)
Opioids, benzodiazepines (for only if used to treat RLS), long-acting dopamine agonists: 
≥14 days
Previous medication and previous non-medication therapy are defined respectively as the 
medication and non-medication therapy used by the day before the start of the run-in period.  
In terms of all previous medications and therapies up to 28 days before the start of the run-in 
period, the data below will be collected and recorded on the eCRF. No recording on the 
eCRF will be required for drugs used to treat common cold or other transient conditions or 
past otorhinolaryngologic diseases, dental diseases, skin diseases, ophthalmologic diseases, 
etc., or for pre-treatment before endoscopy, etc.


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●
Previous medication: name of the drug, route of administration, duration of treatment, 
therapy dates, reason for use
●
Previous non-medication therapy: name of the therapy, duration of treatment, therapy 
dates, reason for use
5.1.3.2 Concomitant Treatment (Medication and Non-medication Therapy)
For all drugs and therapies used after the start of the run-in period through the end of the 
study period, the following data will be recorded on the eCRF:
●
Concomitant medication: name of the drug, route of administration, therapy duration, 
therapy dates, reason for use
●
Concomitant non-medication therapies: name of the therapy, therapy duration, therapy 
dates, reason for use
[Excluded concomitant medications/therapies, etc.]
1)
Concomitant use of the following drugs will be prohibited from 14 days before the first 
day of the run-in period through the end of the study period:
●
Benzodiazepines (for only if used to treat RLS): clonazepam, etc.
●
Opioids: codeine, oxycodone, morphine, etc.
●
Long-acting dopamine agonists: cabergoline, etc.
2)
Concomitant use of the following drugs will be prohibited from 7 days before the first 
day of the run-in period through the end of the study period:
●
Dopamine agonists: pramipexole (BI-Sifrol), talipexole, rotigotine (Neupro Patch), 
ropinirole, etc.
●
Dopamine preparations: levodopa/carbidopa combined drug, etc.
●
Gabapentin: Gabapen
●
Gabapentin enacarbil: Regnite
●
Pregabalin: Lyrica
3)
Concomitant use of the following drugs will be prohibited from the first day of the run-in 
period through the end of the study period:
●
Dopamine receptor inhibitors: Primperan (metoclopramide), Nauzelin (domperidone), etc.
●
Central depressants (hypnotics, antianxiety drugs, antipsychotic drugs, antidepressants, 
antimanic drugs, antiepileptic drugs)
●
Magnesium preparations*1, iron preparations*1, folic acid*1, vitamin B12 preparations*1
●
Other investigational products or post-marketing clinical study drugs
*1These apply to prescription drugs


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4)
The following drugs are prohibited for concomitant use from 7 days before a visit (day of 
IRLS score assessment) until the time of the IRLS score assessment at the visit, between 
the first day of the run-in period and the end of the study period:
●Antihistamines
[Rationale for the excluded concomitant medications/therapies, etc.]
These drugs/therapies are prohibited to avoid possible effects on evaluation of the efficacy of 
gabapentin enacarbil.
5.1.4
Treatment Compliance
The treatment compliance status of each subject will be recorded on the eCRF at each visit. 
At dispensing of the study drug to the subject, the investigator/sub-investigator and the study 
drug storage manager will explain how to take the study drug, with particular caution to the 
following:
1)
The subject must never take more one dose at a time, even if a dose of the study drug has 
been missed.
2)
The subject must bring the remaining study drug and empty bottles at the next visit.
The investigator/sub-investigator or clinical research coordinator will record each subject’s 
treatment compliance status during the study period on the eCRF, based on the study drug 
prescription date, number of the study drugs prescribed, number of the study drugs retrieved, 
number of the study drugs lost, start and end date of administration, interview with the subject, 
etc.  If the compliance rate is judged to be problematic, the reason will be investigated, and 
instruction on proper medication will again be given to the subject to improve the compliance 
rate.
5.1.5
Emergency Procedures and Management of Overdose
If gabapentin enacarbil overdose has caused certain symptoms, the investigator/sub-
investigator will perform emergency treatment according to the symptoms, and secure the 
safety of the subject.  Oral administration of gabapentin enacarbil up to 6 g has been reported 
overseas.  Typical symptoms of overdose have been psychomotor retardation, vertigo, 
sedation, and somnolence.  In the event of overdose, symptomatic treatment should be given.  
Gabapentin, which is the active metabolite of gabapentin enacarbil, can be removed by 
hemodialysis.  Implementation of hemodialysis should be considered depending on the 
symptoms.
5.1.6
Criteria for Continuation of Treatment
Study treatment will not be extended in this study.
5.1.7
Restrictions During the Study
The investigator/sub-investigator will explain the compliance rules to the subjects, with 
particular caution to the following, when explaining how to take the study drug, etc.:


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●
Subjects will visit the study site according to the schedule stipulated in the protocol, and 
undergo scheduled tests and other procedures.
●
Subjects are not allowed to take drugs that may affect assessment of the drug efficacy on 
the target disease (excluded concomitant medications) during the study period.  The use 
of magnesium preparations, iron preparations, over-the-counter drugs or supplements 
containing folic acid or vitamin B12, and dietary supplements should be avoided as far as 
possible.  Subjects are not allowed to take other drugs (including over-the-counter drugs 
such as combination cold remedies) at their own discretion without approval by the 
investigator, etc.  If subjects desire to use such drugs, they should consult the investigator, 
etc. first.
●
Subjects should notify the investigator/sub-investigator as far as possible beforehand if 
they will visit another hospital/department, newly visit another hospital/department, or 
use other drugs, including over-the-counter drugs, than those prescribed by the 
investigator/sub-investigator.  If not beforehand, the investigator/sub-investigator should 
be notified afterwards.
●
Subjects should use contraceptives during the study period, in line with inclusion criteria 
8 to 10.
●
Subjects with a history of regular alcohol consumption should avoid drinking alcohol 
during the study period as instructed by the investigator/sub-investigator.
●
Subjects should store the study drug at room temperature.
●
Subjects should take the study drug once daily after the evening meal, with water and 
without chewing or crushing the tablet.  If a dose is missed after the evening meal, the 
dose may only be taken before bedtime.
●
Subjects should take each dose of the study drug as instructed by the investigator/sub-
investigator.  When a dose is missed, the missed dose should not be taken together with 
the next dose.
●
The study drug should not be taken with alcohol.
●
Subjects should return any remaining portions of the study drug due to missed doses, etc., 
to the investigator/sub-investigator, and report the compliance status.
●
If a subject has stopped taking the study drug at his or her own discretion, the subject 
should visit the study site as early as possible to undergo physical assessment by the
investigator/sub-investigator.
Since the study drug may cause dizziness or sleepiness, subjects should be advised to exercise 
caution when working in high places, driving, or operating potentially hazardous machinery, 
etc.


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5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
The investigator/sub-investigator will collect the data below at the time of informed consent 
(or at provisional registration) via a medical interview, etc., and check the eligibility (see 
Section 3.2 Inclusion Criteria and Section 3.3 Exclusion Criteria).  At the time of formal 
registration, the investigator/sub-investigator will again check the eligibility (see Section 3.2
Inclusion Criteria and Section 3.3 Exclusion Criteria) and enter the details on the eCRF.
1) Sex, date of birth 
2) Height, body weight
3) Family history (RLS)
4) Date of informed consent
5.2.2
Medical History
At selection of potential subjects, the investigator/sub-investigator will collect information on 
past diseases and concurrent diseases on the basis of existing medical records.  Also at the 
time of informed consent as necessary, information on past diseases and concurrent diseases 
will be collected by way of medical interview with each potential subject.  Patients should be 
excluded from this study if the collected information meets any of the exclusion criteria.
1)
Past diseases
(1) Diseases that already resolved at the start of the run-in period are regarded as past diseases.
2)
Concurrent diseases
(1) Diseases that have not resolved at the start of the run-in period are regarded as concurrent 
diseases.
(2) For the concurrent diseases judged by the investigator/sub-investigator to be present at the 
start of the run-in period, the diagnoses will be entered on the eCRF.
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease
The investigator/sub-investigator will collect information on the diagnosis, time of onset, and 
current symptoms (according to the RLS diagnostic criteria established by the International 
RLS Study Group) by way of medical interview, etc. at the time of informed consent (or at 
provisional registration), and enter the following data on the eCRF:
- Time of onset of the target disease (RLS)
5.3
Efficacy Assessment
The following data will be collected and entered on the eCRF:
Both the investigator/sub-investigator and the subjects will assess symptoms without referring 
to previous assessments.  The investigator/sub-investigator should not answer questions from 
the subjects regarding previous assessments.


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[Primary endpoint]
IRLS score: Week −1 (run-in period), Week 0 (baseline), Week 1, Week 2, Week 4, Week 6, 
Week 8, Week 10, Week 12, Week 13 (follow-up period), discontinuation
[Secondary endpoints]
1)
ICGI and PCGI: Week 1, Week 2, Week 4, Week 8, Week 12, Week 13 (follow-up
period), discontinuation
2)
Pittsburgh Sleep Quality Index: Week 0 (baseline), Week 4, Week 8, Week 12, 
discontinuation
3)
Athens Insomnia Scale: Week 0 (baseline), Week 4, Week 8, Week 12, discontinuation
4)
RLS Pain score: Week −1 (run-in period), Week 0 (baseline), Week 1, Week 2, Week 4, 
Week 6, Week 8, Week 10, Week 12, Week 13 (follow-up period), discontinuation
5)
EQ-5D-5L: Week 0 (baseline), Week 4, Week 8, Week 12, discontinuation
5.4
Safety Assessment
The following data will be collected and entered on the eCRF:
5.4.1
Vital Signs
Vital signs (sitting blood pressure and sitting pulse rate): Week −1 (run-in period), Week 0 
(baseline), Week 1, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, discontinuation 
5.4.2
Adverse Events
Abnormal findings noted after the start of the run-in period will be collected.  See Section 5.5
Adverse Events and Other Safety Aspects, for information regarding AE collection and data 
handling.
5.4.3
Laboratory Assessments
Specimens for the hematology tests, biochemistry tests, thyroid function tests, and urinalysis 
(qualitative) below will be collected at the study site.  The laboratory will retrieve the 
specimens and perform measurements.
The laboratory will report the measurement results to the investigator/sub-investigator and the 
Sponsor using the test result report form.  The investigator/sub-investigator will confirm the 
data on the test result report form, enter the date of confirmation, comments, and signature or 
seal, and appropriately retain the test result report form.  For any laboratory data outside the 
normal range, the investigator/sub-investigator will assess the clinical significance, and record 
the result in the source document.
The following data will be entered on the eCRF:
1.
Hematology tests: Week −1 (run-in period), Week 0 (baseline), Week 2, Week 4, Week 8, 
Week 12, discontinuation


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Red blood cell count, white blood cell count, white blood cell differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes), platelet count, hemoglobin, hematocrit, 
MCV
2.
Biochemistry tests: Week −1 (run-in period), Week 0 (baseline), Week 2, Week 4, Week 
8, Week 12, discontinuation
Serum total protein, serum albumin, total bilirubin, ALP, ALT, AST, γ-GTP, calcium, 
chloride, potassium, sodium, inorganic phosphorus, glucose, serum creatinine, urea nitrogen, 
uric acid, CPK, HbA1c*
*Week −1 (run-in period) only
3.
Thyroid function tests: Week 0 (baseline), Week 12, discontinuation 
TSH, free T4
4.
Urinalysis (qualitative): Week −1 (run-in period), Week 0 (baseline), Week 2, Week 4, 
Week 8, Week 12, discontinuation 
Protein, glucose, urobilinogen
5.
Immunology test: Week −1 (run-in period)
Ferritin
5.4.4
Physical Examination
Body weight: Week −1 (run-in period), Week 0 (baseline), Week 4, Week 8, Week 12, 
discontinuation 
5.4.5
Imaging
Not applicable.
5.4.6
Other
Epworth Sleepiness Scale: Week 0 (baseline), Week 1, Week 2, Week 4, Week 6, Week 8, 
Week 10, Week 12, Week 13, discontinuation
5.5
Adverse Events and Other Safety Aspects
5.5.1
Definition of Adverse Events (AEs)
An AE is any untoward medical occurrence in a subject, temporally associated with the use of 
the study drug, whether or not considered related to the medicinal product.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of the study 
drug.
For AEs noted during the run-in period, the event term, event onset date, time to event onset, 
event end date, severity, seriousness, other actions taken, and outcome will be entered on the 
eCRF.


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For AEs noted during the treatment period, the event term, event onset date, time to event 
onset, event end date, severity, seriousness, action taken with the study drug, other actions 
taken, outcome, causal relationship to the study drug for the treatment period, and basis for 
the causality assessment will be collected and entered on the eCRF.  However, the basis for 
the causality assessment will be required on the eCRF only for SAEs, AEs leading to 
discontinuation, and other AEs for which description of the basis is requested by the sponsor.  
In addition, as necessary, the investigator will record details of the treatment and clinical 
course in an appropriate document.
AEs during the follow-up period will also be collected, and the event term, event onset date, 
time to event onset, event end date, severity, seriousness, action taken with the study drug, 
causal relationship to the study drug for the treatment period, basis for the causality 
assessment, other actions taken, and outcome will be entered on the eCRF.  However, the 
basis for the causality assessment will be required on the eCRF only for SAEs, AEs leading to 
discontinuation, and other AEs for which description of the basis is requested by the sponsor.  
In addition, as necessary, the investigator will record details of the treatment and clinical 
course in an appropriate document.
Whenever a diagnosis is determined on the basis of signs or symptoms, the diagnosis should 
be recorded rather than individual signs and symptoms.  When no diagnosis can be 
determined on the basis of signs or symptoms, the investigator/sub-investigator will handle 
individual signs and symptoms as AEs.  If an AE once disappeared but recurred, then the 
recurrence will be recorded as a new AE.  If an AE is judged to have worsened in severity, 
then the worsening will be handled as a new AE.  In addition, worsening of a concurrent 
disease will be handled as an AE.
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, 
physical examination) should be defined as an AE only if the abnormality meets one of the 
following criteria:
●
Induces clinical signs or symptoms
●
Requires active intervention
●
Requires interruption or discontinuation of study drug
●
The abnormality or test value is clinically significant in the opinion of the investigator.
5.5.2
Definition of Serious Adverse Events (SAEs)
An AE is considered “serious” if, in the view of either the investigator or Sponsor, it results in
any of the following outcomes:
●
Results in death
●
Is life-threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or Sponsor, its occurrence places the subject at immediate risk of death.  It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death)
●
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions


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●
Results in congenital anomaly, or birth defect
●
Requires inpatient hospitalization (except for planned procedures as allowed per study) or 
leads to prolongation of hospitalization (hospitalization for 
treatment/observation/examination caused by AE is to be considered as serious)
●
Other medically important events (defined in paragraph below)
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above.  These events, including those that may result in disability/incapacity, 
should also usually be considered serious.  Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood disorders or convulsions that 
do not result in hospitalization; or development of drug dependency or drug abuse.
The Sponsor has a list of events that they classify as “always serious” events (Section 12.4
Events Handled as Serious).  If an AE is reported that is considered to be an event per this 
classification as “always serious,” the investigator will need to report this event as a SAE, 
even if it does not meet the above criteria.
5.5.3
Criteria for Causal Relationship to the Study Drug
AEs that fall under the categories of “Possible,” “Probable,” or “Not assessable” are defined 
as “AEs for which relationship to the study drugs could not be ruled out.” For SAEs, AEs 
leading to discontinuation, and other AEs for which description of the basis for causality 
assessment is requested by the sponsor, the investigator/sub-investigator will enter the basis 
for the causality assessment on the eCRF.


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Causal relationship to 
the study drug
Criteria for causal relationship
Not related
A clinical event, including laboratory test abnormality, with a 
temporal relationship to drug administration which makes a causal 
relationship improbable, and/or in which other drugs, chemicals or 
underlying disease provide plausible explanations.
Possible
A clinical event, including laboratory test abnormality, with a 
reasonable temporal relationship to administration of the drug, but 
that could also be explained by concurrent disease or other drugs 
or chemicals.  Information on drug withdrawal may be lacking or 
unclear.
Probable
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to 
be attributed to concurrent disease or other drugs or chemicals, 
and which follows a clinically reasonable response on re-
administration (rechallenge) or withdrawal (dechallenge).
Not assessable
A report suggesting an adverse reaction which cannot be judged 
because information is insufficient or contradictory, and which
cannot be supplemented or verified.
5.5.4
Criteria for Defining the Severity of an Adverse Event
The severity of each AE will be assessed and recorded on the eCRF, with reference to the 
“Criteria for Seriousness/Severity Grading of Adverse Drug Reactions” (Notification No. 80 
of the Safety Division, Pharmaceutical Affairs Bureau, dated June 29, 1992), or according to 
the following criteria for AEs not included in the above-mentioned document:
●
Mild: No disruption of normal daily activities
●
Moderate: Affect normal daily activities
●
Severe: Inability to perform daily activities
5.5.5
Reporting of Serious Adverse Events (SAEs)
In the case of an SAE, the investigator or sub-investigator will report to the head of the study 
site and must contact the Sponsor or the CRO by telephone or fax immediately (within 24 
hours of awareness).
The investigator will complete the “Serious Adverse Event Report Form” containing all 
information required by the regulatory authorities, and submit it to the Sponsor or CRO 
promptly (within 24 hours of becoming aware of the event) by fax, and also to the head of the 
hospital. If the faxing of the “Serious Adverse Event Report Form” is not possible or is not 
possible within 24 hours, the Sponsor or CRO should be informed by phone.
For contact details, see Section II Contact Details of Key Sponsor’s Personnel.
The “Serious Adverse Event Report Form” should be faxed to the following contact 
personnel:


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Sponsor contact information:
 Astellas Pharma Inc.
Phone No.:
Fax: 
Contract research organization (CRO) contact information:
Phone No.:
(Representative person)
Fax: 
5.5.6
Follow-up of Adverse Events
All AEs occurring during the study or before final observation are to be followed until they 
resolve or are judged to be no longer clinically significant, or until they become chronic to the 
extent that they can be fully characterized by the investigator.
If during AE follow-up, the AE progresses to an “SAE,” or if a subject experiences a new 
SAE, the investigator will immediately report the information to the Sponsor.
Even when the subject has not returned to normal or the level noted before administration of 
the study drug, if the investigator/sub-investigator judges that the follow-up of the subject is 
unnecessary or is completed and if the reason is appropriately specified in the source 
document, the follow-up may be unnecessary or completed.
5.5.7
Monitoring of Common Serious Adverse Events
Not applicable.
5.5.8
Procedure in Case of Pregnancy
If a female subject or male subject partner becomes pregnant during the study dosing period 
or within 28 days from the completion or discontinuation of study treatment, the investigator 
is to report the information to the Sponsor/CRO according to the procedures same as those for 
SAEs. This information should include the expected date of delivery, starting day of last 
menstruation, estimated conception date, pregnancy outcome, and neonatal data.
The investigator will follow-up the pregnancy in terms of the maternal and fetal medical 
conditions according to the same procedures as those for SAEs, and notify the Sponsor.
When the outcome of the pregnancy falls under the criteria for SAEs (spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly [including anomaly in a 
miscarried fetus]), the investigator should respond in accordance with the procedures for 


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SAEs.  Additional information regarding the outcome of a pregnancy (which is categorized as 
an SAE) is mentioned below.
●
“Spontaneous abortion” includes miscarriage, abortion, and missed abortion.
●
Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug.
●
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as “possible” by 
the investigator.
●
In the case of a delivery of a living newborn, the “normality” of the infant is evaluated at 
the birth.
●
Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination.
5.5.9
Emergency Procedures and Management of Overdose
In the event of suspected overdose of gabapentin enacarbil, the subject should receive 
appropriate treatment and monitoring.
5.5.10
Supply of New Information Affecting the Conduct of the Study 
1.
When information is obtained regarding adverse drug reactions, etc., as specified in the 
Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, 
Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics 
(PMD Act), the Sponsor should inform all the investigators involved in the clinical study, 
the head of each study site, and the regulatory authorities of such information in 
compliance with Article 80-2 Paragraph 6 of the PMD Act.  The investigator will supply 
the new information to the subjects, in compliance with Section 8.2.3.2 Supply of New 
and Important Information Influencing the Subject’s Consent, and Revision of the 
Written Information.
2.
In addition to the above item (1), when the head of the study site receives the revisions of 
the Investigator’s Brochure, protocol, written information, information on the matters 
covering the quality of the study drug, efficacy and safety, information necessary for 
conducting the clinical study properly, or documents to be examined by the IRB, these 
documents should be sent to the IRB.
5.5.11
Deviations from the Protocol and Other Actions Taken to Avoid Life-
Threatening Risks to Subjects
The investigator must not deviate from or amend the protocol, excluding an emergency case 
for avoiding risks to the subjects.  When the investigator does not follow the protocol, in order 
to avoid urgent risks for subjects, the investigator should take the following actions:
1.
Describe the contents of the deviation or amendment and the reasons for it in a written 
notice, and immediately send the document stating the deviation or amendment and the 
reasons to the Sponsor and the head of the study site.  Keep a copy of the notice.


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2.
Consult with the Sponsor at the earliest possibility for cases in which it is necessary to 
amend the protocol.  Obtain approval for a draft of the amended protocol from the IRB 
and the head of the study site as well as written approval from the Sponsor.
5.6
Test Drug Concentration
Not applicable.
5.7
Other Measurements, Assessments or Methods
All of the following data will be entered on the eCRF:
1)
Pregnancy testing: Week −1 (run-in period), Week 12, discontinuation
Pregnancy testing (using a simple test kit on urine) will be performed before the start of the 
run-in period only in women, with the exception of women who are at least one year 
postmenopausal or with a history of hysterectomy, bilateral oophorectomy, etc., in whom a 
possibility of pregnancy is clearly excluded.
2)
Estimated creatinine clearance: Week −1 (run-in period)
The estimated creatinine clearance is calculated using the Cockcroft-Gault equation, based on 
the creatinine level measured by laboratory testing.  The age and body weight at the time of 
the creatinine measurement will be used for the calculation.
[Cockcroft-Gault equation]
[(140 − Age) × Body weight (kg)]
Estimated creatinine clearance (mL/min) =
[72 × Serum creatinine*(mg/dL)]
< For females, multiply by 0.85. >
*Serum creatinine by central measurement 
5.8
Total Amount of Blood Collected
The schedule of blood sampling in this study and the total amount of blood collected in each 
subject are shown below.  If follow-up laboratory tests are needed, additional blood sampling 
will be performed as needed, irrespective of this preplanned total amount of blood.
Amount of blood collected at a time:


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Week
−1
Week 0
Week 2
Week 4
Week 8
Week 12
At discontinuation
Hematology tests
2 mL
2 mL
2 mL
2 mL
2 mL
2 mL
2 mL
Biochemistry tests
5 mL
Including 
ferritin
5 mL
5 mL
5 mL
5 mL
5 mL
5 mL
Thyroid function tests
(TSH, Free T4)
2 mL
2 mL
2 mL
Glucose
2 mL
2 mL
2 mL
2 mL
2 mL
2 mL
2 mL
HbA1c
2 mL
Number of blood sampling time points: 6 times
Total amount of blood collected: 60 mL
6
DISCONTINUATION
6.1
Discontinuation of Individual Subjects
Discontinuation is defined as permanent withdrawal of enrolled subjects from the study, 
before completion of all protocol-specified procedures in the study.
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice.  The 
investigator is also free to discontinue the subject from study treatment or to terminate a 
subject's involvement in the study at any time if the subject's clinical condition warrants it.
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant (see
Section 5.5.6 Follow-up of Adverse Events).
Discontinuation Criteria from Treatment for Individual Subjects:
1.
Adverse events
●
Subject experiences an AE, and further participation in the study is judged to be difficult.
2.
Lack of efficacy (Worsening of the target disease)
●
Subject has insufficient improvement with the study drug, and is judged to require change 
of treatment.
●
Subject has worsening of the target disease, and further participation in the study is 
judged to be difficult.
3.
Withdrawal of consent
●
Subject requests to withdraw from the study.
4.
Lost to follow-up
●
Subject changed residence or is referred to another clinic/hospital, or has other personal 
reasons such as busy schedule, which prevent further participation in the study


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●
Subject does not return to the study site (or lost contact with the study site)
5.
Ineligibility (i.e., not fulfilling the inclusion criteria or meeting any of the exclusion 
criteria)
●
Subject is found not to fulfil the inclusion criteria or to meet any of the exclusion criteria, 
on the basis of the results of tests or observations performed after the informed consent 
and before formal registration.
6.
Protocol deviation
●
Subject is found not to have met the inclusion/exclusion criteria, after formal registration 
as an eligible subject.
●
Subject is found to have any other major deviation from the protocol.
7.
Suicide
●
Subject attempted suicide, or is judged by the investigator/sub-investigator to be at high 
risk for suicide.
8.
Death
●
Subject died (from any cause).
9.
Pregnancy
●
Female subject is found to be pregnant during the study period.
10. Other
●
The investigator/sub-investigator judges that further study treatment is inappropriate in 
the subject, or the Sponsor requests to discontinue study treatment in the subject because 
of safety issues.
For the subjects discontinued after administration of the study drug for the treatment period, 
the tests/observations required at discontinuation (see Section V FLOW CHART AND 
SCHEDULE OF ASSESSMENTS) will be promptly performed, and a post-treatment 
follow-up period will be provided as far as possible.  For the subjects discontinued during the 
post-treatment follow-up period, the Week 13 procedures will be performed as the 
tests/observations at discontinuation.
For the subjects discontinued during the run-in period, the compliance status and any AEs will 
be investigated.  Any AEs that are ongoing at the time of final observation will be followed 
(see Section 5.5.6 Follow-up of Adverse Events).
For the subjects discontinued from the study, the investigator/sub-investigator should collect 
all study data up to the final observation.
For the subjects discontinued after administration of the study drug, the investigator/sub-
investigator will specify the date of discontinuation and reason for the discontinuation on the 
eCRF.  In addition, the investigator/sub-investigator should retain all study data from the 
discontinued subjects, and also enter these data on the eCRF and submit them to the Sponsor.  
For the patients withdrawn before the start of the run-in period, the reason for the withdrawal 
will be entered on the eCRF.


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6.2
Discontinuation of the Site
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the Sponsor and the head of the study site.
6.3
Discontinuation of the Study
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination.  Advance notice is not required if the study is stopped due to safety concerns.  If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.
7
STATISTICAL METHODOLOGY
The statistical analysis will be performed by the statistician of the Sponsor.  A Statistical 
Analysis Plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings, and figures to be produced.  The SAP will be finalized 
before the treatment code breaking.  Any changes from the analyses planned in  SAP will be 
justified in the Clinical Study Report (CSR).
7.1
Sample Size
180 subjects per group (360 subjects in the two groups) as participants in the treatment period
[Rationale for the sample size]
The Japanese phase II/III study [CL-0003] demonstrated the change in IRLS score (mean and 
standard deviation) at the end of treatment period (Week 12) as shown in Table 8.  Of the 
randomized subjects, 11.8% in the placebo group and 17.5% in the 600 mg group were 
discontinued during the treatment period.
Table 8:
Change in IRLS score (mean and standard deviation) at the end of 
treatment period (i.e., Week 12 of study treatment) in the Japanese phase 
II/III study [CL-0003]: FAS
Placebo
ASP8825 600 mg
N
Mean (SD)
N
Mean (SD)
Week 12 (LOCF)
116
−8.96 (7.286)
120
−11.10 (7.921)
Week 12 (Treatment period 
completers)
105
−9.27 (6.996)
98
−11.54 (7.793)
SD: Standard Deviation. LOCF: Last Observation Carried Forward
In addition, a repeated measures analysis of variance of the data from the patients given 
placebo or ASP8825 600 mg in the Japanese phase II/III study [CL-0003] and included in the 


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Full Analysis Set showed that the adjusted means of the change from baseline in IRLS score 
at the end of treatment period (Week 12) were −9.15 in the placebo group and −11.71 in the 
600 mg group. The difference between the adjusted means from the two groups was −2.56.
On the basis of these results, the difference between treatment groups in the change from 
baseline in IRLS score at the end of treatment period (Week 12) as the primary endpoint of 
this study was assumed to be −2.56, with a standard deviation of 8.000 in both groups. Under
these assumptions, to detect a statistically significant difference between gabapentin enacarbil 
and placebo using a 2-sample t-test with a two-sided significance level of 0.05 and a power of 
80%, 155 subjects per group would be required. Assuming the discontinuation rate during the 
treatment period was approximately 15.0% in each group, the sample size has been set to 180 
per group.
7.2
Analysis Sets
In principle, the analysis sets below will be used.  However, the final decision on handling of 
cases for analyses will be made in a case review before the treatment code breaking, in light 
of opinions/advice from medical expert, statistical advisor, and others.
7.2.1
Full Analysis Set (FAS)
The Full Analysis Set (FAS) will consist of all subjects who received the study drug for the 
treatment period and were evaluated for at least one efficacy (either primary or secondary) 
endpoint during the treatment period.  The FAS will be the primary analysis set for efficacy 
analyses.
7.2.2
Per Protocol Set (PPS)
The Per Protocol Set (PPS) will consist of the subjects in the FAS who meet the following 
criteria:
●
Subjects meeting the inclusion criteria
●
Subjects not meeting any of the exclusion criteria that can affect efficacy assessments
●
Subjects not using excluded concomitant medications or therapies that can affect efficacy 
assessments
●
Subjects given the study drug for the treatment period for at least 2 weeks from the start 
of the treatment period
●
Subjects with ≥70% compliance with study treatment during the treatment period
7.2.3
Safety Analysis Set (SAF)
The Safety Analysis Set (SAF) will consist of all subjects given at least one dose of the study
drug for the treatment period.
7.3
Demographic and Baseline Characteristics
Using the FAS, PPS, and SAF, the subject demographic and other baseline characteristics will 
be summarized by treatment group.  For continuous variables, the descriptive statistics will 


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include the number of subjects, mean, standard deviation, minimum, median, and maximum.  
For categorical variables, the descriptive statistics will include the frequency and proportion.
7.4
Analysis of Efficacy
The efficacy analyses below will be performed using the FAS as the primary analysis set. 
Unless otherwise stated, the analyses will be performed by treatment group.
7.4.1
Analysis of Primary Endpoint
7.4.1.1 Primary Analysis
The primary efficacy endpoint is the change from baseline in IRLS score at the end of 
treatment period. Using a repeated measures analysis of variance model having the following 
average structure, the adjusted mean in each treatment group and its difference (gabapentin 
enacarbil group −placebo group) at the end of treatment period (Week 12) will be calculated, 
with comparison between the placebo group and the gabapentin enacarbil group:
Change in IRLS score at each time point
= IRLS score at baseline + Age category*1 + Estimated creatinine clearance category*2 + 
Treatment group + Time point + Treatment group × Time point
*1Age category: < 50 years and ≥50 years
*2Estimated creatinine clearance category: ≥60 to < 90 mL/min and ≥90 mL/min
Compound symmetry will be used as the covariance structure for repeated measures of the 
response variable.  A two-sided significance level of 0.05 will be used for statistical tests.
7.4.1.2 Secondary Analysis
●
The analysis stated in Section 7.4.1.1 Primary Analysis, will be performed using the PPS. 
●
The sensitivity analysis of Section 7.4.1.1 Primary Analysis, will be performed using
analysis of covariance with LOCF or other approaches taking into account missing data
mechanisms. Details of sensitivity analysis will be specified in the SAP.
7.4.2
Analysis of Secondary Endpoints
1.
Change from baseline in IRLS score at each time point
●
The measured value and its change from baseline will be summarized using descriptive 
statistics. Comparison between the placebo group and the gabapentin enacarbil group 
will be performed using analysis of covariance.
●
For the measured value and its change from baseline, the mean ± standard deviation will 
be plotted.
2.
ICGI responder rate at each time point


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●
The responder rate and its 95% confidence interval will be calculated. Comparison 
between the placebo group and the gabapentin enacarbil group will be performed using 
Fisher’s exact test.
●
The responder rate and its 95% confidence interval will be plotted.
3.
PCGI responder rate at each time point
●
The responder rate and its 95% confidence interval will be calculated. Comparison 
between the placebo group and the gabapentin enacarbil group will be performed using 
Fisher’s exact test.
●
The responder rate and its 95% confidence interval will be plotted.
4.
Change from baseline in Pittsburgh Sleep Quality Index at each time point
●
The measured value and its change from baseline will be summarized using descriptive 
statistics. Comparison between the placebo group and the gabapentin enacarbil group 
will be performed using analysis of covariance.
●
For the measured value and its change from baseline, the mean ± standard deviation will 
be plotted.
5.
Change from baseline in Athens Insomnia Scale each time point
●
The measured value and its change from baseline will be summarized using descriptive 
statistics. Comparison between the placebo group and the gabapentin enacarbil group 
will be performed using analysis of covariance.
●
For the measured value and its change from baseline, the mean ± standard deviation will 
be plotted.
6.
Change from baseline in RLS Pain score at each time point
●
The measured value and its change from baseline will be summarized using descriptive 
statistics. Comparison between the placebo group and the gabapentin enacarbil group 
will be performed using analysis of covariance.
●
For the measured value and its change from baseline, the mean ± standard deviation will 
be plotted.
7.
Change from baseline in EQ-5D-5L at each time point
●
The measured value and its change from baseline will be summarized using descriptive 
statistics.


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7.5
Analysis of Safety
Using the SAF, the following safety analyses will be performed by treatment group.
7.5.1
Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
AEs, SAEs, AEs leading to discontinuation, and AEs related to the study drug will be 
summarized by System Organ Class, Preferred Term, and treatment group, with tabulation of 
the number and percentage of subjects.  In addition, the number and percentage of subjects 
with AE will be tabulated by severity.
7.5.2
Laboratory Assessments
For laboratory test values (continuous values), the measured value and its change from 
baseline at each time point will be summarized using descriptive statistics.  Shift tables will 
be constructed for the laboratory test values relative to the normal ranges from baseline to 
each time point during the treatment period. For discrete values, the frequency will be 
summarized for each time point.
7.5.3
Vital Signs
For vital signs, the measured value and its change from baseline at each time point will be 
summarized using descriptive statistics.
7.5.4
Body Weight
For body weight, the measured value and its change from baseline at each time point will be 
summarized using descriptive statistics.
7.5.5
Epworth Sleepiness Scale
For the Epworth Sleepiness Scale, the measured value and its change from baseline at each 
time point will be summarized using descriptive statistics.
7.6
Analysis of Pharmacokinetics
Not applicable.
7.7
Other Analyses
Not applicable.
7.8
Interim Analysis (and Early Discontinuation of the Study)
No interim analysis is planned.
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
Final decision on handling of missing data and outliers for analyses will be made before 
treatment code breaking, in light of opinions/advice from medical expert, statistical advisor, 
and others.  In terms of the handling of data time points for analysis, if two or more observed 


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values are available for one time interval, the value collected closer to the protocol-specified 
time point will be used.  If the difference from the reference time point is the same for two 
values, the value collected at a later point will be used.
7.9.1
IRLS score and RLS Pain score
For the IRLS score and the RLS Pain score, the allowed time windows for analyses are shown 
in the table below.  For data in the treatment period, the data obtained up to 7 days after the 
day of last dosing in the treatment period will be used.
Analysis visit
Allowable time window
Reference day
Run-in
Day −10 to Day −7 
Day 1
Week 0
Day 1
Day 1
Week 1
Day 5 to Day 11
Day 8
Week 2
Day 12 to Day 18
Day 15
Week 4
Day 26 to Day 32
Day 29
Week 6
Day 40 to Day 46
Day 43
Week 8
Day 54 to Day 60
Day 57
Week 10
Day 68 to Day 74
Day 71
Week 12
Day 82 to Day 88
Day 85
End of 
treatment
Day 2 to Reference day +7 days
Day of last dosing in the 
treatment period
Follow-up
Reference day +5 days to Reference
day +11 days
Day of last dosing in the 
treatment period
7.9.2
ICGI and PCGI
For the ICGI and PCGI, the allowed time windows for analyses are shown in the table below.  
For data in the treatment period, the data obtained up to 7 days after the day of last dosing in 
the treatment period will be used.
Analysis visit
Allowable time window
Reference day
Week 1
Day 5 to Day 11
Day 8
Week 2
Day 12 to Day 18
Day 15
Week 4
Day 26 to Day 32
Day 29
Week 8
Day 54 to Day 60
Day 57
Week 12
Day 82 to Day 88
Day 85
End of treatment
Day 2 to Reference day +7 days
Day of last dosing in 
the treatment period
Follow-up
Reference day +5 days to Reference day
+11 days
Day of last dosing in 
the treatment period


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7.9.3
Pittsburgh Sleep Quality Index, Athens Insomnia Scale, and EQ-5D-5L
For the Pittsburgh Sleep Quality Index, Athens Insomnia Scale, and EQ-5D-5L, the allowed 
time windows for analyses are shown in the table below.  For data in the treatment period, the 
data obtained up to 7 days after the day of last dosing in the treatment period will be used.
Analysis visit
Allowable time window
Reference day
Week 0
Day 1
Day 1
Week 4
Day 26 to Day 32
Day 29
Week 8
Day 54 to Day 60
Day 57
Week 12
Day 82 to Day 88
Day 85
End of treatment
Day 2 to Reference day +7 days
Day of last dosing in 
the treatment period
7.9.4
Laboratory Tests
For laboratory tests, the allowed time windows for analyses are shown in the table below.  For 
data in the treatment period, the data obtained up to 7 days after the day of last dosing in the
treatment period will be used.
Analysis visit
Allowable time window
Reference day
Run-in
Day −10 to Day −7
Day 1
Week 0
Day 1
Day 1
Week 2
Day 12 to Day 18
Day 15
Week 4
Day 26 to Day 32
Day 29
Week 8
Day 54 to Day 60
Day 57
Week 12
Day 82 to Day 88
Day 85
End of treatment
Day 2 to Reference day +7 days
Day of last dosing in 
the treatment period
7.9.5
Vital Signs
For the vital signs, the allowed time windows for analyses are shown in the table below.  For 
data in the treatment period, the data obtained up to 7 days after the day of last dosing in the 
treatment period will be used.


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Analysis visit
Allowable time window
Reference day
Run-in
Day −10 to Day −7 
Day 1
Week 0
Day 1
Day 1
Week 1
Day 5 to Day 11
Day 8
Week 2
Day 12 to Day 18
Day 15
Week 4
Day 26 to Day 32
Day 29
Week 6
Day 40 to Day 46
Day 43
Week 8
Day 54 to Day 60
Day 57
Week 10
Day 68 to Day 74
Day 71
Week 12
Day 82 to Day 88
Day 85
End of treatment
Day 2 to Reference day +7 days
Day of last dosing in 
the treatment period
7.9.6
Body Weight 
For body weight, the allowed time windows for analyses are shown in the table below.  For 
data in the treatment period, the data obtained up to 7 days after the day of last dosing in the
treatment period will be used.
Analysis visit
Allowable time window
Reference day
Run-in
Day −10 to Day −7
Day 1
Week 0
Day 1
Day 1
Week 4
Day 26 to Day 32
Day 29
Week 8
Day 54 to Day 60
Day 57
Week 12
Day 82 to Day 88
Day 85
End of treatment
Day 2 to Reference day +7 days
Day of last dosing in 
the treatment period
7.9.7
Epworth Sleepiness Scale
For the Epworth Sleepiness Scale, the allowed time windows for analyses are shown in the 
table below.  For data in the treatment period, the data obtained up to 7 days after the day of 
last dosing in the treatment period will be used.


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Analysis visit
Allowable time window
Reference day
Week 0
Day 1
Day 1
Week 1
Day 5 to Day 11
Day 8
Week 2
Day 12 to Day 18
Day 15
Week 4
Day 26 to Day 32
Day 29
Week 6
Day 40 to Day 46
Day 43
Week 8
Day 54 to Day 60
Day 57
Week 10
Day 68 to Day 74
Day 71
Week 12
Day 82 to Day 88
Day 85
End of treatment
Day 2 to Reference day +7 days
Day of last dosing in 
the treatment period
Follow-up
Reference day +5 days to Reference day
+11 days
Day of last dosing in 
the treatment period
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The investigator, sub-investigator, or clinical research coordinator will enter data using an 
Electronic Data Capture (EDC) system.  For efficient data collection, the investigator, sub-
investigator, or clinical research coordinator should record data (including laboratory values, 
if applicable) on the eCRF within 5 days after the subject visit.
For questionnaires completed by subjects (i.e., PCGI, Pittsburgh Sleep Quality Index, Athens 
Insomnia Scale, RLS Pain score, EQ-5D-5L, and Epworth Sleepiness Scale), the investigator, 
sub-investigator, or clinical research coordinator will check the entries and enter these data 
into the eCRF.  The subject will review the entries together with a clinical research 
coordinator after completing the questionnaires.  If any entry is unclear, the subject will make 
an additional entry or correct the entry as necessary, and enter the date of the correction and 
sign or affix his or her personal seal.
The investigator, sub-investigator, or clinical research coordinator is responsible to ensure that 
all data on the eCRFs and queries are accurate and complete and that all entries are verifiable 
with source documents.  These documents will be appropriately maintained by the site.
The monitor should verify the data on the eCRFs with source documents and confirm that 
there are no inconsistencies between them.
Laboratory tests will be performed at a central laboratory. Central laboratory data will be 
transferred electronically from the central laboratory to the Sponsor at predefined times.  The 
central laboratory will provide the Sponsor with a complete copy of the data. 


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For the patients withdrawn before the start of the run-in period, the date of informed consent, 
minimum patient background data (sex, date of birth), and reason for withdrawal will be 
entered on the eCRF.
For the patients withdrawn during the run-in period, the date of informed consent, patient 
background data (sex, date of birth, family history of RLS), visit days, date of provisional 
registration, date of final observation, any discontinuation of study drug, date of 
discontinuation, reason for discontinuation, date of run-in period study drug prescription, 
number of the study drugs prescribed, start and end date of study drug administration, number 
of the study drugs retrieved, number of the study drugs lost, AEs, and IRLS score will be 
entered on the eCRF.
8.1.2
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected.  Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.
The following information should be included in the source medical records:
●
Demographic data (date of birth, sex, height, body weight)
●
Inclusion and exclusion criteria-related detailed records
●
Documentation of participation in the study and the original signed and dated informed 
consent form
●
Visit dates
●
Medical history and physical examination details
●
Key efficacy and safety data
●
AEs and symptomatic treatments
●
Results of relevant examinations
●
Laboratory printout
●
Details of dispensing and return of study drug
●
Reason for premature discontinuation
●
Subject ID number
●
Questionnaire forms (IRLS score, ICGI, PCGI, Pittsburgh Sleep Quality Index, Athens 
Insomnia Scale, RLS Pain score, EQ-5D-5L, Epworth Sleepiness Scale)
8.1.3
Clinical Study Monitoring
The Sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with
study-related records such as source documents.  The Sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring.  They will monitor the study in 
accordance with planned monitoring procedures.


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8.1.4
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the Sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities.  
In these instances, they must provide all study-related records, such as source documents 
(refer to Section 8.1.2 Specification of Source Documents) when they are requested by the 
Sponsor monitors and auditors, the IRB/IEC, or regulatory authorities.  The confidentiality of 
the subject's identities shall be well protected consistent with local and national regulations, 
when the source documents are subject to direct access.
8.1.5
Data Management
Data management will be coordinated by the Data Science department of the Sponsor in 
accordance with the SOPs for data management.  All study-specific processes and definitions 
will be documented by the Data Management department.  The methods for eCRF completion 
and correction will be described in the eCRF instructions.  Coding of medical terms and 
medications will be performed using MedDRA and Iyakuhinmei Data File (IDF), respectively.
8.2
Ethics and Protection of Subject Confidentiality
8.2.1
Institutional Review Board (IRB)
Before the contract for the study is executed, the institutional review board of the study site 
will need to review and approve the study protocol and various materials used for the patient 
informed consent procedure, to protect human rights of the patients and secure the safety and 
welfare of the patients.
8.2.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct, and the ethical principles that 
have their origin in the Declaration of Helsinki.
8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
The investigator or his/her representative will explain the contents of the study to the subjects
using the written information, and answer all questions regarding this study.  Prior to any 
study-related screening procedures being started in the subject, the subject should read 
through and fully understand the informed consent form and provide voluntary written 
consent to participate in the study.  The consent form will be signed (or seal affixed with 
name) and dated by the investigator or his/her representative who provided the explanation 
(including a clinical research coordinator who provided supplementary explanation where 
applicable) and the subject.  The investigator or his/her representative will provide the subject 
with a copy of the signed (or seal affixed with name) consent form, while retaining the 
original in the subject’s source documents.  The investigator will confirm that the original 
consent form was dated by the subject, and also confirm that the consent was obtained before 


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the study-related screening procedure and the subject received a copy of the signed consent 
form.
The investigator will retain the signed consent forms, and will have them available (for review 
only) to the study monitor, audit/inspection personnel of regulatory authorities, and other 
authorized persons upon request.
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent, 
and Revision of the Written Information
1.
The investigator will immediately inform the subject orally whenever new information 
becomes available that may be relevant to the subject’s consent or may influence the 
subject’s willingness to continue to participate in the study (e.g., report of serious drug 
adverse drug reaction).  The communication must be documented in the subject’s medical 
records, and whether the subject willing to remain in the study or not must be confirmed 
and documented.
2.
The investigator must update the ICF and submit it for approval to the IRB/IEC.  The 
investigator must obtain written informed consent from the subject on all updated ICFs 
throughout their participation in the study.  The investigator or his/her designee must 
reconsent subjects with the updated ICF even if relevant information was provided orally.  
The investigator who obtained the written informed consent (including a clinical research 
coordinator who provided supplementary explanation where applicable) and the subject 
should sign (or affix seal with name) and date the informed consent form.  A copy of the 
signed (or seal affixed with name) informed consent form will be given to the subject and 
the original will be retained in the subject’s medical record.  The re-consent process 
should be documented in the subject’s record.
8.2.4
Subject Confidentiality and Privacy
Individual subject medical information obtained as a result of this study is considered 
confidential, and disclosure to third parties is prohibited.  Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being.
The Sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons.
All persons and organizations involved in this study shall pay utmost respect to protect 
privacy of the subjects, for example by prohibiting the use of personally identifiable 
information (e.g., name, address).  The details of privacy protection should comply with laws 
and regulatory requirements (e.g., Privacy Protection Laws).
Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to subject's privacy due to direct access to source documents, 
or from other sources, they may not leak the content to third parties.


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8.3
Administrative Matters
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, and other pertinent information is confidential and remains the property of the Sponsor. 
Details should be disclosed only to the persons involved in the approval or conduct of the 
study. The investigator may use this information for the purpose of the study only. It is 
understood by the investigator that the Sponsor will use the information obtained during the 
clinical study in connection with the development of the drug and therefore may disclose it as 
required to other clinical investigators or to regulatory agencies. In order to allow for the use 
of the information derived from this clinical study, the investigator understands that he/she 
has an obligation to provide the Sponsor with all data obtained during the study.
Publication of the study results is discussed in the clinical study agreement.
After agreement between the investigator and the Sponsor, the investigator may submit a 
manuscript for publication.
8.3.2
Documents and Records Related to the Clinical Study
The Sponsor will provide the investigator and the study site with the following:
●
Study protocol (and amendments where applicable)
●
Package insert (and revisions where applicable)
●
CRF and Serious Adverse Event Report Form
●
Study drug with all necessary documents
●
Study contract and memoranda
Before initiation of the study, the investigator and the study site will provide the Sponsor with 
the following:
●
Written agreement on the protocol between the Sponsor and the investigator
●
Curriculum Vitae of the investigator
●
List of sub-investigators and clinical research coordinators
●
Copy of the IRB approval of the protocol, protocol amendments (if applicable), and other 
study documents (including a member list and quality assurance documentation)
●
Instructions provided and decisions made by the head of the study site
●
Study contract and memoranda
●
Laboratory normal values and ranges (if applicable) (including updates or revisions) 
At the end of the study, the Sponsor will retrieve the following:
●
Study-related documents
●
Unused study drugs
The investigator will retain all study data (e.g., subject screening list, source data, CRFs, 
investigator’s file) and related communications.  These documents are to be kept on file for 
the appropriate term determined by the local regulation.


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The records to be retained at the study sites are the ones listed as essential documents in GCP.  
These records shall be retained by either the head of the study site or a responsible record 
keeper designated by the head of the study site, until a notice issued by the Sponsor on 
completion of the retention period is received.  These documents are also subject to direct 
access and should be provided upon request from the Sponsor or regulatory authorities.
The head of the study site will retain the essential documents that should be stored at the study 
site in an appropriate manner according to the rules of the study site.  The document retention 
period will be until completion of re-review/reevaluation of the study drug.
The following are the major records to be retained at the study site:
1.
Source documents (clinical data, documents, and records for preparing the eCRF) 
Hospital records, medical records, test records, memoranda, subject diary or check lists 
for evaluation, dosing records, data recorded by automatic measuring instruments, 
reproductions or transcripts verified as precise copies, microfiche, negative films, 
microfilms/magnetic media, X-ray films, subject files, study-related records kept at the 
pharmacy/laboratory/medical technical office, subject registration forms, laboratory test 
slips including central measurements, worksheets specified by the Sponsor, records by 
clinical coordinators, and records related to the clinical study selected from those verified 
in other department/hospital
2.
Contracts, written informed consent forms, written information, and other documents or 
copies prepared by the study personnel
Study request form (including a request for continuation/amendment), review request 
form, notice of study contract, study contract and memoranda, notification of study 
discontinuation/completion, written information for informed consent (including 
revisions), signed and dated written informed consent (including revisions), CV of the 
investigator, list of sub-investigators, list of signatures and seal imprints (copy), and CRF 
(CD-R), etc.
3.
The protocol, documents obtained from the IRB related to the adequacy of conducting the 
clinical study by the head of the study site (Article 32-1, MHW Ordinance No. 28), 
documents obtained from the IRB related to the adequacy of conducting a clinical study 
for which the period exceeds one year or the adequacy of continuously conducting the 
clinical study from which information on adverse drug reactions is obtained, and other 
documents obtained.
An agreed-upon protocol (including amendments), package insert (including revisions), 
operational procedures for the investigator, materials and information supplied by the 
Sponsor (e.g., AE reports), matters reported by the investigator (e.g., protocol 
amendments, AE reports), IRB operational procedures, IRB member list, materials for 
IRB reviews (including continuous review), IRB review records (including continuous 
review), and IRB review result reports (including continuous review), etc.
4.
Documents and records related to study drug management and other study-related tasks 


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Written procedure for study drug management, study drug inventory and accountability 
records, study drug receipt/retrieval forms, and concomitant medication prescription 
records
8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments or revisions.  Depending on the nature of the changes, approval of or 
notification to the IRB and regulatory authorities may be required.  The changes will become 
effective only after the approval of the Sponsor, the investigator, and the IRB, followed by 
approval of the head of the study site.
8.3.4
Insurance of Subjects and Others
If a subject suffers any study-related injury, the Sponsor will compensate appropriately 
according to the severity and duration of the damage.  However, if the injury was caused 
intentionally or was due to gross negligence by the study site, the Sponsor will discuss with 
the study site about handling the injury, based on the agreed study contract.  Compensation 
for the study-related injury is provided by the following procedures:
1.
If a subject incurs an injury as a result of participation in the clinical study, the study site 
should provide medical treatment and take other necessary measures, and notify the 
Sponsor of the injury.
2.
When the subject has claimed or may claim compensation from the study site for the 
above study-related injury, the study site will immediately communicate the fact to the 
Sponsor.  Both parties will work together towards compensation settlement.
3.
The Sponsor shall pay compensation or indemnification and bear expenses necessary for 
the settlement as provided in the clinical contract.
4.
The Sponsor shall make an arranging for insurance and take measures necessary to ensure 
the compensation or indemnification mentioned above.
8.3.5
Signatory Investigator for Clinical Study Report
Not established.
9
QUALITY ASSURANCE
The Sponsor will prepare written standard operating procedures (SOPs), and establish and 
maintain a system for quality assurance and quality control systems, to ensure that the study is 
conducted and data are generated, documented, recorded, and reported in compliance with the 
protocol, GCP, and applicable regulatory requirements.
The Sponsor or its designee may inspect or audit any or all study sites and facilities.  The site 
audit will include verification of regulatory documents, CRFs, source documents, and other 
documents via direct access by the auditor.


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10
STUDY ORGANIZATION
10.1
Independent Data-Monitoring Committee (IDMC) | Data and Safety 
Monitoring Board (DSMB) | Monitoring Committee | Other 
Evaluation Committee(s)
Not established.
10.2
Other Study Organizations
See Appendix 1 and Appendix 2.


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10.3
Registration of Subjects
The procedures for subject registration will be defined in a separate written procedure or other 
documents.
Note) Also after the formal registration, the study drug with a drug number provided by the 
Web registration system will be prescribed on each occasion of study drug prescription.
Screening
Informed consent
Assessment against inclusion/exclusion criteria (formal 
registration)
Assessment against inclusion/exclusion criteria
(provisional registration)
Provisional 
registration
Patient data entry
Confirmation of the entered 
patient data
Prescription of the study 
drug with the designated 
drug number
Formal 
registration
Patient data entry
Confirmation of the entered 
patient data
Prescription of the study 
drug with the designated 
drug number
Run-in period
Treatment period
Web
Web
Web
Web


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11
REFERENCES
Adler CH. Treatment of restless legs syndrome with gabapentin. Clin Neuropharmacol. 
1997;20(2):148-51.
Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW et al. Restless 
legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs 
Syndrome Study Group (IRLSSG) consensus criteria-history, rationale, description, and 
significance. Sleep Medicine. 2014;15(8):860-73.
Beydoun A, Uthman B, Sackellares J. Gabapentin: pharmacokinetics, efficacy, and safety. Clin 
Neuropharmacol. 1995;18(6):469-81.
Boyd RA, Truck D, Abel RB, Sedman A, Bockbrader HN. Effects of age and gender on single-dose 
pharmacokinetics of gabapentin. Epilepsia. 1999;40(4):474-9.
Buysse DJ, Reynolds CF III, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh sleep quality index: A 
new instrument for psychiatric practice and research. Psychiatry Research. 1989;28(2):193-213.
Fink K, Meder W, Dooley DJ, Göthert M. Inhibition of neuronal (Ca2+) influx by gabapentin and 
subsequent reduction of neurotransmitter release from rat neocortical slices. Br J Pharmacol. 
2000;130(4):900-6.
Garcia-Borreguero D, Larrosa O, de la Llave Y, Verger K, Masramon X, Hernandez G. Treatment of 
restless legs syndrome with gabapentin: a double-blind, cross-over study. Neurology. 
2002;59(10):1573-9.
Gidal BE, DeCerce J, Bockbrader HN, Gonzalez J, Kruger S, Pitterle ME et al. Gabapentin 
bioavailability: effect of dose and frequency of administration in adult patients with epilepsy. 
Epilepsy Res. 1998;31(2):91-9.
Gidal BE, Radulovic LL, Kruger S, Rutecki P, Pitterle M, Bockbrader HN. Inter-and intra-subject 
variability in gabapentin absorption and absolute bioavailability. Epilepsy Res. 2000;40(2-
3):123-7.
Happe S, Klösch G, Saletu B, Zeitlhofer J. Treatment of idiopathic restless legs syndrome (RLS) with 
gabapentin. Neurology. 2001;57(9):1717-9.
Herdman M, Gudex C, Lloyd C, Janssen MF, Kind P, Parkin D et al. Development and preliminary 
testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-
36.
International Restless Legs Syndrome Study Group. Validation of International Restless Legs 
Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. 2003;4(2):121-32.
Jensen MP, Karoly P, Braver S. The measurement of clinical pain intensity: a comparison of six 
methods pain. 1986;27(1):117-26.
Marais E, Klugbauer N, Hofmann F. Calcium channel α2δ subunits-structure and Gabapentin binding. 
Mol Pharmacol. 2001;59(5):1243-8.


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Mellick GA, Mellick LB. Management of restless legs syndrome with gabapentin (Neurontin®). Sleep. 
1996;19(3):224-6.
Murray WJ. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 
1991;14(6):540-5.
Kaneko S. Pharmacological profile of gabapentin enacarbil (Regnite® Tablets) as a new drug to treat 
restless legs syndrome. Jpn J Clin Psychopharmacol. 2012;15(4):497-504.
Rinaldi F, Galbiati A, Marelli S, Srtambi LF, Zucconi M. Treatment Options in Intractable Restless 
Legs Syndrome/Willis-Ekbom Disease (RLS/WED). Curr Treat Options Neurol. 2016;18(2):7.
Silber MH, Becker PM, Earley C, Garcia-Borreguero D, Ondo WG. Willis-Ekdom Disease 
Foundation revised consensus statement on the management of restless legs syndrome. Mayo 
Clin Proc. 2013;88(9):977-86.
Silber MH, Ehrenberg BL, Allen RP, Buchfuhrer MJ, Earley CJ, Hening WA et al. An algorithm for 
the management of restless legs syndrome. Mayo Clin Proc. 2004;79(7):916-22.
Soldatos CR, Dikeos DG, Paparrigopoulos TJ. Athens Insomnia Scale: validation of an instrument 
based on ICD-10 criteria. Journal of Psychosomatic Research. 2000;48(6):555-60.
Nomura T, Nakashima K. II Epidemiology of restless legs syndrome. Standard Neurological Therapy:
Restless Legs Syndrome. 2012.
Thorp ML, Morris CD, Bagby SP. A crossover study of gabapentin in treatment of restless legs 
syndrome among hemodialysis patients. Am J Kidney Dis. 2001;38(1):104-8.
Yuriko D, Masumi M, Makoto U, Masako O, Keiko K, Kayo S et al. Psychometric assessment of 
subjective sleep quality using the Japanese version of the Pittsburgh Sleep Quality Index (PSQI-
J) in psychiatric disordered and control subjects. Psychiatry Research. 2000;97(2-3):165-72.
Doi Y, Minowa M, Uchiyama M, Okawa M. Development of the Pittsburgh Sleep Quality Index 
Japanese version. Jpn J Psychiatr Treat. 1998;13:755-63.
12
APPENDICES
12.1
List of Excluded Concomitant Medications
For excluded concomitant medications, a list of excluded concomitant medications, etc., will 
be provided separately.


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12.2
Laboratory Tests
Analyte
Visit
Test tube
Hematology 
tests
Red blood cell count (RBC) 
White blood cell count 
(WBC)
White blood cell differential 
count
Platelet count
Hemoglobin
Hematocrit
MCV
Week −1 (run-in 
period), Week 0, Week 
2, Week 4, Week 8, 
Week 12, 
discontinuation
EDTA-2K tube 
2 mL
Biochemistry
tests
Serum total protein (TP)
Serum albumin (BCG assay)
Total bilirubin
ALP
AST (GOT)
ALT (GPT)
Gamma-GTP
Sodium (Na)
Potassium (K)
Calcium (Ca)
Chloride (Cl)
Inorganic phosphorus
Serum creatinine 
Urea nitrogen
Uric acid
CPK
Week −1 (run-in 
period), Week 0, Week 
2, Week 4, Week 8, 
Week 12, 
Discontinuation
Serum tube 
5 mL*1
Glucose
Week −1 (run-in 
period), Week 0, Week 
2, Week 4, Week 8, 
Week 12, 
Discontinuation
Sodium fluoride 
(NaF) tube 
2 mL
HbA1c*2
Week −1 (run-in 
period) 
EDTA-2K tube 
2 mL
Immunology 
test
Ferritin*2
Week −1 (run-in 
period)
(Same as for 
biochemistry
tests)
Thyroid 
function tests
TSH, Free T4
Week 0, Week 12, 
Discontinuation
(Same as for 
biochemistry
tests)
Urinalysis
Protein
Glucose
Urobilinogen
Week −1 (run-in 
period), Week 0, Week 
2, Week 4, Week 8, 
Week 12, 
Discontinuation
Urine test tube
*1 At Week 0, Week 12 or discontinuation, 7 mL will be drawn for measurements including TSH and free T4.
*2 Ferritin and HbA1c are not handled as safety variables of this study.


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12.3
Common Serious Adverse Events
Not applicable.
12.4
Events Handled as Serious
If any of the events listed below are noted during the study, they should be regarded as SAEs 
and reported in accordance with Section 5.5.5 Reporting of Serious Adverse Events (SAEs).
●
Acute liver failure
●
Acute renal failure
●
Acute respiratory failure
●
Agranulocytosis
●
Anaphylaxis
●
Any malignancy
●
Aplastic anemia
●
Confirmed or suspected transmission of infectious agents by marketed product)
●
Congenital anomalies
●
Hepatic necrosis
●
Malignant hypertension
●
Pulmonary hypertension
●
Convulsion
●
Torsades de pointes
●
Toxic epidermal necrolysis
●
Ventricular fibrillation
●
Hemolytic anemia
●
Bone marrow failure
●
Myocardial infarction
●
Cardiac arrest
●
Deafness
●
Blindness
●
Pancreatitis acute
●
Acute graft versus host disease
●
Septic shock
●
Sepsis
●
Rhabdomyolysis
●
Respiratory failure
●
Stevens-Johnson syndrome


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12.5
Criteria for Seriousness/Severity Grading of Adverse Drug 
Reactions (Notification No. 80 of the Safety Division, Pharmaceutical 
Affairs Bureau, dated June 29, 1992)
Liver
Seriousness/severity of liver disorder is graded on the basis of the laboratory test values, 
symptoms, etc., shown in the table below, in principle.  When liver disorder is suspected 
because of the presence of clinical symptoms such as general malaise, inappetence, nausea, 
pyrexia, and rash, laboratory data, including GOT and GPT, in the patient should be checked, 
and the table below should be used similarly for grading.  Results of a liver biopsy, if 
available, should also be taken into account.
Grade of adverse drug 
reaction
Grade 1
Grade 2
Grade 3
Total bilirubin (mg/dL)
≥1.6, < 3.0
≥3.0, < 10
≥10
GOT, GPT (U)
≥1.25 × N, < 2.5 × N
≥50, < 100
≥2.5 × N, < 12 × N
≥100, < 500
≥12 × N
≥500
ALP
≥1.25 × N, < 2.5 × N
≥2.5 × N, < 5 × N
≥5 × N
γ-GTP
≥1.5 × N
LDH
≥1.5 × N
PTNote)
≤40%
Symptoms, etc.
Jaundice
Hepatomegaly
Pain in the right 
hypochondrium
Hepatic steatosis
Bleeding tendency, 
disturbed consciousness, 
or other symptoms of 
hepatic failure (fulminant 
hepatitis)
Hepatic cirrhosis
Liver tumor
Jaundice lasting ≥6 
months
N: Upper normal limit of the institution
Note) prothrombin


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Kidney
Seriousness/severity of renal disorder is graded on the basis of the laboratory test values, 
symptoms, etc., shown in the table below, in principle.  When renal disorder is suspected 
because of the presence of clinical symptoms such as general malaise, inappetence, nausea, 
edema, hypertension, dull headache, and/or urine findings, the patient’s BUN, creatinine, and 
other data will be checked, and the table below will be used similarly for grading.  Results of 
a kidney biopsy, if available, should also be taken into account. 
Grade of adverse drug 
reaction
Grade 1
Grade 2
Grade 3
BUN (mg/dL)
> 1 × N and < 25
≥25, < 40
≥40
Creatinine (mg/dL)
> 1 × N and < 2
≥2, < 4
≥4
Proteinuria
1 +
2 + or 3 +
> 3 +
Hematuria
Microscopic
Gross
Gross, blood clots
urine volume
≤500 mL/24hr, or 
oliguria/polyuriaNote)
≤100 mL/24hr, 
or anuria
Serum potassium (mEq/l)
≥5.0, < 5.5
≥5.5
Other manifestations
Nephrotic syndrome
Acute renal failure
(interstitial nephritis, renal 
tubular necrosis, renal 
necrosis, renal papillary 
necrosis, renal cortical 
necrosis)
Chronic renal failure
(interstitial nephritis, renal 
tubular necrosis, renal 
necrosis, renal papillary 
necrosis, renal cortical 
necrosis)
Uremia
Hydronephrosis
N: Upper normal limit of the institution
Note) Nephrogenic diabetes insipidus.


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Blood
Seriousness/severity of blood disorder is graded on the basis of the laboratory test values, 
symptoms, etc., shown in the table below, in principle.
Grade of adverse drug 
reaction
Grade 1
Grade 2
Grade 3
Red blood cells
< 3.5 million, ≥3 million
< 3 million, ≥2.5 million
< 2.5 million
Hb (g/dL)
< 11, ≥9.5
< 9.5, ≥8
< 8
White blood cells
< 4000, ≥3000
< 3000, ≥2000
< 2000
Granulocytes
< 2000, ≥1500
< 1500, ≥1000
< 1000
Platelets
< 100000, ≥75000
< 75000, ≥50000
< 50000
Bleeding tendency
Mild hemorrhage 
(Subcutaneous 
hemorrhage)
Moderate hemorrhage
(Mucosal hemorrhage) Note 1)
Severe hemorrhage
(Internal hemorrhage of 
organ) Note 2)
Other manifestations
Pancytopenia
(e.g., aplastic anemia)
Pure red cell aplasia
Agranulocytosis
Note 1) Mucosal hemorrhage = gingival bleeding, epistaxis
Note 2) Internal hemorrhage of organ = intracranial hemorrhage, gastrointestinal hemorrhage, pulmonary 
hemorrhage, renal hemorrhage, genital hemorrhage, muscle hemorrhage, joint internal hemorrhage


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Hypersensitivity symptoms
Seriousness/severity of hypersensitivity symptoms is graded on the basis of the manifestations 
shown in the table below, in principle.
Grade of adverse drug 
reaction
Grade 1
Grade 2
Grade 3
Cutaneous symptoms
Local rash (e.g., local 
erythema, papules)
Itching
Diffuse rash
(e.g., generalized erythema, 
purpura, blisters)
Oculomucocutaneous 
syndrome
Toxic epidermal 
necrolysis
Erythroderma (exfoliative
dermatitis)
(e.g., photosensitivity, fixed eruption, erosions/ulcers, 
pigmentation)
Weber-Christian disease
SLE-like symptomsNote 1)
Scleroderma
Pemphigoid lesions
Generalized
symptoms
Pyrexia
PyrexiaNote 2)Note 3)
Allergy 
Shock
Anaphylactoid 
symptomsNote 4)
Angioedema (face edema, eyelid edema, etc., except 
for laryngeal edema) Note 3)
Angioedema (Laryngeal 
edema)
Vasculitis
Hypersensitivity vasculitisNote 5)
Local symptoms
ArthralgiaNote 3)
Lymph node swellingNote 3)
Note 1) For SLE-like symptoms, generalized symptoms should also be taken into account.
Note 2) This pyrexia refers to so-called “drug fever.”
Note 3) Grade 1 or Grade 2 is determined at the discretion of the attending physician, etc.
Note 4) Anaphylactoid symptoms refer to either the onset of a combination of multiple generalized serious 
symptoms including dyspnea, generalized flushing, angioedema (e.g., face edema, laryngeal edema), or 
urticaria, or the onset of allergic-appearing acute serious dyspnea, without decrease in blood pressure.
Note 5) Grade 2 or Grade 3 is determined at the discretion of the attending physician, etc.


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Respiratory system
Seriousness/severity of respiratory disorder is graded on the basis of the laboratory test values, 
symptoms, etc., shown in the table below, in principle.
Grade of adverse drug 
reaction
Grade 1
Grade 2
Grade 3
Respiratory 
state
Dyspnea
Shortness of breath
HJ Class IINote 1)
Exertional dyspnea
HJ Class III to IVNote 1)
Dyspnea at rest
HJ Class VNote 1)
Respiratory 
rhythm 
disorder
Transient hyperventilation
Sleep apnea without clinical 
symptoms or hypoxemiaNote 2)
Respiratory arrest (apnea)
Respiratory depression
(Hypoventilation, carbon 
dioxide narcosis)
Persistent hyperventilation
(respiratory distress, 
hyperpnoea)
Cheyne-Stokes respiration
Sleep apnea with clinical 
symptoms or hypoxemia Note 
2)
Arterial blood partial 
pressure of oxygen
  PaO2 (mmHg)
< 70, ≥60
< 60, ≥50
< 50
Decrease by 20 from baseline
Arterial blood partial 
pressure of carbon dioxide
PaCO2 (mmHg)
≥50 (Hypoventilation)
≤30 (Hyperventilation)
%VC
FEV1.0%
< 70%, ≥50%
< 70%, ≥50%
< 50%
< 50%
Chest X-ray
findings
Infiltrative 
shadow
< 1/3 of one lungNote 3)
≥1/3 of one lungNote 3)
Interstitial 
shadow
Diffuse interstitial shadow
Pleural 
effusion
< 1/3of one lungNote 3)
≥1/3 of one lungNote 3)
Asthmatic attack
Wheezing,
mild attacksNote 4)
Moderate attacks, severe 
attacksNote 4)
Status asthmaticus
Hemoptysis
Bloody sputum
Hemoptysis
Other manifestations
Hiccups, yawning, 
hoarseness, sneezing, nasal 
congestion/intranasal 
abnormality, cough, 
increased sputum/ sputum 
excretion difficulty, 
laryngopharyngeal 
discomfort, throat pain, 
respiratory tract irritation, 
chest tightness
ARDS (adult respiratory 
distress syndrome), interstitial 
pneumonia, PIE syndrome,
pulmonary fibrosis, 
hypersensitivity pneumonitis, 
pulmonary edema, 
pulmonary embolism, 
pulmonary vasculitis, 
glossoptosis, laryngospasm, 
glottis edema, pulmonary 
hypertensionNote 6)
Chest pain, laryngeal narrowing sensation 
(laryngopharyngeal abnormal sensation) Note 5)
Note 1) Hugh-Jones (HJ) classification of dyspnea:
Class I = Able to walk and go up and down slopes and stairs similarly to healthy people of the same age.
Has no shortness of breath.
Class II = Able to walk similarly to healthy persons of the same age, but unable to go up and down 
slopes and stairs.
Class III = Able to walk 1600 meters or more, though slower than healthy people of the same age


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Class IV = Needs to stop for breath when walking 45 meters
Class V = Has shortness of breath when changing clothes or speaking, and is too breathless to leave 
home
Note 2) Sleep apnea refers to stopping of breathing for 10 seconds or longer, occurring approximately five times 
in one hour of sleep.  Clinical symptoms include headache, erectile dysfunction, hypertension, cardiac failure, 
and excessive daytime lethargy.
Note 3) If no severity information is available regarding infiltrative shadow or pleural effusion, Grade 3 should 
be used.
Note 4) Asthmatic attacks are classified roughly as follows:
Mild attacks: Difficult to breathe, but able to lie down.  Able to talk normally and move normally.
Moderate attacks: Unable to lie down because of difficulty breathing.  Somewhat difficult to talk.  Considerably 
difficult to move.
Severe attacks: Unable to move because of difficulty breathing.  Difficult to talk.  Unable to move.
For pediatric patients, the “Pediatric Allergy Study Group Severity Grading Committee Criteria” (see the next 
page) regarding the severity of pediatric bronchial asthma attacks should be referred to.
Note 5) Grade 1 or Grade 2 is determined at the discretion of the attending physician, etc.
Note 6) For severity of pulmonary arterial pressure, the seriousness/severity grading of pulmonary capillary 
pressure under the cardiovascular system should also be referred to.


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(Reference) Pediatric Allergy Study Group Severity Grading Committee Criteria
Severity of pediatric bronchial asthma attacks
Breathing status 
Living activities
Playing
Sleeping
Mood
(Talking)
Eating
Mild 
attack
Mild wheezing without 
dyspnea, possibly with slight 
intercostal retractions
Normal
Normal
Normal
Talk normally
Normal
Moderate 
attack
Obvious wheezing and 
intercostal retractions with 
dyspnea
Somewhat 
difficult
Occasionally
wake during 
sleep
Somewhat 
poor
Able to talk 
back when 
talked to
Somewhat 
poor
Severe 
attack
Orthopnea with marked 
wheezing and dyspnea, 
orthopnea, possibly with 
cyanosis
Impossible or
almost 
impossible
Impossible or
almost 
impossible
Poor
Unable to talk
back even 
when talked to
Impossible or
almost 
impossible
1. The severity of an attack should be assessed primarily on the basis of the breathing status, with supportive use 
of other items.
2. Decreased breath sounds and disturbed consciousness (e.g., excitement, decreased consciousness, decreased 
response to pain) are life-threatening signs.


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Gastrointestinal system
Seriousness/severity of gastrointestinal disorder is graded on the basis of the laboratory test 
values, symptoms, etc., shown in the table below, in principle.
Grade of adverse drug 
reaction
Grade 1
Grade 2
Grade 3
Nausea, Vomiting
Nausea (Queasy)
VomitingNote 1)
Diarrhea
Soft stools, mushy stools
Watery stools not meting 
Grade 3
Watery stools with 
dehydration and electrolyte 
abnormality
Gastrointestinal hemorrhage 
Occult blood (+)
Bloody stools, hematemesis, 
or melena without any shock 
and decreased hemoglobin 
(≤8.0 g/dL)
Bloody stools, hematemesis, 
or melena with shock and 
decreased hemoglobin 
(≤8.0 g/dL)
Intraoral abnormality
Subjective intraoral discomfort
Ulcerative stomatitis
(Example) Lip dryness, 
intraoral discomfort, intraoral 
numbness, tasting bitter, tongue 
numbness, abnormal tongue 
feeling
Intraoral abnormality with objective inflammation, etc.Note 1)
(Example) Angular stomatitis, cheilitis (lip vesicles), 
stomatitis (rough intraoral mucosa, gingival pain), glossitis 
(tongue eruption, rough tongue, glossodynia), coated tongue, 
black tongue, gingival hypertrophy
Esophageal abnormality
Subjective esophageal 
discomfort
Esophageal abnormality with objective inflammation, ulcers, 
etc.Note 2)
(Example) Choking sensation, 
sensation of esophageal 
obstruction
(Example) Esophagitis, esophageal ulcer
Dysphagia
Swallowing difficulty
Swallowing inability
Gastrointestinal 
abnormality
Subjective gastrointestinal 
discomfort
(Example) Heartburn, 
dyspepsia, heavy stomach 
feeling, stomach discomfort, 
abdominal discomfort, rumbling 
of the intestine, Inappetence
Pain
Pain in the stomach or 
abdominal not meeting Grade
2 which is tolerable or requires 
no treatment
Colic pain (stomach cramps, 
abdominal cramps, intestinal 
cramps)
Inflammation
Gastritis, enterocolitis, colitisNote 3)
Proctitis (rectal mucosal edema, rectal mucosal irritation) Note 
1)
Hemorrhagic colitis, pseudomembranous colitisNote 2)


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Grade of adverse drug 
reaction
Grade 1
Grade 2
Grade 3
Gastrointestinal 
abnormality
Ulcer
Erosion
Gastric ulcer, duodenal ulcer, 
hemorrhagic ulcer, small intestine 
ulcer, large intestine ulcerNote 2)
Gastrointestinal 
perforation
Intestinal 
paralysis
ConstipationNote 1)
Ileus paralytic
Anal abnormality
Subjective anal discomfort
(Example) Anal pain, anal 
discomfort, anal distress, anal 
itching
Anal abnormality with objective inflammation, etc. Note 1)
(Example) Periproctitis (anal roughness, anal erosion), 
hemorrhoidal hemorrhage, hemorrhoidal prolapse
Pancreatic disorder
Abnormal amylase level only Pancreatitis not meeting Grade 
3
Pancreatic necrosis, 
hemorrhagic pancreatitis
Other manifestations
Hiccups, thirst (dry mouth), 
belching (eructation, burping),
colon mucosal pigmentation, 
flatulence, flatus, sulfurous 
smell, frequent bowel 
movements (defecation desire, 
defecation urgency, tenesmus)
Sialoadenitis, fecal incontinenceNote 1)
Note 1) Grade 1 or Grade 2 is determined at the discretion of the attending physician, etc.
Note 2) Grade 2 or Grade 3 is determined on the basis of the severity of concurrent clinical symptoms such as 
diarrhea, gastrointestinal hemorrhage, and dysphagia.
Note 3) The terms gastritis, enterocolitis, and colitis are typically used when the patient has clinical symptoms 
such as vomiting, gastralgia, abdominal pain, diarrhea, irrespective of any presence of objective 
inflammation.  Gastritis, enterocolitis, and colitis should thus be graded on the basis of the intensity of 
clinical symptoms such as vomiting.


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Cardiovascular system
Seriousness/severity of cardiovascular disorder is graded on the basis of the laboratory test 
values, symptoms, etc., shown in the table below, in principle.
Grade of adverse drug 
reaction
Grade 1
Grade 2
Grade 3
Blood pressure 
abnormality
Decreased
Systolic
blood 
pressure 
(mmHg) 
< 90, ≥80
< 80
Symptoms
Dizziness on standing up, orthostatic dizziness, orthostatic 
hypotension
No palpable pulse
Increased
Increased blood pressure (abnormal increase in blood 
pressure, abrupt increase in blood pressure), hypertension
Circulatory disorder
Shock, cyanosis, peripheral 
circulatory failure
Heart rate
Tachycardia
≥110, < 130
≥130
(bpm)
Bradycardia
< 50, ≥40
< 40
Arrhythmia
Palpitations, arrhythmia
(without ECG measurements)
Supraventricular 
extrasystoles
Supraventricular tachycardia
Ventricular extrasystole
(solitary)
Ventricular extrasystoles
(two consecutive 
extrasystoles)
Bigeminy
Ventricular extrasystoles
(multifocal) (three or more 
consecutive extrasystoles),
Ventricular tachycardia (six 
or more consecutive beats),
Ventricular fibrillation,
Torsades de pointes
Atrial fibrillation (including 
paroxysmal)
Atrial flutter
Tachycardia paroxysmal
First degree atrioventricular 
block (atrioventricular 
conduction time 
prolongation)
Second degree 
atrioventricular block, 
atrioventricular dissociation, 
sinus arrest, bundle branch 
block (intraventricular block)
(defect conduction 
intraventricular), nodal 
rhythm, ventricular rhythm
Third degree atrioventricular 
block (complete
atrioventricular block), 
cardiac arrest (cessation of 
heartbeat), Adams-Stokes
syndrome
Electrocardiogram abnormal
P wave absent
PR or PQ prolongation
ST elevation,
ST depression,
T wave inversion,
T wave flattening,
U wave appearance,
QT prolongation,
QRS widening


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Grade of adverse drug 
reaction
Grade 1
Grade 2
Grade 3
Cardiac failure-like 
symptoms
Edema (generalized, 
peripheral)
Cardiac failure (congestive 
cardiac failure), right cardiac 
failure, left cardiac failure 
(cardiac asthma), acute 
cardiac failure, cardiomegaly 
(increased cardiac ratio)
Reference
Myocardial 
contractility
60% ≥left ventricular 
ejection fraction (LVEF) > 
50%
50% ≥LVEF >40%
40% ≥LVEF
Cardiac output
(cardiac index) 
2.5 l/min/m2 ≥
2.2 l/min/m2 ≥
Pulmonary 
capillary pressure 
(Pulmonary 
arterial systolic 
pressure) (mmHg) 
≥20, < 30
≥30, < 40
≥40
Dyspnea
See the grading 
criteria in the 
Respiratory 
system section
Shortness of breath
HJ Class II
Exertional dyspnea
HJ Class III to IV
Dyspnea at rest
HJ Class V
Ischemic heart disease-like 
symptoms
Chest discomfort
Chest distressed feeling of
Chest pressure
Worsening of angina pectoris
Angina pectoris attack 
(induction)
Myocardial infarction 
(coronary artery thrombosis)
Myocardial necrosis
Chest pain, anginal pain (angina-like pain), myocardial 
ischemia, coronary failure Note)
Myocardial, pericardial, or 
endocardial disorder
Pericarditis
Pericardial effusion
Endocarditis
Myocarditis
Myocardial fibrosis
Myocardial disorderNote)
Vascular disorder
Vascular pain
Angiospasm
Intermittent claudication
Arteriosclerosis
Gangrene
Vasculitis
Thrombophlebitis
Thrombosis
Arterial or venous thrombosis
Thromboembolism
Pulmonary embolism 
(Infarction)
Cerebral embolism 
(Infarction)
Mesenteric embolism
Raynaud-like syndrome Note)
(without gangrene) 
Other symptoms
Flushed face (hot flush)
Feeling hot
Burning sensation
Face flush
Note) Grade 1 or Grade 2 is determined at the discretion of the attending physician, etc.


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Psychoneurological system
Seriousness/severity of psychoneurological disorder is graded on the basis of manifestations 
shown in the table below, in principle, taking into account of their nature such as whether 
subjective or objective, whether manageable or not, whether assistance is required or not, 
whether transient or persistent, and whether reversible or irreversible.


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Grade of adverse 
drug reaction
Grade 1
Grade 2
Grade 3
Abnormal 
mental 
activities 
and 
behaviors
Hyperthymia
or unstable 
mood
Subjective hyperthymia or unstable 
mood
Symptoms stated under Grade 1 
are objectively notable, and 
accompanied by abnormal 
behaviors
Symptoms stated under 
Grade 2 are severe and 
uncontrollable
(Example) Emotional instability, 
mood swings, labile affect, 
nervousness, irritable mood, 
irritability, bad mood, anxiety
(feeling), feeling irritated, 
talkativeness, hyperthymia, 
cheerfulness, euphoria (euphoric 
mood)
(Example) Manic depression/Manic 
state, change to manic state, 
aggression, irritable excitation, 
excitement, irritability, unrest, 
irritable hyperkinesis, poriomania, 
impulsive behavior, lack of 
suppression, affective incontinence
Insomnia (sleep disorder)
Decreased 
mood/
volition/
behavior
Subjective decrease of 
mood/volition
Symptoms stated under Grade 1 
are objectively notable
Symptoms stated under 
Grade 2 are severe and 
uncontrollable
(Example) Hypobulia, dullness, lack of motivation, sensation of lack of 
motivation, listlessness, avolition, vague head, absent mindedness, 
dream-like state, decreased mental concentration, depressed state, 
depression (state), depressed mood, melancholia
(Example) Suicidal 
ideation/attempt, 
depressive stupor
Psychosis-
like 
symptoms
Transient 
illusion/hallucination/delirium
(e.g., nocturnal delirium)
Persistent 
illusion/hallucination/
delirium, confusion, 
delusion
Cognitive 
disorder
Reduced subjective cognitive 
ability
Reduced objective cognitive 
ability
Symptoms stated under 
Grade 2 are severe and 
persistent
(Example) Forgetfulness, decreased 
memory ability
(Example) Anterograde amnesia, 
retrograde amnesia
(Example) Dementia
Consciousness disorder
Subjective consciousness disorder
Objective consciousness disorder
Symptoms stated under 
Grade 2 are severe and 
persistent
(Example) Arousal difficult, delayed 
awaking, feeling drunk, feeling of 
residual sleepiness after sleeping, 
sedation, excessive sedation, 
nightmare, excessive dreaming
(Example) Somnolence, lethargy, 
drowsiness, light-headedness state, 
clouding of consciousness, 
transient loss of consciousness, 
syncope, disturbed orientation, 
disorientation
(Example) Coma, 
persistent loss of 
consciousness
Movement 
disorder
Coordinated 
movement 
Subjective impairment of 
coordinated movement
Objective impairment of 
coordinated movement
Symptoms stated under 
Grade 2 are severe and 
significantly interfere with 
activities of daily living, 
and require assistance
(Example) light-headed feeling, 
dizziness, vertigo, swaying
(feeling)
(Example) Ataxia, coordinated 
movement disorder
Gait
Objective gait disturbance
Symptoms stated under 
Grade 2 are severe and 
significantly interfere with 
activities of daily living, 
and require assistance
(Example) Frozen gait, gait 
disturbance, difficulty in walking, 
ataxic gait, abnormal gait
(Example) Abasia


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Grade of adverse 
drug reaction
Grade 1
Grade 2
Grade 3
Movement 
disorder
Muscle 
strength/
Paralysis
Objective muscle strength decrease 
and impairment
Symptoms stated under 
Grade 2 are severe and 
significantly interfere with 
activities of daily living, and 
require assistance
(Example) Hypotonia, muscle 
weakness, Muscular weakness, 
Paresis
(Example) Facial paralysis, 
quadriplegia, hemiplegia, 
monoplegia
Myalgia/
Arthralgia
Symptoms tolerable or requiring 
no treatment
Severe and persistent symptoms
(Example) Arthralgia, myalgia, back pain, low back pain, nuchal pain, 
neck pain
Extrapyramidal symptoms 
Involuntary movement
Transient mild involuntary
movements
Persistent involuntary movement that 
recognized as a neurological 
manifestation
Symptoms stated under 
Grade 2 are severe and 
significantly interfere with 
activities of daily living, and 
require assistance
(Example) Transient tremor (limb 
tremor, finger tremor), hand 
tremor, tremor
(Example) Marked or persistent 
tremor, perioral involuntary 
movement, facial tic, protrusion 
tongue, mask-like face, dyskinesia, 
hyperkinesia, akathisia, hyperkinesis, 
Parkinson’s syndrome (Parkinson 
symptoms, Parkinson-like symptoms, 
or their worsening)
Muscle tightness
Subjective muscle tightness
abnormality
Severe muscle tightness recognized 
as a neurological manifestation
Symptoms stated under 
Grade 2 are severe and 
significantly interfere with 
activities of daily living, and 
require assistance
(Example) Hypokinesia, slow 
movement, stiff shoulder, 
anteversion-anteflexion posture, 
a feeling of tension in lower limb
(Example) Facial or perioral tension, 
hypertonia, rigidity, muscle rigidity, 
myotonia, muscle stiffness, muscle 
spasticity, neck [limb] ankylosis, 
stiffness of body
Language 
disorder
Subjective language disorder
Objective language disorder
Symptoms stated under 
Grade 2 are severe and 
significantly interfere with 
activities of daily living, and 
require assistance
(Example) Slurred speech due to 
impaired tongue (mouth)
movement, tongue movement 
disturbance
(Example) Dyslalia, Dysarthria
(Example) Aphasia
Eye 
movement 
disorder
Transient eye movement disorder
Symptoms stated under 
Grade 2 are severe and 
persistent
(Example) Ocular deviation, 
oculogyric crisis, ocular lateral crisis, 
eyeballs raise upward, nystagmus, 
diplopia
Reflex
Decreased reflex
Pathological increase of reflex
Appearance of pathological 
reflex
(Example) Decreased tendon 
reflex, decreased reflex
movement ability
Loss of reflex
(Example) Babinski reflex
Convulsion/Cramp
Subjective
Local cramp
Generalized convulsion
(Example) Bodily shaking
(Example) Twitching, muscle 
twitching, head/facial spasm, upper 
limb extension, muscle cramps
(Example) Generalised 
convulsion, epileptic 
seizure, epilepsy-like 
seizure, clonic convulsion, 
tonic convulsion, seizure, 
induction of seizure, 
opisthotonos


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Grade of adverse 
drug reaction
Grade 1
Grade 2
Grade 3
Sensory 
dysfunction
Auditory 
disorder
Subjective auditory disorder
Objective transient auditory disorder
Irreversible auditory 
disorder
(Example) Tinnitus, ear 
congestion sensation
(Example) Decreased hearing, 
hypoacusis
(Example) Irreversible 
deafness, no hearing (total 
deafness)
Visual 
disorder
Subjective visual disorder
Objective transient visual disorder
Irreversible visual disorder
(Example) Photophobia, 
sensation of decreased visual 
acuity, visual flashes, blurred
vision, visual accommodation 
disorder
(Example) Visual acuity reduced 
transiently, transient color blindness
(Example) Optic neuritis, 
blindness, visual field 
disorder
Olfactory 
disorder
Transient smell disorderNote)
Irreversible smell disorder
(Example) Dysosmia, strange smell sensation
(Example) Loss of smell
Taste 
disorder
Transient taste disorderNote)
Irreversible taste disorder
(Example) Tongue sensation abnormal, dysgeusia, hypogeusia
(Example) Loss of taste
Perception
(sensation)
disorder
Transient perception (sensation) disorderNote)
Irreversible perception
(sensation) disorder
(Example) Limb numbness, tongue numbness, lip numbness, ear pain, 
perceptual (sensation) alteration, perceptual (tactile) loss
(Example) Loss of 
perception (sensation)
Peripheral nerve (nerve 
disorder)
Transient neuralgia
Persistent neuralgia
Symptoms stated under 
Grade 2 are severe and 
significantly interfere with 
activities of daily living, and 
require assistance
(Example) Guillain-Barre 
syndrome, polyneuritis, 
peripheral neuritis, 
myopathy
Dependence
Slight psychological dependence, 
with a tendency toward dose increase 
(tendency toward drug tolerance)
Physical dependence, 
withdrawal symptoms 
(abstinence syndrome)
Other
Yawning, cerebral anemia-like of 
symptoms, floating sensation, 
unstable feeling, headache, 
heaviness of head (feeling), head 
pressure, strange sensation, 
abnormal physical feeling, 
fatigue, general malaise, feeling 
of weakness, discomfort, 
unpleasant feeling
Swallowing difficulty (decreased 
swallowing ability), salivation
Aphagia, neuroleptic 
malignant syndrome, 
malignant hyperthermia, 
encephalopathy/leukoencep
halopathy, 
meningitis/meningitis-like 
symptoms, cerebrovascular 
disorders (e.g., cerebral 
hemorrhage, cerebral 
infarction)
Note) Grade 1 or Grade 2 is determined at the discretion of the attending physician, etc.


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‐ CONFIDENTIAL ‐
13 January 2017
Astellas
Page 102 of 105
Metabolism and electrolyte abnormality
Seriousness/severity of metabolism or electrolyte abnormality is graded on the basis of the 
laboratory test values, symptoms, etc., shown in the table below, in principle.
Grade of adverse drug 
reaction
Grade 1
Grade 2
Grade 3
Blood glucose 
abnormality 
(mg/dL)
Increased 
blood glucose
Casual blood glucose 120–200
or
Fasting 120–140
Postprandial 160–200
Casual blood glucose 201–300
or
Fasting 141–200
Postprandial 201–300
Casual blood glucose ≥301
Symptoms
Diabetic coma
Decreased 
blood glucose
69–60
59–51
≤50
Symptoms
Hypoglycemic symptoms such 
as dizziness, headache, hunger, 
irritated feeling, and marked 
sweating
Hypoglycemic coma, 
convulsion
Metabolic 
acidosis
Arterial blood 
pH
< 7.35, ≥7.20
< 7.20, ≥7.15
< 7.15
Symptoms
Disturbed consciousness, 
decreased blood pressure, 
convulsion, respiratory 
disorder (Kussmaul breathing)
Metabolic 
alkalosis
Arterial blood 
pH
≥7.46, < 7.50
≥7.50, < 7.60
≥7.60
Symptoms
Convulsion, tetany, 
hypertension, arrhythmia
Serum calcium
abnormality
Increased
≥10.6, < 12.1
≥12.1, < 15.0
≥15.0
Symptoms
Disturbed consciousness
(mg/dL)
Decreased
< 8.5, ≥8.0
< 8.0, ≥6.5
< 6.5
Symptoms
Tetany, decreased blood 
pressure, arrhythmia, 
psychiatric symptoms
Serum 
potassium 
abnormality
IncreasedNote)
≥5.0, < 5.5
≥5.5, < 6.0
≥6.0
(mEq/l)
Symptoms
Arrhythmia, muscle paralysis
Decreased
< 3.5, ≥3.1
< 3.1, ≥2.5
< 2.5
Symptoms
Weakness, muscle paralysis, 
arrhythmia
Serum sodium 
abnormality
Increased
≥150, < 155
≥155, < 160
≥160
Symptoms
CNS symptoms (disturbed
consciousness, 
convulsion)
(mEq/l)
Decreased
< 135, ≥125
< 125, ≥115
< 115
Symptoms
Psychiatric disorders, 
convulsion, disturbed
consciousness, pathological 
reflex


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‐ CONFIDENTIAL ‐
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Page 103 of 105
12.6
International Restless Legs Syndrome Study Group Rating Scale 
(IRLS) (Investigator Version 2.2)
Ask the patient to rate his/her symptoms for the following ten questions.  The patient, and not 
the examiner, should make the ratings, but the examiner should be available to clarify any 
misunderstandings the patient may have about the questions. The examiner should mark the 
patient’s answers on the form.
In the past week
(1) Overall, how would you rate the RLS discomfort in your legs or arms?
4□  Very severe
3□  Severe
2□  Moderate
1□  Mild
0□  None
In the past week
(2) Overall, how would you rate the need to move around because of your RLS symptoms?
4□  Very severe
3□  Severe
2□  Moderate
1□  Mild
0□  None
In the past week
(3) Overall, how much relief of your RLS arm or leg discomfort did you get from moving 
around?
4□  No relief 
3□  Mild relief
2□  Moderate relief
1□  Either complete or almost complete relief
0□  No RLS symptoms to be relieved


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In the past week
(4) How severe was your sleep disturbance due to your RLS symptoms?
4□Very severe 
3□  Severe
2□  Moderate 
1□  Mild 
0□  None 
In the past week
(5) How severe was your tiredness or sleepiness during the day due to your RLS symptoms?
4□  Very severe
3□  Severe
2□  Moderate
1□  Mild
0□  None
In the past week
(6) How severe was your RLS on the whole?
4□  Very severe
3□  Severe
2□  Moderate
1□  Mild
0□  None
In the past week
(7) How often did you get RLS symptoms?
4□  Very often (This means 6 to 7 days a week.)
3□  Often (This means 4 to 5 days a week.)
2□  Sometimes (This means 2 to 3 days a week.)
1□  Occasionally (This means 1 day a week or less.)


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0□  Never
In the past week
(8) When you had RLS symptoms, how severe were they on average?
4□  Very severe (This means 8 hours or more per 24 hour day or more.)
3□  Severe (This means 3 to 8 hours per 24 hour day.)
2□  Moderate (This means 1 to 3 hours per 24 hour day.)
1□  Mild (This means less than 1 hour per 24 hour day.)
0□  None
In the past week
(9) Overall, how severe was the impact of your RLS symptoms on your ability to carry out 
your daily affairs, for example carrying out a satisfactory family, home, social, school, or 
work life?
4□  Very severe
3□  Severe
2□  Moderate
1□  Mild
0□  None
In the past week
(10) How severe was your mood disturbance from your RLS symptoms–for example angry, 
depressed, sad, anxious, or irritable?
4□  Very severe
3□  Severe
2□  Moderate
1□  Mild
0□  None
(GPF 4.1J)

SAP_001.pdf: 
Sponsor: Astellas Pharma Inc.
SAP Final Version 1.00
ISN/Protocol 8825-CL-0101
03-Sep-2018
Astellas
Page 1 of 46
STATISTICAL ANALYSIS PLAN
Final Version 1.00, dated 03-Sep 2018
Gabapentin Enacarbil post-marketing clinical study
- A Randomized, Double-blind, Placebo-controlled, Parallel-group Study 
in Subjects With Restless Legs Syndrome -
ISN: 8825-CL-0101
Astellas Pharma Inc. (API)
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.00
ISN/Protocol 8825-CL-0101
03-Sep-2018
Astellas
Page 2 of 46
Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 4
1
INTRODUCTION·················································································· 6
2
FLOW CHART AND VISIT SCHEDULE···················································· 7
3
STUDY OBJECTIVE AND DESIGN ·························································11
3.1
Study Objective ···············································································11
3.2
Study Design···················································································11
3.3
Randomization·················································································11
4
SAMPLE SIZE ····················································································11
5
ANALYSIS SETS ·················································································12
5.1
Full Analysis Set (FAS) ······································································12
5.2
Per Protocol Set (PPS)········································································12
5.3
Safety Analysis Set (SAF) ···································································13
6
ANALYSIS VARIABLES ·······································································13
6.1
Efficacy Endpoints············································································13
6.1.1
Primary Efficacy Endpoint·····························································13
6.1.2
Secondary Efficacy Endpoints·························································13
6.2
Safety Variables···············································································14
6.2.1
Adverse Events ··········································································14
6.3
Other Variables················································································14
6.3.1
Variables Related to Study Drugs ·····················································14
6.3.2
Demographic Characteristic Variables················································16
6.3.3
Previous and Concomitant Medication ···············································16
7
STATISTICAL METHODOLOGY ···························································16
7.1
General Considerations·······································································16
7.2
Study Population ··············································································17
7.2.1
Disposition of Subjects ·································································17
7.2.2
Demographic and Other Baseline Characteristics ···································18
7.2.3
Previous and Concomitant Medications ··············································19
7.3
Study Drugs····················································································20
7.3.1
Exposure··················································································20
7.3.2
Study drug Compliance·································································20


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.00
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03-Sep-2018
Astellas
Page 3 of 46
7.4
Analysis of Efficacy ··········································································20
7.4.1
Analysis of Primary Endpoint ·························································20
7.4.2
Analysis of Secondary Endpoints ·····················································26
7.5
Analysis of Safety·············································································28
7.5.1
Adverse Events ··········································································28
7.5.2
Clinical Laboratory Evaluation ························································29
7.5.3
Vital Signs················································································31
7.5.4
Body Weight ·············································································31
7.5.5
Epworth Sleepiness Scale ······························································31
7.6
Analysis of PK·················································································31
7.7
Analysis of PD·················································································31
7.8
Subgroups of Interest ·········································································31
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)····················32
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········32
7.10.1
Missing Data ·············································································32
7.10.2
Outliers ···················································································32
7.10.3
Visit Windows ···········································································32
8
DOCUMENT REVISION HISTORY·························································35
9
REFERENCES ····················································································35
10
APPENDICES ·····················································································36
10.1
Appendix 1: Pittsburgh Sleep Quality Index···············································36
10.1.1
Pittsburgh Sleep Quality Index Questionnaire·······································36
10.1.2
Pittsburgh Sleep Quality Index Scoring ··············································41
10.2
Appendix 2: Key Contributors and Approvers ············································45


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.00
ISN/Protocol 8825-CL-0101
03-Sep-2018
Astellas
Page 4 of 46
I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase (GPT)
ANCOVA
Analysis of covariance
API
Astellas Pharma Inc. 
AST
Aspartate aminotransferase (GOT) 
CI
Confidence interval
CRF
Case report form
Dev
Development
eCRF
Electronic case report form
FAS
Full analysis set
H
High
ICGI
Investigator-rated clinical global impression
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IRLS
International restless legs scale
ISN
International study number 
L
Low
LOCF
Last observation carried forward
MAR
Missing at random
MCMC
Markov chain Monte Carlo
MedDRA
Medical dictionary for regulatory activities
MI
Multiple imputation
MMRM
Mixed model of repeated measurements
MNAR
Missing not at random
N
Normal
PCGI
Patient-rated clinical global impression
PD
Pharmacodynamic
PK
Pharmacokinetics 
PMM
Pattern mixture model
PPS
Per protocol set
PSQI
Pittsburgh sleep quality index
PT
Prothrombin time (second) 
QOL
Quality of life 
RLS
Restless legs syndrome
SAE
Serious adverse event
SAF
Safety analysis set
SAS 
Statistical Analysis Software
SD
Standard deviation
SOC
System organ class
TEAE
Treatment-emergent adverse event
TLF
Tables, Listings and Figures
ULN
Upper limit of normal
WHODDE
WHO drug dictionary enhanced


Sponsor: Astellas Pharma Inc.
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List of Key Terms
Term
Definition of terms
Follow-up period
The period from the start of administration of the study drug for the 
follow-up period to the final observation
Gabapentin
An antiepileptic drug synthesized in Germany in 1973; the active 
metabolite of gabapentin enacarbil
Gabapentin 
enacarbil
The active substance of Regnite Tablets; nonproprietary name of the 
drug
Registration failure
A subject who provided informed consent but did not fulfill the 
inclusion/exclusion criteria for formal registration and thus was not 
randomized or did not receive open-label study drug, or who 
withdrew consent during the run-in period.
Study period
The period from informed consent of the subject to completion of 
protocol-specified last evaluation/observation in the subject
Screening
A process of active consideration of potential subjects for enrollment 
in the study, conducted during the run-in period to determine the 
eligibility for the study
Enroll
To register or enter a patient into a clinical trial as a subject; NOTE: 
Once a subject is enrolled into the study, the clinical study protocol 
applies to the subject.
Subject
Study participant
Subject ID number
A number assigned to a subject who provided consent to participate in 
the study by signing the consent form
Endpoint
An attribute, phenomenon, or event that varies in quality or quantity 
and serves as a variable
Baseline
Measurement or finding obtained at a time point judged to be 
initiation of observation for comparison
Run-in period
The period from the start of administration of the study drug for the 
run-in period to before the start of administration of the study drug for 
the treatment period
Randomization
A process of assigning study subjects to treatment or control groups in 
which an element of chance is used in the determination of 
assignments to reduce bias
Regnite® Tablets
Alternative name for the study drug gabapentin enacarbil; brand name 
of the drug product approved for marketing in January 2012 
ASP8825
Alternative name for the study drug gabapentin enacarbil; a drug 
substance code used by Astellas Pharma Inc.
GSK1838262
Alternative name for the study drug gabapentin enacarbil; a drug 
substance code used by GlaxoSmithKline K.K.
XP13512
Alternative name for the study drug gabapentin enacarbil; a Drug 
substance code used by XenoPort, Inc.


Sponsor: Astellas Pharma Inc.
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03-Sep-2018
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Page 6 of 46
1
INTRODUCTION
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data.
The SAP is finalized and signed prior to unblinding.
This statistical analysis is coordinated by the responsible biostatistician of Dev, API. Any 
changes from the analyses planned in the SAP will be justified in the Clinical Study Report
(CSR).


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.00
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03-Sep-2018
Astellas
Page 7 of 46
2
FLOW CHART AND VISIT SCHEDULE
Flow Chart
< Gabapentin enacarbil 600 mg group >
Estimated creatinine clearance at 
the start of the run-in period: 
≥90 mL/min
Estimated creatinine clearance 
at the start of the run-in period: 
≥60 to < 90 mL/min
Treatment period (12 weeks) 
(double-blind)
Gabapentin enacarbil
300 mg 2 tablets
Treatment period (upward 
titration period, 1 week)
(double-blind)
Gabapentin enacarbil
300 mg 1 tablet
+
Placebo 1 tablet
↓
Treatment period (11 weeks) 
(double-blind)
Gabapentin enacarbil 
300 mg 2 tablets
< Placebo group >
Treatment period (12 weeks) 
(double-blind)
Placebo 2 tablets
Formal registration
Provisional registration
Run-in period (1 week) (single-blind)
Placebo 2 tablets
Assessment against inclusion/exclusion
criteria (Formal registration)
Follow-up period (1 week)** (single-blind)
Placebo 2 tablets
Assessment against inclusion/exclusion criteria 
(Provisional registration)
Washout period*
Informed consent


Sponsor: Astellas Pharma Inc.
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Page 8 of 46
*
Subjects using the following drugs before the start of the run-in period will require the specified washout 
period:
1. Dopamine agonists, dopamine preparations, gabapentin, pregabalin: ≥7 days
2. Opioids, benzodiazepines (for only if used to treat RLS), long-acting dopamine agonists: ≥14 days
** For the subjects discontinued during the treatment period, the tests/observations required at discontinuation 
will be performed and then post-treatment follow-up will be performed as far as possible, but this does not 
require the use of placebo during the follow-up period.
< Start and end of the post-marketing clinical study >
The time of the start of this post-marketing clinical study is defined as the time at which 
informed consent is obtained from the first subject. The time of the end of this post-
marketing clinical study is defined as the time at which protocol-specified final assessment is 
implemented in the last subject.


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.00
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Schedule of Assessments
Run-in 
period
Treatment period 
Follow-up period Discontinuation*5
W-1
W0
W1
W2
W4
W6
W8
W10
W12
W13
Day of observation
−7
1
8
15
29
43
57
71
85
Last dosing of the 
study drug for the 
treatment period 
+ 8 days*4
Allowed visit 
window
−10 to −7
1
5 to 
11
12 to 
18
26 to 
32
40 to 
46
54 to 
60
68 to 
74
82 to 
88
Last dosing of the 
study drug for the 
treatment period
+ 5 to 11 days*4
Visit











Informed consent 

Subject 
characteristics

Assessment against 
inclusion/
exclusion criteria


Patient registration

Provisional

Formal

Discontinuation
Prescription of the 
study drug


*3






Compliance status










Concomitant 
medication 
monitoring











IRLS score











ICGI







PCGI







Pittsburgh Sleep 
Quality Index





Athens Insomnia 
Scale 





EQ-5D-5L





RLS Pain score 











Epworth Sleepiness 
Scale










Laboratory tests







Thyroid function 
tests
(TSH, Free T4)



HbA1c

Ferritin

Estimated creatinine 
clearance

Pregnancy test*1



Height

Body weight






Vital signs










Adverse event 
monitoring*2


*3








Central measurements


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.00
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03-Sep-2018
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Page 10 of 46
*1 Not required in men, postmenopausal women (no menstruation for at least 1 year), or other women with a 
history of hysterectomy, bilateral oophorectomy, etc. in whom a possibility of pregnancy is clearly excluded.
*2 A medical interview should determine any occurrence of eye disorders such as blurred vision or 
accommodation disorder.
*3 In subjects with an estimated creatinine clearance of ≥60 to < 90 mL/min at the start of the run-in period 
randomized to the gabapentin enacarbil group, in whom the dose is titrated from 300 mg to 600 mg, any 
occurrence of AEs should be carefully assessed and the subject’s condition should be adequately observed, 
based on which whether the subject can continue with the study should be carefully determined.
*4 Follow-up observation will occur on the day of “last dosing of the study drug for the treatment period +8 
days,” which will be Day 92 in subjects who take the study drug for the treatment period up to Day 84 per 
protocol.
*5 For the subjects discontinued during the run-in period, the compliance status and any AEs will be 
investigated.
For the subjects discontinued during the treatment period, the tests/observations required at discontinuation 
will be performed, and then post-treatment follow-up (i.e., the Week 13 procedure) will be performed as far 
as possible, but this does not require the use of placebo during the follow-up period.
For the subjects discontinued during the follow-up period, the Week 13 procedure will be performed as the 
tests/observations at discontinuation.


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3
STUDY OBJECTIVE AND DESIGN
3.1
Study Objective
- To verify the efficacy of oral gabapentin enacarbil 600 mg once daily compared with 
placebo on the basis of the change from baseline in IRLS score in patients with moderate to 
severe idiopathic restless legs syndrome (RLS), using a multicenter, randomized, double-
blind, parallel-group, comparative design.
- To evaluate the safety of gabapentin enacarbil 600 mg.
3.2
Study Design
Gabapentin enacarbil 600 mg or placebo will be administered orally once daily after the 
evening meal.  Patients meeting the inclusion and exclusion criteria at provisional registration 
will receive single-blind placebo for 1 week (run-in period). Of these, patients meeting the 
inclusion and exclusion criteria at formal registration will be randomized to receive double-
blind treatment with either gabapentin enacarbil 600 mg or placebo for 12 weeks (treatment 
period). After the end of the 12-week treatment period, single-blind placebo will be given for 
1 week (follow-up period) for follow-up observation.
However, of the patients meeting the inclusion and exclusion criteria at formal registration, 
those with an estimated creatinine clearance of ≥ 60 to < 90 mL/min at the start of the run-in 
period will receive randomized double-blind treatment initially with either gabapentin 
enacarbil 300 mg or placebo for 1 week (upward titration period) followed by gabapentin 
enacarbil 600 mg or placebo for 11 weeks, totaling 12 weeks (treatment period including the 
upward titration period).
3.3
Randomization
The person responsible for study drug randomization will prepare the treatment codes for 
randomization of the study drug for the double-blind period, and retain them under lock and 
key until the time of treatment code breaking.
Stratified allocation will be performed with stratification factors of age (< 50 years and 50 
years) at the start of the run-in period and estimated creatinine clearance (≥ 60 to < 90 
mL/min and ≥ 90 mL/min) at the start of the run-in period, to minimize imbalance in subject 
characteristics between the treatment groups to allow for proper comparison. The patient 
registration center will assign the drug numbers to the subjects in accordance with the patient 
registration procedures.
4
SAMPLE SIZE
180 subjects per group (360 subjects in the two groups) as participants in the treatment 
period.
[Rationale for sample size]


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The Japanese phase II/III study [CL-0003] demonstrated the change in IRLS score (mean and 
standard deviation) at the end of treatment period (Week 12) as shown in Table 1.  Of the 
randomized subjects, 11.8% in the placebo group and 17.5% in the 600 mg group were 
discontinued during the treatment period.
Table 1: Change in IRLS score (mean and standard deviation) at the end of treatment 
period (i.e., Week 12 of study treatment) in the Japanese phase II/III study 
[CL-0003]: FAS
Placebo
ASP8825 600 mg
N
Mean (SD)
N
Mean (SD)
Week 12 (LOCF)
116
−8.96 (7.286)
120
−11.10 (7.921)
Week 12 (Treatment period completers)
105
−9.27 (6.996)
98
−11.54 (7.793)
SD: Standard Deviation. LOCF: Last Observation Carried Forward
In addition, a repeated measures analysis of variance of the data from the patients given 
placebo or ASP8825 600 mg in the Japanese phase II/III study [CL-0003] and included in the 
Full Analysis Set showed that the adjusted means of the change from baseline in IRLS score 
at the end of treatment period (Week 12) were −9.15 in the placebo group and −11.71 in the 
600 mg group. The difference between the adjusted means from the two groups was −2.56.
On the basis of these results, the difference between treatment groups in the change from 
baseline in IRLS score at the end of treatment period (Week 12) as the primary endpoint of 
this study was assumed to be −2.56, with a standard deviation of 8.000 in both groups. Under 
these assumptions, to detect a statistically significant difference between gabapentin 
enacarbil and placebo using a 2-sample t-test with a two-sided significance level of 0.05 and 
a power of 80%, 155 subjects per group would be required. Assuming the discontinuation 
rate during the treatment period was approximately 15.0% in each group, the sample size has 
been set to 180 per group.
5
ANALYSIS SETS
In principle, the analysis sets below will be used.  However, the final decision on handling of 
cases for analyses will be made in a case review before the treatment code breaking, in light 
of opinions/advice from medical expert, statistical advisor, and others.
5.1
Full Analysis Set (FAS)
The Full Analysis Set (FAS) will consist of all subjects who received the study drug for the 
treatment period and were evaluated for at least one efficacy (either primary or secondary) 
endpoint during the treatment period.  The FAS will be the primary analysis set for efficacy 
analyses.
5.2
Per Protocol Set (PPS)
The Per Protocol Set (PPS) will consist of the subjects in the FAS who meet the following 
criteria:


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●
Subjects meeting the inclusion criteria
●
Subjects not meeting any of the exclusion criteria that can affect efficacy assessments
●
Subjects not using excluded concomitant medications or therapies that can affect 
efficacy assessments
●
Subjects given the study drug for the treatment period for at least 2 weeks from the start 
of the treatment period
●
Subjects with ≥ 70% compliance with study treatment during the treatment period
5.3
Safety Analysis Set (SAF)
The Safety Analysis Set (SAF) will consist of all subjects given at least one dose of the study 
drug for the treatment period.
6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
6.1.1
Primary Efficacy Endpoint
Change from baseline in IRLS score at the end of treatment period (Week 12)
6.1.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows:
●
Change from baseline in IRLS score at each time point
●
ICGI responder rate at each time point
●
PCGI responder rate at each time point
●
Change from baseline in Pittsburgh Sleep Quality Index at each time point
●
Change from baseline in Athens Insomnia Scale at each time point
●
Change from baseline in RLS Pain score at each time point
●
Change from baseline in EQ-5D-5L at each time point
6.1.2.1 ICGI and PCGI
In terms of Investigator-rated Clinical Global Impression (ICGI) and Patient-rated Clinical 
Global Impression (PCGI), a subject with “Very much improved” or “Much improved” is 
defined as “Responder”; otherwise, “Non-responder”.
6.1.2.2 Pittsburgh Sleep Quality Index
The Pittsburgh Sleep Quality Index (PSQI) is a self-administered questionnaire to assess 
subjective sleep quality during the previous month (see Appendix 1: Pittsburgh Sleep Quality 
Index). The self-rated items of the PSQI generate seven component scores (range of subscale 
scores, 0-3): sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep 
disturbance, use of sleeping medication, and daytime dysfunction. The sum of these seven 
component scores yields one global score of subjective sleep quality (range, 0-21); higher 
scores represent poorer subjective sleep quality. For more details and description of the 
component and global scores, refer to Appendix 1: Pittsburgh Sleep Quality Index.


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6.1.2.3 EQ-5D-5L
The EQ-5D-5L is an international standardized non-disease specific (i.e. generic) instrument 
for describing and valuing health status, and a multi-dimensional measure of health-related 
QOL.
EQ-5D-5L includes two main components: (1) a VAS scale rating perception of overall 
health and (2) 5 qualitative domains: Mobility, Self-Care, Usual Activities, Pain/Discomfort, 
and Anxiety/Depression. No imputation will be performed in case of a missing item.
6.2
Safety Variables
Safety will be assessed by evaluation of the following variables:
●
Vital signs
●
Adverse events
●
Laboratory tests
●
Body weight
●
Epworth Sleepiness Scale
6.2.1
Adverse Events
TEAE is defined as an adverse event observed after starting administration of the study drug 
in the treatment period. If the adverse event occurs on the date of first dose of study drug 
(treatment period) and the onset check box is marked “ONSET BETWEEN FIRST DOSE 
OF STUDY DRUG IN TREATMENT PERIOD AND FIRST DOSE OF STUDY DRUG IN 
FOLLOW UP PERIOD”, then the adverse event will be considered treatment-emergent.
A drug-related TEAE is defined as any TEAE with at least possible relationship to study 
treatment as assessed by the investigator or with missing assessment of the causal 
relationship.
6.3
Other Variables
6.3.1
Variables Related to Study Drugs
Treatment Groups
Table 2 below presents the groups to which subjects are randomized.
Table 2   Treatment groups
Randomization Arm 
Code (ARMCD)
Randomization Arm (ARM)
Treatment Group (Labels in TLFs)
G600
GABAPENTIN ENACARBIL 
600 mg QD
Gabapentin enacarbil
Total
P
PLACEBO
Placebo
Analysis Date of First Dose
Dates of first dose of study drug in run-in period, treatment period and follow-up period are
collected in the Study Drug Dosing 3 eCRF. Analysis dates of first dose in run-in period, 
treatment period and follow-up period are defined as Date of First Dose of Study Drug 


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(RUN-IN PERIOD), Date of First Dose of Study Drug (TREATMENT PERIOD) and Date 
of First Dose of Study Drug (FOLLOW UP PERIOD), respectively.
Analysis Date of Last Dose
Dates of last dose of study drug in run-in period, treatment period and follow-up period are 
collected in the Study Drug Dosing 3 eCRF. Analysis dates of last dose in run-in period, 
treatment period and follow-up period are defined as Date of Last Dose of Study Drug 
(RUN-IN PERIOD), Date of Last Dose of Study Drug (TREATMENT PERIOD) and Date of 
Last Dose of Study Drug (FOLLOW UP PERIOD), respectively.
Duration of Exposure in Treatment Period
For each subject, duration of exposure in treatment period will be calculated in days, using 
the following formula:
(‘Analysis Date of Last Dose in Treatment Period’ - ‘Analysis Date of First Dose in 
Treatment Period’) + 1
Duration of Exposure in Entire Period
For each subject, duration of exposure in entire period will be calculated in days, using the 
following formula:
(‘Analysis Date of Last Dose in Follow-up Period’ - ‘Analysis Date of First Dose in Run-in 
Period’) + 1
If subjects do not take any study drugs in follow-up period, ‘Analysis Date of Last Dose in 
Follow-up Period’ will be replaced with ‘Analysis Date of Last Dose in Treatment Period’.
Compliance in Treatment Period
For each subject, compliance of study drug in treatment period will be calculated in %, using 
the following formula:
Total number of study drugs actually taken in treatment period
Duration of Exposure in Treatment Period × 2
×100
where
‘Total number of study drugs actually taken in treatment period’ =
(Sum of “Number Dispensed” for 0WEEK, 1WEEK, 2WEEK, 4WEEK, 6WEEK, 
8WEEK and 10WEEK in the Study Drug Accountability 2 eCRF) minus (Sum of 
“Number Returned” for 0WEEK, 1WEEK, 2WEEK, 4WEEK, 6WEEK, 8WEEK and 
10WEEK in the Study Drug Accountability 2 eCRF) minus (Sum of “Number Lost” for 
0WEEK, 1WEEK, 2WEEK, 4WEEK, 6WEEK, 8WEEK and 10WEEK in the Study Drug 
Accountability 2 eCRF)
Compliance in Entire Period
For each subject, compliance of study drug in entire period will be calculated in %, using the 
following formula:


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Total number of study drugs actually taken in entire period
Duration of Exposure in Entire Period × 2
×100
where
‘Total number of study drugs actually taken in entire period’ =
(Sum of “Number Dispensed” for -1WEEK, 0WEEK, 1WEEK, 2WEEK, 4WEEK, 
6WEEK, 8WEEK, 10WEEK and 12WEEK in the Study Drug Accountability 2 eCRF)
minus (Sum of “Number Returned” for -1WEEK, 0WEEK, 1WEEK, 2WEEK, 4WEEK, 
6WEEK, 8WEEK, 10WEEK and 12WEEK in the Study Drug Accountability 2 eCRF) 
minus (Sum of “Number Lost” for -1WEEK, 0WEEK, 1WEEK, 2WEEK, 4WEEK, 
6WEEK, 8WEEK, 10WEEK and 12WEEK in the Study Drug Accountability 2 eCRF)
6.3.2
Demographic Characteristic Variables
Duration of Onset of Restless Legs Syndrome
Duration of Onset of Restless Legs Syndrome in years is defined as:
(‘Date of Visit of Run-in Period’ - ‘Date of Diagnosis’)/365.25
where ‘Date of Diagnosis’ is imputed by the following rules;
Reported Date (from the eCRF)
Date of Diagnosis (Derived)
MM/YYYY
01/MM/YYYY
--/YYYY
01/01/YYYY
MM/----, or --/---- (Unknown)
No imputation
6.3.3
Previous and Concomitant Medication
Previous medication is defined as medication with at least one dose taken before ‘Date of 
Visit of Run-in Period’ (exclusive).
Concomitant medication is defined as medication with at least one dose taken between ‘Date 
of Visit of Run-in Period’ (inclusive) and ‘Date of Last Study Evaluation’ (inclusive).
7
STATISTICAL METHODOLOGY
7.1
General Considerations
●
For continuous variables, descriptive statistics will include the number of subjects (n), 
mean, standard deviation, median, minimum and maximum.
●
The number of digits to be used for the mean, standard deviation and median will be 
added one more digit to raw data with rounding off. The minimum and maximum will be 
presented with the same number of digit(s) as raw data.
●
Frequencies and percentages will be displayed for categorical data. Percentages by 
categories will be based on the number of subjects with no missing data, i.e. will add up 
to 100%.
●
Frequencies and percentages will be rounded to one decimal place.


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●
For time-to-event variables, the number and percentage of subjects with the event using 
Kaplan-Meier method, the cumulative event rate will be estimated and a plot will be 
constructed.
●
All data processing, summarization, and analyses will be performed using SAS Drug 
Development version 4.5 and SAS version 9.4. Specifications for tables, figures, and 
data listing formats can be found in the TLF specifications for this study.
●
For continuous variables that are recorded as “< X” or “> X”, the value of “X” will be 
used in the calculation of summary statistics. The original values will be used for the 
listings.
●
MedDRA/J (version 19.0) will be used as the coding dictionary for adverse event and 
medical history.
●
WHODDE (J-Drug(2016H1)) will be used as the coding dictionary for previous and 
concomitant medication.
●
All statistical results will be presented, as appropriate, by treatment group, and by 
scheduled visit; the schedule of assessments is provided in section 7.10.
●
For the definition of subgroups of interest please refer to section 7.8.
7.2
Study Population
7.2.1
Disposition of Subjects
The following subject data will be summarized and presented:
[Analysis population: All subjects with informed consent, Analysis group: Total]
●
Number of subjects with informed consent, discontinued before run-in period,
administered at least one dose of study drug in run-in period, discontinued in run-in 
period, randomized, and
●
Number and percentage of subjects discontinued before run-in period, by primary reason 
for study discontinuation.
[Analysis population: All subjects with administered at least one dose of study drug in run-in 
period, Analysis group: Total]
●
Number and percentage of subjects discontinued in run-in period, by primary reason for 
study discontinuation.
[Analysis population: All randomized subjects, Analysis group: Placebo, Gabapentin 
enacarbil, Total]
●
Number and percentage of subjects randomized in each analysis set, administered at least 
one dose of study drug in treatment period,
●
Number and percentage of subjects completed and discontinued the treatment period, by 
primary reason for study discontinuation, and
●
Number and percentage of subjects excluded from FAS, PPS and SAF by reason for 
exclusion defined in section 5.1, 5.2 and 5.3.
Following data will be presented graphically by treatment group for the all randomized 
subjects. Subjects who complete the study will be censored at the date of last evaluation.


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●
Time to study discontinuation using a Kaplan-Meier plot.
[Analysis population: All subjects with administered at least one dose of study drug in follow 
up period, Analysis group: Placebo, Gabapentin enacarbil, Total]
●
Number and percentage of subjects completed and discontinued the follow up period, by 
primary reason for study discontinuation.
7.2.2
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized by descriptive statistics 
and frequency tabulations (Table 3), by treatment group for the SAF, FAS and PPS.
Baseline values of efficacy variables will be summarized by descriptive statistics and 
frequency tabulations (Table 4), by treatment group for the FAS and PPS.
Medical history is coded in MedDRA, and will be summarized by System Organ Class 
(SOC) and Preferred Term (PT), by treatment group for the SAF.
Table 3  Demographic and baseline characteristics
Item
Classification
Sex
1: Male
2: Female
Age (Years)
[Informed Consent]
Measurement value
1: < 65
2: >= 65
Height (cm)
[Run-in Period]
Measurement value
Weight (kg)
[Run-in Period]
Measurement value
1: < 60
2: >= 60
BMI (kg/m^2)
[Run-in Period]
Measurement value
1: < 25
2: >= 25
Duration of Onset of Restless Legs 
Syndrome (Years)
Measurement value
1: < 1
2: >= 1 to < 5
3: >= 5 to < 10
4: >= 10
5: Unknown
Family History of RLS
1: No
2: Yes
Age (Years)
[Run-in Period]
Measurement value
1: < 50
2: >= 50
Estimated creatinine clearance (mL/min)
[Run-in Period]
Measurement value
1: >= 60 to < 90
2: >= 90


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Table 4   Baseline values of efficacy variables
Item
Classification
IRLS score
Measurement value
1: <= 20
2: > 20 to <= 30
3: > 30 to <= 40
PSQI Sleep Quality
Measurement value
PSQI Sleep Latency
Measurement value
PSQI Sleep Duration
Measurement value
PSQI Habitual Sleep Efficiency
Measurement value
PSQI Sleep Disturbance
Measurement value
PSQI Use of Sleeping Medication
Measurement value
PSQI Daytime Dysfunction
Measurement value
PSQI Global Score
Measurement value
Total Score of Athens Insomnia Scale
Measurement value
RLS pain score
Measurement value
EQ-5D-5L VAS Score
Measurement value
EQ-5D-5L Mobility
1: I have no problems in walking about
2: I have slight problems in walking about
3: I have moderate problems in walking about
4: I have severe problems in walking about
5: I am unable to walk about
EQ-5D-5L Self-Care
1: I have no problems washing or dressing myself
2: I have slight problems washing or dressing myself
3: I have moderate problems washing or dressing myself
4: I have severe problems washing or dressing myself
5: I am unable to wash or dress myself
EQ-5D-5L Usual Activities
1: I have no problems doing my usual activities
2: I have slight problems doing my usual activities
3: I have moderate problems doing my usual activities
4: I have severe problems doing my usual activities
5: I am unable to do my usual activities
EQ-5D-5L Pain/Discomfort
1: I have no pain or discomfort
2: I have slight pain or discomfort
3: I have moderate pain or discomfort
4: I have severe pain or discomfort
5: I have extreme pain or discomfort
EQ-5D-5L Anxiety/Depression
1: I am not anxious or depressed
2: I am slightly anxious or depressed
3: I am moderately anxious or depressed
4: I am severely anxious or depressed
5: I am extremely anxious or depressed
7.2.3
Previous and Concomitant Medications
Previous and concomitant medications are coded with WHODDE, and will be summarized 
by preferred WHO name, by treatment group for the SAF.
The following specific medications uses will be summarized by frequency tabulations, by 
treatment group for the SAF, FAS and PPS.
Prior Dopamine agonists Use
No, Yes


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7.3
Study Drugs
7.3.1
Exposure
Durations of exposure in treatment and entire period will be summarized by descriptive 
statistics and frequency tabulations, by treatment group for the SAF. The following 
categories of the durations of exposure (days) will be defined:
○
< 29 (4 weeks)
○
>= 29 (4 weeks) to < 57 (8 weeks)
○
>= 57 (8 weeks) to < 85 (12 weeks)
○
>= 85 (12 weeks)
7.3.2
Study drug Compliance
Study drug compliances in treatment and entire period will be summarized by descriptive 
statistics and frequency tabulations, by treatment group for the SAF. The following 
categories of the study drug compliances (%) will be defined:
○
< 50
○
>= 50 to < 75
○
>= 75 to < 90
○
>= 90
○
Unknown
7.4
Analysis of Efficacy
7.4.1
Analysis of Primary Endpoint
7.4.1.1 Primary Analysis
The primary analysis will be performed using the FAS.
The primary efficacy endpoint is the change from baseline in IRLS score at the end of 
treatment period. Using a repeated measures analysis of variance model, so-called Mixed 
Model of Repeated Measurements (MMRM) model, having the following average structure, 
the adjusted mean in each treatment group and its difference (gabapentin enacarbil group -
placebo group) at the end of treatment period (Week 12) will be calculated, with comparison 
between the placebo group and the gabapentin enacarbil group:
Change in IRLS score at each time point
= Baseline IRLS score + Age category*1 + Estimated creatinine clearance category*2 + 
Treatment group + Time point + Treatment group × Time point
*1 Age category: < 50 years and ≥50 years
*2 Estimated creatinine clearance category: ≥60 to < 90 mL/min and ≥90 mL/min
Compound symmetry will be used as the covariance structure for repeated measures of the 
response variable.  A two-sided significance level of 0.05 will be used for statistical tests.


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The least-squares mean estimates of the change from baseline in IRLS score at Week 12, the 
estimates of treatment effect (e.g., least-squares mean change form baseline in IRLS score for 
gabapentin enacarbil group minus the least-squares mean change from baseline in IRLS score
for placebo group) and the corresponding 95% CIs will be reported.
MMRM
The SAS procedure will be similar to the following:
proc mixed;
class SUBJECT GROUP VISIT AGE ECC;
model CHANGE = GROUP BASE VISIT AGE ECC GROUP*VISIT / ddfm=sat;
repeated VISIT /subject = SUBJECT type = cs;
lsmestimate
GROUP*VISIT
“GABAPENTIN ENACARBIL v.s. PLACEBO”
0 0 ... 0 1 0 0 ... 0 1 / cl alpha=0.05 om; 
where VISIT in (’Week1’,’Week2’, ...,’Week12’);
run;
7.4.1.2 Secondary Analysis
The primary analysis will be repeated on the PPS. Additionally, the analysis to confirm the 
robustness will be presented.
7.4.1.3 Sensitivity Analysis
The primary endpoint will be analyzed using the following approaches:
●
Analysis of Covariance (ANCOVA) model with Last Observation Carried Forward 
(LOCF),
●
Analysis of Covariance (ANCOVA) model with Multiple Imputation (MI), and
●
Pattern Mixture Model (PMM) with different assumptions for missing patterns.
For all sensitivity analyses, confidence intervals will be presented.
Table 5 summarizes all sensitivity analyses to be performed with the primary endpoint.


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Table 5  Primary, Secondary and Sensitivity Analyses for Primary Endpoint
Code
Set
Endpoint
Model
Covariates
Primary
FAS
Change from 
baseline in IRLS 
score at the end of 
treatment period 
(Week 12)
MMRM
Treatment group, Visit, Baseline 
IRLS score, Age category, Estimated 
creatinine clearance category, Visit 
by Treatment group interaction
Secondary
PPS
Change from 
baseline in IRLS 
score at the end of 
treatment period 
(Week 12)
MMRM
Treatment group, Visit, Baseline 
IRLS score, Age category, Estimated 
creatinine clearance category, Visit 
by Treatment group interaction
S1
FAS
Change from 
baseline in IRLS 
score at the end of 
treatment period 
(Week 12)
ANCOVA with 
LOCF
Treatment group,  Baseline IRLS 
score, Age category, Estimated 
creatinine clearance category
S2
FAS
Change from 
baseline in IRLS 
score at the end of 
treatment period 
(Week 12)
ANCOVA with 
MI
Treatment group,  Baseline IRLS 
score, Age category, Estimated 
creatinine clearance category
S3
FAS
Change from 
baseline in IRLS 
score at the end of 
treatment period 
(Week 12)
PMM (Last 
Mean Carried 
Forward)
Treatment group,  Baseline IRLS 
score, Age category, Estimated 
creatinine clearance category
S4
FAS
Change from 
baseline in IRLS 
score at the end of 
treatment period 
(Week 12)
PMM (Last 
Mean Carried 
Forward for 
Gabapentin 
Enacarbil and 
Randomized 
Arm MAR for 
Placebo)
Treatment group,  Baseline IRLS 
score, Age category, Estimated 
creatinine clearance category
S5
FAS
Change from 
baseline in IRLS 
score at the end of 
treatment period 
(Week 12)
PMM (Copy 
Reference)
Treatment group,  Baseline IRLS 
score, Age category, Estimated 
creatinine clearance category
S6
FAS
Change from 
baseline in IRLS 
score at the end of 
treatment period 
(Week 12)
PMM (Jump to 
Reference)
Treatment group,  Baseline IRLS 
score, Age category, Estimated 
creatinine clearance category
S7
FAS
Change from 
baseline in IRLS 
score at the end of 
treatment period 
(Week 12)
PMM (Copy 
Increment from 
Reference)
Treatment group,  Baseline IRLS 
score, Age category, Estimated 
creatinine clearance category


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ANCOVA with MI
The MI ANCOVA model will be used to compare gabapentin enacarbil and placebo group in 
a fixed sequence procedure:
1.
Generate 1000 datasets, using seed 394852, where intermittent missing IRLS score will 
be imputed for each treatment relying on non-missing data from all subjects within each 
treatment group using the Monte Carlo Markov Chain (MCMC) imputation model with 
treatment and the available non-missing IRLS score for each scheduled Week. The 
MCMC statement in the SAS PROC MI procedure with monotone option will be used. 
As a result, each dataset will only have missing ending data, or a monotone missing data 
pattern.
2.
For each dataset from step 1, missing ending data (IRLS score up through end of 
treatment period) will be imputed using seed 394852. As a result, 1000 imputed 
complete datasets will be generated.
●
Missing data at Week 1 will be imputed using the regression imputation model with 
the stratification factors, baseline and IRLS score from Week 1, using the SAS 
PROC MI procedure with the REGRESSION option in the MONOTONE statement.
●
The SAS PROC MI procedure will use data separately from each treatment subjects 
to impute the missing data for a specific Week (i.e., only those that need the 
imputation for the Week). Since subjects from the different treatment groups for that 
Week are excluded from the step, they will not contribute to the imputation for the 
Week.
●
Repeat for all other scheduled Weeks sequentially (Week 2 to the end of evaluation 
period). Subjects whose missing data were imputed for previous Weeks will 
contribute to the imputation for the current Week.
The regression imputation model includes an intercept and the slopes of the IRLS score
from previous Weeks and the stratification factors.
3.
Analyze each imputed dataset using the ANCOVA using the observed or imputed IRLS 
score at Week 12. The model will contain terms for baseline IRLS score measurement as 
a covariate and treatment group and the other stratification factors as fixed effects.
4.
Combine estimates from the results of each of the 1000 ANCOVA runs using SAS 
PROC MIANALYZE.
The least-squares mean estimates of the change from baseline in IRLS score at Week 12, the 
estimates of treatment effect (e.g., least-squares mean change form baseline in IRLS score for 
gabapentin enacarbil group minus the least-squares mean change from baseline in IRLS score
for placebo group) and the corresponding 95% CIs will be reported.
Pattern Mixture Models (PMM)
PMMs will be used as an alternative to impute missing values, using different assumptions 
for missing patterns.


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PMMs provide a general and flexible framework for sensitivity analyses that allows 
formulating assumptions regarding missing data in a transparent and clinically interpretable 
manner. This is expected to address the possibility of the data being missing not at random 
(MNAR).
The following aspects of data missingness, may affect the estimates.
●
Timing and extent of missingness
●
Assumed underlying mechanism for data missingness
A. Timing and Extent of Missing Data
To assess the potential effect of data missingness on the estimate of treatment effect, subjects 
will be classified as full data or missing data cases. Patterns of missingness will be based on 
non-missing IRLS score before the end of the treatment period.
●
Full data cases are defined as subjects with non-missing IRLS score for all scheduled 
weeks of the treatment period.
●
Missing data cases are defined as subjects with a missing IRLS score on at least one 
scheduled Week of the treatment period. The missing data cases are further grouped into 
intermittent missing and monotone missing cases.
-
Intermittent missing hemoglobin cases are defined as subjects with a missing IRLS 
score for at least one scheduled week of but not on consecutive scheduled weeks up 
to end of the treatment period.
-
Monotone missing IRLS score cases are defined as subjects who have consecutive 
scheduled Weeks with missing IRLS score up to the end of treatment period. A 
subject who is a Monotone missing case could have intermittent missing IRLS score
prior to the ending Week.
Subjects will be grouped as follows:
●
Full data cases
●
Intermittent missing data cases
●
Monotone missing data cases
Should the incidence of Monotone missing data cases and intermittent missing data cases be 
relatively small, then those cases will be combined so that the groups are full data cases and 
missing data cases.
B. Assumptions on Missing Data Mechanism
In addition to the extent of data missingness, the mechanism under which missing data occur 
may affect the estimate of the parameter of interest.
The potential impact of missing efficacy endpoints on the estimates of treatment effects will 
be assessed using alternative statistical models with different underlying assumptions on the 
missing data mechanism for MNAR (Little and Rubin, 2002).
C. PMM - Last Mean Carried Forward


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A pattern-mixture model using a last mean carried forward multiple imputation method 
(Carpenter et al., 2013) will be used as another sensitivity analysis to explore the robustness 
of the MMRM, ANCOVA with LOCF and ANCOVA with MI results for the primary 
efficacy variables. Using this method, missing data after ending week will be imputed based 
on the last non-missing mean from its own treatment group.
D. PMM - Last Mean Carried Forward for Gabapentin Enacarbil and Randomized 
Arm MAR for Placebo
This method is a combination of PMM-Last Mean Carried forward for gabapentin enacarbil
and PMM-Randomized Arm MAR for placebo group. The imputation data will be generated 
based on last mean carried forward method described above for the gabapentin enacarbil
group, while for the placebo group, the imputation data will be generated using the 
Randomized Arm MAR group described below.
The Randomized Arm MAR is similar to PMM-Last Mean Carried Forward except that the 
joint distribution of the patient’s observed and missing data is multivariate normal with mean 
and covariance matrix from their randomized arms.
E. PMM - Copy Reference
For the purpose of imputing the missing response data, a patient’s whole distribution, both 
pre- and post-discontinuation, is assumed to be the same as placebo group. Post-
discontinuation data in the placebo group will be imputed under Randomized Arm MAR.
F. PMM - Jump to Reference
For post-discontinuation, subject’s mean response distribution is assumed to be the same as 
that of the placebo group. Such a change may be seen as extreme, and choosing the placebo
group might be used as a worst-case scenario in terms of reducing any treatment effect since 
withdrawn patients on active will lose the effect of their period on treatment. Post-
discontinuation data in the reference arm will be imputed under Randomized Arm MAR.
G. PMM - Copy Increment from Reference
After the subject discontinuation, the subject’s post-discontinuation mean increments copy 
those from the placebo group. Post-discontinuation data in the placebo arm will be imputed 
under Randomized Arm MAR.
H. Analysis Model and Reporting
The ANCOVA model will then be performed for each combined imputed complete data set. 
Similarly, the Rubin’s method will be then used to combine the estimates and the differences 
between the least square mean differences between the two treatment groups from each of the 
ANCOVA analyses.
The least-squares mean estimates of the change from baseline in IRLS score at Week 12, the 
estimates of treatment effect (e.g., least-squares mean change form baseline in IRLS score for 
gabapentin enacarbil group minus the least-squares mean change from baseline in IRLS score
for placebo group) and the corresponding 95% CIs will be reported.


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7.4.2
Analysis of Secondary Endpoints
The analyses of secondary endpoints will be performed using the FAS.
7.4.2.1 Change from baseline in IRLS score at each time point
The baseline visit is the measurement at Week 0.
IRLS score and its change from baseline will be summarized by descriptive statistics, by 
treatment group and visit.
Least square mean difference (gabapentin enacarbil group minus placebo group) of the 
changes in IRLS score from baseline will be calculated by visit, using ANCOVA model with 
the baseline value as a covariate. 95% CI and two-sided p-value of the difference will be 
presented.
Change from baseline in IRLS score will be summarized by subgroups defined in section 7.8.
Following data will be presented graphically by treatment group:
●
IRLS score using mean (+/- SD) plot,
●
Change in IRLS score from baseline using mean (+/- SD) plot.
7.4.2.2 ICGI responder rate at each time point
The ICGI responder rate will be presented by treatment group. 95% CIs of the responder rate 
will be calculated using Clopper-Pearson method.
Difference (gabapentin enacarbil group minus placebo group) of the ICGI responder rates 
and its 95% CI (normal approximation with continuity correction) will be calculated. The 
two treatment groups will be compared using Fisher’s exact test.
Following data will be presented graphically by treatment group:
●
ICGI responder rate (+/- 95% CI) plot.
7.4.2.3 PCGI responder rate at each time point
The PCGI responder rate will be presented by treatment group. 95% CIs of the responder rate 
will be calculated using Clopper-Pearson method.
Difference (gabapentin enacarbil group minus placebo group) of the PCGI responder rates 
and its 95% CI (normal approximation with continuity correction) will be calculated. The 
two treatment groups will be compared using Fisher’s exact test.
Following data will be presented graphically by treatment group:
●
PCGI responder rate (+/- 95% CI) plot.
7.4.2.4 Change from baseline in Pittsburgh Sleep Quality Index at each time point
The baseline visit is the measurement at Week 0.
PSQI component scores (sleep quality, sleep latency, sleep duration, habitual sleep 
efficiency, sleep disturbance, use of sleeping medication, and daytime dysfunction) and PSQI 


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global score, and their change from baseline will be summarized by descriptive statistics, by 
treatment group and visit.
Least square mean difference (gabapentin enacarbil group minus placebo group) of the 
changes in PSQI component and global scores from baseline will be calculated by visit, using 
the ANCOVA model with the baseline value as a covariate. 95% CI and two-sided p-value of 
the difference will be presented.
Following data will be presented graphically by treatment group:
●
PSQI component scores (sleep quality, sleep latency, sleep duration, habitual sleep 
efficiency, sleep disturbance, use of sleeping medication, and daytime dysfunction) and 
PSQI global score using mean (+/- SD) plot,
●
Change in PSQI component scores (sleep quality, sleep latency, sleep duration, habitual 
sleep efficiency, sleep disturbance, use of sleeping medication, and daytime dysfunction) 
and PSQI global score from baseline using mean (+/- SD) plot.
7.4.2.5 Change from baseline in Athens Insomnia Scale at each time point
The baseline visit is the measurement at Week 0.
Total score of Athens insomnia scale and its change from baseline will be summarized by 
descriptive statistics, by treatment group and visit.
Least square mean difference (gabapentin enacarbil group minus placebo group) of the 
changes in total score of Athens insomnia scale from baseline will be calculated by visit, 
using the ANCOVA model with the baseline value as a covariate. 95% CI and two-sided p-
value of the difference will be presented.
Following data will be presented graphically by treatment group:
●
Total score of Athens insomnia scale using mean (+/- SD) plot,
●
Change in total score of Athens insomnia scale from baseline using mean (+/- SD) plot.
7.4.2.6 Change from baseline in RLS Pain score at each time point
The baseline visit is the measurement at Week 0.
RLS pain score and its change from baseline will be summarized by descriptive statistics, by 
treatment group and visit.
Least square mean difference (gabapentin enacarbil group minus placebo group) of the 
changes in RLS pain score from baseline will be calculated by visit, using the ANCOVA 
model with the baseline value as a covariate. 95% CI and two-sided p-value of the difference 
will be presented.
Following data will be presented graphically by treatment group:
●
RLS pain score using mean (+/- SD) plot,
●
Change in RLS pain score from baseline using mean (+/- SD) plot.


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7.4.2.7 Change from baseline in EQ-5D-5L at each time point
The baseline visit is the measurement at Week 0.
Descriptive statistics for EQ-5D-5L VAS score and change from baseline at each visit will be 
presented by treatment group. For the EQ-5D-5L qualitative domains, the number and 
percentage of subjects in each response level value will be reported by treatment group and 
visit. In addition, a plot for EQ-5D-5L VAS score of mean (+/- SD) and that of change from 
baseline will be produced.
7.5
Analysis of Safety
All analysis of safety will be presented by treatment group for the SAF, unless specified 
otherwise.
7.5.1
Adverse Events
An overview table will include the following details:
●
Number of TEAEs,
●
Number and percentage of subjects with TEAEs,
●
Number of drug related TEAEs,
●
Number and percentage of subjects with drug related TEAEs,
●
Number of serious TEAEs,
●
Number and percentage of subjects with serious TEAEs,
●
Number of serious drug related TEAEs,
●
Number and percentage of subjects with serious drug related TEAEs,
●
Number of TEAEs leading to withdrawal of treatment,
●
Number and percentage of subjects with TEAEs leading to withdrawal of treatment,
●
Number of drug related TEAEs leading to withdrawal of treatment,
●
Number and percentage of subjects with drug related TEAEs leading to withdrawal of 
treatment, and
●
Number of deaths.
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized for each treatment group. Summaries will be provided for:
●
TEAEs,
●
Drug related TEAEs,
●
Serious TEAEs,
●
Serious drug related TEAEs,
●
TEAEs leading to withdrawal of treatment,
●
Drug related TEAEs leading to withdrawal of treatment,
●
TEAEs excluding serious adverse event that equal to or exceed a threshold of 5.0% in 
any treatment group,
●
Common TEAEs that equal to or exceed a threshold of 5.0% in any treatment group,
●
Common drug related TEAEs that equal to or exceed a threshold of 5.0% in any 
treatment group.


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The number of TEAEs and the number and percentage of subjects with TEAEs, as classified 
by SOC and PT will also be summarized by severity and by relationship to study drug. In the 
subject count, if a subject has multiple TEAEs with the same SOC or PT, but with differing 
severity or relationship, then the subject will be counted only once with the worst severity or
highest degree of relationship, however, if any of the severity or relationship values are 
missing then the subject will be counted only once with missing severity or relationship. In 
the adverse event count, the adverse events will be presented in each category they were 
classified to. Drug related TEAEs will be presented in a similar way by severity only.
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized by time interval. For each adverse event in a particular interval, a subject will be 
counted if there is an onset of TEAEs regardless of onset in other intervals. Time intervals 
will be categorized according to the following categories (days from the first dosing of study 
drug in the treatment period):
○
>= 1 (0 weeks) to <= 29 (4 weeks)
○
> 29 (4 weeks) to <= 57 (8 weeks)
○
> 57 (8 weeks) to <= 85 (12 weeks)
○
> 85 (12 weeks)
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized by subgroups defined in section 7.8.
7.5.1.1 Adverse Events of special interest
For the adverse events of Nervous system disorders, the following analysis will be 
performed:
●
The number and percentage of subjects with TEAEs of Nervous system disorders, as 
classified by SOC and PT will be summarized for each treatment group,
●
Time to first onset of selected TEAE using a Kaplan-Meier plot based on the date of first 
dosing of study drug in the treatment period. Subjects who complete the study without 
having any TEAEs of Nervous system disorders will be censored at the date of last 
evaluation. Subjects who discontinued the study without having any TEAEs of Nervous 
system disorders will be censored at the date of discontinuation.
The following PT terms are defined as TEAEs of Nervous system disorders:
PT term
PT code
Somnolence
10041349
Dizziness
10013573
7.5.2
Clinical Laboratory Evaluation
The baseline visit is the measurement at Week 0.
Quantitative clinical laboratory variables, i.e. hematology, biochemistry, and thyroid function 
tests will be summarized in SI unit, using mean, standard deviation, minimum, maximum and 


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median, for each treatment group at each visit. Additionally, a within-subject change will be 
calculated as the post-baseline measurement minus the baseline measurement and 
summarized in the same way. Each laboratory result will be classified as low (L), normal (N), 
or high (H) at each visit according to the laboratory supplied reference ranges.
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be 
presented for each treatment group at each visit. 
For hematology, biochemistry and thyroid function tests, shift tables will be presented for 
each treatment group:
●
Summary shifts of reference range changes from baseline to each visit (shift from normal 
or high to low, shift from normal or low to high, categorized increase [shift from low to 
normal or from normal to high], categorized no change [value stays in the same 
reference range], categorized decrease [shift from high to normal or from normal to 
low]).
Following data will be presented graphically by treatment group:
●
Quantitative clinical laboratory test results using mean (+/- SD) plot.
7.5.2.1 Liver Enzymes and Total Bilirubin 
The following potentially clinically significant criteria for liver tests – defined as Alkaline 
Phosphatase (ALP), Alanine Transaminase (ALT), total bilirubin, Aspartate Transaminase 
(AST) and their combination are defined. The subject’s highest value after the date of first 
dosing will be used.
Parameter
Criteria
ALT
> 3xULN
> 5xULN
> 10xULN
> 20xULN
AST
> 3xULN
> 5xULN
> 10xULN
> 20xULN
ALT or AST
> 3xULN
Total Bilirubin
> 2xULN
ALP
> 1.5xULN
ALT and/or AST AND Total Bilirubin(*)
(ALT and/or AST > 3xULN) and 
total bilirubin > 2xULN
(*) Combination of values measured within same sample
The number and percentage of subjects with potentially clinically significant values in liver 
enzyme and total bilirubin tests during the investigational period will be presented by 
treatment group.


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7.5.3
Vital Signs
The baseline visit is the measurement at Week 0.
Vital signs (systolic blood pressure, diastolic blood pressure and pulse rate) will be 
summarized using mean, standard deviation, minimum, maximum and median by treatment 
group and visit. Additionally, a within-subject change will be calculated as the post-baseline 
measurement minus the baseline measurement and summarized by treatment group and visit.
Following data will be presented graphically by treatment group:
●
Vital sign results using mean (+/- SD) plot.
7.5.4
Body Weight
The baseline visit is the measurement at Week 0.
Body weight will be summarized using mean, standard deviation, minimum, maximum and 
median by treatment group and visit. Additionally, a within-subject change will be calculated 
as the post-baseline measurement minus the baseline measurement and summarized by 
treatment group and visit.
Following data will be presented graphically by treatment group:
●
Body weight results using mean (+/- SD) plot.
7.5.5
Epworth Sleepiness Scale
The baseline visit is the measurement at Week 0.
Total score of Epworth sleepiness scale will be summarized using mean, standard deviation, 
minimum, maximum and median by treatment group and visit. Additionally, a within-subject 
change will be calculated as the post-baseline measurement minus the baseline measurement 
and summarized by treatment group and visit.
Following data will be presented graphically by treatment group:
●
Total score of Epworth sleepiness scale using mean (+/- SD) plot.
7.6
Analysis of PK
Not applicable.
7.7
Analysis of PD
Not applicable.
7.8
Subgroups of Interest 
Selected efficacy and safety variables will be summarized by the treatment group for the 
subgroups defined on the basis of the categorized variables listed in Table 6.


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Table 6  Subgroup factors and their categories
Item
Classification
Endpoints to be assessed
Sex
1: Male
2: Female
Change from baseline in IRLS score
TEAE
Age (Years)
[Informed Consent]
1: < 65
2: >= 65
Change from baseline in IRLS score
TEAE
Family History of RLS
1: No
2: Yes
Change from baseline in IRLS score
Baseline IRLS score
1: <= 20
2: > 20 to <= 30
3: > 30 to <= 40
Change from baseline in IRLS score
Previous Dopamine agonists Use
1: No
2: Yes
Change from baseline in IRLS score
Duration of Onset of Restless 
Legs Syndrome (Years)
1: < 1
2: >= 1 to < 5
3: >= 5 to < 10
4: >= 10
Change from baseline in IRLS score
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)
No interim analyses are planned.
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
Final decision on handling of missing data and outliers for analyses will be made before 
treatment code breaking, in light of opinions/advice from medical expert, statistical advisor, 
and others.
7.10.1
Missing Data
As a general principle, no imputation of missing data will be done. Exception is the primary 
efficacy endpoint. The following imputations will be performed:
●
An MMRM model will be run for the purpose of implicit imputation of missing data by 
using all the available information from the observed data via the within-patient 
correlation structure for continuous endpoints with inferential analysis (section 7.4.1.1).
●
An ANCOVA model with Last Observation Carried Forward (LOCF), an ANCOVA 
model with multiple imputations (MI) and PMM models with different missingness 
patterns assumptions will be run as the sensitivity analysis for the primary analysis 
(section 7.4.1.3).
7.10.2
Outliers
All values will be included in the analyses.
7.10.3
Visit Windows
In terms of the handling of data time points for analysis, if two or more observed values are 
available for one time interval, the value collected closer to the protocol-specified time point 


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will be used.  If the difference from the reference time point is the same for two values, the 
value collected at a later point will be used. Day 1 and Day −1 are defined as the day of the 
formal registration and its prior day, respectively.
7.10.3.1     IRLS score and RLS Pain score
For the IRLS score and the RLS Pain score, the allowed time windows for analyses are 
shown in the table below.  For data in the treatment period, the data obtained up to 7 days 
after the day of last dosing in the treatment period will be used.
Analysis visit
Allowable time window
Reference day
Run-in
Day −10 to Day −7 
Day 1
Week 0
Day 1
Day 1
Week 1
Day 5 to Day 11
Day 8
Week 2
Day 12 to Day 18
Day 15
Week 4
Day 26 to Day 32
Day 29
Week 6
Day 40 to Day 46
Day 43
Week 8
Day 54 to Day 60
Day 57
Week 10
Day 68 to Day 74
Day 71
Week 12
Day 82 to Day 88
Day 85
End of treatment
Day 2 to Reference day +7 days
Day of last dosing in 
the treatment period
Follow-up
Reference day +5 days to Reference
day +11 days
Day of last dosing in 
the treatment period
7.10.3.2     ICGI and PCGI
For the ICGI and PCGI, the allowed time windows for analyses are shown in the table below.  
For data in the treatment period, the data obtained up to 7 days after the day of last dosing in 
the treatment period will be used.
Analysis visit
Allowable time window
Reference day
Week 1
Day 5 to Day 11
Day 8
Week 2
Day 12 to Day 18
Day 15
Week 4
Day 26 to Day 32
Day 29
Week 8
Day 54 to Day 60
Day 57
Week 12
Day 82 to Day 88
Day 85
End of treatment
Day 2 to Reference day +7 days
Day of last dosing in 
the treatment period
Follow-up
Reference day +5 days to Reference
day +11 days
Day of last dosing in 
the treatment period
7.10.3.3     Pittsburgh Sleep Quality Index, Athens Insomnia Scale, and EQ-5D-5L
For the Pittsburgh Sleep Quality Index, Athens Insomnia Scale, and EQ-5D-5L, the allowed 
time windows for analyses are shown in the table below.  For data in the treatment period, the 
data obtained up to 7 days after the day of last dosing in the treatment period will be used.


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Analysis visit
Allowable time window
Reference day
Week 0
Day 1
Day 1
Week 4
Day 26 to Day 32
Day 29
Week 8
Day 54 to Day 60
Day 57
Week 12
Day 82 to Day 88
Day 85
End of treatment
Day 2 to Reference day +7 days
Day of last dosing in 
the treatment period
7.10.3.4     Laboratory Tests
For laboratory tests, the allowed time windows for analyses are shown in the table below.  
For data in the treatment period, the data obtained up to 7 days after the day of last dosing in 
the treatment period will be used.
Analysis visit
Allowable time window
Reference day
Run-in
Day −10 to Day −7
Day 1
Week 0
Day 1
Day 1
Week 2
Day 12 to Day 18
Day 15
Week 4
Day 26 to Day 32
Day 29
Week 8
Day 54 to Day 60
Day 57
Week 12
Day 82 to Day 88
Day 85
End of treatment
Day 2 to Reference day +7 days
Day of last dosing in 
the treatment period
7.10.3.5     Vital Signs
For the vital signs, the allowed time windows for analyses are shown in the table below.  For 
data in the treatment period, the data obtained up to 7 days after the day of last dosing in the 
treatment period will be used.
Analysis visit
Allowable time window
Reference day
Run-in
Day −10 to Day −7 
Day 1
Week 0
Day 1
Day 1
Week 1
Day 5 to Day 11
Day 8
Week 2
Day 12 to Day 18
Day 15
Week 4
Day 26 to Day 32
Day 29
Week 6
Day 40 to Day 46
Day 43
Week 8
Day 54 to Day 60
Day 57
Week 10
Day 68 to Day 74
Day 71
Week 12
Day 82 to Day 88
Day 85
End of treatment
Day 2 to Reference day +7 days
Day of last dosing in 
the treatment period
7.10.3.6     Body Weight
For body weight, the allowed time windows for analyses are shown in the table below.  For 
data in the treatment period, the data obtained up to 7 days after the day of last dosing in the 
treatment period will be used.


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Analysis visit
Allowable time window
Reference day
Run-in
Day −10 to Day −7
Day 1
Week 0
Day 1
Day 1
Week 4
Day 26 to Day 32
Day 29
Week 8
Day 54 to Day 60
Day 57
Week 12
Day 82 to Day 88
Day 85
End of treatment
Day 2 to Reference day +7 days
Day of last dosing in 
the treatment period
7.10.3.7     Epworth Sleepiness Scale
For the Epworth Sleepiness Scale, the allowed time windows for analyses are shown in the 
table below.  For data in the treatment period, the data obtained up to 7 days after the day of 
last dosing in the treatment period will be used.
Analysis visit
Allowable time window
Reference day
Week 0
Day 1
Day 1
Week 1
Day 5 to Day 11
Day 8
Week 2
Day 12 to Day 18
Day 15
Week 4
Day 26 to Day 32
Day 29
Week 6
Day 40 to Day 46
Day 43
Week 8
Day 54 to Day 60
Day 57
Week 10
Day 68 to Day 74
Day 71
Week 12
Day 82 to Day 88
Day 85
End of treatment
Day 2 to Reference day +7 days
Day of last dosing in 
the treatment period
Follow-up
Reference day +5 days to Reference
day +11 days
Day of last dosing in 
the treatment period
8
DOCUMENT REVISION HISTORY 
Version
Date
Changes
Comment/rationale for change
1.00
03-SEP-2018
NA
Document finalized
9
REFERENCES
Carpenter JR, Roger JH and Kenward MG. Analysis of longitudinal trials with protocol deviation: A 
framework for relevant, accessible assumption, and inference via multiple imputation. Journal 
of Biopharmaceutical Statistics 2013; 23:1352 - 1371.
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics)
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics)
Little RJA and Rubin DB. Statistical Analysis with Missing Data, Second Edition. John Wiley & 
Sons; New Jersey: 2002.


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10
APPENDICES
10.1
Appendix 1: Pittsburgh Sleep Quality Index
10.1.1
Pittsburgh Sleep Quality Index Questionnaire
PITTSBURGH SLEEP QUALITY INDEX
INSTRUCTIONS:
The following questions relate to your usual sleep habits during the past month only. 
Your answers should indicate the most accurate reply for the majority of days and nights 
in the past month.
Please answer all questions.
1.
During the past month, what time have you usually gone to bed at night?
BED TIME
2.
During the past month, how long (in minutes) has it usually taken you to fall
asleep each night?
NUMBER OF MINUTES
3.
During the past month, what time have you usually gotten up in the morning?
GETTING UP TIME
4.
During the past month, how many hours of actual sleep did you get at night?
(This may be different than the number of hours you spent in bed.)
HOURS OF SLEEP PER NIGHT
For each of the remaining questions, check the one best response. Please answer all
questions.
5.
During the past month, how often have you had trouble sleeping because you . . .
a)
Cannot get to sleep within 30 minutes
Not during the
Less than
Once or twice
Three or more
past month              once a week
           a week               times a week   


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b)
Wake up in the middle of the night or early morning
Not during the
Less than
Once or twice
Three or more
past month              once a week
           a week               times a week   
c)
Have to get up to use the bathroom
Not during the
Less than
Once or twice
Three or more
past month              once a week
           a week               times a week   
d)
Cannot breathe comfortably
Not during the
Less than
Once or twice
Three or more
past month              once a week
           a week               times a week   
e)
Cough or snore loudly
Not during the
Less than
Once or twice
Three or more
past month              once a week
           a week               times a week   
f)
Feel too cold
Not during the
Less than
Once or twice
Three or more
past month              once a week
           a week               times a week   
g)
Feel too hot
Not during the
Less than
Once or twice
Three or more
past month              once a week
           a week               times a week   
h)
Had bad dreams
Not during the
Less than
Once or twice
Three or more
past month              once a week
           a week               times a week   


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i)
Have pain
Not during the
Less than
Once or twice
Three or more
past month              once a week
           a week               times a week   
j)
Other reason(s), please describe
   
How often during the past month have you had trouble sleeping because of this?
Not during the
Less than
Once or twice
Three or more
past month              once a week
           a week               times a week   
6.
During the past month, how would you rate your sleep quality overall? 
Very good         
Fairly good      
Fairly bad
Very bad
7.
During the past month, how often have you taken medicine to help you sleep
(prescribed or "over the counter")?
Not during the
Less than
Once or twice
Three or more
past month              once a week
           a week               times a week   
8.
During the past month, how often have you had trouble staying awake while
driving, eating meals, or engaging in social activity?
Not during the
Less than
Once or twice
Three or more
past month              once a week
           a week               times a week   


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9.
During the past month, how much of a problem has it been for you to keep up
enough enthusiasm to get things done?
No problem at all                  
Only a very slight problem   
Somewhat of a problem
A very big problem
10.
Do you have a bed partner or room mate?
No bed partner or room mate                          
Partner/room mate in other room                 
Partner in same room, but not same bed
Partner in same bed
If you have a room mate or bed partner, ask him/her how often in the past month you 
have had . . .
a)
Loud snoring
Not during the
Less than
Once or twice
Three or more
past month              once a week
           a week               times a week   
b)
Long pauses between breaths while asleep
Not during the
Less than
Once or twice
Three or more
past month              once a week
           a week               times a week   
c)
Legs twitching or jerking while you sleep
Not during the
Less than
Once or twice
Three or more
past month              once a week
           a week               times a week   


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d)
Episodes of disorientation or confusion during sleep
Not during the
Less than
Once or twice
Three or more
past month              once a week
           a week               times a week   
e)
Other restlessness while you sleep; please describe
Not during the
Less than
Once or twice
Three or more
past month              once a week
           a week               times a week   


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10.1.2
Pittsburgh Sleep Quality Index Scoring
Questions 1 through 9 are not allowed to be missing except as noted below. If these 
questions are missing, then any scores calculated using missing questions are also 
missing.
Inthe event that a range is given for an answer (for example, ‘30to 60’iswritten as the
answer to Q2, minutestofall asleep), split the differenceand enter45.
Reference
Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer OJ: The Pittsburgh Sleep 
Quality Index: A new instrument for psychiatric practice and research.  Psychiatry
Research 28:193-213, 1989.
Scores - reportable in publications
On May 20, 2005, on the instruction of Dr. Daniel J. Buysse, the scoring of the PSQI 
was changed to set the score for Q5J to 0 if either the comment or the value was
missing. This may reduce the DISTB score by 1 point and the PSQI Total Score by 1 
point.
1.
Sleep quality
The sleep quality is scored by the response of question 6.
The response of question 6
Sleep quality score
Very good
0
Fairly good
1
Fairly bad
2
Very bad
3
2.
Sleep latency
The sleep latency is scored by the sum of scores of question 2 and 5 (a).
The response of question 2
The score of question 2
>=0 to <=15 minutes
0
>15 to <=30 minutes
1
>30 to <=60 minutes
2
>60 minutes
3
The response of question 5 (a)
The score of question 5 (a)
Not during the past month
0


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Less than once a week
1
Once or twice a week
2
Three or more times a week
3
The sum of scores of question 2 and 5(a)
Sleep latency score
0
0
1 to 2
1
3 to 4
2
5 to 6
3
3.
Sleep duration
The sleep duration is scored by the response of question 4.
The response of question 4
Sleep duration score
>=7 hours
0
>=6 to <7 hours
1
>=5 to <6 hours
2
<5 hours
3
4.
Habitual sleep efficiency
The habitual sleep efficiency is scored by the sleep efficiency which is calculated from 
the responses of question 1, 3 and 4, using the following formula:
●
Bed time: The response of question 1.
●
Getting up time: The response of question 3.
●
Diffhour: 
If Bed time >= Getting up time, then Diffhour = (Getting up time + 24 hours) – Bed 
time.
If Bed time < Getting up time, then Diffhour = Getting up time – Bed time. 
●
Sleep efficiency = (The response of question 4)/ Diffhour * 100.
Sleep efficiency
Sleep duration score
>= 85 %
0
>=75 to <85 %
1
>=65 to <75 %
2
<65 %
3


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5.
Sleep disturbance
The sleep disturbance is scored by the sum of scores of question 5 (b) to 5 (j). If 
question 5 (j) comment is null or question 5 (j) is null, set the value of question 5 (j) to 0.
The response of question 5 (b), 
(c), (d), (e), (f), (g), (h), (i), (j)
The score of question 5 (b), 
(c), (d), (e), (f), (g), (h), (i), (j)
Not during the past month
0
Less than once a week
1
Once or twice a week
2
Three or more times a week
3
The sum of scores of question 5 (b) to 5 (j)
Sleep disturbance score
0
0
1 to 9
1
10 to 18
2
19 to 27
3
6.
Use of sleeping medication
The use of sleeping medication is scored by the response of question 7.
The response of question 7
Use of sleeping medication score
Not during the past month
0
Less than once a week
1
Once or twice a week
2
Three or more times a week
3
7.
Daytime dysfunction
The daytime dysfunction is scored by the sum of scores of question 8 and 9.
The response of question 8
The score of question 8
Not during the past month
0
Less than once a week
1
Once or twice a week
2
Three or more times a week
3
The response of question 9
The score of question 5 (a)
No problem at all
0
Only a very slight problem
1
Somewhat of a problem
2


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A very big problem
3
The sum of scores of question 2 and 5(a)
Sleep latency score
0
0
1 to 2
1
3 to 4
2
5 to 6
3
8.
Global score of subjective sleep quality
The global score of subjective sleep quality is the sum of above 7 component scores.


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10.2
Appendix 2: Key Contributors and Approvers
List of Key Contributors and Approvers
Key Contributors
The following contributed to or reviewed this Statistical Analysis Plan as relevant to their 
indicated discipline or role.
Primary author (s)
 
Contributors and Reviewers
, 
, 
 
 
 
 


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Author and Approver Signatories 
(E-signatures are attached at end of document) 
, 
, was the study 
statistician for this study.
, 
, was the 
biostatistics peer reviewer of this Statistical Analysis Plan 
This Statistical Analysis Plan was approved by:
This Statistical Analysis Plan was approved by: