Clinical trial NCT03901352
Conditions: Central Neuropathic Pain
Keywords: Central neuropathic pain Developmental phase III
Sponsor: Daiichi Sankyo Co., Ltd.
Start date: 2019-03-12; Completion date: 2020-12-28
Enrollment: 300 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Investigate the efficacy and safety of mirogabalin in participants with central neuropathic pain in comparison to placebo

Detailed description:
\[Double Blind Phase\] The primary objective is to compare change in the Average Daily Pain Score (ADPS) from baseline to Week 14 in Asian participants with central neuropathic pain (central neuropathic pain after spinal cord injury) receiving mirogabalin versus placebo.

\[Open Extension Phase\] The objective is to assess the long-term safety and efficacy of mirogabalin in participants with central neuropathic pain (central neuropathic pain after spinal cord injury, central post stroke pain, and central neuropathic pain in Parkinson's disease).

Arms: arm 1: The patients with creatinine clearance (CLcr) ≥ 60 mL/min: Mirogabalin 20 mg or 30 mg, oral administration, Treatment period; 2-weeks titration and 12-weeks maintenance dose.

The patients with creatinine clearance (CLcr) 30 to \< 60 mL/min: Mirogabalin 10 mg or 15 mg, oral administration, Treatment period; 2-weeks titration and 12-weeks maintenance dose arm 2: Placebo (14-weeks)
Interventions: intervention 1: Placebo intervention 2: Mirogabalin
Intervention descriptions: intervention 1: Matching placebo tablets for oral administration intervention 2: Mirogabalin tablets for oral administration

Protocol documents:
Prot_SAP_000.pdf: 
Protocol DS5565-A-J314 (Double-Blind Phase) 
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CLINICAL STUDY PROTOCOL 
 
AMELA study 
-An Asian, multicenter, randomized, double-blind, 
placebo-controlled 14-week study of mirogabalin in 
patients with central neuropathic pain followed by a 
52-week open-label extension- 
 
-For Double-Blind Phase- 
DS5565-A-J314 
 
VERSION 1.0, 18 SEP 2018 
VERSION 1.1, 22 OCT 2018 
VERSION 2.0, 11 JAN 2019 
VERSION 2.1, 10 FEB 2020 
VERSION 2.2, 30 SEP 2020 
 
 
DAIICHI SANKYO 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo.  The information 
is provided to you in confidence which is requested under an agreed upon and signed 
Confidentiality and Disclosure Agreement.  Do not give this document or any copy of it or 
reveal any proprietary information contained in it to any third party (other than those in 
your organization who are assisting you in this work and are bound by the Confidentiality 
and Disclosure Agreement) without the prior written permission of an authorized 
representative of Daiichi Sankyo. 
 


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INVESTIGATOR AGREEMENT 
AN ASIAN, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED 14-WEEK STUDY OF MIROGABALIN IN PATIENTS WITH 
CENTRAL NEUROPATHIC PAIN FOLLOWED BY A 52-WEEK OPEN-LABEL 
EXTENSION 
Sponsor Approval: 
This clinical study protocol has been reviewed and approved by the Daiichi Sankyo 
representative listed below. 
Print Name 
Signature 
Title 
Date (DD MMM YYYY) 
Investigator’s Signature: 
I have fully discussed the objectives of this study and the contents of this protocol with 
the Sponsor’s representative. 
I understand that information contained in or pertaining to this protocol is confidential 
and should not be disclosed, other than to those directly involved in the execution or the 
ethical review of the study, without written authorization from the Sponsor.  It is, 
however, permissible to provide information to a subject in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its 
requirements, subject to ethical and safety considerations and guidelines, and to conduct 
the study in accordance with the Declaration of Helsinki, International Council for 
Harmonisation guidelines on Good Clinical Practice (ICH E6), and applicable regional 
regulatory requirements. 
I agree to make available to Sponsor personnel, their representatives and relevant 
regulatory authorities, my subjects’ study records in order to verify the data that I have 
entered into the case report forms.  I am aware of my responsibilities as a Principal 
Investigator as provided by the Sponsor. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study 
at any time for whatever reason; such a decision will be communicated to me in writing.  
Conversely, should I decide to withdraw from execution of the study, I will communicate 
my intention immediately in writing to the Sponsor. 
Print Name 
Signature 
Title 
Date (DD MMM YYYY) 


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PROTOCOL SYNOPSIS 
EudraCT: 
Not Applicable 
IND Number: 
Not Applicable 
Protocol Number: 
DS5565-A-J314 
Investigational Product: 
mirogabalin 
Active Ingredient(s)/INN: 
[(1R,5S,6S)-6-(Aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-
en-6-yl] acetic acid monobenzenesulfonate 
Study Title: 
An Asian, multicenter, randomized, double-blind, placebo-
controlled 14-week study of mirogabalin in patients with 
central neuropathic pain followed by a 52-week open-label 
extension 
Study Phase: 
Phase 3 
Indication Under 
Investigation: 
Central Neuropathic Pain (CNeP) 
Study Objectives: 
Primary Objective 
• To compare change from baseline in the weekly 
average daily pain score (ADPS) at Week 14 in patients 
with CNeP after spinal cord injury (SCI) receiving 
mirogabalin versus placebo. 
Secondary Objective 
• To compare the ADPS responder rate at Week 14 
(proportion of subjects with ≥ 30% and ≥ 50% 
reduction in ADPS from baseline at Week 14) between 
mirogabalin and placebo 
• To evaluate the effect of mirogabalin on additional pain 
questionnaires, including Short-Form McGill Pain 
Questionnaire (SF-MPQ), and the Neuropathic Pain 
Symptom Inventory (NPSI),  
• To assess the effect of mirogabalin on quality of life 
(QOL), activities of daily living (ADL), mood and 
sleep, patient impressions in pain, and allodynia  
• 
To characterize the safety and tolerability of 
mirogabalin based on body weight, adverse event (AE), 
clinical laboratory values, vital sign, 12-lead 
electrocardiogram (ECG), medical interview, 
Columbia-Suicide Severity Rating Scale (C-SSRS), 


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Hospital Anxiety and Depression Scale (HADS), and 
edema.   
Estimand:  
Estimand in this study is the mean difference mirogabalin 
vs. placebo for change from baseline in weekly ADPS at 
Week 14 in patients with moderate and over chronic CNeP 
due to traumatic SCI. The missing weekly ADPS due to 
study treatment discontinuation will be imputed as if the 
subjects continue the study up to Week 14 without any 
study treatment after the discontinuation. 
Study Design: 
Multinational, randomized, double-blind, placebo-
controlled, parallel-group study 
The planned study duration for each subject will be 
approximately 16 weeks, consisting of 1-week observation 
period, 14-week treatment period and 1-week follow-up 
period after last dose. After completion of the observation 
period, the eligible subjects will be randomized into one of 
the mirogabalin-arm or placebo-arm at the ratio of 1:1, with 
stratification factors of baseline ADPS (< 6.0 or ≥ 6.0) and 
region (Japan and the others). 
Planned Study Duration: 
First patient enrolled: Mar 2019 
Last patient last visit (including follow-up): Jan 2021 
Study Sites and Location: 
Approximately 120 sites in Japan, Korea, and Taiwan 
Subject Eligibility Criteria: 
Inclusion Criteria: 
Subjects must satisfy all of the following criteria to be 
included.  
1. Age ≥ 20 years at informed consent 
2. Able to give informed consent for the study 
participation, understand procedures of this study, 
and complete patient-reported questionnaires 
adequately 
3. Spinal cord injury due to trauma (eg, turnover, fall, 
traffic accident, sports accident) 
4. C4-T12 spinal cord injury identified on MRI 
5. American Spinal Injury Association (ASIA) 
impairment scale A, B, C, or D 
6. Neuropathic pain region expressed at level and/or 
below level of spinal cord injury 
7. ≥ 6 months after SCI at screening 


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8. Stable CNePSCI at least for 3 months prior to 
screening 
9. At screening, a pain scale of ≥ 40 mm on Visual 
Analog Scale (VAS) of SF-MPQ 
10. At randomization, a pain scale of ≥ 40 mm on VAS 
of SF-MPQ, and completion of at least 4 days of 
daily pain diaries with an ADPS of ≥ 4 over the past 
7 days on the 11-point Numerical Rating Scale 
(NRS) 
Exclusion Criteria: 
Subjects who meet any of the following criteria to be 
excluded from participation in the study. 
1. On any one day during the observation period, pain 
score of 10 on a scale of 0 (no pain) to 10 (worst 
possible pain)  
2. Other severe pain at screening or randomization, 
unrelated to CNePSCI, that may confound the 
assessment of CNePSCI 
3. Neurologic disorders at screening or randomization, 
unrelated to CNePSCI, that may confound the 
assessment of CNePSCI 
4. Major psychiatric disorders within 1 year prior to 
screening 
5. Patient who has secondary-gain from CNePSCI (eg, 
legal dispute, settlement negotiations) at screening 
or randomization 
6. Spinal cord injury due to suicidal behavior 
7. Patient who blames the third party for his/her spinal 
cord injury, in the case of spinal cord injury due to 
the third party act (Those patients can rarely 
overcome the pain due to the psychiatric factor) 
8. Previous administration of pregabalin ≥ 300 mg/day 
for subjects with creatinine clearance (CLcr: using 
the Cockcroft-Gault equation) ≥ 60 mL/min 
or pregabalin ≥ 150 mg/day for subjects with CLcr 
30 to < 60 mL/min for at least 4 weeks, declared 
lack of effect 
9. Previous administration of gabapentin 
≥ 1200 mg/day for subjects with CLcr ≥ 60 mL/min 
or gabapentin ≥ 600 mg/day for subjects with CLcr 


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30 to < 60, for at least 4 weeks, declared lack of 
effect 
10. Use of mirogabalin, pregabalin, or gabapentin 
within 28 days prior to screening 
11. Use of strong opioids for analgesic of CNePSCI 
within 3 months prior to screening 
12. CLcr (using the Cockcroft-Gault equation) 
< 30 mL/min at screening 
13. Malignancy other than basal cell carcinoma within 
the past 2 years prior to screening 
14. Clinically significant unstable endocrine (eg, 
diabetes mellitus), neurologic, ophthalmologic, 
hepatobiliary, respiratory, hematologic illness, or 
cardiovascular disease (eg, uncontrolled cardiac 
arrhythmia, or myocardial infarction) at screening 
or randomization 
15. Clinically significant findings on ECG at screening 
16. History of pernicious anemia, untreated 
hypothyroidism, or human immunodeficiency virus 
infection 
17. Pregnancy, potential pregnancy, breast feeding, or 
subject unwilling to take reliable contraceptive 
measures during the study or for 4 weeks after study 
completion 
18. Known hypersensitivity to mirogabalin, pregabalin, 
or gabapentin 
19. Participation in another clinical study, either 
currently or within 30 days prior to providing of 
informed consent 
20. Experience of participating mirogabalin clinical 
study and receiving investigational product 
21. Abuse of illicit drugs or alcohol history 
22. Response of “yes” to any of the questions on the C-
SSRS at screening or randomization in relation to 
events occurring within the past 12 months 
23. At screening, clinical laboratory values exceeding 
limits listed in Table 4.1 


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24. The subject who is considered inappropriate for the 
study at the discretion of the investigator or sub-
investigator 
Dosage Form, Dose and 
Route of Administration: 
One tablet of either mirogabalin or matching placebo will 
be administered orally twice daily (BID) (in the morning 
and at bedtime). 
In mirogabalin group, patients with CLcr ≥ 60 mL/min at 
screening, will start with 5 mg BID of mirogabalin at first 
week, followed by 10 mg BID at second week as titration 
phase.  From the third week, if there are no problems in 
safety, the patients will escalate the dose to 15 mg BID.  
For the following visits, the dosage may be changed to 
either 10 mg BID or 15 mg BID depending on safety 
findings at the time of each visit.  Patients in placebo group 
take matching placebo throughout the entire period. 
In mirogabalin group, patients with CLcr 30 to 
< 60 mL/min at screening, will start 2.5 mg BID of 
mirogabalin at first week, followed by 5 mg BID at second 
week as titration phase.  From the third week, if there are 
no problems in safety, the patients will escalate the dose to 
7.5 mg BID.  For the following visits, the dosage may be 
changed to either 5 mg BID or 7.5 mg BID depending on 
safety findings at the time of each visit.  Patients in placebo 
group take matching placebo throughout the entire period. 
Study Endpoints: 
Primary efficacy endpoint: 
• Change from baseline in the weekly ADPS at Week 14  
Secondary efficacy endpoints: 
• ADPS Responder rate defined as the proportion of 
subjects with ≥ 30%, and ≥ 50% reduction from 
baseline to Week 14   
• Change from baseline in parameters assessed using the 
SF-MPQ 
• Patient Global Impression of Change (PGIC) 
• Change from baseline in parameters assessed using the 
NPSI 
• Change from baseline in average daily sleep 
interference score (ADSIS) 
• Change from baseline in Medical Outcomes Study 
(MOS) sleep scales 
• Change from baseline in the HADS 


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• Changes from baseline in parameters assessed using 
Five Level EQ-5D version (EQ-5D-5L) 
• Changes from baseline in parameters assessed using 
Spinal Cord Independence Measure (SCIM) III 
• Change from baseline of allodynia 
Planned Sample Size: 
A total of 274 patients will be randomized to one of the 
placebo-arm or mirogabalin-arm at the ratio of 1:1. 
Statistical Analyses: 
Efficacy: 
Modified intent-to-treat (mITT) analysis set will be used as 
a primary for all efficacy analyses.   
Mean change from baseline in the weekly ADPS at Week 
14 will be compared between mirogabalin arm and placebo 
using the following multiple imputation (MI) method and 
analysis of covariance (ANCOVA). 
The primary imputation will be based on “nonfuture 
dependence" model using the pattern mixture approach 
with shifting parameters under the missing not at random 
(MNAR) mechanism for the missing weekly ADPS data.  
Reason for dropout together with the time of dropout will 
be used for constructing the missing data pattern.  The 
statistical model used for the MI data generation will be the 
Markov Chain Monte Carlo (MCMC) method with 
adjustment for relevant covariates to produce a monotone 
pattern first, and then the imputation will continue using the 
Regression with Predictive Mean Matching (REGPMM) 
method for the monotone pattern with the same set of 
covariates.  Each complete imputed dataset will be 
analyzed using the ANCOVA with treatment as the fixed 
effects, and baseline ADPS as the covariate.  The results of 
ANCOVA analysis from each complete imputed dataset 
will be combined using Rubin’s rule. 
All reasons for discontinuation will be categorized, to the 
extent possible, into either lack of efficacy (LOE) or AE 
based on detail specified in the case report form (CRF).  
Only reasons that cannot be classified into the above two 
categories will be considered as “any other reasons 
(AOR).”  The primary shifting parameter values 
corresponding to the three categories in the pattern mixture 
model (PMM) will be chosen as (1.0, 1.0, 0.5) for dropouts 
due to AE, LOE and AOR, respectively, and the 
corresponding shifting amount of the weekly ADPS 


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imputed at first missing week is given by (1.0, 1.0, 
0.5)*residual standard deviation (RSD)*U(0,1) where 
U(0,1) is a random variable from a uniform distribution 
with a range of 0 to 1, and RSD is the RSD at first missing 
week after imputation. 
Sensitivity analysis for the primary endpoint includes the 
followings:   
• The primary analysis on the mITT analysis set 
using “nonfuture dependence” MNAR model 
with different shift parameters including (3, 3, 
1.5), (5, 5, 2.5), and (0, 0, 0). 
Supplementary analysis for the primary endpoint includes 
the followings: 
• The primary analysis on the mITT analysis set 
using placebo multiple imputation 
• ANCOVA with baseline ADPS and treatment as 
covariates on the mITT analysis set using 
baseline observation carried forward 
• ANCOVA with baseline ADPS and treatment as 
covariates on the mITT analysis set using last 
observation carried forward 
• The primary analysis on the PPS using 
“nonfuture dependence” MNAR model with the 
shift parameters of (1, 1, 0.5). 
Response rate, defined as the proportion of subjects with 
≥ 30%, and ≥ 50% reduction from baseline in ADPS at 
Week 14, will be compared between each mirogabalin arm 
and placebo, using logistic regression model.  
Safety: 
The treatment-emergent AEs, clinical laboratory tests 
results, vital signs, body weight, 12-lead ECG, evaluation 
of edema, C-SSRS, and HADS will be summarized using 
the safety analysis set. 
 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT......................................................................... 2 
PROTOCOL SYNOPSIS ...................................................................................... 3 
TABLE OF CONTENTS ..................................................................................... 10 
LIST OF TABLES ............................................................................................... 17 
LIST OF ABBREVIATIONS .............................................................................. 18 
1. 
INTRODUCTION ................................................................................. 21 
1.1. 
Background ............................................................................................ 21 
1.2. 
Study Rationale ..................................................................................... 22 
1.2.1. 
Description of Investigational Drug ...................................................... 22 
1.2.2. 
Nonclinical Studies ................................................................................ 22 
1.2.3. 
Clinical Experience ............................................................................... 22 
1.2.3.1. Phase 3 Study in Patients With Diabetic Peripheral Neuropathic Pain . 22 
1.2.3.2. Phase 3 Study in Patients With Post-Herpetic Neuralgia ...................... 23 
1.2.3.3. Study for DPNP or PHN Patients With Renal Impairment ................... 24 
1.2.3.4. Clinical Pharmacology Studies in Subjects With Renal Impairment .... 25 
1.2.4. 
Study Rationale ..................................................................................... 25 
1.2.5. 
Risks and Benefits for the Study Subjects ............................................. 25 
2. 
STUDY OBJECTIVES AND HYPOTHESIS ...................................... 27 
2.1. 
Study Objectives .................................................................................... 27 
2.1.1. 
Primary Objectives ................................................................................ 27 
2.1.2. 
Secondary Objectives ............................................................................ 27 
2.1.3. 
Exploratory Objectives .......................................................................... 27 
2.2. 
Study Hypotheses .................................................................................. 27 
2.3. 
Study Endpoints ..................................................................................... 27 
2.3.1. 
Primary Efficacy Endpoint .................................................................... 27 
2.3.2. 
Secondary Efficacy Endpoint(s) ............................................................ 27 
2.3.3. 
Exploratory Efficacy Endpoint .............................................................. 28 
2.3.4. 
Pharmacokinetic/Pharmacodynamic/Biomarker Endpoint(s) ............... 28 
2.3.5. 
Safety Endpoint(s) ................................................................................. 28 
2.3.6. 
Other Endpoints ..................................................................................... 28 
3. 
STUDY DESIGN .................................................................................. 29 


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3.1. 
Overall Design ....................................................................................... 29 
3.1.1. 
Study Type ............................................................................................. 29 
3.1.2. 
Study Scheme ........................................................................................ 29 
3.2. 
Discussion of Study Design ................................................................... 30 
3.2.1. 
Dosage of Mirogabalin .......................................................................... 30 
3.2.2. 
Duration of Study Treatment ................................................................. 31 
3.2.3. 
Control Treatment ................................................................................. 31 
3.2.4. 
Study Endpoints ..................................................................................... 31 
4. 
STUDY POPULATION ........................................................................ 32 
4.1. 
Inclusion Criteria ................................................................................... 32 
4.2. 
Exclusion Criteria .................................................................................. 32 
5. 
STUDY TREATMENT(S) .................................................................... 35 
5.1. 
Assigning Subjects to Treatments and Blinding ................................... 35 
5.1.1. 
Treatment Group(s)/Sequences ............................................................. 35 
5.1.2. 
Method of Treatment Allocation ........................................................... 35 
5.1.2.1. Enrollment ............................................................................................. 35 
5.1.2.2. Procedures for Subject Enrollment ........................................................ 35 
5.1.3. 
Blinding ................................................................................................. 36 
5.1.4. 
Emergency Unblinding Procedure ........................................................ 36 
5.2. 
Study Drug(s) ........................................................................................ 37 
5.2.1. 
Description ............................................................................................ 37 
5.2.2. 
Labeling and Packaging ........................................................................ 37 
5.2.3. 
Preparation ............................................................................................. 38 
5.2.4. 
Administration ....................................................................................... 38 
5.2.5. 
Storage ................................................................................................... 40 
5.2.6. 
Drug Accountability .............................................................................. 40 
5.3. 
Control Treatment ................................................................................. 40 
5.4. 
Dose Interruptions and Reductions ....................................................... 40 
5.5. 
Method of Assessing Treatment Compliance ........................................ 41 
5.6. 
Concomitant Medications ...................................................................... 41 
5.6.1. 
Prohibited Concomitant Medications .................................................... 41 
5.6.2. 
Restricted Concomitant Medications .................................................... 41 
5.6.3. 
Rescue Medications ............................................................................... 42 


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5.6.4. 
Restricted Concomitant Therapies ........................................................ 42 
5.6.5. 
Other ...................................................................................................... 42 
5.7. 
Subject Withdrawal/Discontinuation ..................................................... 43 
5.7.1. 
Withdrawal Criteria ............................................................................... 43 
5.7.2. 
Reasons for Withdrawal ........................................................................ 43 
5.7.3. 
Withdrawal Procedures ......................................................................... 44 
5.7.4. 
Subject Replacement ............................................................................. 44 
5.7.5. 
Subject Re-screening Procedures .......................................................... 44 
6. 
STUDY PROCEDURES ....................................................................... 45 
6.1. 
Screening (Visit 1) ................................................................................. 45 
6.2. 
Randomization (Visit 2) ........................................................................ 46 
6.3. 
Treatment Period ................................................................................... 47 
6.3.1. 
Visit 3 and Visit 4 .................................................................................. 47 
6.3.2. 
Visit 5 and Visit 6 .................................................................................. 47 
6.4. 
End of Treatment (Visit 7)/Early Termination ...................................... 48 
6.5. 
Follow-up .............................................................................................. 49 
7. 
EFFICACY ASSESSMENTS ............................................................... 50 
7.1. 
Assessments for Efficacy Endpoint(s) ................................................... 50 
7.1.1. 
Primary Efficacy Endpoint .................................................................... 50 
7.1.1.1. Change from Baseline in the Weekly Average Daily Pain Score at Week 
14 50 
7.1.2. 
Secondary Efficacy Endpoint ................................................................ 50 
7.1.2.1. Average Daily Pain Score Response Rate ............................................. 50 
7.1.2.2. Change from Baseline in Parameters Assessed Using Short-Form 
McGill Pain Questionnaire .................................................................... 50 
7.1.2.3. Patient Global Impression of Change .................................................... 50 
7.1.2.4. Change from Baseline in Sleep-interference Score ............................... 51 
7.1.2.5. Change from Baseline in Medical Outcomes Study Sleep Scale .......... 51 
7.1.2.6. Change from Baseline in Hospital Anxiety and Depression Scale ....... 52 
7.1.2.7. Change from Baseline in Neuropathic Pain Symptom Inventory ......... 52 
7.1.2.8. Change from Baseline in Five Level EQ-5D version ............................ 52 
7.1.2.9. Change from Baseline in Spinal Cord Independence Measure ............. 52 
7.1.2.10. Change from Baseline in Allodynia ...................................................... 53 


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7.1.3. 
Exploratory Efficacy Endpoint .............................................................. 53 
7.1.3.1. Change from baseline in the average daily micturition frequency ........ 53 
7.1.3.2. Change from baseline in the average daily urinary incontinence 
episodes ................................................................................................. 53 
7.1.3.3. Change from baseline in parameters assessed using Overactive Bladder 
Symptom Score (OAB-SS) .................................................................... 53 
7.2. 
Appropriateness of Selected Efficacy Assessment(s) ........................... 53 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS . 54 
8.1. 
Pharmacokinetic Assessment(s) ............................................................ 54 
8.2. 
Pharmacodynamic Assessment(s) ......................................................... 54 
8.3. 
Biomarker Assessment(s) ...................................................................... 54 
8.4. 
Immunogenicity ..................................................................................... 54 
8.5. 
Pharmacogenomic Analysis .................................................................. 54 
9. 
SAFETY EVALUATION AND REPORTING .................................... 55 
9.1. 
Assessment of Safety Endpoint(s) ......................................................... 55 
9.2. 
Adverse Event Collection and Reporting .............................................. 55 
9.3. 
Adverse Events of Special Interest ........................................................ 56 
9.4. 
Adverse Event ....................................................................................... 57 
9.4.1. 
Definition of Adverse Event .................................................................. 57 
9.4.2. 
Serious Adverse Event .......................................................................... 57 
9.4.3. 
Severity Assessment .............................................................................. 58 
9.4.4. 
Causality Assessment ............................................................................ 58 
9.4.5. 
Action Taken Regarding Study Drug(s) ................................................ 59 
9.4.6. 
Other Action Taken for Event ............................................................... 59 
9.4.7. 
Adverse Event Outcome ........................................................................ 59 
9.4.8. 
Definition of Adverse Drug Reaction .................................................... 60 
9.5. 
Serious Adverse Events and Adverse Event of Special Interest 
Reporting–Procedure For Investigators ................................................. 60 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee .......................................................... 61 
9.7. 
Exposure In Utero During Clinical Studies ........................................... 61 
9.8. 
Clinical Laboratory Evaluations ............................................................ 61 
9.9. 
Vital Signs ............................................................................................. 64 
9.10. 
Electrocardiograms ................................................................................ 65 


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9.11. 
Physical Findings ................................................................................... 65 
9.11.1. Body Height and Weight ....................................................................... 65 
9.11.2. Medical Interview .................................................................................. 65 
9.11.3. Evaluation of Edema ............................................................................. 65 
9.12. 
Other Examinations ............................................................................... 65 
9.12.1. Columbia-Suicide Severity Rating Scale .............................................. 65 
9.12.2. Hospital Anxiety and Depression Scale ................................................ 65 
9.12.3. Pregnancy Test ...................................................................................... 66 
10. 
OTHER ASSESSMENTS ..................................................................... 67 
11. 
STATISTICAL METHODS ................................................................. 68 
11.1. 
General Statistical Considerations ......................................................... 68 
11.2. 
Analysis Sets ......................................................................................... 68 
11.3. 
Study Population Data ........................................................................... 69 
11.4. 
Efficacy Analyses .................................................................................. 69 
11.4.1. Primary Efficacy Analyses .................................................................... 69 
11.4.2. Secondary Efficacy Analyses ................................................................ 70 
11.4.2.1. Key Secondary Efficacy Analyses ........................................................ 70 
11.4.2.2. Other Secondary Efficacy Analyses ...................................................... 72 
11.4.3. Exploratory Efficacy Analyses .............................................................. 72 
11.4.4. Pharmacokinetic/Pharmacodynamic/Biomarker Analyses.................... 72 
11.4.5. Safety Analyses ..................................................................................... 72 
11.4.5.1. Adverse Event Analyses ........................................................................ 72 
11.4.5.2. Clinical Laboratory Evaluation Analyses .............................................. 73 
11.4.5.3. Vital Sign Analyses ............................................................................... 73 
11.4.5.4. Electrocardiogram Analyses .................................................................. 73 
11.4.5.5. Physical Findings ................................................................................... 73 
11.4.5.6. Columbia-Suicide Severity Rating Scale .............................................. 73 
11.4.5.7. Hospital Anxiety and Depression Scale ................................................ 73 
11.4.6. Other Endpoint Analysis ....................................................................... 73 
11.5. 
Interim Analyses .................................................................................... 73 
11.6. 
Sample Size Determination ................................................................... 73 
11.7. 
Statistical Analysis Process ................................................................... 74 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE ........................ 75 


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12.1. 
Monitoring and Inspections ................................................................... 75 
12.2. 
Data Collection ...................................................................................... 75 
12.3. 
Data Management .................................................................................. 76 
12.4. 
Study Documentation and Storage ........................................................ 76 
12.5. 
Record Keeping ..................................................................................... 77 
13. 
FINANCING AND INSURANCE ........................................................ 78 
13.1. 
Finances ................................................................................................. 78 
13.2. 
Reimbursement, Indemnity, and Insurance ........................................... 78 
14. 
PUBLICATION POLICY AND PUBLIC DISCLOSURE OF 
CLINICAL TRIAL INFORMATION ................................................... 79 
15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION ......... 80 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance ................ 80 
15.2. 
Subject Confidentiality .......................................................................... 80 
15.3. 
Informed Consent .................................................................................. 80 
15.4. 
Regulatory Compliance ......................................................................... 81 
15.5. 
Protocol Deviations ............................................................................... 82 
15.6. 
Supply of New Information Affecting the Conduct of the Study ......... 82 
15.7. 
Protocol Amendments ........................................................................... 82 
15.8. 
Study Termination ................................................................................. 83 
15.9. 
Data and Safety Monitoring Board ........................................................ 83 
15.10. 
Address List ........................................................................................... 83 
15.10.1. Sponsor’s Responsible Medical Officer ................................................ 83 
15.10.2. Sponsor’s Responsible Medical Adviser ............................................... 84 
15.10.3. Sponsor’s Clinical Scientist ................................................................... 84 
15.10.4. Sponsor’s Study Manager ...................................................................... 84 
15.10.5. Coordinating Investigator ...................................................................... 84 
15.10.6. Contract Research Organization in Charge of Monitoring in Japan ..... 85 
15.10.7. Contract Research Organization in Charge of Monitoring in Korea ..... 85 
15.10.8. Contract Research Organization in Charge of Monitoring in Taiwan .. 85 
15.10.9. EDC Vendor Development .................................................................... 85 
15.10.10. 
EDC System Support ........................................................................ 85 
15.10.11. 
IRT Vendor ....................................................................................... 86 
15.10.12. 
Central Laboratory in Japan .............................................................. 86 


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15.10.13. 
Central Laboratory in Korea ............................................................. 86 
15.10.14. 
Central Laboratory in Taiwan ........................................................... 86 
15.10.15. 
Sponsor’s Biostatistician .................................................................. 86 
16. 
REFERENCES ...................................................................................... 87 
17. 
APPENDICES ....................................................................................... 89 
17.1. 
Schedule of Events ................................................................................ 89 
 


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LIST OF TABLES 
Table 4.1: Hematology/Blood Chemistry Limits............................................... 34 
Table 5.1: Drug Combinations During the Treatment Period (Week 1) ............ 37 
Table 5.2: Drug Combinations During the Treatment Period (Week 2) ............ 38 
Table 5.3: Drug Combinations During the Treatment Period (Week 3 to Week 
14) ..................................................................................................... 38 
Table 5.4: Method of Administration During the Treatment Period ................. 39 
Table 9.1: Laboratory Parameters to be Assessed, and Time of Assessment .... 62 
Table 17.1: Study Visit ........................................................................................ 90 
Table 17.2: Efficacy Assessment by Visit ........................................................... 91 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
ADL 
activities of daily living 
ADPS 
average daily pain score 
ADR 
adverse drug reaction 
ADSIS 
average daily sleep interference score 
AE 
adverse event 
A/G ratio 
albumin/globulin ratio 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AOR 
any other reasons 
ASIA 
American Spinal Injury Association 
AST 
aspartate aminotransferase 
BID 
twice daily 
BUN 
blood urea nitrogen 
CNeP 
central neuropathic pain 
CNePSCI 
CNeP after SCI 
CNS 
central nervous system 
CLcr 
creatinine clearance 
CRF 
case report form 
CRO 
contract research organization 
CRP 
C-reactive protein 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DPNP 
diabetic peripheral neuropathic pain 
eCRF 
electronic case report form 
EC 
Independent Ethics Committee 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EIU 
exposure in utero 
EMA 
European Medicines Agency 
EQ-5D-5L 
Five Level EQ-5D version 
ESRD 
end stage renal disease 


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ABBREVIATION 
DEFINITION 
GCP 
Good Clinical Practice (refers to ICH and Code of Federal 
Regulations) 
γ-GT (γ-GTP) 
gamma-glutamyl transpeptidase 
GOT 
glutamic oxaloacetic transaminase 
GPT 
glutamic pyruvic transaminase 
HADS 
Hospital Anxiety and Depression Scale 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
INN 
International Nonproprietary Names 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISFLB 
independent sub-functional lead of biostatistics 
ISNCSCI 
International Standards for Neurological Classification of Spinal Cord 
Injury 
LDH 
Lactate Dehydrogenase 
LOE 
lack of efficacy 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
mITT 
modified intent-to-treat 
MMRM 
mixed effects model for repeated measurements 
MNAR 
missing not at random 
MOS 
Medical Outcomes Study 
NeP 
Neuropathic pain 
NPSI 
Neuropathic Pain Symptom Inventory 
NRS 
Numerical Rating Scale 
OAB-SS 
Overactive Bladder Symptom Score 
PGIC 
Patient Global Impression of Change 
PHN 
post-herpetic neuralgia 
PK 
pharmacokinetic(s) 
PMM 
pattern mixture model  
PNeP 
peripheral neuropathic pain 
PPS 
per-protocol set 


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ABBREVIATION 
DEFINITION 
PT 
Preferred term 
QD 
once daily 
QOL 
quality of life 
RBC 
red blood cell 
REGPMM 
Regression with Predictive Mean Matching 
RSD 
residual standard deviation 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System 
SCI 
spinal cord injury 
SCIM 
Spinal Cord Independence Measure 
SD 
standard deviation 
SF-MPQ 
Short-Form McGill Pain Questionnaire 
SOC 
system organ class 
T-Bil 
total bilirubin 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
VAS 
Visual Analog Scale 
WBC 
white blood cell 
 


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1. 
INTRODUCTION 
1.1. 
Background 
Neuropathic pain is defined as pain initiated or caused by a lesion or dysfunction in the 
nervous system.  Neuropathic pain has a variety of causes, including diabetes mellitus, 
viral infection, and spinal cord injury.  Typical symptoms are spontaneous pain, 
hyperalgesia, and allodynia.  The severity and duration of these symptoms vary greatly, 
depending on the etiology of the condition.1  Findings from research in animal models 
suggest a relationship between the induction of neural lesions and changes in the level of 
ion channel and receptor expression in the cell membrane (cell membrane remodeling).2  
Those findings indicate that cell membrane remodeling lowers the action potential 
threshold and causes abnormal heterotopic firing among primary neurons and dorsal root 
ganglions.  This in turn elicits the symptoms of neuropathic pain (NeP).1,3  However, the 
relationship remains unclear between cell membrane remodeling and the lesions that 
cause this remodeling.  This lack of clarity contributes to difficulties in the formulation of 
treatment plans and in the selection of therapeutic drugs.   
Because a wide variety of pathologies can contribute to NeP, the patient population is 
extremely diverse.3,4,5  Neuropathic pain can be treated with agents such as 
anticonvulsants (including α2δ ligands and carbamazepine), tricyclic antidepressants, and 
serotonin/norepinephrine reuptake inhibitors.  Combination drug therapy is the usual 
form of treatment; mono-therapy is insufficient for effect.5,6,7,8  The mechanisms of action 
are well-known for the drugs for treatment of this condition.  Existing assessment 
methods can be used to estimate the mechanism of pain onset and continuation, based on 
the extent of pain relief that is provided by each drug.  Unfortunately, however, these 
drugs do not provide adequate pain relief in many cases.  In addition, all of these drugs 
are associated with adverse drug reactions (ADRs) that are related to the central nervous 
system (CNS).  The question of tolerability is thus important for many patients, and 
especially for patients who receive combination drug therapy.5,8  Because of insufficient 
drug efficacy and the prevalence of ADRs, considerable unmet need remains in this 
therapeutic area.   
Gabapentin and pregabalin, which are commercially available α2δ ligands, are associated 
with fewer problems related to tolerability and drug interactions than other available 
drugs.5  The α2δ ligand bind to the α2δ subunits of voltage-dependent Ca2+ channels that 
are expressed in nerve cell membranes.  The α2δ ligand is thought to relieve pain through 
the inhibition of abnormal neural transmissions, primarily in the posterior horn of the 
spinal cord.9,10,11,12  The mechanism of action is not completely understood.  However, in 
animal models of NeP, research findings indicate that the α2δ ligand reduces calcium 
flow through voltage-dependent Ca2+ channels and inhibits the release of excitatory 
neurotransmitters such as glutaminic acid, norepinephrine, and substance P.9,10,11,12  
Gabapentin and pregabalin are currently considered first-line drugs for NeP in Europe 
and the United States.  However, the dose is limited for both drugs because of the 
incidence of significant ADRs at high dose levels.  As a result, these drugs do not provide 
adequate pain relief in many cases.  The most common ADRs are dizziness and 


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somnolence, but weight gain and peripheral edema can also be of clinical importance.13  
Greater efficacy and safety are still needed in this class of drugs.   
1.2. 
Study Rationale 
1.2.1. 
Description of Investigational Drug 
Mirogabalin binds with high affinity to the α2δ subunit of voltage-dependent Ca2+ 
channels. The α2δ subunit is expressed in the neural synapses, and analgesic action 
appears to be elicited when mirogabalin binds to this subunit.   
Nonclinical studies (see Section 1.2.2) and clinical studies for diabetic peripheral 
neuropathic pain (DPNP) and post-herpetic neuralgia (PHN) (see Section 1.2.3) indicate 
that mirogabalin is strongly expected to be useful in the treatment of NeP, including 
patients with renal impairment.   
1.2.2. 
Nonclinical Studies 
Evidence from nonclinical studies suggests that NeP symptoms may be due to changes in 
the protein content of membranes of injured neurons (“membrane remodeling”).  This 
process can lower the threshold for action potential generation, resulting in abnormal and 
spontaneous firing in peripheral and primary afferent and dorsal root ganglionic neurons.  
Treatment with an α2δ ligand is reported to reduce the calcium ion (Ca2+) influx through 
voltage-dependent Ca2+ channels, and therefore to reduce the subsequent release of 
excitatory neurotransmitters such as glutamate, norepinephrine, and substance P.9,10,11,12   
In nonclinical experiments, mirogabalin showed potent and highly specific binding 
affinity to the α2δ subunit.  Mirogabalin also demonstrated a stronger analgesic effect 
than pregabalin in rodent models of peripheral neuropathic pain (PNeP).  In spinal cord 
injury model rats, single oral administration of mirogabalin (2.5, 5, and 10 mg/kg) 
significantly increased the pain threshold. The increase in the pain threshold was still 
significant 8 hours after administration of either 2.5 mg/kg or 10 mg/kg.  Additional 
information on nonclinical studies can be found in the Investigator’s Brochure.   
1.2.3. 
Clinical Experience 
The efficacy, safety, and tolerability of mirogabalin were evaluated in 20 Phase 1 studies, 
2 Phase 2 studies, 8 Phase 3 studies. In this section, pivotal two Phase 3 studies in 
patients with DPNP and PHN, the study in patients DPNP and PHN with renal 
impairment, and clinical pharmacology studies in subjects with renal impairment are 
shown.    
1.2.3.1. 
Phase 3 Study in Patients With Diabetic Peripheral Neuropathic Pain 
This was a multi-center, randomized, double-blind, placebo-controlled, 14 week study of 
mirogabalin in Asian subjects with DPNP followed by a 52-week open label extension 
(DS5565-A-J303).  This study was conducted in Japan, Korea, Taiwan and Malaysia.  
The patients with creatinine clearance (CLcr) < 60 mL/min were excluded.    


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1.2.3.1.1. Double-blind Phase of the Study 
In this phase, mirogabalin was administered at doses of 15 mg once daily (QD), 10 mg 
twice daily (BID), or 15 mg BID for 14 weeks, including the titration period, to evaluate 
the efficacy and safety of mirogabalin in Asian patients with DPNP.  The mean ADPS at 
Week 14 decreased from baseline in all treatment groups.  The 10-mg BID group and 
15-mg BID group showed improvement in ADPS compared with the placebo group, and 
the differences versus placebo were statistically significant in the 15-mg BID group.  The 
results of some secondary efficacy endpoints showed the efficacy of mirogabalin 
(especially 10 mg BID and 15 mg BID) with statistically significant differences 
compared with placebo.  Although, in the primary efficacy endpoint, the 10 mg BID 
group did not show a statistically significant difference compared with the placebo group, 
the results of the primary and secondary efficacy endpoints suggested the efficacy of 
10 mg BID of mirogabalin.  Therefore, mirogabalin 15 mg BID is considered effective, 
and the efficacy of 10 mg BID is also suggested.   
Overall, the incidence of treatment-emergent adverse events (TEAEs) and the most 
common TEAEs of nasopharyngitis, somnolence, dizziness, and weight increased were 
higher as the daily dose of mirogabalin was increased; and the vast majority of these 
events were mild.  Two deaths were reported, but were considered unrelated to the study 
drug.  No specific safety concerns in other reported serious TEAEs, or otherwise, were 
found.  Therefore, mirogabalin 15 mg QD, 10 mg BID, and 15 mg BID are considered 
well tolerated in patients with DPNP.   
1.2.3.1.2. Open Label Extension Phase of the Study 
In this phase, mirogabalin was administered in a flexible dosage of 10 mg BID and 15 mg 
BID for 52 weeks in Asian subjects with DPNP, including the titration period, to evaluate 
the safety and efficacy of mirogabalin in patients with DPNP.   
In terms of safety, the incidence of TEAEs leading to treatment discontinuation was low.  
The most common TEAEs were similar to those in the DB study and no increased risks 
with a long term administration of mirogabalin were observed in this study.  The results 
indicated that mirogabalin administered in a flexible dosage of 10 mg BID and 15 mg 
BID for up to 52 weeks in subjects with DPNP was well tolerated.   
In terms of efficacy, certain improvement of SF-MPQ subscales (sensory score, affective 
score, total score, VAS, and present pain intensity) was observed throughout the 
treatment period compared to the baseline.  Mirogabalin administered in a flexible dosage 
of 10 mg BID and 15 mg BID for up to 52 weeks indicated a long-term efficacy of 
mirogabalin in pain relief in subjects with DPNP.   
1.2.3.2. 
Phase 3 Study in Patients With Post-Herpetic Neuralgia 
This was a multi-center, randomized, double-blind, placebo-controlled, 14 week study of 
mirogabalin in Asian subjects with PHN followed by a 52-week open label extension 
(DS5565-A-J304).  This study was conducted in Japan, Korea, Taiwan, Singapore, 
Malaysia, and Thailand. The patients with CLcr < 60 mL/min were excluded.   


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1.2.3.2.1. Double-Blind Phase of the Study 
In this phase, mirogabalin was administered at doses of 15 mg QD, 10 mg BID, or 15 mg 
BID for 14 weeks in Asian subjects with PHN, including the titration period, to evaluate 
the efficacy and safety of DS-5565 in patients with PHN.  The mean ADPS at Week 14 
decreased from baseline in all treatment groups.  The efficacy of 10 mg BID and 15 mg 
BID of mirogabalin was superior to placebo in the change in ADPS from baseline at 
Week 14.  The efficacy of 15 mg QD of mirogabalin was also superior to placebo in the 
change in ADPS from baseline at Week 14.  The results of secondary efficacy endpoints 
also showed trends consistent with the result of the primary efficacy endpoint and 
supported the results of the primary analysis.  It is considered that mirogabalin 
administered at doses of 15 mg QD, 10 mg BID, or 15 mg BID in patients with PHN is 
effective.   
Overall, the incidence of TEAEs and the most common TEAEs of somnolence, dizziness, 
and edema were higher as the daily dose of mirogabalin was increased, and the vast 
majority of these events were mild.  No deaths were reported, and no specific safety 
concerns in other reported serious TEAEs, or otherwise, were found.  No other specific 
safety concerns were found.  Therefore, mirogabalin 15 mg QD, 10 mg BID, and 15 mg 
BID are considered well tolerated in patients with PHN.  
In conclusion, mirogabalin 15 mg QD, 10 mg BID, and 15 mg BID are considered 
efficacious, and well tolerated in patients with PHN.   
1.2.3.2.2. Open Label Extension Phase of the Study 
In this phase, mirogabalin was administered in a flexible dosage of 10 mg BID and 15 mg 
BID for up to 52 weeks in Asian subjects with PHN, including the titration period, to 
evaluate the long-term safety and efficacy of mirogabalin in patients with PHN.   
In terms of safety, the incidence of TEAEs leading to treatment discontinuation was low.  
The most common TEAEs were similar to those in the DB study and no increased risks 
with a long term administration of mirogabalin were observed in this study.  The results 
indicated that mirogabalin administered in a flexible dosage of 10 mg BID and 15 mg 
BID for up to 52 weeks in subjects with PHN was well tolerated. 
In terms of efficacy, certain improvement of SF-MPQ subscales (sensory score, affective 
score, total score, VAS, and present pain intensity) was observed throughout the 
treatment period compared to the baseline.  Mirogabalin administered in a flexible dosage 
of 10 mg BID and 15 mg BID for up to 52 weeks indicated a long-term efficacy of 
mirogabalin in pain relief in subjects with PHN.   
1.2.3.3. 
Study for DPNP or PHN Patients With Renal Impairment  
This was an open-label 14-week study for treatment of DPNP or PHN in subjects with 
moderate or severe renal impairment in Japan. Mirogabalin was administered at doses of 
7.5 mg BID for subject with CLcr 30 to < 60 mL/min, and at dose of 7.5 mg QD for 
subjects with CLcr 15 to < 30 mL/min, including the titration period, to evaluate the 
safety of mirogabalin in patients with renal impairment.  In terms of safety, the incidence 
of TEAEs were similar to those being observed in the pivotal Phase 3 studies in patients 


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with DPNP and PHN, and specific concerns for patients with renal impairment were not 
observed. In efficacy, change in ADPS from baseline at week-14 were almost same as the 
changes of 15 mg BID in the 2 Phase 3 studies described in Section 1.2.3.1 and Section 
1.2.3.2, regardless of the degree of renal impairment.   
1.2.3.4. 
Clinical Pharmacology Studies in Subjects With Renal Impairment 
A clinical pharmacology study was conducted to assess PK of mirogabalin in Japanese 
subjects with renal impairment.  In this study, following administration of single oral 
doses of 5 mg mirogabalin to healthy subjects, subjects with mild (50 to 
≤ 80 mL/min/1.73 m2), moderate (30 to < 50 mL/min/1.73 m2), or severe renal 
impairment (< 30 mL/min/1.73 m2), and subjects with end stage renal disease (ESRD), 
the overall exposure to mirogabalin, based on AUC, increased with severity of renal 
impairment.  As assessed using the geometric least squares mean ratios, exposure was 
approximately 1.3, 1.9, 3.6, and 5.3 fold greater for subjects with mild, moderate, and 
severe renal impairment and ESRD, respectively, compared to subjects with normal renal 
function.  Apparent clearance and renal clearance of A200-0700 decreased with 
increasing severity of renal impairment.  
1.2.4. 
Study Rationale 
In the two phase 3 studies in patients with DPNP and PHN which are different etiologies, 
pain improvement of mirogabalin was proved and degree of the improvement showed 
similar dose response in DPNP and PHN.  In addition, exogenous and endogenous factors 
except for renal function are considered to have a little effect on efficacy of mirogabalin, 
as a result of pooled analysis of two phase 3 studies.  Therefore, mirogabalin is expected 
to be useful in the treatment of PNeP.  Nonclinical study in using rat with spinal cord 
injury as the typical experimental central neuropathic pain (CNeP) model indicated that 
mirogabalin single dose significantly improved mechanical allodynia of the rat, and time 
course and effective dose of analgesic effect in the CNeP rat model are similar those of 
analgesic effect in PNeP rat model.  PNeP and CNeP have a common pathology that both 
pain are caused by a lesion or dysfunction of nerve system.  In fact, clinical studies of 
pregabalin, which has the same mechanism of action of mirogabalin, in patients for PNeP 
and CNeP showed same efficacy profile.  These results suggest that mirogabalin is 
expected to have same efficacy profile in patients with CNeP as PNeP.  CNeP after spinal 
cord injury (SCI) (CNePSCI) is mentioned as major CNeP.  Therefore, in this study, 
CNePSCI is selected as target disease.   
1.2.5. 
Risks and Benefits for the Study Subjects 
Anticipated risks of mirogabalin include the occurrence of adverse reactions related to 
CNS depression, such as dizziness and somnolence, peripheral edema, weight gain, loss 
of consciousness, ophthalmologic disorders, abrupt or rapid discontinuation, as well as 
glucose intolerance.  Other notable TEAEs that have been observed in conducted clinical 
studies include elevations of hepatic transaminases and suicide-related events.  For the 
approved other α2δ ligands, in addition to dizziness, somnolence, and peripheral edema, 
certain adverse reactions requiring caution have also been reported, including but not 
limited to: weight gain, ophthalmologic disorders, suicidal behavior and ideation, 


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angioedema, hypersensitivity, abrupt or rapid discontinuation, abuse potential, congestive 
heart failure, renal failure, and creatine kinase elevations. 
Clinical studies of mirogabalin for CNeP has not been performed yet, however, 
mirogabalin is expected to have enough efficacy profile in patients with CNeP, in the 
dose range which are proved to improve PNeP in patient with DPNP and PHN. (see 
Section 1.2.4).   
 


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2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
• To compare change from baseline in the weekly average daily pain score 
(ADPS) at Week 14 in patients with CNePSCI receiving mirogabalin versus 
placebo.   
2.1.2. 
Secondary Objectives 
• To compare the ADPS responder rate at Week 14 (proportion of subjects with 
≥ 30% and ≥ 50% reduction in ADPS from baseline at Week 14) between 
mirogabalin and placebo   
• To evaluate the effect of mirogabalin on additional pain questionnaires, 
including the Short-Form McGill Pain Questionnaire ([SF-MPQ]: sensory, 
affective, and total subscales, Visual Analog Scale [VAS], and present pain 
intensity) and the Neuropathic Pain Symptom Inventory (NPSI)   
• To assess the effect of mirogabalin on quality of life (QOL), activities of daily 
living (ADL), mood, sleep, patient impressions in pain, and allodynia   
• To characterize the safety and tolerability of mirogabalin based on weight 
gain, adverse event (AE), clinical laboratory values, vital sign, 12-lead ECG, 
medical interview, Columbia-Suicide Severity Rating Scale (C-SSRS), 
HADS, and edema.  
2.1.3. 
Exploratory Objectives 
• To evaluate the effect of mirogabalin on overactive bladder   
2.2. 
Study Hypotheses 
The primary hypothesis of this Phase 3 double-blind study is that mirogabalin will be 
superior to placebo in managing CNePSCI as measured by ADPS and will be generally 
well tolerated.   
2.3. 
Study Endpoints 
2.3.1. 
Primary Efficacy Endpoint 
• Change from baseline in the weekly ADPS at Week 14 
2.3.2. 
Secondary Efficacy Endpoint(s) 
• ADPS Responder rate defined as the proportion of subjects with ≥ 30%, and ≥ 
50% reduction from baseline to Week 14   
• Change from baseline in parameters assessed using SF-MPQ   


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• Change from baseline in scores assessed using the NPSI   
• Change from baseline in average daily sleep interference score (ADSIS)  
• Change from baseline in Medical Outcomes Study (MOS) sleep scale 
including average time to fall asleep, average sleep time per night, and the 5-
point scales related to sleep disturbance   
• Change from baseline in the Hospital Anxiety and Depression Scale (HADS)  
• Changes from baseline in parameters assessed using the Five Level EQ-5D 
version (EQ-5D-5L) 
• Changes from baseline in parameters assessed using the SCI Measure (SCIM 
III)  
• Patient Global Impression of Change (PGIC) 
• Change from baseline in allodynia 
Details on how to calculate the secondary efficacy endpoints and impute the missing data 
will be specified in the statistical analysis plan (SAP).   
2.3.3. 
Exploratory Efficacy Endpoint 
• Change from baseline in the average daily micturition frequency  
• Change from baseline in the average daily urinary incontinence episodes   
• Change from baseline in parameters assessed using Overactive Bladder 
Symptom Score (OAB-SS)   
Details on how to calculate the exploratory endpoints and impute the missing data will be 
specified in SAP, etc.   
2.3.4. 
Pharmacokinetic/Pharmacodynamic/Biomarker Endpoint(s) 
Not Applicable.   
2.3.5. 
Safety Endpoint(s) 
Treatment-emergent AEs, clinical laboratory tests, vital signs, body weight, 12-lead 
ECG, edema, C-SSRS, and HADS   
2.3.6. 
Other Endpoints 
Not Applicable.   


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3. 
STUDY DESIGN 
3.1. 
Overall Design 
3.1.1. 
Study Type 
This is a multinational, randomized, double-blind, placebo-controlled, parallel-group 
Phase 3 study for treatment of CNePSCI.   
Study sites: Approximately 120 study sites in Japan, Korea, Taiwan.   
Planned sample size: Approximately 274 subjects will be randomized in the study.   
3.1.2. 
Study Scheme 
The planned study duration will be approximately 16 weeks, consisting of 1-week 
observation period, 14-week treatment period, and 1-week follow-up period after last 
dose. After completion of the observation period, the eligible patients will be randomized 
into one of 2 arms, placebo or mirogabalin at the ratio of 1:1, respectively.  The 
randomization will be stratified with the factors of baseline ADPS (< 6.0 or ≥ 6.0) and 
region (Japan and others).   
The duration of investigational product administration will be 14 weeks, consisting of a 
titration period and a maintenance dose period.  During the treatment period, 1 tablet of 
either mirogabalin or matching placebo will be administered orally BID (in the morning 
and at bedtime).   
Written informed consent should be obtained before starting any examination and 
observations to be performed at Visit 1.  After informed consent is obtained, patients who 
are under treatment with mirogabalin, pregabalin, or gabapentin will undergo a washout 
period of 28 days or more (see Section 5.6.1).  Enrollment will be limited to subjects who 
meet the inclusion/exclusion criteria described in Section 4.1 and Section 4.2.  
In mirogabalin group, patients with CLcr ≥ 60 mL/min at screening will start with 5 mg 
BID of mirogabalin at first week, followed by 10 mg BID at second week as titration 
phase.  From the third week, if there are no problems in safety, the patients will escalate 
the dose to 15 mg BID.  For the following visits, the dosage may be changed to either 
10 mg BID or 15 mg BID depending on safety findings at the time of each visit.  Patients 
in placebo group take matching placebo throughout the entire period. 
In mirogabalin group, patients with CLcr 30 to < 60 mL/min at screening, will start 
2.5 mg BID of mirogabalin at first week, followed by 5 mg BID at second week as 
titration phase.  From the third week, if there are no problems in safety, the patients will 
escalate the dose to 7.5 mg BID.  For the following visits, the dosage may be changed to 
either 5 mg BID or 7.5 mg BID depending on safety findings at the time of each visit.  
Patients in placebo group take matching placebo throughout the entire period. 
After the completion or early termination of administration, subjects will be monitored 
for an additional follow-up observation period of 1 week. Follow-up observation is not 
required for subjects who are enrolled in an open-label extension study.   




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decreased appropriately in the range between 10 mg and 15 mg twice daily, based on 
individual patient age or symptoms.”  For patients with CLcr ≥ 60 mL/min, 5 mg BID 
will be the initial dose, 10 mg BID will be the lowest effective dose, and 15 mg BID will 
be the recommended effective dose.  For patients with CLcr 30 to < 60 mL/min, 2.5 mg 
BID will be the initial dose, 5 mg BID will be the lowest effective dose, and 7.5 mg BID 
will be the recommended effective dose. 
Nonclinical trial in using rat with spinal cord injury as typical experimental CNePSCI 
model indicated that mirogabalin single dose significantly improved mechanical 
allodynia of the rat, and time course and effective dose of analgesic effect in the 
CNePSCI rat model are similar that of analgesic effect in PNeP rat model.  In addition, 
clinical studies of pregabalin, which has the same mechanism of action of mirogabalin, in 
patients for PNeP and CNePSCI showed same efficacy and safety profile in both PNeP 
and CNePSCI, in the same dose range.   
Therefore, the dosage of mirogabalin in this study is selected as the same dosage as the 
possible dose regimen in the Japanese package insert.  Dosage of mirogabalin for 
CNePSCI patients with CLcr ≥ 60 mL/min is 5 mg BID at first week, followed by 10 mg 
BID at second week as titration phase, and from the third week, if there are no problems 
in safety, escalated to 15 mg BID.  For the following visits, the dosage may be changed to 
either 10 mg BID or 15 mg BID depending on safety findings.  Dosage of mirogabalin 
for CNePSCI patients with CLcr 30 to < 60 mL/min is 2.5 mg BID at first week, 
followed by 5 mg BID at second week as titration phase, and from the third week, if there 
are no problems in safety, escalated to 7.5 mg BID.  For the following visits, the dosage 
may be changed to either 5 mg BID or 7.5 mg BID depending on safety findings. 
3.2.2. 
Duration of Study Treatment 
In the double-blind study, the efficacy of mirogabalin versus placebo in CNePSCI, one of 
the typical NeP will be evaluated.  The European Medicines Agency (EMA) guideline13 
recommends that the treatment duration for maintenance dose period be 12 weeks or 
longer.  Therefore, the study will have 12 weeks of maintenance dose period.  In addition, 
taking into consideration for subject safety, the study will have 2 weeks of titration period 
before the maintenance dose period.   
3.2.3. 
Control Treatment 
Placebo will be used as the control treatment in the study.  Inclusion of placebo is 
required in the EMA guideline.13 
3.2.4. 
Study Endpoints 
In accordance with recommendations from the EMA guideline,13 the primary endpoint 
was selected as amount of change in findings on an 11-point pain scale.  Patients with 
CNePSCI can experience seriously decreased QOL, ADL, not only from pain but also 
from factors such as poor sleep.  Moreover, it seems that pain reduction by mirogabalin 
may improve the QOL and the ADL of the subjects.  To assess these factors, secondary 
endpoints were selected in areas such as sleep, QOL and ADL. 
 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included in the study.   
1. Age ≥ 20 years at informed consent   
2. Able to give informed consent for the study participation, understand procedures 
of this study, and complete patient-reported questionnaires adequately   
3. SCI due to trauma (eg, turnover, fall, traffic accident, sports accident)   
4. C4-T12 spinal cord injury identified on MRI   
5. American Spinal Injury Association (ASIA) impairment scale A, B, C, or D   
6. NeP region expressed at level and/or below level of spinal cord injury   
7. ≥ 6 months after SCI at screening   
8. Stable CNePSCI at least for 3 months prior to screening   
9. At screening, a pain scale of ≥ 40 mm on VAS of SF-MPQ 
10. At randomization, a pain scale of ≥ 40 mm on VAS of SF-MPQ, and completion 
of at least 4 days of daily pain diaries with an ADPS of ≥ 4 over the past 7 days 
on the 11-point Numerical Rating Scale (NRS) 
Rationale 
1.: Phase 1, Phase 2 and Phase 3 studies in elderly subjects showed no notable 
differences from the results obtained in non-elderly subjects with regard to safety, 
tolerability, and PK.  Thus, no upper limit was placed on age in this study.  
Because the safety of this drug have not been established in children, and in order 
to obtain appropriate informed consent from the subjects themselves, the lower 
age limit was set at 20 years of age.   
2.: The study will be conducted in accordance with Good Clinical Practice (GCP). 
3., 4., 5., 6., 7., 8.: The study will investigate CNePSCI.   
9., 10.: In order to assess the efficacy of the investigational product appropriately, 
the study will be limited to subjects who experience pain of moderate or greater 
intensity.   
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the 
study:   
1. On any one day during the observation period, pain score of 10 on a scale of 0 (no 
pain) to 10 (worst possible pain)   
2. Other severe pain at screening or randomization, unrelated to CNePSCI, that may 
confound the assessment of CNePSCI   


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3. Neurologic disorders at screening or randomization, unrelated to CNePSCI, that 
may confound the assessment of CNePSCI   
4. Major psychiatric disorders within 1 year prior to screening   
5. Patient who has secondary-gain from CNePSCI (eg, legal dispute or settlement 
negotiations) at screening or randomization   
6. SCI due to suicidal behavior   
7. Patient who blames the third party for his/her spinal cord injury, in the case of 
spinal cord injury due to the third party act (Those patients can rarely overcome 
the pain due to the psychiatric factor)   
8. Previous administration of pregabalin ≥ 300 mg/day for subjects with CLcr (using 
the Cockcroft-Gault) ≥ 60 mL/min or ≥ pregabalin 150 mg/day for subjects with 
CLcr 30 to < 60 mL/min for at least 4 weeks, declared lack of effect 
9. Previous administration of gabapentin ≥ 1200 mg/day for subjects with CLcr 
≥ 60 mL/min or gabapentin ≥ 600 mg/day for subjects with CLcr 30 to < 60, for at 
least 4 weeks, declared lack of effect   
10. Use of mirogabalin, pregabalin, or gabapentin within 28 days prior to screening   
11. Use of strong opioids for analgesic of CNePSCI within 3 months prior to 
screening   
12. CLcr (using the Cockcroft-Gault equation) < 30 mL/min at screening   
13. Malignancy other than basal cell carcinoma within the past 2 years prior to 
screening   
14. Clinically significant unstable endocrine (eg, diabetes mellitus), neurologic, 
ophthalmologic, hepatobiliary, respiratory, hematologic illness, or cardiovascular 
disease (eg, uncontrolled cardiac arrhythmia, or myocardial infarction) at 
screening or randomization   
15. Clinically significant findings on electrocardiogram (ECG) at screening   
16. History of pernicious anemia, untreated hypothyroidism,  or human 
immunodeficiency virus infection   
17. Pregnancy, potential pregnancy, breast feeding, or subject unwilling to take 
reliable contraceptive measures during the study or for 4 weeks after study 
completion   
18. Known hypersensitivity to mirogabalin, pregabalin, or gabapentin 
19. Participation in another clinical study, either currently or within 30 days prior to 
providing of informed consent   
20. Experience of participating mirogabalin clinical study and receiving 
investigational product   
21. Abuse of illicit drugs or alcohol history   


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22. Response of “yes” to any of the questions on the C-SSRS at screening or 
randomization in relation to events occurring within the past 12 months   
23. At screening, clinical laboratory values exceeding limits listed in Table 4.1   
24. The subject who is considered inappropriate for the study at the discretion of the 
investigator or sub-investigator   
Rationale 
1.: This criteria was selected so that efficacy could not be appropriately assessed 
in these subjects, because reporting extreme pain may reflect psychosocial 
distress, and may reflect patients’ lack of comprehension to accurately rate their 
pain.   
2., 3., 4., 5., 6., 7., 10.: These criteria were selected so that efficacy and safety 
could be appropriately assessed in subjects.   
8., 9., 11: These criteria were selected out of consideration for efficacy assessment 
in subjects.   
12., 13., 14., 15., 16., 17., 18., 19., 20., 21., 22., 23., 24.: These criteria were 
selected out of consideration for the safety of subjects.   
 
Table 4.1: 
Hematology/Blood Chemistry Limits 
Hematology 
Platelet Count 
< 100,000/mm3 
Blood Chemistry 
AST (GOT) 
> 2.0 × ULN 
ALT (GPT) 
> 2.0 × ULN 
ALP 
> 1.5 × ULN 
T-Bil 
> 1.5a × ULN 
a: If a subject has T-Bil 1.5 > ULN: unconjugated and conjugated bilirubin fractions should be analyzed 
and only subjects documented to have Gilbert’s syndrome may be enrolled. 
 


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5. 
STUDY TREATMENT(S) 
5.1. 
Assigning Subjects to Treatments and Blinding 
5.1.1. 
Treatment Group(s)/Sequences 
After completion of the observation period, the eligible patients will be randomized into 
one of 2 arms, placebo or mirogabalin at the ratio of 1:1, respectively. The duration of 
investigational product administration will be 14 weeks, consisting of a titration period 
and a maintenance dose period.   
In mirogabalin group, patients with CLcr ≥ 60 mL/min at screening, will start with 5 mg 
BID of mirogabalin at first week, followed by 10 mg BID at second week as titration 
phase.  From the third week, if there are no problems in safety, the patients will escalate 
the dose to 15 mg BID.  For the following visits, the dosage may be changed to either 
10 mg BID or 15 mg BID depending on safety findings at the time of each visit.  Patients 
in placebo group take matching placebo throughout the entire period. 
In mirogabalin group, patients with CLcr 30 to < 60 mL/min at screening, will start 
2.5 mg BID of mirogabalin at first week, followed by 5 mg BID at second week as 
titration phase.  From the third week, if there are no problems in safety, the patients will 
escalate the dose to 7.5 mg BID.  For the following visits, the dosage may be changed to 
either 5 mg BID or 7.5 mg BID depending on safety findings at the time of each visit.  
Patients in placebo group take matching placebo throughout the entire period. 
5.1.2. 
Method of Treatment Allocation 
5.1.2.1. 
Enrollment 
Subjects are to be enrolled in this study using the Interactive Response Technology (IRT) 
in accordance with the procedures specified below.  IRT will assign each consenting 
subject a unique subject identification code, and that identification code will be recorded 
in a subject identification log.   
5.1.2.2. 
Procedures for Subject Enrollment 
The investigator or sub-investigator will perform a mandatory interview to assess the 
eligibility of subjects for the study, after obtaining each subject’s written informed 
consent, and will make necessary entries in the IRT at screening. When conducting 
overactive bladder evaluation (exploratory evaluation for only Japanese subjects with 
self-urination), informed consent for the evaluation also must be obtained.  Any subjects 
who have been taking prohibited concomitant drugs will undergo a washout period (see 
Section 5.6.1), prior to the observation period.  After the screening visit (Visit 1), a 7-day 
observation period will be implemented before randomization.   
At randomization (Visit 2), after completion of the observation period, the investigator or 
sub-investigator will again perform a mandatory interview to assess the eligibility of 
subjects for the study and will make necessary entries in the subject registration system.   


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The subject who are considered to be eligible for participation in the study, on the basis 
of evaluation prior to randomization, will be randomized to one of the mirogabalin-arm 
or placebo-arm at the ratio of 1:1, with stratification factors of baseline ADPS (< 6.0 or 
≥ 6.0) and region (Japan or the others).  The randomization schedule for the IRT will be 
generated by the independent biostatistician.  The investigational product for each study 
drug identifier will be dispensed specifically to 1 subject, and will not be used by any 
other subjects.   
If the enrolled subject is confirmed to be eligible, the investigator or sub-investigator will 
be notified of the study drug identifier assigned to the subject by the IRT.  The 
investigator or sub-investigator will confirm the reported study drug identifier, and will 
assign the investigational products labeled with the study drug identifier for the subject.  
If the subject is considered ineligible for the study, the investigator or sub-investigator 
will inform the subject, and will provide standard care.   
5.1.3. 
Blinding 
The study will be a double-blind study, using matching placebo.  Blinding will be applied 
to all personnel related to the study (subjects, investigators, sub-investigators, sponsor, 
and contact research organization), with the exception of the independent biostatistician, 
the independent sub-functional lead of biostatistics (ISFLB), and other staff involved in 
the preparation, release and shipment of IMP.   
Randomization schedule will be generated by the independent biostatistician and 
approved by the ISFLB.  The independent biostatistician will share the randomization 
schedule with personnel specified in the randomization schedule request form.  Until the 
study is unblinded, the randomization schedule will be kept securely.   
5.1.4. 
Emergency Unblinding Procedure 
In the case of an emergency where, in the opinion of the Investigator, discontinuation of 
study drug is not sufficient and the study treatment must be unblinded in order to evaluate 
further a course of medical treatment, the Investigator can perform the unblinding by 
directly accessing the IRT.   
In the event of an emergency unblinding, the subject will be informed about their 
treatment assigned.  Information about the treatment assignment must be restricted to 
designated study site staff/ personnel who are providing immediate care to the subject.  
Any documentation of the treatment assignment must be maintained separately (ie, a 
secured file).  The information must not be included in the subject’s source files to ensure 
the treatment assignment will remain blinded to the study monitors and other study 
personnel not involved with the subject’s immediate care.   
Once the study treatment has been unblinded for a specific subject, the study treatment 
should be discontinued for the subject, and the subject should leave the study treatment 
phase.  The end of treatment and follow-up assessments for the subjects will be 
performed as defined in the protocol.   


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5.2. 
Study Drug(s) 
5.2.1. 
Description 
The investigator must ensure that the investigational product will be used only in 
accordance with the protocol. 
The investigational products for this study are: 
• Mirogabalin 2.5 mg, 5 mg, 7.5 mg, 10 mg, and 15 mg tablets 
• Placebo tablets matching mirogabalin 2.5 mg, 5 mg, 7.5 mg, 10 mg, and 
15 mg tablets 
For details and handling of the investigational product, refer to the Investigator’s 
Brochure, and the manual for management of the investigational product.   
5.2.2. 
Labeling and Packaging 
Mirogabalin and matching placebo, will be packaged in aluminum blister packs.  
Packages for treatment period will be prepared for the combinations shown in Table 5.1, 
Table 5.2, and Table 5.3. The packaging will be clearly labeled "For Clinical Study Use 
Only," and will show the display name of the investigational product, the investigational-
product-manufacturing code, the study drug identifier, the name and address of the 
sponsor, and the expired date of the investigational product in accordance with local 
regulations.  Each wallet card of the investigational product will contain sufficient extra 
doses to cover the permitted visit window for each subject.   
Table 5.1: 
Drug Combinations During the Treatment Period (Week 1) 
Treatment group 
Investigational product combination 
Morning 
Bedtime 
Mirogabalin  group 
CLcr ≥ 60 mL/min 
5 
5 
Mirogabalin  group 
CLcr 30 to < 60 mL/min 
2.5 
2.5 
Placebo 
P 
P 
5: mirogabalin 5 mg tablet 
2.5: mirogabalin 2.5 mg tablet 
P: mirogabalin matching placebo tablet 
 


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Table 5.2: 
Drug Combinations During the Treatment Period (Week 2) 
Treatment group 
Investigational product combination 
Morning 
Bedtime 
Mirogabalin group 
CLcr ≥ 60 mL/min 
10 
10 
Mirogabalin group 
CLcr 30 to < 60 mL/min 
5 
5 
Placebo 
P 
P 
10: mirogabalin 10 mg tablet 
5: mirogabalin 5 mg tablet 
P: mirogabalin matching placebo tablet 
 
Table 5.3: 
Drug Combinations During the Treatment Period (Week 3 to Week 
14) 
Treatment group 
Investigational product combination 
Morning 
Bedtime 
Mirogabalin group 
CLcr ≥ 60 mL/min 
10 or 15 
10 or 15 
Mirogabalin  group 
CLcr 30 to < 60 mL/min 
5 or 7.5 
5 or 7.5 
Placebo 
P 
P 
10: mirogabalin 10 mg tablet, 15: mirogabalin 15 mg tablet 
5: mirogabalin 5 mg tablet, 7.5: mirogabalin 7.5 mg tablet 
P: mirogabalin matching placebo tablet 
5.2.3. 
Preparation 
Preparation of the study drug is detailed in the Pharmacy Manual.   
5.2.4. 
Administration 
During the treatment period, 1 tablet of either mirogabalin or matching placebo will be 
administered orally BID (in the morning and at bedtime), as shown in Table 5.4.   
 


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Table 5.4: 
Method of Administration During the Treatment Period 
Group 
Day 1 
Day 2 to 7 
Day 8 
Day 9 to 14 
Day 15 
Day 16 to 98 
Day 99 
Mornin
g 
Bedtime Mornin
g 
Bedtime Mornin
g 
Bedtime Mornin
g 
Bedtime Mornin
g 
Bedtime Mornin
g 
Bedtime Mornin
g 
Bedtime 
Mirogabalin 
CLcr ≥ 60 mL/min 
- 
5 
5 
5 
5 
10 
10 
10 
10 
10 or 15 10 or 15 10 or 15 10 or 15 
- 
Mirogabalin 
CLcr 30 to 
< 60 mL/min 
- 
2.5 
2.5 
2.5 
2.5 
5 
5 
5 
5 
5 or 7.5 5 or 7.5 5 or 7.5 5 or 7.5 
- 
Placebo 
- 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
- 
 
 


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5.2.5. 
Storage 
Up to 25°C; do not freeze (excursion permitted up to 30°C).   
Drug supplies must be stored appropriately in a locked cabinet in a room with limited and 
controlled access under the recommended storage conditions.   
If storage conditions go outside of the recommended storage conditions, the site must not 
dispense the affected supplies (affected supplies should be placed in quarantine) and must 
contact Daiichi Sankyo Clinical Supply Operations personnel or designee to determine if 
the affected supplies can be used.   
5.2.6. 
Drug Accountability 
When a drug shipment is received, the Investigator or designee will check the amount and 
condition of the drug, check for appropriate local language in the label, drug expiration 
date, and sign the Receipt of Shipment Form provided.   
In addition, the Investigator or designee shall contact Sponsor as soon as possible if there 
is a problem with the shipment.   
A Drug Accountability Record will be provided for the study drug.  The record must be 
kept current and should contain the dates and quantities of study drug received, subject’s 
(identification number or supply number as applicable), for whom the study drug was 
dispensed, the date and quantity of study drug dispensed and remaining, as well as the 
initials of the dispenser.   
At the end of the study, or as directed, all study drug with all discrepancy resolved, 
including unused, partially used, or empty containers, will be returned to a designee as 
instructed by Sponsor.  Study drug will be returned only after the study monitor has 
completed a final inventory to verify the quantity to be returned.  The return of study drug 
must be documented and the documentation included in the shipment.  At the end of the 
study, a final study drug reconciliation statement must be completed by the Investigator or 
designee and provided to the Sponsor.   
5.3. 
Control Treatment 
Placebo will serve as control treatments.  Inclusion of placebo is required in light of the 
known placebo effect in pain studies.   
5.4. 
Dose Interruptions and Reductions 
Dose interruption will be occurred only if investigators or sub-investigators decide 
administration should be interrupted due to safety concerns.  During a maintenance dose 
period, dose will be reduced from 15 mg BID to 10 mg BID or from 7.5 mg BID to 5 mg 
BID in patients with CLcr ≥ 60 mL/min or CLcr 30 to < 60 mL/min respectively, only if 
drug related adverse events occur and investigators or sub-investigators judge continuation 
of 15 mg BID or 7.5 mg BID dosing is difficult due to the adverse events. 


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5.5. 
Method of Assessing Treatment Compliance 
All subjects in this study will commence therapy as outpatients or inpatients, and the 
investigational product will be self-administered orally.  Subjects will be sent home with 
the investigational product.  Each subject is to return the investigational product at every 
visit.  Compliance will be assessed by returned tablet count.  Administration of the 
investigational product will be recorded in the electronic case report form (eCRF)/Drug 
Accountability Record (number of tablets taken) at all treatment visits.  If no tablets are 
returned, the subject will be asked whether any were discarded or thrown away, or if all of 
the tablets were taken orally.   
5.6. 
Concomitant Medications 
Any concomitant medications and any concomitant treatments conducted to a subject 
(except for subjects who are withdrawn prior to randomization but after signing informed 
consent) during the period from the time of obtaining informed consent until Visit 8, will 
be documented in the case report form (CRF).  The route of administration, the total daily 
dose, the duration of use, the indication for use, and the classification of therapies will also 
be documented in the CRF.   
5.6.1. 
Prohibited Concomitant Medications 
The following drugs are prohibited for concomitant use from the screening (Visit 1) 
through the post-treatment follow-up (Visit 8).  After informed consent is obtained, 
subjects who are under treatment with Mirogabalin, Pregabalin, or Gabapentin will 
undergo for 28 days as a minimum washout period.  Visit 1 will occur after completion of 
this washout period.   
• Mirogabalin, Pregabalin, and Gabapentin 
• Strong opioids 
• Other investigational products 
5.6.2. 
Restricted Concomitant Medications 
The following drugs are permitted for concomitant use if their dosage has not changed for 
28 days prior to Visit 1.  These drugs may be used concomitantly from the screening (Visit 
1) through Visit 7, but the dosage may not be changed.   
• Antiepileptics except for gabapentin and pregabalin 
• Antidepressants 
• Hypnotics, anxiolytics 
• Tramadol 
• Neurotropin® 
• N-methyl-D-aspartate receptor antagonists (dextromethorphan, ketamine, 
memantine, etc.) 


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• Non-steroidal anti-inflammatory drugs (Acceptable for external use and for 
purposes other than CNePSCI analgesia) 
• Muscle relaxants 
• Topical capsaicin for analgesic of CNePSCI 
• Local anesthetics for analgesic of CNePSCI (lidocaine, etc.) 
• Na channel blockers (mexiletine, etc.) 
• Centrally acting sympatholytic agents (clonidine, etc.) 
• Steroids for analgesic of CNePSCI 
• Cilostazol, prostaglandin (Acceptable for external use and for purposes other 
than CNePSCI analgesia) 
• Baclofen 
5.6.3. 
Rescue Medications 
Acetaminophen will be permitted as a "rescue medication," to be used when in need of 
treatment for CNePSCI, and not to exceed the maximum dose stipulated in the package 
insert.  Each subject should record dose(s) of acetaminophen used in the patient diary from 
Visit 1 to Visit 7, if he/she takes acetaminophen.   
5.6.4. 
Restricted Concomitant Therapies 
The following therapies are permitted for concomitant use if their frequency has not 
changed for 28 days prior to Visit 1.  These therapies may be used concomitantly from the 
screening (Visit 1) through Visit 7, but the frequency may not be changed.   
1. Nerve blocks 
2. Laser therapy 
3. Acupuncture treatment 
4. Spinal cord stimulation 
5. Surgery that might confound the assessment of CNePSCI 
6. Psychological approach (eg, psychoeducation, behavioral therapy, cognitive-
behavioral therapy) 
7. Rehabilitation (eg, physical therapy, occupational therapy) 
8. Other forms of pain reduction therapy that might confound the assessment of 
CNePSCI 
5.6.5. 
Other 
Subjects should be instructed to avoid excessive consumption of alcohol during the 
treatment period, as combination with investigational drugs and alcohol may enhance 
impaired attention and impaired equilibrium function.   


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5.7. 
Subject Withdrawal/Discontinuation 
5.7.1. 
Withdrawal Criteria 
If a subject meets the following withdrawal criteria, that subject should discontinue the 
study treatment and the study.   
• Difficulty of continuing the study due to AE 
• AE related to suicide (if there are any “yes” responses to any of the questions 
in the C-SSRS) 
• Subjects with any of the following elevations in clinical laboratory values 
− Increase in alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) ≥ 5 × upper limit of normal (ULN) 
− ALT or AST rises to ≥ 3 × ULN and persists for more than 2 weeks 
− Concurrent increases in ALT or AST ≥ 3 × ULN and total bilirubin (T-Bil) 
≥ 2 × ULN 
− ALT or AST ≥ 3 × ULN associated with a clinical presentation suggestive 
of liver injury (ie, including the appearance of fatigue, nausea, vomiting, 
jaundice, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia) 
• Withdrawal by subject (ie, withdrawal of consent) 
• Major protocol deviation (difficulty of continuing the study in terms of 
ensuring safety of subjects) 
5.7.2. 
Reasons for Withdrawal 
If a subject is withdrawn from the study, the date and the reason for withdrawal must be 
recorded on the eCRF using the following options.  If the subject receiving at least one 
study medication and withdrew/was withdrawn from the study treatment, the reason for 
the withdrawal of study treatment must be recorded on the eCRF. 
For subjects withdrawn prior to enrollment but after signing informed consent   
• Screen Failure 
• Withdrawal by Subject (eg, AE, lack of efficacy [LOE], Other) 
• Physician Decision 
• Other 
For subjects withdrawn after randomization but before completing the study as per 
protocol 
• AE 
• Death 


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• LOE 
• Lost to Follow-up 
• Protocol violation 
• Pregnancy 
• Study Terminated by Sponsor 
• Withdrawal by Subject (eg, AE, LOE, Other)  
• Other 
If a subject is withdrawn due to need for a prohibited medication, the reason may be 
recorded as LOE, as appropriate.  Reasons recorded under “Protocol violation” may 
include failure to comply with protocol requirements or study procedures.   
For all subjects who withdraw from the study, the investigator must complete and report 
pertinent observations as thoroughly as possible up to the date of withdrawal, including 
the date of last treatment and the reason for withdrawal.   
If a subject is withdrawn due to an AE, the investigator should follow the subject until the 
AE has resolved or stabilized.   
All subjects who are withdrawn from the study should complete protocol-specified 
withdrawal procedures (see Section 5.7.3 and Section 6.4).   
5.7.3. 
Withdrawal Procedures 
If the subject withdraws or is withdrawn from the study before the completion of 
investigational product administration, appropriate measures will be implemented.  In 
addition, to the extent that the subject’s cooperation can be obtained, all observations and 
tests scheduled for the End of Treatment (Visit 7)/Early Termination Visit will be 
conducted, assessments will be made at that time point, all observations and tests 
scheduled for the Post-treatment Follow-up Visit (Visit 8) will be conducted, and 
assessments will be made 5 to 14 days after the last dose.  This will be done for all 
subjects who were treated with even one dose of the investigational product.  If the 
withdrawal was due to AEs, the outcome for that subject will be recorded to the extent 
possible in the CRF.  If the withdrawal was due to suicidal behavior and/or suicidal 
ideation, appropriate measures will be implemented such as referring the subject to a 
specialist. 
5.7.4. 
Subject Replacement 
Subjects removed from the study for any reason will not be replaced.   
5.7.5. 
Subject Re-screening Procedures 
Re-screening is allowed to only subjects who violate Inclusion Criteria 4, Exclusion 
Criteria 10, 12, 19, or 23, only if the subjects are not randomized.  The re-screening is 
permitted only once. 
 


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6. 
STUDY PROCEDURES 
A study visit schedule in tabular format is provided in Section 17.1.   
In principle, all of the activities and/or examinations will be recorded with the date in the 
CRF.   
Missing visits are strongly discouraged in this study.  It is expected that investigator site 
staff thoroughly explain the visit schedule with potential subjects.  If it is felt that a subject 
is not able to adhere to the visit schedule, then that subject should not be randomized into 
the study.  Any missed visit that occurs during the double-blind treatment period must be 
rescheduled within 1 week.   
6.1. 
Screening (Visit 1) 
Written informed consent should be obtained before starting any examination and 
observations to be performed at Visit 1.  After informed consent is obtained, patients who 
are under treatment with mirogabalin, pregabalin, or gabapentin will undergo a washout 
period of 28 days or more (Section 5.6.1).  The following activities and/or examinations 
will be performed at screening.   
• Evaluate inclusion criteria and exclusion criteria 
• Record demographics (birth date, sex, causality of SCI [turnover, fall, traffic 
accident, sports accident, or other], type of SCI [quadriplegia or paraplegia], 
site of SCI [C4-C8, T1-T12], duration of SCI, duration of CNePSCI, NeP 
region [at level or below level], medical/surgical history related to exclusion 
criteria) 
• Identify SCI by MRI 
− If SCI has been identified previously on MRI, MRI inspection for this 
study is not needed.   
• Conduct ASIA International Standards for Neurological Classification of 
Spinal Cord Injury (ISNCSCI) and evaluate ASIA impairment scale 
• Provide explanation regarding patient diaries including pain and sleep 
interference, and issue the diaries 
• Complete SF-MPQ 
• Complete HADS 
• Measure body height and weight 
• Perform medical interview 
• Perform evaluation of edema 
• Measure blood pressure and pulse rate 
• Perform 12-lead ECG 
• Collect blood and urine samples for laboratory tests 


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• Evaluate serious AEs (SAEs) 
• Complete C-SSRS 
• Perform pregnancy test (only in women of childbearing potential) 
• Evaluate prior drug treatment, concomitant drugs, and concomitant therapy 
• Complete OAB-SS (for only Japanese subjects with self-urination) 
• Provide explanation regarding bladder diary, and issue the diary (for only 
Japanese subjects with self-urination, and who meet the diagnostic criteria of 
overactive bladder in OAB-SS) 
6.2. 
Randomization (Visit 2) 
Subjects will be randomized to treatment groups after screening.  The following activities 
and/or examinations will be performed at randomization.   
• Evaluate inclusion criteria and exclusion criteria 
• Collect and review patient diaries 
• Measure body weight 
• Perform medical interview 
• Measure blood pressure and pulse rate 
• Collect blood and urine samples for laboratory tests 
• Evaluate SAEs 
• Complete C-SSRS 
• Complete HADS 
• Record and evaluate concomitant drugs and concomitant therapy 
• Confirm eligibility and randomization 
• Issue the investigational product 
• Issue the patient diaries 
• Complete SF-MPQ 
• Complete NPSI 
• Complete MOS sleep scale 
• Complete EQ-5D-5L 
• Complete SCIM 
• Perform evaluation of allodynia 


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• Collect and review bladder diary (for only Japanese subjects with self-
urination, and who meet the diagnostic criteria of overactive bladder in OAB-
SS at Visit 1) 
6.3. 
Treatment Period 
The treatment period will be 14 weeks in duration.   
6.3.1. 
Visit 3 and Visit 4 
From Visit 2 to Visit 4, subjects will come to the study site every week (Visit 3, Visit 4).  
The investigator or sub-investigator will confirm tolerability and review continuation of 
the treatment before issuing the new investigational product.  The following activities 
and/or examinations will be performed at Visit 3 and Visit 4.   
• Collect and review patient diaries 
• Measure body weight 
• Perform medical interview 
• Measure blood pressure and pulse rate 
• Collect blood and urine samples for laboratory tests 
• Complete SF-MPQ 
• Complete C-SSRS 
• Complete HADS 
• Evaluate AEs 
• Record and evaluate concomitant drugs and concomitant therapy 
• Collect unused investigational product and record and review drug-taking 
compliance 
• Record the date of the first dose taken (only Visit 3) 
• Issue the investigational product 
• Issue the patient diaries 
6.3.2. 
Visit 5 and Visit 6 
From Visit 4 to Visit 6, subjects will come to the study site once every 4 weeks (Visit 5, 
Visit 6).  The investigator or sub-investigator will confirm tolerability and review 
continuation of the treatment before issuing the new investigational product.  The 
following activities and/or examinations will be performed at Visit 5, and Visit 6.   
• Collect and review patient diaries 
• Measure body weight 
• Perform medical interview 


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• Measure blood pressure and pulse rate 
• Collect blood and urine samples for laboratory tests 
• Complete SF-MPQ 
• Complete C-SSRS 
• Complete HADS 
• Evaluate AEs 
• Record and evaluate concomitant drugs and concomitant therapy 
• Collect unused investigational product and record and review drug-taking 
compliance 
• Issue the investigational product 
• Issue the patient diaries 
• Issue bladder diary (for only Japanese subjects with self-urination, and who 
meet the diagnostic criteria of overactive bladder in OAB-SS at Visit 1); only 
Visit 6 
6.4. 
End of Treatment (Visit 7)/Early Termination 
The treatment period will be completed at Visit 7.  The following activities and/or 
examinations will be performed at the end of treatment/early termination.   
• Collect and review patient diaries 
• Conduct ASIA ISNCSCI and evaluate ASIA impairment scale 
• Measure body weight 
• Perform medical interview 
• Evaluation of edema 
• Perform evaluation of allodynia 
• Measure blood pressure and pulse rate 
• Perform 12-lead ECG 
• Collect blood and urine samples for laboratory tests 
• Complete C-SSRS 
• Complete HADS 
• Perform pregnancy test (only in women of childbearing potential) 
• Evaluate AEs 
• Record and evaluate concomitant drugs and concomitant therapy 


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• Collect unused investigational product and record and review drug-taking 
compliance 
• Record the date of the last dose taken 
• Complete SF-MPQ 
• Complete NPSI 
• Complete MOS sleep scale 
• Complete PGIC 
• Complete EQ-5D-5L 
• Complete SCIM 
• Collect and review bladder diary (for only Japanese subjects with self-
urination, and who meet the diagnostic criteria of overactive bladder in OAB-
SS at Visit 1) 
• Complete OAB-SS (for only Japanese subjects with self-urination, and who 
meet the diagnostic criteria of overactive bladder in OAB-SS at Visit 1) 
6.5. 
Follow-up 
Follow-up observations will be conducted 7 days after the completion of administration 
(Visit 8).  The following activities and/or examinations will be performed at post-
treatment follow-up.  No follow-up observation is required for subjects enrolled in an 
open-label extension study.   
• Measure body weight 
• Perform medical interview 
• Measure blood pressure and pulse rate 
• Collect blood and urine samples for laboratory tests 
• Complete C-SSRS 
• Complete HADS 
• Evaluate AEs 
• Record and evaluate concomitant drugs and concomitant therapy 
 


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7. 
EFFICACY ASSESSMENTS 
7.1. 
Assessments for Efficacy Endpoint(s) 
7.1.1. 
Primary Efficacy Endpoint 
7.1.1.1. 
Change from Baseline in the Weekly Average Daily Pain Score at Week 
1414 
Subjects will record a pain score in the patient diary once daily from the day after Visit 1 
through Visit 7.  Every morning upon awakening, prior to taking study medication, the 
subject will check the number that best describes his or her pain over the past 24 hours on 
a scale of 0 (no pain) to 10 (worst possible pain).  The weekly ADPS is defined as being 
weekly average of the pain scores.   
Details on how to calculate the primary efficacy endpoints and impute the missing data 
will be specified in the SAP.   
7.1.2. 
Secondary Efficacy Endpoint 
7.1.2.1. 
Average Daily Pain Score Response Rate13 
ADPS Response rate is defined as the proportion of subjects with ≥ 30%, and ≥ 50% 
reduction from baseline to week 14 in ADPS.   
7.1.2.2. 
Change from Baseline in Parameters Assessed Using Short-Form McGill 
Pain Questionnaire15 
At Visit 1, Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, Visit 8, subjects will provide a 
self-assessment using the SF-MPQ.  The SF-MPQ consists of 3 parts: 
• Fifteen pain descriptors that are given a score of 0 (none) to 3 (severe) based 
on intensity.  The scores are summarized as a sensory score of 11 descriptors, 
an affective score of 4 descriptors, and a total score of 15 descriptors. 
• A VAS, in which the subject rates pain intensity on a 100 mm-long horizontal 
line, where 0 mm = no pain and 100 mm = worst possible pain. 
• A Present Pain Intensity index that provides a score of 0 to 5 based on intensity 
7.1.2.3. 
Patient Global Impression of Change14 
At Visit 7, subjects will provide a self-assessment in comparison to Visit 2, using the 7-
point scale in the PGIC. 
1: very much improved 
2: much improved 
3: minimally improved 
4: no change 
5: minimally worse 


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6: much worse 
7: very much worse 
Two types of PGIC responder rate are defined as the proportion of subjects who satisfy the 
following PGIC score: 
Minimally improved or better (ie, Score ≤ 3) 
Much improved or better (ie, Score ≤ 2) 
7.1.2.4. 
Change from Baseline in Sleep-interference Score 
The Daily Sleep Interference Diary consists of an 11-point NRS which will be used to 
assess how pain has interfered with the subject’s sleep during the past 24 hours. Subjects 
will record a sleep-interference score in the patient diary once daily from the day after 
Visit 1 through Visit 7.  Every morning upon awakening, prior to taking study medication, 
the subject will select the number that best describes his or her sleep interference 
experience during the past 24 hours on a scale of 0 (pain did not interfere with sleep) to 10 
(pain completely interfered with sleep).  The weekly ADSIS is based on the sleep 
interference scores from the patient daily pain diaries.   
7.1.2.5. 
Change from Baseline in Medical Outcomes Study Sleep Scale16,17 
At Visit 2 and Visit 7, subjects will provide a self-assessment using the MOS sleep scale.  
The MOS sleep scale is based on questions about sleep quality during the past 4 weeks, 
and consists of 3 parts: 
• The average time required to fall asleep 
− 0 to 15 minutes........................1 
− 16 to 30 minutes......................2 
− 31 to 45 minutes......................3 
− 46 to 60 minutes......................4 
− More than 60 minutes.............5 
• The average hours of sleep per night, given as number of hours per night.  
Ten questions that are given a score of 1 (all of the time) to 5 (none of the time), based on 
sleep disturbance in the following areas: difficulty in falling asleep or remaining asleep, 
difficulty in staying awake during the day, difficulty in breathing, and snoring during 
sleep. 
Based on the 12 questions above, the following scales will be calculated for the analyses: 
• Sleep disturbance 
• Snoring 
• Awakening due to shortness of breath or due to headache 
• Sleep adequacy 


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• Sleep somnolence 
• 9-item sleep problems index 
• Sleep quantity 
• Optimal sleep 
7.1.2.6. 
Change from Baseline in Hospital Anxiety and Depression Scale18 
At Visit 2 and Visit 7, subjects will provide a self-assessment using the HADS, which will 
be adopted as efficacy evaluation.  The HADS consists of 7 items to score depression (4-
point scale) and 7 items to score anxiety (4-point scale).  Two types of subscale, 
depression and anxiety, will be calculated by the summing the corresponding scores for 7 
items.   
7.1.2.7. 
Change from Baseline in Neuropathic Pain Symptom Inventory19 
At Visit 2 and Visit 7, subject will provide a self-assessment using the NPSI, which 
reflects four distinct dimensions of NeP: spontaneous pain, paroxysmal pain, evoked pain, 
and paresthesia/dysesthesia.  Each questionnaire in the dimensions has 11-point scale from 
0 (no pain) to 10 (the most intense pain imaginable) to report the mean intensity of each of 
these items during the last 24 hours.  
• spontaneous pain: burning, squeezing, and pressure 
• paroxysmal pain: electric shock, stabbing 
• evoked pain: brushing,  pressure, contact with something cold 
• paresthesia/dysesthesia: pins and needles, tingling 
Additionally, the duration of spontaneous pain (ie number of hours during the last 24 
hours) and frequency of paroxysmal pain (ie number of paroxysms during the last 24 
hours) will be evaluated.   
7.1.2.8. 
Change from Baseline in Five Level EQ-5D version20 
At Visit 2 and Visit 7, subjects will provide a self-assessment using the EQ-5D-5L. The 
questionnaire yields a 5-scale profile of the subject's self-assessed QOL in the following 
dimension: mobility (5-point scale), self-care (5-point scale), usual activities (5-point 
scale), pain/discomfort (5-point scale), and anxiety/depression (5-point scale) that are 
combined into an overall health utilities index, and an Visual Analogue Scale (VAS) that 
measures perception of overall health, with zero indicating worst health and 100 
representing best imaginable health.   
7.1.2.9. 
Change from Baseline in Spinal Cord Independence Measure21 
At Visit 2 and Visit 7, the investigator, sub-investigator, or site stuff will assess the 
subjects’ ADL using SCIM.  The SCIM instrument yield a profile of the subject’s ADL in 
the following categories: total SCIM score (0 to 100), self-care (scored 0 to 20), 
respiration and sphincter management (0 to 40) and mobility (0 to 40).   


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7.1.2.10. Change from Baseline in Allodynia 
At Visit 2 and Visit 7, the investigator or sub-investigator will perform the test for 
allodynia ([at level] and [below level]), using the following 2-points scale. The 
assessments of allodynia are detailed in the Procedures Manual.   
1: present 
2: absent 
7.1.3. 
Exploratory Efficacy Endpoint 
7.1.3.1. 
Change from baseline in the average daily micturition frequency  
Japanese subjects with self-urination, and who meet the diagnostic criteria of overactive 
bladder in OAB-SS at Visit 1 will record the micturition frequency in the bladder diary 
from Visit 1 to Visit 2, and from Visit 6 to Visit 7.   
7.1.3.2. 
Change from baseline in the average daily urinary incontinence episodes   
Japanese subjects with self-urination, and who meet the diagnostic criteria of overactive 
bladder in OAB-SS at Visit 1 will record the incontinence episodes in the bladder diary 
from Visit 1 to Visit 2, and from Visit 6 to Visit 7.   
7.1.3.3. 
Change from baseline in parameters assessed using Overactive Bladder 
Symptom Score (OAB-SS)22 
At Visit 1 and Visit 7, subjects will provide a self-assessment using the OAB-SS.  The 
questionnaire yields the micturition frequency from waking in the morning until sleeping 
at night, the micturition frequency of waking up to urinate from sleeping at night until 
waking in the morning, frequency of sudden desire to urinate, and frequency of leaking 
urine.   
7.2. 
Appropriateness of Selected Efficacy Assessment(s) 
The primary efficacy endpoint was selected based on the EMA guideline for clinical trial 
on NeP indication, which recommends the use of an instrument that assesse the average 
pain over a short period, and no longer than 24 hours. The pain score instrument is 
validated and is utilized in this manner.   
The secondary efficacy endpoints were selected for this study because these endpoints 
were suitable for assessing the main symptom of CNePSCI (pain) and associated 
symptoms of CNePSCI (poor sleep, anxiety, depression, etc).  Moreover, patients with 
CNePSCI can experience seriously decreased QOL and ADL from pain or poor sleep.  All 
questionnaires are validated and widely used for clinical trials.   


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8. 
PHARMACOKINETIC/PHARMACODYNAMIC 
ASSESSMENTS 
8.1. 
Pharmacokinetic Assessment(s) 
No PK analysis will be performed.   
8.2. 
Pharmacodynamic Assessment(s) 
No pharmacodynamic analysis will be performed.   
8.3. 
Biomarker Assessment(s) 
No biomarker analysis will be performed.   
8.4. 
Immunogenicity 
No immunogenicity analysis will be performed.   
8.5. 
Pharmacogenomic Analysis 
No pharmacogenomic analysis will be performed.   
 


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9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Assessment of Safety Endpoint(s) 
Safety endpoints will be body weight, TEAEs, clinical laboratory tests, vital signs, 12-lead 
ECG, medical interview, C-SSRS, HADS, and edema.   
9.2. 
Adverse Event Collection and Reporting 
All SAEs (see Section 9.4.1 and Section 9.4.2 for definitions) occurring after the subject 
signs the ICF and up to 7 days after the last dose of study medication (ie, the follow-up 
period), whether observed by the Investigator or reported by the subject, will be recorded 
on the AE section in CRF.  All SAEs will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up.   
All non-SAEs occurring after the subject has taken the first dose of study medication until 
7 days after the last dose of study medication (Visit 8) will be recorded on the AE section 
in CRF.  
When an AE occurs, the investigator or sub-investigator will provide appropriate 
treatment and to the extent possible will monitor progress until the AE is resolved or 
resolving.  However, the investigator or sub-investigator can terminate the monitoring as 
the clinical trial after explaining it to the subject that he/she deems medically impossible to 
resolve it at the end of the study (although the treatment for the AE will be continued).  In 
addition, the investigator or sub-investigator can also terminate it, if he/she decides further 
follow-up is unnecessary because of an AE for which a causal relationship with the 
investigational product can be ruled out, or if the subject refuses further follow-up. 
Any symptom that the investigator or sub-investigator considers associated with CNePSCI 
will be evaluated as an efficacy variable and will not be regarded as an AE.  However, if 
the symptom is considered potentially related to the investigational product, such 
symptom will be regarded as an AE.  Medical conditions (including clinically significant 
laboratory values that are not symptoms of CNePSCI  /vital signs that are out of range) 
that were diagnosed or known to exist prior to the first dose will be recorded as part of 
medical history.   
All AEs, SAEs, and AEs of special interest (AESI) are to be reported according to the 
procedures in Section 9.5.   
Exacerbation of a pre-existing medical occurrence and symptom after the first dose of 
study medication including increase in severity of the symptom will be recorded as an AE 
on the AE section, unless it is the condition of CNePSCI. 
All clinical laboratory results, vital signs, and ECG results or findings should be appraised 
by the Investigator to determine their clinical significance.  Isolated abnormal laboratory 
results, vital sign findings, or ECG findings (ie, not part of a reported diagnosis) should be 
reported as AEs if they are symptomatic, lead to study drug discontinuation, dose 
reduction, require corrective treatment, or constitute an AE in the Investigator’s clinical 
judgment.   


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At each visit, the Investigator will determine whether any AEs have occurred by 
evaluating the subject.  AEs may be directly observed, reported spontaneously by the 
subject or by questioning the subject at each study visit.  Subjects should be questioned in 
a general way, without asking about the occurrence of any specific symptoms.  The 
Investigator must assess all AEs to determine seriousness, severity, and causality, in 
accordance with the definitions in Section 9.4.  The Investigator’s assessment must be 
clearly documented in the site’s source documentation with the Investigator’s signature.   
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, 
report the primary sign or symptom as the AE or SAE term with additional details 
included in the narrative until the diagnosis becomes available.  If the signs and symptoms 
are distinct and do not suggest a common diagnosis, report them as individual entries of 
AE or SAE.   
For events that are serious due to hospitalization, the reason for hospitalization must be 
reported as the SAE (diagnosis or symptom requiring hospitalization).  A procedure is not 
an AE or SAE, but the reason for the procedure may be an AE or SAE.  Pre-planned (prior 
to signing the ICF) procedures or treatments requiring hospitalization for pre-existing 
conditions that do not worsen in severity should not be reported as SAEs (see Section 
9.4.2 for Definitions).   
For deaths, the underlying or immediate cause of death should always be reported as an 
SAE.   
Any serious, untoward event that may occur subsequent to the reporting period that the 
Investigator assesses as related to study drug should also be reported and managed as an 
SAE.   
9.3. 
Adverse Events of Special Interest 
All antiepileptic drugs carry a risk of increased suicidal behavior and ideation.  
Furthermore, increased hepatic transaminases have been observed in the mirogabalin 
development program.  Therefore, the following “suicidal behavior and ideation” and 
“liver enzyme elevations/liver dysfunction” will be treated as AESI.   
• Increase in ALT or AST ≥ 5 × ULN 
• ALT or AST rises to ≥ 3 × ULN and persists for more than 2 weeks 
• Concurrent increases in ALT or AST ≥ 3 × ULN and T-Bil ≥ 2 × ULN 
• ALT or AST ≥ 3 × ULN associated with a clinical presentation suggestive of 
liver injury (ie, including the appearance of fatigue, nausea, vomiting, jaundice, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia) 
• Serious hepatobiliary AE 
• Severe hepatobiliary AE 
• Hepatobiliary AE leading to discontinuation 
• Any transaminase elevation associated with a clinical presentation suggestive 
of liver injury 


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• As elevation of ALT or AST ≥ 3 × ULN (without clinical presentation 
suggestive of liver injury) 
• AE related to suicide (if there are any “yes” responses to any of the questions 
in the C-SSRS) 
9.4. 
Adverse Event 
9.4.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical 
product and that does not necessarily have to have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal 
product (International Council for Harmonisation [ICH] E2A Guideline.  Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting, Oct 1994).   
Dizziness, somnolence, edema, and weight gain are defined as significant AE.  Any other 
significant AEs to be added will be specified in the SAP. 
It is the responsibility of Investigators, based on their knowledge and experience, to 
determine those circumstances or abnormal laboratory findings which should be 
considered AEs.   
9.4.2. 
Serious Adverse Event 
A SAE is any untoward medical occurrence that at any dose:   
• Results in death, 
• Is life-threatening, 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability/incapacity, 
• Is a congenital anomaly/birth defect, or 
• Is an important medical event. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe (ICH E2A Guideline.  
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, 
Oct 1994).   
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.  Examples include allergic bronchospasm, convulsions, and blood 
dyscrasias or development of drug dependency or drug abuse.   


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Note:   
• Procedures are not AEs or SAEs, but the reason for the procedure may be an 
AE or SAE.   
• Pre-planned (prior to signing the ICF) procedures or treatments requiring 
hospitalizations for pre-existing conditions that do not worsen in severity are 
not SAEs. 
9.4.3. 
Severity Assessment 
The following definitions should be used to assess intensity of AEs:   
• Mild: Awareness of sign or symptom, but easily tolerated, ie, does not interfere 
with subject’s usual function.   
• Moderate: Discomfort enough to cause interference with usual activity.   
• Severe: Incapacitating with inability to work or do usual activity, ie, interferes 
significantly with subject’s usual function.   
Severity vs. Seriousness: Severity is used to describe the intensity of a specific event while 
the event itself, however, may be of relatively minor medical significance (such as severe 
headache).  This is not the same as "seriousness," which is based on patient/event outcome 
at the time of the event.   
9.4.4. 
Causality Assessment 
The Investigator should assess causal relationship between an AE and the study drug on 
the basis of his/her clinical judgment and the following definitions.  The causality 
assessment must be made based on the available information and can be updated as new 
information becomes available.   
• Related:   
− The AE follows a reasonable temporal sequence from study drug 
administration, and cannot be reasonably explained by the subject’s clinical 
state or other factors (eg, disease under study, concurrent diseases, and 
concomitant medications).   
or 
− The AE follows a reasonable temporal sequence from study drug 
administration, and is a known reaction to the drug under study or its 
chemical group, or is predicted by known pharmacology.   
• Not Related:   
− The AE does not follow a reasonable sequence from study drug 
administration, or can be reasonably explained by the subject’s clinical 
state or other factors (eg, disease under study, concurrent diseases, and 
concomitant medications).   


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9.4.5. 
Action Taken Regarding Study Drug(s) 
• Dose Not Changed: No change in study drug dosage was made.   
• Drug Withdrawn: The study drug was permanently stopped.   
• Dose Reduced: The dosage of study drug was reduced.   
• Drug Interrupted: The study drug was temporarily stopped.   
• Not Applicable: Subject died, study treatment had been completed prior to 
reaction/event, or reaction/event occurred prior to start of treatment.   
9.4.6. 
Other Action Taken for Event 
• None.   
− No treatment was required.   
• Medication required.   
− Prescription and/or OTC medication was required to treat the AE.   
• Hospitalization or prolongation of hospitalization required.   
− Hospitalization was required or prolonged due to the AE, whether or not 
medication was required.   
• Other.   
9.4.7. 
Adverse Event Outcome 
• Recovered/Resolved 
− The subject fully recovered from the AE with no residual effect observed.   
• Recovering/Resolving 
− The AE improved but has not fully resolved.   
• Not Recovered/Not Resolved 
− The AE itself is still present and observable.   
• Recovered/Resolved with Sequelae 
− The residual effects of the AE are still present and observable.   
− Include sequelae/residual effects.   
• Fatal 
− Fatal should be used when death is a direct outcome of the AE.   
• Unknown 


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9.4.8. 
Definition of Adverse Drug Reaction 
Those AEs for which the relationship to the investigational product is considered 
“Related” will be handled as adverse drug reactions (ADRs). 
9.5. 
Serious Adverse Events and Adverse Event of Special Interest 
Reporting–Procedure For Investigators 
All AEs, SAEs, and AESI, will be reported in the CRF.   
The following types of events should be reported to the sponsor within 24 hours after 
becoming aware of the event in the designated form to the eCRF:   
• SAEs (see Section 9.4.2 for definition) 
• Increase in ALT or AST ≥ 5 × ULN 
• ALT or AST rises to ≥ 3 × ULN and persists for more than 2 weeks 
• Concurrent increases in ALT or AST ≥ 3 × ULN and T-Bil ≥ 2 × ULN 
• ALT or AST ≥ 3 × ULN associated with a clinical presentation suggestive of 
liver injury (ie, including the appearance of fatigue, nausea, vomiting, jaundice, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia) 
• AE related to suicide (if there are any “yes” responses to any of the questions 
in the C-SSRS) 
The following types of events should be reported to the sponsor as promptly as possible 
after becoming aware of the event in the designated form to the eCRF: 
• Severe hepatobiliary AE 
• Hepatobiliary AE leading to discontinuation 
• Any transaminase elevation associated with a clinical presentation suggestive 
of liver injury 
• As elevation of ALT or AST ≥ 3 × ULN (without clinical presentation 
suggestive of liver injury) 
All events (serious and non-serious) must be reported with Investigator’s assessment of 
the event’s seriousness, severity, and causality to the blinded study drug.  A detailed 
narrative summarizing the course of the event, including its evaluation, treatment, and 
outcome should be provided.  Specific or estimated dates of event onset, treatment, and 
resolution should be included when available.  Medical history, concomitant medications, 
and laboratory data that are relevant to the event should also be summarized in the 
narrative.  For fatal events, the narrative should state whether an autopsy was or will be 
performed, and include the results if available.  Source documents (including medical 
reports) will be retained at the study site and should not be submitted to the Sponsor for 
SAE reporting purposes.   


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Urgent safety queries must be followed up and addressed promptly.  Follow-up 
information and response to non-urgent safety queries should be combined for reporting to 
provide the most complete data possible within each follow-up.   
In the event that eCRF is unavailable, report SAEs/AESIs on a Serious Adverse Event 
Report (SAVER) form.  All completed SAVER forms must be signed by the Investigator, 
and e-mailed to CMIC. 
9.6. 
Notifying Regulatory Authorities, Investigators, and 
Institutional Review Board/Ethics Committee 
Daiichi Sankyo and/or CMIC will inform Investigators, Institutional Review 
Boards/Ethics Committees (IRBs/ECs), and regulatory authorities of any suspected 
unexpected serious adverse reactions occurring in other study sites or other studies of the 
investigational drug, as appropriate per local reporting requirements.  Daiichi Sankyo 
and/or CMIC will comply with any additional local safety reporting requirements.  The 
section of “Reference Safety Information” in the updated investigator's brochure should be 
referred to judge “Unexpected”.   
9.7. 
Exposure In Utero During Clinical Studies 
Daiichi Sankyo must be notified of any subject who becomes pregnant while receiving or 
at the time of discontinuing the study drug.   
Although pregnancy is not technically an AE, all pregnancies must be followed to 
conclusion to determine their outcome.  This information is important for both drug safety 
and public health concerns.  It is the responsibility of the Investigator, or designee, to 
report any pregnancy in a female subject or a male subject’s female partner using the 
exposure in utero (EIU) reporting form.  Please contact your study monitor to receive the 
EIU Reporting Form upon learning of a pregnancy.  The Investigator should make every 
effort to follow the subject until completion of the pregnancy and complete the EIU 
Reporting Form with complete pregnancy outcome information, including normal delivery 
and induced abortion.  The adverse pregnancy outcome, either serious or non-serious, 
should be reported in accordance with study procedures.  If the outcome of the pregnancy 
meets the criteria for immediate classification as a SAE (ie, post-partum complications, 
spontaneous or induced abortion, stillbirth, neonatal death, or congenital anomaly, 
including that in an aborted fetus), the Investigator should follow the procedures for 
reporting SAEs outlined in Section 9.5.   
9.8. 
Clinical Laboratory Evaluations 
The study site staff will collect blood and urine specimens for routine laboratory tests at 
specified times.  Specimens will be stored under conditions stipulated in the Sample 
Handling Manual until they are transported for measurement.  Specimens will be 
transported and measured by a central laboratory. 
Table 9.1 summarizes the laboratory parameters to be assessed and the times of 
assessment.   


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Results of all laboratory tests will be reported from the central laboratory to the site. 
A value or finding that represents a clinically significant abnormal change should be 
regarded as an AE, and should be described (diagnosed) appropriately in the CRF. 
Table 9.1: 
Laboratory Parameters to be Assessed, and Time of Assessment 
 
Parameters 
Time of assessment 
Hematology 
WBC, RBC, hemoglobin, hematocrit, platelet 
count, differential leukocyte (neutrophil, 
eosinophil, basophil, monocyte, lymphocyte) 
counts, reticulocyte count 
Visit 1, Visit 2, Visit 3, 
Visit 4, Visit 5, Visit 6, 
Visit 7, Visit 8, Early 
Termination   
Blood chemistry 
Total protein, albumin, A/G ratio, T-Bil, AST 
(GOT), ALT (GPT), ALP, γ-GT (γ-GTP), 
LDH, BUN, creatinine, uric acid, creatine 
kinase, total cholesterol, triglycerides, Na, K, 
Cl, Ca, Mg, inorganic phosphorus, bicarbonate, 
CRP 
Urinalysis 
Standard urinalysis, including microscopic 
examination   
Specific gravity, pH, protein, glucose, ketones, 
urobilinogen, occult blood, RBC, WBC, 
bilirubin 
HbA1c 
HbA1c 
Visit 2 and Visit 7, 
Early Termination   
Pregnancy 
Qualitative test (urine) 
Visit 1 and Visit 7, 
Early Termination   
In cases of liver laboratory abnormalities, it is important to ensure that the nature and the 
extent of liver injury is identified and study subjects are monitored until the liver 
laboratory assessments return to normal.  Subjects who have any transaminase elevation 
associated with a clinical presentation suggestive of liver injury (ie, including the 
appearance of fatigue, nausea, vomiting, jaundice, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia) or an elevation of ALT or AST ≥ 3 × ULN (without 
clinical presentation suggestive of liver injury) at any visit should be monitored closely, 
according to the following:   
• Repeat liver tests of at least all four of the usual serum measures (ALT, AST, 
alkaline phosphatase [ALP]), and T-Bil at least 2 times weekly (the first repeat 
should be within 48 to 72 hours of initial abnormality) until values have 
decreased to < 2 × ULN, then at least every 1 or 2 weeks until resolution or 
return to baseline.  An additional serum separating tube of blood will be 
collected at time of event and until values return to baseline.  Samples will be 
stored for further analysis, as required.   
• Review or obtain a detailed history of symptoms and prior or concurrent 
diseases.   


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• Review or obtain a history of the use of concomitant drugs, including 
nonprescription medications, herbal and dietary supplements, alcohol, 
recreational drugs, and special diets.   
• Rule out alcoholic hepatitis; non-alcoholic steatohepatitis; hypoxic/ischemic 
hepatopathy; and biliary tract disease.   
• Obtain a history of exposure to environmental chemical agents. 
• Perform additional liver function tests (eg, serum lactate dehydrogenase, ALP, 
gamma-glutamyl transpeptidase, prothrombin time), evaluations for potential 
viral etiologies (including hepatitis A, B, C, E; cytomegalovirus; Epstein-Barr 
virus) and autoimmune etiologies (anti-nuclear antibody, anti-smooth muscle 
antibody, anti-mitochondrial antibody).   
Combined elevations of aminotransferases and bilirubin meeting the criteria of a potential 
Hy’s Law case [ALT or AST ≥ 3 × ULN with simultaneous T-Bil ≥ 2 × ULN], either 
serious or non-serious and whether or not causally related, should always be reported to 
the sponsor within 24 hours (refer to Section 9.2), with the investigator’s assessment of 
seriousness, causality, and a detailed narrative. (Food Drug Administration’s Guidance for 
Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation; July 2009; 
http://www.fda.gov/downloads/Drugs/Guidance/UCM174090.pdf).  These events should 
be reported as soon as possible following the procedures outlined in Section 9.5 for SAE 
reporting.  Criteria for discontinuing subjects based on transaminase increases are 
provided in Section 5.7.1.   
For subjects discontinued from the study due to any transaminase increase or hepatic 
event, the following should be performed:   
• Gastroenterology or hepatology consultation   
• Hepatobiliary ultrasound   


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9.9. 
Vital Signs 
Vital signs will be recorded at all visits and will include pulse rate and blood pressure in a 
supine position in principle.  For measurement of supine blood pressure, subjects should 


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be in a supine or semirecumbent position for a minimum of 5 minutes before the blood 
pressure measurement.  Measurement of blood pressure should be conducted using a 
calibrated manometer or automatic inflatable cuff monitor.  Results will be recorded in the 
CRF.   
9.10. 
Electrocardiograms 
At the stipulated times (Visit 1 and Visit 7), 12-lead ECG will be performed.  Results 
(Normal/Abnormal, not clinically significant/Abnormal, clinically significant) will be 
recorded in the CRF.   
9.11. 
Physical Findings 
9.11.1. 
Body Height and Weight 
At Screening (Visit 1), body height will be measured.  Body weight will be measured at 
each visit.  Results will be recorded in the CRF.   
9.11.2. 
Medical Interview 
Medical interview will be performed at each visit.  Results will be recorded in the CRF.   
9.11.3. 
Evaluation of Edema 
At Visit 1 and Visit 7, evaluation of edema will be performed including medical interview 
and pitting.  Results (presence or absence of edema and expression site) will be recorded 
in the CRF.   
9.12. 
Other Examinations 
9.12.1. 
Columbia-Suicide Severity Rating Scale23 
The C-SSRS is a tool designed to systematically assess and track suicidal AEs (behavior 
and ideation).  The C-SSRS assesses lifetime suicidality during an initial baseline 
evaluation using standardized questions, and then prospectively monitors ideations and 
behaviors at subsequent follow-up assessments throughout the trial.  The reviewer is an 
investigator, sub-investigator or clinical study coordinator who has completed training 
prior to the study using the training material.  The C-SSRS will be administered by the 
reviewer at each visit.  Answers to all relevant questions will be recorded in the CRF.  If 
the subject is judged to have suicidal behavior and/or suicidal ideation, appropriate 
measures will be implemented such as referring the subject to a specialist as described in 
the withdrawal procedures (see Section 5.7.3).   
9.12.2. 
Hospital Anxiety and Depression Scale18 
At each visit, subjects will provide a self-assessment using the HADS.  The HADS 
consists of 7 items to score depression (4-point scale) and 7 items to score anxiety (4-point 
scale).  The subject will respond to each item on the questionnaire.  Based on the results, 
the investigator will check for the presence or absence of depression and/or anxiety.  If the 


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subject is judged to have an AE, appropriate measures will be implemented such as 
referring the subject to a specialist.  Result will be recorded in the CRF.   
9.12.3. 
Pregnancy Test 
Pregnancy tests (urine tests) will be conducted at the stipulated times (Visit 1 and Visit 7), 
for women of child-bearing potential only.  All female subjects will be considered as 
women of child-bearing potential unless they have undergone surgical sterilization (with 
documented bilateral oophorectomy) or are postmenopausal and have experienced no 
menses within the previous 6 months.  The subject is considered to be postmenopausal 
when 12 consecutive months of absence of menstruation is confirmed with no pathological 
or physiological factors.  Results will be recorded in the CRF.   


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10. 
OTHER ASSESSMENTS 
Not Applicable.   
 


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11. 
STATISTICAL METHODS  
11.1. 
General Statistical Considerations 
The modified intent-to-treat (mITT) analysis set will be used as primary efficacy analysis 
set for all efficacy analyses and the per-protocol set (PPS) will be used as supplementary 
analysis.  All safety analyses will be conducted for the safety analysis set and, 
respectively. Patients with CLcr ≥60 mL and 30 to < 60 mL/min will be merged and 
analyzed. 
The primary imputation will be based on “nonfuture dependence" model using the pattern 
mixture approach under the missing not at random (MNAR) mechanism for the missing 
weekly ADPS.26, 27  Reason for dropout together with the time of dropout will be used for 
constructing the missing data pattern.  Detail will be at Section 11.4.1 and in the SAP. 
Missing weekly ADPS after the discontinuation will be imputed using multiple imputation 
(MI) method, and pattern mixture model (PMM) with different shift parameters depending 
on the reason for discontinuation (AE, LOE, or the others) will be used in the MI to 
impose penalty (ie, bad score) on the imputed weekly ADPS. 
Intercurrent event of this study is treatment discontinuation. In order to supplement the 
pain score when continuing with no administration after this situation, the above 
imputation method was adopted. 
Raw data will be presented to the exact precision at which they were collected. 
For summary statistics, means and medians will be displayed to one more decimal place 
than was determined for raw data, dispersion statistics will have two more decimal places, 
and the minimum and maximum will be displayed to the same number of decimal places 
as the raw data. 
Quantitative data will be tabulated with descriptive summary statistics: arithmetic mean, 
standard deviation (SD), median, minimum and maximum values, and number of 
observations.  For categorical data, frequency tables will be provided. 
All hypothesis testing will provide the P values and their corresponding two-sided 95% 
confidence intervals if applicable.  The significance level is 0.05 (two-sided) for all 
hypothesis testing.  No adjustment for multiple comparisons will be made for all analyses. 
Analysis for the change from baseline, including the shift table, will be conducted for the 
subjects who have an available baseline value and at least one post-randomization value. 
Subgroup analyses will be pre-specified in the SAP.   
11.2. 
Analysis Sets 
All enrolled subjects will include all subjects who sign the ICF.   
All randomized subjects will include all subjects who signed the ICF and were 
randomized.   
The safety analysis set will include all subjects who signed the ICF and received at least 
one dose of study medication.   


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The mITT analysis set, primary analysis set for the efficacy analyses, will include all 
randomized subjects who received at least one dose of study medication.   
The PPS will include all randomized subjects who received at least one dose of study 
medication, and who were sufficiently compliant with the protocol.  The PPS will be used 
for supplementary analyses.   
11.3. 
Study Population Data 
The number of enrolled subjects and randomized subjects will be summarized.  The 
number and percentage will be tabulated for subjects who completed the study, 
prematurely discontinued from the study, and the reason for the study discontinuation.  In 
addition, the number and percentage of subjects for each analysis set will be tabulated.   
Demographic and baseline characteristics will be summarized for the randomized subjects, 
the safety analysis set, mITT analysis set, and PPS.   
Treatment compliance for each subject will be summarized.   
11.4. 
Efficacy Analyses 
The mITT analysis set will be used for all efficacy analyses and the PPS will be only for 
the primary efficacy analysis described in Section 11.4.1 as supplementary analysis.  All 
statistical tests will be 2-sided hypothesis tests performed at the 5% level of significance 
and all confidence intervals (CIs) will be 2-sided 95% CIs, unless stated otherwise.   
11.4.1. 
Primary Efficacy Analyses 
Missing weekly ADPS will be imputed using a MI method.  In the MI method, a PMM 
under the assumption of nonfuture dependence.26, 27, which has different shift parameters 
depending on the reason for discontinuation (AE, LOE, or any other reasons), will be used 
to impose penalty (ie, bad score) on the weekly ADPS.  This imputation is based on a 
MNAR mechanism for missing weekly ADPS.   
In the MI step, Markov Chain Monte Carlo (MCMC) with relevant covariates (specified in 
the SAP) will be used to generate a monotone missing pattern.  Subsequently, Regression 
with Predictive Mean Matching (REGPMM) with the same covariates as the MCMC 
above was applied to the monotone missing pattern data to impute all missing weekly 
ADPS for completed datasets.  In the REGPMM step, the following shifting amount will 
be put on the imputed weekly ADPS at the first missing week for each subjects: 
1.0*residual standard deviation (RSD)*U(0.1) for subjects who discontinued due to AE 
1.0*RSD*U(0,1) for subjects who discontinued due to LOE 
0.5*RSD*U(0,1) for subjects who discontinued due to any other reasons 
where the coefficients (1.0, 1.0, 0.5) are shifting parameter to impose different penalty 
depending on the reason for discontinuation, RSD is a RSD at the week which will be 
estimated using a regression model in the REGPMM step, and U(0,1) is a random variable 
from a uniform distribution with a range of 0 to 1.   


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For subjects who completed the study but had missing weekly ADPS, the missing weekly 
ADPS will be imputed under the missing at random mechanism.   
The imputed weekly ADPS which is greater than 10 will be replaced with 10 (theoretical 
maximal value for weekly ADPS).  Additionally, regarding the subjects who discontinued 
due to LOE, the imputed weekly ADPS which is lower than the baseline ADPS for the 
corresponding subject will be replaced with the baseline ADPS for the subject.   
Each complete dataset will be analyzed using the ANCOVA with treatment as fixed 
effects and baseline ADPS as covariate to compare the change from baseline in weekly 
ADPS at Week 14 between mirogabalin and placebo.  The results will be combined using 
Rubin’s rule.   
 
Sensitivity analysis for the primary endpoint includes the followings:   
• The primary analysis on the mITT analysis set using “nonfuture dependence” 
MNAR model26, 27 with different shift parameters including (3, 3, 1.5), (5, 5, 
2.5), and (0, 0, 0). 
 
Supplementary analysis for the primary endpoint includes the followings:  
• The primary analysis on the mITT analysis set using placebo multiple 
imputation 
• ANCOVA with baseline ADPS and treatment as covariates on the mITT 
analysis set using baseline observation carried forward 
• ANCOVA with baseline ADPS and treatment as covariates on the mITT 
analysis set using last observation carried forward 
• The primary analysis on the PPS using “nonfuture dependence” MNAR model 
with the shift parameters of (1, 1, 0.5). 
 
11.4.2. 
Secondary Efficacy Analyses 
For all secondary efficacy analyses, the summary statistics or frequency tables will be 
created for values in the parameters and changes from baseline (if applicable) by treatment 
group and scheduled visit/week.   
11.4.2.1. Key Secondary Efficacy Analyses 
11.4.2.1.1. ADPS Responder Rate 
ADPS responder rate, defined as the proportion of subjects with ≥ 30%, and ≥ 50% 
reduction from baseline to Week 14, will be calculated by treatment group.  ADPS 
responder rate of each arm of DS-5565 will be compared with that of placebo using 
logistic regression model. The cumulative distribution of reduction from baseline in ADPS 
will be provided as a continuous responder analysis. 


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The cumulative distribution of reduction from the baseline in weekly ADPS at Week 14 
will be graphically displayed.   
11.4.2.1.2. Short-Form McGill Pain Questionnaire 
For the sensory score, affective score, total score, VAS, and the present pain intensity 
index, the measured value and the change from baseline will be summarized at each 
scheduled visit.  The change from baseline in the parameters above will be compared 
between each arm of mirogabalin and placebo. 
11.4.2.1.3. Sleep-interference Score 
The summary statistics will be computed for the ADSIS and their change from baseline at 
each week.  The change from baseline in sleep interference score will be compared 
between each arm of mirogabalin and placebo. 
11.4.2.1.4. Patient Global Impression of Change 
The PGIC responder rates of much improved or better (ie, score≤ 2) for the mirogabalin 
will be compared with that for the placebo.  The same analysis will be repeated for the 
PGIC responder rate of minimally improved or better (ie, score ≤ 3).   
11.4.2.1.5. Medical Outcomes Study Sleep Scale 
For the subscales of sleep disturbance, snoring, awakening short of breath or with a 
headache, somnolence, sleep adequacy, sleep problems index, and quantity of sleep, the 
change from baseline in the subscales will be compared between the mirogabalin and the 
placebo. The optimal sleep which is dichotomized version of optimal sleep findings, the 
summary will be provided as frequency tables and the parameter will also be compared 
between the mirogabalin and the placebo.   
11.4.2.1.6. Hospital Anxiety and Depression Scale 
The change from baseline in the subscales of Anxiety and Depression will be compared 
between the mirogabalin and the placebo.   
11.4.2.1.7. Neuropathic Pain Symptom Inventory 
For the sub-total score of each dimension (spontaneous ongoing pain, spontaneous 
paroxysmal pain, evoked pain, and paresthesia/dysesthesia) and total score, the change 
from baseline will be compared between the mirogabalin and the placebo.   
11.4.2.1.8. EQ-5D-5L 
The change from baseline in the converted single index value will be compared between 
the mirogabalin and the placebo.  The change from baseline in VAS will be also compared 
between the treatments.   


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11.4.2.1.9. Spinal Cord Independence Measure 
For the sub-total score of each category (self-care, respiration and sphincter management, 
and mobility) and the total score, the change from baseline will be compared between the 
mirogabalin and the placebo.   
11.4.2.1.10. 
Evaluation of allodynia 
The change from baseline in of allodynia will be compared between each arm of 
mirogabalin and placebo. 
11.4.2.2. Other Secondary Efficacy Analyses 
Not Applicable.   
11.4.3. 
Exploratory Efficacy Analyses 
Detail procedures for exploratory efficacy analysis are specified in SAP, etc.   
11.4.4. 
Pharmacokinetic/Pharmacodynamic/Biomarker Analyses 
Not Applicable.   
11.4.5. 
Safety Analyses 
All safety analyses will be performed using the safety analysis set.   
11.4.5.1. Adverse Event Analyses 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
TEAEs are defined as AEs that newly emerges or worsen in severity after the first 
administration of the study drug until the following dates:   
• Follow-up visit for the subjects who did not participate in the open-label 
extension study.   
• 14 days after the last dose of study drug in the double-blind study or the first 
dose of study drug in the open-label extension study whichever is earlier for 
the subjects who participated in the open-label extension study.   
The number and percentage of subjects reporting TEAE and treatment-emergent ADR 
(TEADR) will be calculated overall, by system organ class (SOC), and by preferred term 
(PT).  TEAE and TEADR will be further summarized by SOC, PT, and severity and by 
SOC, PT, and relationship to study drug.  Similarly, the number and percentage of subjects 
with serious TEAE, serious TEADR, significant TEAE, significant TEADR, TEAE 
leading to treatment discontinuation, and TEADR leading to treatment discontinuation 
will be tabulated.   
Time to first dizziness and somnolence, defined as the duration from first administration 
of investigational product to the first TEAE, will be summarized based on the Kaplan-
Meier product limit method.   


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11.4.5.2. Clinical Laboratory Evaluation Analyses 
Summary statistics will be provided for the measured value and change from baseline in 
the clinical laboratory tests results by scheduled visit. Shift table will be created for the 
categorical data (eg, abnormal low, normal, abnormal high”) between baseline and each 
scheduled visit of evaluation.   
Additionally, for ALT, AST, T-Bil, and ALP, the number and percentage of subjects who 
meet the criteria specified in Food Drug Administration Drug-Induced Liver Injury 
guideline24 will be tabulated and evaluation of drug-induced serious hepatotoxicity plot 
will also be provided.   
11.4.5.3. Vital Sign Analyses 
Summary statistics will be provided for measured value and change from baseline in vital 
signs parameters by scheduled visit.   
11.4.5.4. Electrocardiogram Analyses 
Shift table will be provided for ECG parameters between baseline and visit of End of 
Treatment/Early Termination.   
11.4.5.5. Physical Findings 
Summary statistics will be calculated for the measured value and change from baseline in 
body weight measurements by scheduled. The number and percentage of subjects who 
increased their body weight by 5% or 10% from the baseline will be also tabulated.   
For the evaluation of edema, the results (presence or absence) will be tabulated for each 
expression site.   
11.4.5.6. Columbia-Suicide Severity Rating Scale 
The results from C-SSRS will be tabulated.   
11.4.5.7. Hospital Anxiety and Depression Scale 
The subscales of Anxiety and Depression for HADS will be summarized by scheduled 
visit.   
11.4.6. 
Other Endpoint Analysis 
Not Applicable.   
11.5. 
Interim Analyses 
Not Applicable 
11.6. 
Sample Size Determination 
A total of 274 subjects will be randomized to one of the placebo-arm and mirogabalin-arm 
with randomization ratio of 1:1.  


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We assumed normal distributions with common SD for the change from baseline in ADPS 
at Week 14 in placebo and mirogabalin arms.  Applying Student’s t-test with one-sided 
significant level of 0.025, a total of 270 subjects (135 subjects for each arm) is required to 
provide 80% statistical power under the assumption of 0.6 difference (vs. placebo) and 
common SD of 1.75 for the change from baseline in ADPS at Week 14.  The treatment 
difference and common SD are assumed as expected values from the results of Asian 
Phase 3 studies for DPNP patients (DS5565-A-J303) and PHN patients (DS5565-A-J304).  
As a primary analysis set for the efficacy is a mITT analysis set defined as subjects who 
were randomized and received at least one dose of study drug, we planned 274 subjects to 
be randomized to consider dropouts from the randomization to the first administration of 
the study drug.   
11.7. 
Statistical Analysis Process 
The SAP will provide the statistical methods and definitions for the analysis of the 
efficacy and safety data, as well as describe the approaches to be taken for summarizing 
other clinical study information such as subject disposition, demographic and baseline 
characteristics, study drug exposure, and prior and concomitant medications.  The SAP 
will also include a description of how missing, unused, and spurious data will be 
addressed.   
The SAP will be finalized prior to unblinding to preserve the integrity of the statistical 
analysis and clinical study conclusions.  A change in the planned statistical analysis will 
require a protocol amendment only if it substantively alters the principal features of the 
protocol.  Any deviations from the planned statistical analyses in the protocol will be fully 
described in the SAP. 
All statistical analyses will be performed using Statistical Analysis System (SAS)® 
Version 9.3 or higher (SAS Institute, Cary, NC 27513).   


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12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
12.1. 
Monitoring and Inspections 
The study monitors and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the study (eg, CRFs, source data, and other pertinent 
documents).   
 The verification of adherence to the protocol; completeness, accuracy, and consistency of 
the data; and adherence to ICH GCP and local regulations on the conduct of clinical 
research will be accomplished through a combination of onsite visits by the study 
monitors and review of study data remotely.  The frequency of the monitoring visit will 
vary based on the activity at each study site.  The monitors are responsible for inspecting 
the CRFs and ensuring completeness of the study essential documents.  The monitors 
should have access to subject medical records and other study-related records needed to 
verify the entries on the CRFs.  Detailed information is provided in the monitoring plan. 
The monitors will communicate deviations from the protocol, SOPs, GCP and applicable 
regulations to the Investigator and will ensure that appropriate action (s) designed to 
prevent recurrence of the detected deviations is taken and documented.   
The Investigator agrees to cooperate with the study monitors to ensure that any problems 
detected in the course of these monitoring visits are addressed to the satisfaction of the 
sponsor and documented.   
In accordance with ICH GCP and the Sponsor’s audit plans, this study site may be 
selected for audit by representatives from the Sponsor.  Audit of study site facilities (eg, 
pharmacy, drug storage areas, laboratories) and review of study related records will occur 
in order to evaluate the study conduct and compliance with the protocol, ICH GCP, and 
applicable regulatory requirements.   The Investigator should respond to audit findings.  In 
the event that a regulatory authority informs the Investigator that it intends to conduct an 
inspection, the Sponsor shall be notified immediately.   
12.2. 
Data Collection 
Daiichi Sankyo will supply eCRFs.  An eCRF must be completed for each subject who 
signs an ICF and undergoes any screening procedure.  If a subject is not treated, the reason 
must be recorded on the eCRF.  All data collected during the study will be recorded in this 
individual, subject-specific eCRF.  Instructions will be provided for the completion of the 
eCRF and any corrections made will be automatically documented via the electronic data 
capture (EDC) software’s “audit trail.”   
Completion of the eCRF should be kept current to enable the monitor to review the 
subject’s status throughout the course of the study.  All information and other material to 
be used by subjects and investigative staff must use vocabulary and language that are 
clearly understood.  The eCRF will be completed, reviewed and signed off or e-signed by 
the Investigator.  The Investigator will sign and date the indicated places on the eCRF via 
the EDC system’s electronic signature.  These signatures will indicate that the Investigator 


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inspected or reviewed the data on the eCRF, the data queries, and the site notifications, 
and agrees with the content.   
12.3. 
Data Management 
Each subject will be identified in the database by a unique subject identifier as defined by 
the sponsor.   
To ensure the quality of clinical data across all subjects and study sites, a Clinical Data 
Management review will be performed on subject data according to specifications given to 
Daiichi Sankyo.  Data will be vetted both electronically and manually for CRFs and the 
data will be electronically vetted by programmed data rules within the application.  
Queries generated by rules and raised by reviewers will be generated within the EDC 
application.  During this review, subject data will be checked for consistency, 
completeness and any apparent discrepancies.  
Data received from external sources such as central laboratories will be reconciled to the 
clinical database.   
SAEs in the clinical database will be reconciled with the safety database.   
All AEs will be coded using MedDRA.  Concomitant medication will be coded using 
WHO drug.   
Data that may potentially unblind the treatment assignment (ie, treatment allocation, and 
study drug preparation/accountability data) will be handled with special care during the 
data cleaning and review process.  These data will be handled in such a way that, prior to 
unblinding, any data that may unblind study team personnel will be presented as blinded 
information or otherwise will not be made available.  If applicable, unblinded data may be 
made available to quality assurance representatives for the purposes of conducting 
independent audits.   
12.4. 
Study Documentation and Storage 
Source documents are original documents, data, and records from which the subject’s CRF 
data are obtained.  These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, diaries, microfiches, X-rays, and 
correspondence.   
Records of subjects, source documents, monitoring visit logs, data correction forms, 
CRFs, inventory of study drug, regulatory documents (eg, protocol and amendments, 
IRB/EC correspondence and approvals, approved and signed ICFs, Investigator’s 
Agreement, clinical supplies receipts, distribution and return records), and other sponsor 
correspondence pertaining to the study must be kept in appropriate study files at the study 
site (Trial Master File).  Source documents include all recordings and observations or 
notations of clinical activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical study.  These records will be retained in a secure file for the 
period required by the institution or study site policy.  Prior to transfer or destruction of 
these records, the Sponsor must be notified in writing and be given the opportunity to 
further store such records.   


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12.5. 
Record Keeping 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system (Trial Master File) of all study-related (essential) documentation, 
suitable for inspection at any time by representatives from the Sponsor and/or applicable 
regulatory authorities.  Essential documents contained in the Trial Master File include:   
• Subject files containing completed CRFs, ICFs, and supporting copies of 
source documentation (if kept).   
• Study files containing the protocol with all amendments, Investigator’s 
Brochure, copies of relevant essential documents required prior to commencing 
a clinical study, and all correspondence to and from the EC/IRB and the 
Sponsor.   
• Records related to the study drug(s) including acknowledgment of receipt at 
study site, accountability records and final reconciliation and applicable 
correspondence.   
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available.   
All study related essential documentation will be retained by the Investigator until at least 
2 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 2 years 
have lapsed since the formal discontinuation of clinical development of the investigational 
drug.  These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by an agreement with the sponsor.  It is the 
responsibility of the sponsor to inform the Investigator/institution as to when these 
documents no longer need to be retained.   
Subject's medical files should be retained in accordance with applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or 
private practice.   
No study document should be destroyed without prior written agreement between Sponsor 
and the Investigator.  Should the Investigator wish to assign the study records to another 
party or move them to another location, he/she must notify Sponsor in writing of the new 
responsible person and/or the new location.   


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13. 
FINANCING AND INSURANCE 
13.1. 
Finances 
Prior to starting the study, the Principal Investigator and/or institution will sign a clinical 
study agreement with Daiichi Sankyo and/or the contract research organization (CRO).  
This agreement will include the financial information agreed upon by the parties.   
13.2. 
Reimbursement, Indemnity, and Insurance 
The Sponsor provides insurance for study subjects to make available compensation in case 
of study-related injury.   
Reimbursement, indemnity and insurance shall be addressed in a separate agreement on 
terms agreed upon by the parties.   


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14. 
PUBLICATION POLICY AND PUBLIC DISCLOSURE OF 
CLINICAL TRIAL INFORMATION 
 
 


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15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance 
This study will be conducted in compliance with the protocol, the ethical principles that 
have their origin in the Declaration of Helsinki, the ICH consolidated Guideline E6 for 
GCP (CPMP/ICH/135/95), and applicable regulatory requirement(s).   
15.2. 
Subject Confidentiality 
The Investigators and the Sponsor will preserve the confidentiality of all subjects taking 
part in the study, in accordance with GCP and local regulations.   
The Investigator must ensure that the subject’s anonymity is maintained.  On the CRFs or 
other documents submitted to the Sponsor or the CRO, subjects should be identified by a 
unique subject identifier as designated by the Sponsor.  Documents that are not for 
submission to the Sponsor or the CRO (eg, signed ICF) should be kept in strict confidence 
by the Investigator.   
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the 
IRB/EC direct access to review the subject’s original medical records for verification of 
study-related procedures and data.  The Investigator is obligated to inform the subject that 
his/her study-related records will be reviewed by the above named representatives without 
violating the confidentiality of the subject.   
15.3. 
Informed Consent  
Before a subject’s participation in the study, it is the Investigator’s responsibility to obtain 
freely given consent, in writing, from the subject after adequate explanation of the aims, 
methods, anticipated benefits, and potential hazards of the study and before any protocol-
specific procedures or any study drugs are administered.  Subjects should be given the 
opportunity to ask questions and receive satisfactory answers to their inquiries, and should 
have adequate time to decide whether or not to participate in the study.  The written ICF 
should be prepared in the local language(s) of the potential subject population.   
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles 
that have their origin in the Declaration of Helsinki.  The consent form and any revision(s) 
should be approved by the EC or IRB prior to being provided to potential subjects.   
The subject’s written informed consent should be documented in the subject’s medical 
records.  The ICF should be signed and personally dated by the subject and by the person 
who conducted the informed consent discussion (not necessarily the Investigator).  The 
original signed ICF should be retained in accordance with institutional policy, and a copy 
of the signed consent form should be provided to the subject.  The date and time (if 
applicable) that informed consent was given should be recorded on the CRF.   
If the subject cannot sign by him/herself due to paralysis of spinal cord injury, the ICH-
GCP Section 4.8.9, and impartial witness should be present during the entire informed 


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consent discussion.  This witness should sign the ICF. By signing ICF, the witness attests 
that the information in the ICF and any other written information was adequately 
explained to and apparently understood by the subject and the informed consent was freely 
given by the subject.   
Suggested model text for the ICF for the study are provided in the Sponsor’s ICF template 
for the Investigator to prepare the documents to be used at his or her study site.  Updates 
to applicable forms will be communicated via letter from the Sponsor.   
15.4. 
Regulatory Compliance 
The study protocol, subject information and consent form, the Investigator Brochure, any 
subject written instructions to be given to the subject, available safety information, subject 
recruitment procedures (eg, advertisements), information about payments and 
compensation available to the subjects, and documentation evidencing the Investigator’s 
qualifications should be submitted to the EC or IRB for ethical review and approval 
according to local regulations, prior to the study start.  The written approval should 
identify all documents reviewed by name and version.   
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP.   
The Sponsor will appoint a Coordinating Investigator.  Among other possible duties, the 
Coordinating Investigator will be responsible for testifying to the accuracy of the 
description of the study conduct.  Because the Coordinating Investigator should have 
personal knowledge of the conduct of the study, he or she will normally be chosen from 
among those Investigators who have enrolled and treated at least one subject.   However, 
where an Investigator has special knowledge of the field or of the trial, the Coordinating 
Investigator can be chosen prior to enrollment of the first subject.   In all cases, the 
Coordinating Investigator must be chosen prior to locking the database.    
The Investigator must submit and, where necessary, obtain approval from the EC or IRB 
for all subsequent protocol amendments and changes to the ICF.  The Investigator should 
notify the EC or IRB of deviations from the protocol or SAEs occurring at the study site 
and other AE reports received from the Sponsor/CRO, in accordance with local 
procedures.   
As required by local regulations, the Sponsor’s local Regulatory Affairs group or 
representative to whom this responsibility has been delegated will ensure all legal aspects 
are covered, and approval from the appropriate regulatory bodies obtained, prior to study 
initiation.  If changes to the initial protocol and other relevant study documents are made, 
this representative will also ensure that any revised documents required for submission are 
submitted to regulatory authorities and implementation of these changes happen only after 
approval by the relevant regulatory bodies.   
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
Regulatory Authority(ies) in any area of the world, or if the Investigator is aware of any 
new information which might influence the evaluation of the benefits and risks of the 
investigational drug, the Sponsor should be informed immediately.   


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In addition, the Investigator will inform the Sponsor immediately of any urgent safety 
measures taken by the Investigator to protect the study subjects against any immediate 
hazard, and of any suspected/actual serious GCP non-compliance that the Investigator 
becomes aware of.   
15.5. 
Protocol Deviations 
The Investigator should conduct the study in compliance with the protocol agreed to by 
Sponsor and, if required, by the regulatory authority(ies), and which was given 
approval/favorable opinion by the IRBs/ECs.   
A deviation to any protocol procedure or waiver to any stated criteria will not be allowed 
in this study except where necessary to eliminate immediate hazard(s) to the subject.  
Sponsor must be notified of all intended or unintended deviations to the protocol (eg, 
inclusion/exclusion criteria, dosing, missed study visits) on an expedited basis.   
The Investigator, or person designated by the Investigator, should document and explain 
any deviation from the approved protocol.   
If a subject was ineligible or received the incorrect dose or study treatment, and had at 
least 1 administration of study drug, data should be collected for safety purposes. 
If applicable, the Investigator should notify the IRB of deviations from the protocol in 
accordance with local procedures.   
15.6. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of subjects 
or the conduct of the study, the Sponsor will inform all Investigators involved in the 
clinical study, ECs/IRBs, and regulatory authorities of such information, and when 
needed, will amend the protocol and/or subject information.   
The Investigator should immediately inform the subject whenever new information 
becomes available that may be relevant to the subject’s consent or may influence the 
subject’s willingness to continue participation in the study.  The communication should be 
documented on medical records, for example, and it should be confirmed whether the 
subject is willing to remain in the study.   
If the subject information is revised, it must be re-approved by the IEC/IRB.  The 
Investigator should obtain written informed consent to continue participation with the 
revised written information even if subjects were already informed of the relevant 
information.  The Investigator or other responsible personnel who provided explanations 
and the subject should sign and date the revised ICF.   
15.7. 
Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study progresses 
will be communicated to the Investigator by Daiichi Sankyo or the CRO.  Also, the 
Sponsor will ensure the timely submission of amendments to regulatory authorities.   


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A global protocol amendment will affect study conduct at all study site s in all regions of 
the world.  Such amendments will be incorporated into a revised protocol document.  
Changes made by such amendments will be documented in a Summary of Changes 
document.  These protocol amendments will undergo the same review and approval 
process as the original protocol.   
A local protocol amendment will affect study conduct at a particular study site(s) and/or in 
a particular region/country.  Sponsor approval of local amendments will be clearly 
documented.   
A protocol amendment may be implemented after it has been approved by the IRB/EC 
and, unless immediate implementation of the change is necessary for subject safety.   
15.8. 
Study Termination 
The sponsor will immediately suspend part of the study or the entire study if any of the 
following events makes the sponsor consider it difficult to continue the study: 
1. Any new safety or SAE information becomes available on the investigational 
products. 
2. The sponsor, the study site, or the investigator has implemented any significant 
GCP non-compliance or any significant protocol deviation. 
3. Any other information is obtained during the study. 
The sponsor will decide on whether to prematurely terminate part of the study or the entire 
study and will document the decision. 
If the sponsor decides to prematurely terminate part of the study or the entire study after 
consulting with medical experts and other designated people, the sponsor will promptly 
notify the study site and the investigator in writing of termination and the reason for the 
action.  If the study is prematurely terminated or suspended for any reason, the 
investigator will promptly inform the subjects participating in the study and will provide 
appropriate treatments and follow-up for the subjects to confirm their safety.   
15.9. 
Data and Safety Monitoring Board 
Not Applicable.   
15.10. 
Address List 
15.10.1. 
Sponsor’s Responsible Medical Officer 
 
 Aichi Medical University 
1-1, Yazakokarimata, Nagakute, Aichi, 480-1195, Japan 
TEL: 
 
PPD
PPD
PPD


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15.10.2. 
Sponsor’s Responsible Medical Adviser 
 
Aomori University 
109-18, Takama, Ishie, Aomori, 038-0003, Japan 
TEL: 
 
 
Ehime University Graduate 
School of Medicine 
Shitsukawa, Toon, Ehime, 791-0295, Japan 
TEL: 
 
 
 Aichi Medical University 
1-1, Yazakokarimata, Nagakute, Aichi, 480-1195, Japan 
 
15.10.3. 
Sponsor’s Clinical Scientist 
 
1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan 
TEL: 
 
FAX: 
 
15.10.4. 
Sponsor’s Study Manager 
 
1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan 
TEL: 
 
FAX: 
 
15.10.5. 
Coordinating Investigator 
 
Wakayama Medical  
University 
811-1 Kimiidera, Wakayama, Wakayama, 641-8509, Japan 
TEL: 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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 Sapporo Medical  
University 
291, Minami 1-jo, Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido, 060-8556,  
Japan 
TEL: 
 
 
Tokushima University Hospital 
2-50-1, Kuramoto-cho, Tokushima 770-8503, Japan 
TEL: 
  
15.10.6. 
Contract Research Organization in Charge of Monitoring in Japan 
CMIC Co., Ltd. 
1-1-1, Shibaura, Minato-ku, Tokyo 105-0023, Japan 
TEL: 
 
15.10.7. 
Contract Research Organization in Charge of Monitoring in Korea 
CMIC Korea Co., Ltd. 
10F, Gangnam N Tower, 129, Teheran-ro, Gangnam-gu, Seoul, 06133, Korea 
TEL:
 
15.10.8. 
Contract Research Organization in Charge of Monitoring in Taiwan 
CMIC Asia-Pacific, Pte. Ltd., Taiwan Branch 
5F, No.149, Sec. 3, Xinyi Rd., Da’an Dist., Taipei City 10658, Taiwan 
TEL: 
 
15.10.9. 
EDC Vendor Development 
Medidata Solutions, Inc. 
350 Hudson Street, 9th Floor, New York, NY 10014, USA 
TEL: 
 
FAX: 
 
15.10.10. EDC System Support 
Fujitsu Limited 
Shinagawa season terrace 1-2-70 Konan, Minato-ku, Tokyo 108-0075, Japan 
TEL: 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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FAX: 
 
15.10.11. IRT Vendor 
PAREXEL Informatics 
9F RBM Higashiyaesu Bldg. 2-9-1, Hachobori, Chuo-ku, Tokyo JAPAN 104-0032 
TEL:
 
FAX: 
 
15.10.12. Central Laboratory in Japan 
SRL Inc. 
6-5-1, Nishishinjuku, Shinjuku-ku, Tokyo 163-1310, Japan 
TEL: 
 
FAX: 
 
15.10.13. Central Laboratory in Korea 
SML Meditree Co., Ltd. 
501, 38-3 Baumeoro 41gil, Seocho-gu, Seoul, 06741, Korea 
TEL: 
 
FAX: 
 
15.10.14. Central Laboratory in Taiwan 
Protech Pharmaservices Corporation 
11th Floor, No.3, Park Street, Nangang District, Taipei City, Taiwan 11503 
TEL: 
 
FAX: 
 
15.10.15. Sponsor’s Biostatistician 
 
1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan 
TEL: 
 
FAX: 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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16. 
REFERENCES 
1. Galluzzi KE. Managing neuropathic pain. J Am Osteopath Assoc. 2007;107(10 
Suppl 6):ES39-48. 
2. Markman JD, Dworkin RH. Ion channel targets and treatment efficacy in 
neuropathic pain. J Pain. 2006;7(1 Suppl 1):S38-47. 
3. Baron R. Mechanisms of disease: neuropathic pain--a clinical perspective. Nat Clin 
Pract Neurol. 2006;2(2):95-106. 
4. Segerdahl M. Improving early clinical drug development for neuropathic pain by 
improving patient selection. Pain. 2009;141(1-2):4-5. 
5. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of 
neuropathic pain: evidence-based recommendations. Pain. 2007;132(3):237-51. 
6. Hempenstall K, Nurmikko TJ, Johnson RW, et al. Analgesic therapy in 
postherpetic neuralgia: a quantitative systematic review. PLoS Med. 
2005;2(7):628-44. 
7. Butera JA. Current and emerging targets to treat neuropathic pain. J Med Chem. 
2007;50(11):2543-6. 
8. Ziegler D. Treatment of diabetic neuropathy and neuropathic pain, how far have 
we come? Diabetes Care. 2008;31 Suppl 2:S255-61. 
9. Li CY, Zhang XL, Matthews EA, et al. Calcium channel α2δ1 subunit mediates 
spinal hyperexcitability in pain modulation. Pain. 2006;125(1-2):20-34. 
10. Taylor CP. Mechanisms of analgesia by gabapentin and pregabalin -- calcium 
channel α2-δ [Cavα2-δ] ligands. Pain. 2009;142(1-2):13-6. 
11. Field MJ, Li Z, Schwartz JB. Ca2+ channel α2-δ ligands for the treatment of 
neuropathic pain. J Med Chem. 2007;50(11):2569-75 
12. Field MJ, Cox PJ, Stott E, et al. Identification of the α2-δ-1 subunit of voltage-
dependent calcium channels as a molecular target for pain mediating the analgesic 
actions of pregabalin. Proc Natl Acad Sci USA. 2006;103(46):17537-42. 
13. European Medicines Agency (EMEA), Committee for Medicinal Products for 
Human Use (CHMP), Guideline on Clinical Medicinal Products Intended for the 
Treatment of Neuropathic Pain. July, 2007. 
14. Farrar JT, Young JP Jr, LaMoreaux L, et al. Clinical importance of changes in 
chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 
2001;94(2):149-58. 
15. Melzack R. The short-form McGill Pain Questionnaire. Pain. 1987;30(2):191-7. 
16. Viala-Danten M, Martin S, Guillemin I, et al. Evaluation of the reliability and 
validity of the Medical Outcomes Study sleep scale in patients with painful 
diabetic peripheral neuropathy during an international clinical trial. Health Qual 
Life Outcomes. 2008;6:113-25. 


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17. Hays RD, Stewart AL. Sleep measures. In: Measuring Functioning and Well-
Being. Stewart AL, Ware JE Jr, editors. Durham and London: Duke University 
Press; 1992;235-59. 
18. Bjelland I, Dahl AA, Haug TT, et al. The validity of the Hospital Anxiety and 
Depression Scale. An updated literature review. J Psychosom Res. 2002;52(2):69-
77. 
19. D Bouhassira, N Attal, J Fermanian, et al. Development and validation of the 
Neuropathic Pain Symptom Inventory. Pain. 2004;108(3):248-57. 
20. Herdman M, Gudex C, Lloyd A, 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. 
21. Itzkovich M, Gelernter I, Biering-Sorensen F, et al. The Spinal Cord Independence 
Measure (SCIM) version III: reliability and validity in a multi-center international 
study. Disabil Rehabil. 2007;29(24):1926-33. 
22. Yukio H, Masaki Y, Narihito S, et al. Symptom assessment tool for overactive 
bladder. Urology. 2006;68(2):318-323 
23. Oquendo MA, Halberstam B, Mann JJ. Risk factors for suicidal behavior: utility 
and limitations of research instruments. In: First MB, editor. Standardized 
Evaluation in Clinical Practice. Arlington: American Psychiatric Publishing, Inc; 
2003;103-30. 
24. U.S. Department of Health and Human Services. Food and Drug Administration. 
Center for Drug Evaluation and Research (CDER). Center for Biologics 
Evaluation and Research (CBER). Guidance for Industry Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation. July 2009, Drug Safety.   
25. International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use. ICH E9(R1) Technical Document ‘Estimands 
and Sensitivity Analysis in Clinical Trials’: STEP 2 DRAFT GUIDELINE. June 
2017. 
26. National Academy of Science. The Prevention and Treatment of Missing Data in 
Clinical Trials. Washington: National Academies Press. 2010  
27. Kenward MG, Molenberghs G, Thijs H. Pattern mixture models with proper time 
dependence. Biometrika. 2003;90(1):53-71. 
 


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17. 
APPENDICES 
17.1. 
Schedule of Events 
 


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Table 17.1: 
Study Visit 
 
Screening Randomization 
Treatment period 
End of Treatment 
Post-treatment  
follow-upa 
Early Termination 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
 
Week 
−1 
0 
1 
2 
6 
10 
14 
15 
 
Day 
≤ −7 
1 
8 
15 
43 
71 
99 
Day 7 post-last-dose 
 
Visit window (days) 
−7 to −14 
- 
6 to 10 
13 to 17 
40 to 46 
68 to 74 
96 to 102 
Day 5 to 14  
post-last-dose 
 
Informed consent 
Xb 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
Evaluation of ASIA Impairment 
X 
 
 
 
 
 
X 
 
X 
Efficacy parameter(s) - see next table 
X 
X 
X 
X 
X 
X 
X 
 
X 
Body height and weight 
X 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Medical interviewd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Evaluation of edema 
X 
 
 
 
 
 
X 
 
X 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
X 
 
X 
Clinical safety laboratory tests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HADS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test 
X 
 
 
 
 
 
X 
 
X 
AE reporting 
Non-serious AE 
 
 
 
 
 
 
 
 
 
SAE 
 
 
 
 
 
 
 
 
 
Prior and concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigational product dispensing 
 
X 
X 
X 
X 
X 
 
 
 
Investigational product compliance 
 
 
X 
X 
X 
X 
X 
 
X 
a: Follow-up observation is not required for patients who are enrolled in open-label extension study. 
b: After informed consent is obtained, patients who are under treatment with the prohibited concomitant medications will undergo a washout period of 28 days 
or more. 
c: Body weight only. 
d: Check subject’s health condition through verbal communication. Additional tests may be performed based on any signs or symptoms exhibited by subject.   
e: For blood pressure, supine in principle. 


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Table 17.2: 
Efficacy Assessment by Visit 
 
Screening Randomizatio
n 
Treatment period 
End of 
Treatment 
Post-treatment  
follow-up 
Early 
Termination 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
 
Week 
−1 
0 
1 
2 
6 
10 
14 
15 
 
Day 
≤ −7 
1 
8 
15 
43 
71 
99 
Day 7 post-last-dose 
 
Visit window (days) 
−7 to −14 
- 
6 to 10 
13 to 17 40 to 46 68 to 74 
96 to 102 
Day 5 to 14  
post-last-dose 
 
Pain diaries 
 
 
 
 
 
 
 
 
 
Sleep interference diaries 
 
 
 
 
 
 
 
 
 
Short-Form McGill Pain Questionnaire 
X 
X 
X 
X 
X 
X 
X 
 
X 
Medical Outcome Study sleep scale 
 
X 
 
 
 
 
X 
 
X 
Patient Global Impression of Change 
 
 
 
 
 
 
X 
 
X 
Neuropathic Pain Symptom Inventory 
 
X 
 
 
 
 
X 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
X 
 
X 
Hospital Anxiety and Depression Scale 
 
X 
 
 
 
 
X 
 
X 
Spinal Cord Independence Measure 
 
X 
 
 
 
 
X 
 
X 
Evaluation of allodynia 
 
X 
 
 
 
 
X 
 
X 
Bladder diariesa 
 
 
 
 
 
 
 
 
 
Overactive Bladder Symptom Scorea 
X 
 
 
 
 
 
X 
 
X 
a: For only Japanese subjects with self-urination, and who gave informed consent for overactive bladder evaluation and meet the diagnostic criteria of 
overactive bladder in OAB-SS at Visit 1 (As for Overactive Bladder Symptom Score in Visit 1, for only Japanese subjects with self-urination) 
 


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CLINICAL STUDY PROTOCOL 
 
AMELA study 
-An Asian, multicenter, randomized, double-blind, 
placebo-controlled 14-week study of mirogabalin in 
patients with central neuropathic pain followed by a 
52-week open-label extension- 
 
-For Open-Label Extension Phase- 
DS5565-A-J314 
 
VERSION 1.0, 18 SEP 2018 
VERSION 1.1, 22 OCT 2018 
VERSION 2.0, 11 JAN 2019 
VERSION 2.1, 10 FEB 2020 
VERSION 2.2, 30 SEP 2020 
 
DAIICHI SANKYO 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo.  The 
information is provided to you in confidence which is requested under an agreed upon 
and signed Confidentiality and Disclosure Agreement.  Do not give this document or any 
copy of it or reveal any proprietary information contained in it to any third party (other 
than those in your organization who are assisting you in this work and are bound by the 
Confidentiality and Disclosure Agreement) without the prior written permission of an 
authorized representative of Daiichi Sankyo. 


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PROTOCOL SYNOPSIS 
EudraCT: 
Not Applicable 
IND Number: 
Not Applicable 
Protocol Number: 
DS5565-A-J314 
Investigational Product: 
mirogabalin 
Active Ingredient(s)/INN: 
[(1R,5S,6S)-6-(Aminomethyl)-3-ethylbicyclo[3.2.0]hept-3- 
en-6-yl] acetic acid monobenzenesulfonate 
Study Title: 
An Asian, multicenter, randomized, double-blind, placebo-
controlled 14-week study of mirogabalin in patients with 
central neuropathic pain followed by a 52-week open-label 
extension 
Study Phase: 
Phase 3 
Indication Under 
Investigation: 
Central Neuropathic Pain (CNeP) 
Study Objectives: 
To assess the long-term safety and efficacy of mirogabalin 
when administered for up to 52 weeks in patients with 
CNeP after spinal cord injury (CNePSCI), central post 
stroke pain (CPSP), and CNeP in Parkinson’s disease 
(CNePPD) 
Study Design: 
Open-label, long-term study 
Patients with CNePSCI; After completion of the double 
blind study, the eligible patients will be enrolled.  The 
planned study duration for each subject will be 
approximately 53 weeks, consisting of 52-weeks treatment 
period and 1-week follow-up period after the last dose.  
The treatment period will consist of a titration period (4 
weeks), maintenance dose period (47 weeks) and taper 
period (1 week). 
Patients with CPSP and CNePPD; The planned study 
duration for each subject will be approximately 54 weeks, 
consisting of 1-week observation period, 52-weeks 
treatment period, and 1-week follow-up period after the last 
dose.  The treatment period will consist of a titration period 
(4 weeks), maintenance dose period (47 weeks) and taper 
period (1 week).  After observation period, the eligible 
subjects will be enrolled.  
Planned Study Duration: 
First patient enrolled: Mar 2019 
Last patient last visit (including follow-up): Jan 2021 


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Study Sites and Location: 
Approximately 120 study sites in Japan, Korea, and Taiwan 
Subject Eligibility Criteria: 
Patients with CNePSCI 
Inclusion Criteria: 
Subjects must satisfy all of the following criteria to be 
included in the study 
1. Completed 14 weeks of administration in the 
double-blind study 
2. Able to give informed consent for the study 
participation, understand procedures of this study, 
and complete patient-reported questionnaires 
adequately 
Exclusion Criteria: 
Subjects who meet any of the following criteria will be 
excluded from participation in the study. 
1. Drug compliance < 80% in the double-blind study 
2. Creatinine clearance (CLcr: using the Cockcroft-
Gault equation) < 30 mL/min at Visit 6 of the 
double-blind study 
3. Experienced critical safety issue in the double-blind 
study 
4. Pregnancy, potential pregnancy, breast feeding, or 
subject unwilling to take reliable contraceptive 
measures during the study or for 4 weeks after study 
completion 
5. The subject is considered inappropriate for the 
study at the discretion of the investigator or sub-
investigator 
Patients with CPSP 
Inclusion Criteria : 
Subjects must satisfy all of the following criteria to be 
included in the study. 
3. Age ≥ 20 years at informed consent 
4. Able to give informed consent for the study 
participation, understand procedures of this study, 
and complete patient-reported questionnaires 
adequately 
5. ≥ 6 months after stroke at screening 


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6. Damage of the somatosensory pathways due to 
stroke, which is confirmed by CT or MRI 
inspection 
7. Pain region neurologically matched with damaged 
somatosensory pathways due to stroke 
8. Stable CNeP after stroke at least for 3 months prior 
to screening 
9. At screening and enrollment, a pain scale of 
≥ 40 mm on Visual Analog Scale (VAS) of SF-
MPQ 
Exclusion Criteria: 
Subjects who meet any of the following criteria will be 
excluded from participation in the study. 
6. ≥ Grade 5 of modiﬁed Rankin Scale at screening 
7. Bleeding in any parts of the body at screening 
8. Pain after stroke other than CNeP at screening or 
enrollment, that may confound the assessment of 
CPSP 
9. Neurologic disorders at screening or enrollment, 
unrelated to CPSP, that may confound the 
assessment of CPSP 
10. Major psychiatric disorders within 1 year prior to 
screening 
11. ≤ 23 points on Mini-Mental State Examination at 
screening 
12. Previous administration of pregabalin ≥ 300 mg/day 
for subjects with CLcr ≥ 60 mL/min or pregabalin 
≥ 150 mg/day for subjects with CLcr 30 to 
< 60 mL/min for at least 4 weeks, declared lack of 
effect 
13. Previous Administration of gabapentin 
≥ 1200 mg/day for subjects with CLcr ≥ 60 mL/min 
or gabapentin ≥ 600 mg/day for subjects with CLcr 
30 to < 60, for at least 4 weeks, declared lack of 
effect 
14. Use of mirogabalin, pregabalin, or gabapentin 
within 28 days prior to screening 
15. Use of strong opioids for analgesic of CPSP within 
3 months prior to screening 


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16. CLcr (using the Cockcroft-Gault equation) 
< 30 mL/min at screening 
17. Malignancy other than basal cell carcinoma within 
the past 2 years prior to screening 
18. Clinically significant unstable endocrine (eg, 
diabetes mellitus), neurologic, ophthalmologic, 
hepatobiliary, respiratory, hematologic illness, or 
cardiovascular disease (eg, uncontrolled cardiac 
arrhythmia, or myocardial infarction) at screening 
or enrollment 
19. Clinically significant findings on electrocardiogram 
(ECG) at screening 
20. History of pernicious anemia, untreated 
hypothyroidism, or human immunodeficiency virus 
infection 
21. Pregnancy, potential pregnancy, breast feeding, or 
subject unwilling to take reliable contraceptive 
measures during the study or for 4 weeks after study 
completion 
22. Known hypersensitivity to mirogabalin, pregabalin 
or gabapentin 
23. Participation in another clinical study, either 
currently or within 30 days prior to providing of 
informed consent 
24. Experience of participating mirogabalin clinical 
study and receiving investigational product 
25. Abuse of illicit drugs or alcohol history 
26. Response of “yes” to any of the questions on the 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
at screening or enrollment in relation to events 
occurring within the past 12 months 
27. At screening, clinical laboratory values exceeding 
limits listed in Table 4.1. 
28. The subject who is considered inappropriate for the 
study at the discretion of the investigator or sub-
investigator 
Patients with CNePPD 
Inclusion Criteria: 


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Subjects must satisfy all of the following criteria to be 
included in the study. 
10. Age ≥ 20 years at informed consent 
11. Able to give informed consent for the study 
participation, understand procedures of this study, 
and complete patient-reported questionnaires 
adequately 
12. ≥ 6 months after being diagnosed as Parkinson’s 
disease (Clinically established Parkinson’s Disease 
or Clinically probable Parkinson’s Disease 
according to diagnostic criteria of Movement 
Disorder Society for Parkinson’s disease) at 
screening 
13. Correspond to CNeP in clinical classification of 
painful or unpleasant sensations in Parkinson’s 
disease by the Ford classification 
14. Stable CNePPD at least for 3 months prior to 
screening 
15. At screening and enrollment, a pain scale of 
≥ 40 mm on VAS of SF-MPQ 
Exclusion Criteria: 
Subjects who meet any of the following criteria will be 
excluded from participation in the study. 
29. Stage V of the Hoehn and Yahr scale at screening 
30. Other severe pain at screening or enrollment, 
unrelated to pain in Parkinson’s disease, that may 
confound the assessment of pain in Parkinson’s 
disease 
31. Neurologic disorders at screening or enrollment, 
unrelated to pain in Parkinson’s disease, that may 
confound the assessment of pain in Parkinson’s 
disease 
32. Major psychiatric disorders within 1 year prior to 
screening  
33. ≤ 23 points on Mini-Mental State Examination at 
screening 
34. Previous administration of pregabalin ≥ 300 mg/day 
for subjects with CLcr ≥ 60 mL/min or pregabalin 
≥ 150 mg/day for subjects with CLcr 30 to 


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< 60 mL/min for at least 4 weeks, declared lack of 
effect 
35. Previous Administration of gabapentin 
≥ 1200 mg/day for subjects with CLcr ≥ 60 mL/min 
or gabapentin ≥ 600 mg/day for subjects with CLcr 
30 to < 60, for at least 4 weeks, declared lack of 
effect 
36. Use of mirogabalin, pregabalin, or gabapentin 
within 28 days prior to screening 
37. Use of strong opioids for analgesic of CNePPD 
within 3 months prior to screening 
38. CLcr (using the Cockcroft-Gault equation) 
< 30 mL/min at screening 
39. Malignancy other than basal cell carcinoma within 
the past 2 years prior to screening 
40. Clinically significant unstable endocrine (eg, 
diabetes mellitus), neurologic, ophthalmologic, 
hepatobiliary, respiratory, hematologic illness, or 
cardiovascular disease (eg, uncontrolled cardiac 
arrhythmia, or myocardial infarction) at screening 
or enrollment 
41. Clinically significant findings on ECG at screening 
42. History of pernicious anemia, untreated 
hypothyroidism,  or human immunodeficiency virus 
infection 
43. Pregnancy, potential pregnancy, breast feeding, or 
subject unwilling to take reliable contraceptive 
measures during the study or for 4 weeks after study 
completion 
44. Known hypersensitivity to mirogabalin, pregabalin 
or gabapentin 
45. Participation in another clinical study, either 
currently or within 30 days prior to providing of 
informed consent 
46. Experience of participating mirogabalin clinical 
study and receiving investigational product 
47. Abuse of illicit drugs or alcohol history 


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48. Response of “yes” to any of the questions on the C-
SSRS at screening or enrollment in relation to 
events occurring within the past 12 months 
49. At screening, clinical laboratory values exceeding 
limits listed in Table 4.1 . 
50. The subject who is considered inappropriate for the 
study at the discretion of the investigator or sub-
investigator 
Dosage Form, Dose and 
Route of Administration: 
One tablet of mirogabalin will be administered orally twice 
daily (BID) (in the morning and at bedtime).  Additionally, 
one tablet of mirogabalin will be administered orally once 
daily (QD) (at bedtime) at last week of treatment period. 
Patients with CLcr ≥ 60 mL/min at Visit 6 in the double-
blind phase for patients with CNePSCI or Visit 1 for 
patients with CPSP or CNePPD, will start with 5 mg BID 
of mirogabalin at first 2 weeks, followed by 10 mg BID at 
second 2 weeks as titration phase.  From the fifth week, if 
there are no problems in safety, the patients will escalate 
the dose to 15 mg BID.  For the following visits, the dosage 
may be changed to either 10 mg BID or 15 mg BID 
depending on safety findings at the time of each visit.  At 
taper period (last week of treatment period), if the dosage is 
10 mg BID just before tapering, it will be changed to 10 mg 
QD, and if the dosage is 15 mg BID just before tapering, it 
will be changed to 15 mg QD. 
Patients with CLcr 30 to 60 mL/min at Visit 6 in the 
double-blind phase for patients with CNePSCI or Visit 1 
for patients with CPSP or CNePPD, will start 2.5 mg BID 
of mirogabalin at first 2 weeks, followed by 5 mg BID at 
second 2 weeks as titration phase.  From the fifth week, if 
there are no problems in safety, the patients will escalate 
the dose to 7.5 mg BID.  For the following visits, the 
dosage may be changed to either 5 mg BID or 7.5 mg BID 
depending on safety findings at the time of each visit.  At 
taper period (last week of treatment period), if the dosage is 
5 mg BID just before tapering, it will be changed to 5 mg 
QD, and if the dosage is 7.5 mg BID just before tapering, it 
will be changed to 7.5 mg QD. 
Study Endpoints: 
Safety: 
• Treatment-Emergent Adverse Events (TEAEs) 
• Clinical laboratory tests 


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• Vital sign 
• 12-lead ECG 
• Body weight 
• Edema 
• C-SSRS 
• Hospital Anxiety and Depression Scale (HADS) 
Efficacy: 
• Short–Form McGill Pain Questionnaire (SF-MPQ)  
Planned Sample Size: 
Approximately 180 subjects will be enrolled in the study. 
Statistical Analyses: 
Safety: 
TEAEs, clinical laboratory tests result, vital signs, body 
weight, 12-lead ECG, evaluation of edema, C-SSRS, and 
HADS will be summarized using the safety analysis set.   
Efficacy: 
Scores in the parameters of the SF-MPQ and their change 
from baseline will be summarized by scheduled visit.   
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ...................................................................................... 2 
TABLE OF CONTENTS ..................................................................................... 10 
LIST OF TABLES ............................................................................................... 16 
LIST OF ABBREVIATIONS .............................................................................. 17 
1. 
INTRODUCTION ................................................................................. 19 
1.1. 
Background ............................................................................................ 19 
1.2. 
Study Rationale ..................................................................................... 19 
1.2.1. 
Description of Investigational Drug ...................................................... 19 
1.2.2. 
Nonclinical Studies ................................................................................ 19 
1.2.3. 
Clinical Experience ............................................................................... 19 
1.2.4. 
Study Rationale ..................................................................................... 19 
1.2.5. 
Risks and Benefits for Study Subjects ................................................... 19 
2. 
STUDY OBJECTIVES AND HYPOTHESIS ...................................... 20 
2.1. 
Study Objectives .................................................................................... 20 
2.2. 
Study Hypotheses .................................................................................. 20 
2.3. 
Study Endpoints ..................................................................................... 20 
2.3.1. 
Safety Endpoints .................................................................................... 20 
2.3.2. 
Efficacy Endpoint .................................................................................. 20 
3. 
STUDY DESIGN .................................................................................. 21 
3.1. 
Overall Design ....................................................................................... 21 
3.1.1. 
Study Plan .............................................................................................. 21 
3.1.2. 
Study Scheme ........................................................................................ 21 
3.1.2.1. Patients for Central Neuropathic Pain After Spinal Cord Injury ........... 21 
3.1.2.2. Patients for Central Post Stroke Pain and Central Neuropathic Pain in 
Parkinson’s Disease ............................................................................... 22 
3.2. 
Discussion of Study Design ................................................................... 22 
3.2.1. 
Dosage of Mirogabalin .......................................................................... 22 
3.2.2. 
Duration of Study Treatment ................................................................. 23 
3.2.3. 
Control Treatment ................................................................................. 23 
3.2.4. 
Study Endpoints ..................................................................................... 23 
4. 
STUDY POPULATION ........................................................................ 24 


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4.1. 
Inclusion Criteria ................................................................................... 24 
4.1.1. 
Inclusion Criteria for Patients with Central Neuropathic Pain After 
Spinal Cord Injury ................................................................................. 24 
4.1.2. 
Inclusion Criteria for Patients With Central Post Stroke Pain .............. 24 
4.1.3. 
Inclusion Criteria for Patients With Central Neuropathic Pain in 
Parkinson’s Disease ............................................................................... 25 
4.2. 
Exclusion Criteria .................................................................................. 25 
4.2.1. 
Exclusion Criteria for Patients With Central Neuropathic Pain After 
Spinal Cord Injury ................................................................................. 25 
4.2.2. 
Exclusion Criteria for Patients With Central Post Stroke Pain ............. 26 
4.2.3. 
Exclusion Criteria for Patients With Central Neuropathic Pain in 
Parkinson’s Disease ............................................................................... 27 
5. 
STUDY TREATMENT(S) .................................................................... 30 
5.1. 
Assigning Subjects to Treatments and Blinding ................................... 30 
5.1.1. 
Treatment Group(s)/Sequences ............................................................. 30 
5.1.1.1. Treatment Group(s)/Sequences for Patients With CNePSCI ................ 30 
5.1.1.2. Treatment Group(s)/Sequences for Patients With Central Post Stroke 
pain and Central Neuropathic Pain in Parkinson’s Disease .................. 30 
5.1.2. 
Method of Treatment Allocation ........................................................... 31 
5.1.2.1. Enrollment ............................................................................................. 31 
5.1.2.2. Procedures for Subject Enrollment ........................................................ 31 
5.1.3. 
Blinding ................................................................................................. 31 
5.1.4. 
Emergency Unblinding Procedure ........................................................ 31 
5.2. 
Study Drug(s) ........................................................................................ 31 
5.2.1. 
Description ............................................................................................ 31 
5.2.2. 
Labeling and Packaging ........................................................................ 31 
5.2.3. 
Preparation ............................................................................................. 32 
5.2.4. 
Administration ....................................................................................... 33 
5.2.5. 
Storage ................................................................................................... 35 
5.2.6. 
Drug Accountability .............................................................................. 35 
5.3. 
Control Treatment ................................................................................. 35 
5.4. 
Dose Interruptions and Reductions ....................................................... 35 
5.5. 
Method of Assessing Treatment Compliance ........................................ 36 
5.6. 
Concomitant Medications ...................................................................... 36 


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5.6.1. 
Prohibited Concomitant Medications .................................................... 36 
5.6.1.1. Prohibited Concomitant Medication for Patients With Central 
Neuropathic Pain After Spinal Cord Injury ........................................... 36 
5.6.1.2. Prohibited Concomitant Medication for Patients With Central Post 
Stroke Pain and Central Neuropathic Pain in Parkinson’s Disease ....... 36 
5.6.2. 
Restricted Concomitant Medications .................................................... 37 
5.6.3. 
Rescue Medications ............................................................................... 37 
5.6.4. 
Prohibited Concomitant Therapies ........................................................ 37 
5.6.5. 
Restricted Concomitant Therapies ........................................................ 37 
5.6.6. 
Other ...................................................................................................... 37 
5.7. 
Subject Withdrawal/Discontinuation ..................................................... 37 
5.7.1. 
Withdrawal Criteria ............................................................................... 37 
5.7.2. 
Reasons for Withdrawal ........................................................................ 38 
5.7.3. 
Withdrawal Procedures ......................................................................... 39 
5.7.4. 
Subject Replacement ............................................................................. 39 
5.7.5. 
Subject Re-screening Procedures .......................................................... 39 
6. 
STUDY PROCEDURES ....................................................................... 40 
6.1. 
Screening (Visit 1) ................................................................................. 40 
6.2. 
Visit 7 .................................................................................................... 41 
6.3. 
Visit 8 .................................................................................................... 41 
6.4. 
Visit 9 .................................................................................................... 42 
6.5. 
Visit 10 to Visit 20 ................................................................................ 43 
6.6. 
End of Treatment/Early Termination (Visit 21) .................................... 43 
6.7. 
Post-treatment Follow-up (Visit 22, 7 Days After the Completion of 
Administration) ...................................................................................... 44 
7. 
EFFICACY ASSESSMENTS ............................................................... 45 
7.1. 
Assessments for Efficacy Endpoint(s) ................................................... 45 
7.2. 
Appropriateness of Selected Efficacy Assessment(s) ........................... 45 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS . 46 
8.1. 
Pharmacokinetic Assessment(s) ............................................................ 46 
8.2. 
Pharmacodynamic Assessment(s) ......................................................... 46 
8.3. 
Biomarker Assessment(s) ...................................................................... 46 
8.4. 
Immunogenicity ..................................................................................... 46 


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8.5. 
Pharmacogenomic Analysis .................................................................. 46 
9. 
SAFETY EVALUATION AND REPORTING .................................... 47 
9.1. 
Assessment of Safety Endpoint(s) ......................................................... 47 
9.2. 
Adverse Event Collection and Reporting .............................................. 47 
9.3. 
Adverse Events of Special Interest ........................................................ 48 
9.4. 
Adverse Event ....................................................................................... 49 
9.4.1. 
Definition of Adverse Event .................................................................. 49 
9.4.2. 
Serious Adverse Event .......................................................................... 49 
9.4.3. 
Severity Assessment .............................................................................. 50 
9.4.4. 
Causality Assessment ............................................................................ 50 
9.4.5. 
Action Taken Regarding Study Drug(s) ................................................ 51 
9.4.6. 
Other Action Taken for Event ............................................................... 51 
9.4.7. 
Adverse Event Outcome ........................................................................ 51 
9.4.8. 
Definition of Adverse Drug Reaction .................................................... 52 
9.5. 
Serious Adverse Events and Adverse Event of Special Interest 
Reporting–Procedure for Investigators .................................................. 52 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee .......................................................... 53 
9.7. 
Exposure In Utero During Clinical Studies ........................................... 53 
9.8. 
Clinical Laboratory Evaluations ............................................................ 54 
9.9. 
Vital Signs ............................................................................................. 59 
9.10. 
Electrocardiograms ................................................................................ 59 
9.11. 
Physical Findings ................................................................................... 59 
9.11.1. Body Height and Weight ....................................................................... 59 
9.11.2. Medical Interview .................................................................................. 59 
9.11.3. Evaluation of Edema ............................................................................. 59 
9.12. 
Other Examinations ............................................................................... 60 
9.12.1. Columbia-Suicide Severity Rating Scale .............................................. 60 
9.12.2. Hospital Anxiety and Depression Scale ................................................ 60 
9.12.3. Pregnancy Test ...................................................................................... 60 
10. 
OTHER ASSESSMENTS ..................................................................... 61 
11. 
STATISTICAL METHODS ................................................................. 62 
11.1. 
General Statistical Considerations ......................................................... 62 


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11.2. 
Analysis Sets ......................................................................................... 62 
11.3. 
Study Population Data ........................................................................... 62 
11.4. 
Efficacy Analyses .................................................................................. 62 
11.4.1. Safety Analyses ..................................................................................... 63 
11.4.1.1. Adverse Event Analyses ........................................................................ 63 
11.4.1.2. Clinical Laboratory Evaluation Analyses .............................................. 63 
11.4.1.3. Vital Sign Analyses ............................................................................... 63 
11.4.1.4. Electrocardiogram Analyses .................................................................. 63 
11.4.1.5. Medical Interview .................................................................................. 64 
11.4.1.6. Columbia-Suicide Severity Rating Scale .............................................. 64 
11.4.1.7. Hospital Anxiety and Depression Scale ................................................ 64 
11.4.2. Other Endpoint Analysis ....................................................................... 64 
11.5. 
Interim Analyses .................................................................................... 64 
11.6. 
Sample Size Determination ................................................................... 64 
11.7. 
Statistical Analysis Process ................................................................... 64 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE ........................ 65 
12.1. 
Monitoring and Inspections ................................................................... 65 
12.2. 
Data Collection ...................................................................................... 65 
12.3. 
Data Management .................................................................................. 65 
12.4. 
Study Documentation and Storage ........................................................ 65 
12.5. 
Record Keeping ..................................................................................... 65 
13. 
FINANCING AND INSURANCE ........................................................ 66 
13.1. 
Finances ................................................................................................. 66 
13.2. 
Reimbursement, Indemnity, and Insurance ........................................... 66 
14. 
PUBLICATION POLICY AND PUBLIC DISCLOSURE OF 
CLINICAL TRIAL INFORMATION ................................................... 67 
15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION ......... 68 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance ................ 68 
15.2. 
Subject Confidentiality .......................................................................... 68 
15.3. 
Informed Consent .................................................................................. 68 
15.4. 
Regulatory Compliance ......................................................................... 68 
15.5. 
Protocol Deviations ............................................................................... 68 
15.6. 
Supply of New Information Affecting the Conduct of the Study ......... 68 


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15.7. 
Protocol Amendments ........................................................................... 68 
15.8. 
Study Termination ................................................................................. 68 
15.9. 
Data and Safety Monitoring Board ........................................................ 68 
15.10. 
Address List ........................................................................................... 68 
16. 
REFERENCES ...................................................................................... 69 
17. 
APPENDICES ....................................................................................... 70 
17.1. 
Schedule of Events ................................................................................ 70 
 


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LIST OF TABLES 
Table 4.1: Hematology/Blood Chemistry Limits............................................... 29 
Table 5.1: Drug Combinations During the Treatment Period (Week LT_1-2) . 32 
Table 5.2: Drug Combinations During the Treatment Period (Week LT_3-4) . 32 
Table 5.3: Drug Combinations During the Treatment Period (Week LT_5 to 
Week 52 ) .......................................................................................... 32 
Table 5.4: Method of Administration During the Treatment Period ................. 34 
Table 9.1: Laboratory Parameters to be Assessed, and Time of Assessment for 
Patients With Central Neuropathic Pain After Spinal Cord Injury... 55 
Table 9.2: Laboratory Parameters to be Assessed, and Time of Assessment for 
Patients With Central Post Stroke Pain and CNePPD Central 
Neuropathic Pain in Parkinson’s Disease ......................................... 56 
Table 17.1: Study Visits for Patients with Central Neuropathic Pain After Spinal 
Cord Injury ........................................................................................ 71 
Table 17.2: Study Visits for Patients with Central Post Stroke Pain and Central 
Neuropathic Pain in Parkinson’s Disease ......................................... 72 
 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
ADR 
adverse drug reaction 
AE 
adverse event 
A/G ratio 
albumin/globulin ratio 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice daily 
BUN 
blood urea nitrogen 
CNeP 
central neuropathic pain 
CNePPD 
CNeP in Parkinson’s disease 
CNePSCI 
CNeP after spinal cord injury 
CPSP 
central post stroke pain 
CLcr 
creatinine clearance 
CRF 
case report form 
CRP 
C-reactive protein 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DPNP 
diabetic peripheral neuropathic pain 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EIU 
exposure in utero 
GCP 
Good Clinical Practice (refers to ICH and Code of Federal 
Regulations) 
γ-GT (γ-GTP) 
gamma-glutamyl transpeptidase 
GOT 
glutamic oxaloacetic transaminase 
GPT 
glutamic pyruvic transaminase 
HADS 
Hospital Anxiety and Depression Scale 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
INN 
International Nonproprietary Names 
IRT 
Interactive Response Technology 
LDH 
lactate dehydrogenase 
LOE 
lack of efficacy 
MedDRA 
Medical Dictionary for Regulatory Activities 
PHN 
Post-Herpetic Neuralgia 
PT 
preferred term 


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ABBREVIATION 
DEFINITION 
QD 
once daily 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SF-MPQ 
Short-Form McGill Pain Questionnaire 
SOC 
system organ class 
T-Bil 
total bilirubin 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
VAS 
Visual Analog Scale 
WBC 
white blood cell 
 


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1. 
INTRODUCTION 
1.1. 
Background 
Refer to Section 1.1 of double-blind study in the protocol (DS5565-A-J314).   
1.2. 
Study Rationale 
1.2.1. 
Description of Investigational Drug 
Refer to Section 1.2.1 of double-blind study in the protocol (DS5565-A-J314).   
1.2.2. 
Nonclinical Studies 
Refer to Section 1.2.2 of double-blind study in the protocol (DS5565-A-J314).   
1.2.3. 
Clinical Experience 
Refer to Section 1.2.3 of double-blind study in the protocol (DS5565-A-J314).   
1.2.4. 
Study Rationale 
Mirogabalin is being developed for chronic use in CNeP.  Therefore, this long-term study 
will be conducted to evaluate the long-term safety and efficacy of mirogabalin during the 
course of a 52 week (including titration period) open treatment period.   
Mirogabalin has been shown to ameliorate pain in patients with diabetic peripheral 
neuropathic pain (DPNP) and Post-Herpetic Neuralgia (PHN) and was well tolerated in 
Phase 3 studies during the treatment in 52 weeks.  In nonclinical studies, mirogabalin has 
analgesic effect in not only peripheral but also central neuropathic pain (CNeP) model at 
almost same dose.  Thus, it is expected that mirogabalin also ameliorate CNeP.  As 
mentioned in the Section 1.2.4 of double-blind study in the protocol (DS5565-A-J314), 
CNePSCI is typical CNeP.  In addition, patients with central post stroke pain (CPSP) and 
Parkinson’s disease (CNePPD) are known as having CNeP.  Therefore, in this study, as 
CNeP, CNePSCI, CPSP, and CNePPD are selected.   
1.2.5. 
Risks and Benefits for Study Subjects 
As for risks, refer to Section 1.2.5 of double-blind study in the protocol (DS5565-A-
J314).   
Mirogabalin was administered in a flexible dose of 10 mg twice daily (BID) and 15 mg 
BID for 52 weeks in the Ph3 studies in patients with DPNP and PHN.  In terms of 
efficacy, certain improvement of Short-Form McGill Pain Questionnaire (SF-MPQ) 
subscales (sensory score, affective score, total score, Visual Analog Scale [VAS], and 
present pain intensity) was observed throughout the treatment period compared to the 
baseline.  Therefore, mirogabalin is expected to alleviate CNeP.   
 


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2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
The objective is to assess the long-term safety and efficacy of mirogabalin when 
administered for up to 52 weeks in patients with CNeP after spinal cord injury 
(CNePSCI), Central post stroke pain (CPSP), or CNeP in Parkinson’s disease (CNePPD).   
2.2. 
Study Hypotheses 
The hypothesis of the long-term study is that mirogabalin will be generally well tolerated 
for up to 52 weeks.   
2.3. 
Study Endpoints 
2.3.1. 
Safety Endpoints 
• Treatment-Emergent Adverse events (TEAEs) 
• Clinical laboratory tests 
• Vital sign 
• 12-lead electrocardiogram (ECG) 
• Body weight 
• Edema 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Hospital Anxiety and Depression Scale (HADS) 
2.3.2. 
Efficacy Endpoint 
• Short-Form McGill Pain Questionnaire (SF-MPQ) 


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3. 
STUDY DESIGN 
3.1. 
Overall Design 
3.1.1. 
Study Plan 
This is a multinational, open-label, long-term study for treatment of CNeP.   
Study sites: Approximately 120 study sites in Japan, Korea and Taiwan.   
Planned sample size is approximately 180 subjects (CNePSCI > 60 subjects, CPSP > 60 
subjects, and CNePPD > 10) who will be enrolled in the study.   
3.1.2. 
Study Scheme 
Patients with CNePSCI 
After completion of Visit 7 in the double blind study and obtained written informed 
consent, the eligible patients will be enrolled.  The planned study duration for each 
subject will be approximately 53 weeks, consisting of 52-weeks treatment period and 1-
week follow-up period after the last dose.  The treatment period will consist of a titration 
period (4 weeks), maintenance dose period (47 weeks) and taper period (1 week).  After 
the completion or early termination of administration, subjects will be monitored for an 
additional follow-up observation period of 1 week.   
Patients with CPSP and CNePPD 
The planned study duration for each subject will be approximately 54 weeks, consisting 
of 1-week observation period, 52-weeks treatment period, and 1-week follow-up period 
after the last dose.  The treatment period will consist of a titration period (4 weeks), 
maintenance dose period (47 weeks) and taper period (1 week).  After observation period, 
the eligible subjects will be enrolled.  
Written informed consent should be obtained before starting any examination and 
observations to be performed at Visit 1.  After informed consent is obtained, patients who 
are under treatment with mirogabalin, pregabalin, and gabapentin will undergo a washout 
period of 28 days or more (see Section 5.6.1).  Enrollment will be limited to subjects who 
meet the inclusion/exclusion criteria described in Section 4.1 and Section 4.2.  After the 
completion or early termination of administration, subjects will be monitored for an 
additional follow-up observation period of 1 week.   
 
3.1.2.1. 
Patients for Central Neuropathic Pain After Spinal Cord Injury 
Patients with CLcr ≥ 60 mL/min at Visit 6 of the double-blind phase, will start with 5 mg 
BID of mirogabalin at first 2 weeks, followed by 10 mg BID at second 2 weeks as 
titration phase.  From the fifth week, if there are no problems in safety, the patients will 
escalate the dose to 15 mg BID.  For the following visits, the dosage may be changed to 
either 10 mg BID or 15 mg BID depending on safety findings at the time of each visit.  
At taper period (last week of treatment period), if the dosage is 10 mg BID just before 


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tapering, it will be changed to 10 mg QD, and if the dosage is 15 mg BID just before 
tapering, it will be changed to 15 mg QD. 
Patients with CLcr 30 to < 60 mL/min at Visit 6 of the double-blind phase, will start with 
2.5 mg BID of mirogabalin at first 2 weeks, followed by 5 mg BID at second 2 weeks as 
titration phase.  From the fifth week, if there are no problems in safety, the patients will 
escalate the dose to 7.5 mg BID.  For the following visits, the dosage may be changed to 
either 5 mg BID or 7.5 mg BID depending on safety findings at the time of each visit.  At 
taper period (last week of treatment period), if the dosage is 5 mg BID just before 
tapering, it will be changed to 5 mg QD, and if the dosage is 7.5 mg BID just before 
tapering, it will be changed to 7.5 mg QD. 
Further details of the study procedures are provided in the Schedule of Events 
(Table 17.1) and Study Procedures (Section 6).  
3.1.2.2. 
Patients for Central Post Stroke Pain and Central Neuropathic Pain in 
Parkinson’s Disease 
Patients with CLcr ≥ 60 mL/min at Visit 1, will start with 5 mg BID of mirogabalin at 
first 2 weeks, followed by 10 mg BID at second 2 weeks as titration phase.  From the 
fifth week, if there are no problems in safety, the patients will escalate the dose to 15 mg 
BID.  For the following visits, the dosage may be changed to either 10 mg BID or 15 mg 
BID depending on safety findings at the time of each visit.  At taper period (last week of 
treatment period), if the dosage is 10 mg BID just before tapering, it will be changed to 
10 mg QD, and if the dosage is 15 mg BID just before tapering, it will be changed to 
15 mg QD. 
Patients with CLcr 30 to < 60 mL/min at Visit 1, will start with 2.5 mg BID of 
mirogabalin at first 2 weeks, followed by 5 mg BID at second 2 weeks as titration phase.  
From the fifth week, if there are no problems in safety, the patients will escalate the dose 
to 7.5 mg BID.  For the following visits, the dosage may be changed to either 5 mg BID 
or 7.5 mg BID depending on safety findings at the time of each visit.  At taper period 
(last week of treatment period), if the dosage is 5 mg BID just before tapering, it will be 
changed to 5 mg QD, and if the dosage is 7.5 mg BID just before tapering, it will be 
changed to 7.5 mg QD. 
Further details of the study procedures are provided in the Schedule of Events 
(Table 17.2) and Study Procedures (Section 6).   
3.2. 
Discussion of Study Design 
3.2.1. 
Dosage of Mirogabalin 
As mentioned in Section 1.2.3 of double-blind phase study, administration of flexible 
dosing of mirogabalin 10 mg BID and 15 mg BID for up to 52 weeks was well tolerated, 
and long-term efficacy was demonstrated in the studies with both DPNP and PHN.  In 
addition, for the dosage and administration of mirogabalin for patients with peripheral 
neuropathic pain (CLcr ≥ 60 mL/min), 10 mg BID is defined as the lowest effective dose, 
and 15 mg BID is defined as the recommended effective dose in the Japanese package 


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insert.  In order to evaluate the safety and efficacy in the practical clinical dosage in this 
study, the maintenance dose of mirogabalin is selected as 10 mg BID or 15 mg BID 
which will be used in a clinical setting for the patients with peripheral neuropathic pain, 
the dose can be adjusted between these two doses in this study.   For subject safety, 5 mg 
BID, which is lower than 10 mg BID or 15 mg BID, was selected as an initial dose of 
mirogabalin and will be administered for first 2 weeks of the study treatment, and taper 
period was set for the last week of the study treatment.  Dosage of patients with CLcr 30 
to < 60 mL/min was selected to be half of the dosage above, according to the result of 
Phase 3 study for DPNP and PHN patients with renal impairment.   
3.2.2. 
Duration of Study Treatment 
In accordance to International Council for Harmonisation (ICH)-E1 guideline, 
mirogabalin will be administered for 52 weeks to evaluate the long-term safety.   
3.2.3. 
Control Treatment 
Not Applicable.   
3.2.4. 
Study Endpoints 
The safety endpoints were selected to evaluate the long-term safety of mirogabalin.  
TEAEs, body weight, edema, clinical laboratory tests, ECGs, and vital sign are 
commonly evaluated for safety assessment in clinical studies.  Assessments by HADS 
and C-SSRS were selected to evaluate the risk of anxiety, depression, or suicidal 
tendency.  In addition, the efficacy of mirogabalin will be also evaluated with SF-MPQ, 
which can evaluate affective or sensory score, as well as pain intensity.   
 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included in the study.  
4.1.1. 
Inclusion Criteria for Patients with Central Neuropathic Pain After 
Spinal Cord Injury 
1. Completed 14 weeks of administration in the double-blind study   
2. Able to give informed consent for study participation, understand procedures of 
this study, and complete patient-reported questionnaires adequately.   
Rationale 
1.: This criteria was selected to assess appropriately the long-term safety of the 
investigational product. 
2.: The study will be conducted in accordance with Good Clinical Practice (GCP). 
4.1.2. 
Inclusion Criteria for Patients With Central Post Stroke Pain 
3. Age ≥ 20 years at informed consent 
4. Able to give informed consent for the study participation, understand procedures 
of this study, and complete patient-reported questionnaires adequately 
5. ≥ 6 months after stroke at screening 
6. Damage of the somatosensory pathways due to stroke, which is confirmed by CT 
or MRI inspection 
7. Pain region neurologically matched with damaged somatosensory pathways due 
to stroke 
8. Stable CPSP at least for 3 months prior to screening 
9. At screening and enrollment, a pain scale of ≥ 40 mm on VAS of SF-MPQ 
Rationale 
3.: Phase 1, Phase 2 and Phase 3 studies in elderly subjects showed no notable 
differences from the results obtained in non-elderly subjects with regard to safety, 
tolerability, and pharmacokinetics.  Thus, no upper limit was placed on age in this 
study.  Because the safety of this drug have not been established in children, and 
in order to obtain appropriate informed consent from the subjects themselves, the 
lower age limit was set at 20 years of age.   
4.: The study will be conducted in accordance with GCP. 
5., 6., 7., 8.: The study will investigate CPSP.   
9.: In order to assess the efficacy of the investigational product appropriately, the 
study will be limited to subjects who experience pain of moderate or greater 
intensity. 


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4.1.3. 
Inclusion Criteria for Patients With Central Neuropathic Pain in 
Parkinson’s Disease 
10. Age ≥ 20 years at informed consent 
11. Able to give informed consent for the study participation, understand procedures 
of this study, and complete patient-reported questionnaires adequately 
12. ≥ 6 months after being diagnosed as Parkinson’s disease (Clinically established 
Parkinson’s Disease or Clinically probable Parkinson’s Disease according to 
diagnostic criteria of Movement Disorder Society for Parkinson’s disease)1 at 
screening 
13. Correspond to CNeP in clinical classification of painful or unpleasant sensations 
in Parkinson’s disease by the Ford classification2  
14. Stable CNePPD at least for 3 months prior to screening 
15. At screening and enrollment, a pain scale of ≥ 40 mm on VAS of SF-MPQ 
Rationale 
10.: Phase 1, Phase 2 and Phase 3 studies in elderly subjects showed no notable 
differences from the results obtained in non-elderly subjects with regard to safety, 
tolerability, and pharmacokinetics.  Thus, no upper limit was placed on age in this 
study.  Because the safety of this drug have not been established in children, and 
in order to obtain appropriate informed consent from the subjects themselves, the 
lower age limit was set at 20 years of age.   
11.: The study will be conducted in accordance with GCP. 
12., 13., 14.: Painful or unpleasant sensations in Parkinson’s disease are usually 
classified into musculoskeletal pain, radicular/neuropathic pain, dystonic pain, 
CNeP, pain related to akathisia or somatic pain.  The present study will 
investigate only sensations diagnosed as CNeP.   
15: In order to assess the efficacy of the investigational product appropriately, the 
study will be limited to subjects who experience pain of moderate or greater 
intensity. 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participation in the 
study. 
4.2.1. 
Exclusion Criteria for Patients With Central Neuropathic Pain After 
Spinal Cord Injury 
1. Drug compliance < 80% in the double-blind study   
2. CLcr (using the Cockcroft-Gault equation) < 30 mL/min at Visit 6 of the double-
blind study   
3. Experienced critical safety issue in the double-blind study   


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4. Pregnancy, potential pregnancy, breast feeding, or subject unwilling to take 
reliable contraceptive measures during the study or for 4 weeks after study 
completion   
5. The subject is considered inappropriate for the study at the discretion of the 
investigator or sub-investigator   
Rationale 
1., 2., 3., 4., 5.: These criteria were selected so that efficacy and safety could be 
appropriately assessed in subjects.   
4.2.2. 
Exclusion Criteria for Patients With Central Post Stroke Pain 
6. ≥ Grade 5 of modiﬁed Rankin Scale at screening 
7. Bleeding in any parts of the body at screening 
8. Pain after stroke other than CNeP at screening or enrollment, that may confound 
the assessment of CPSP 
9. Neurologic disorders at screening or enrollment, unrelated to CPSP, that may 
confound the assessment of CPSP 
10. Major psychiatric disorders within 1 year prior to screening 
11. ≤ 23 points on Mini-Mental State Examination at screening 
12. Previous administration of pregabalin ≥ 300 mg/day for subjects with CLcr 
≥ 60 mL/min or pregabalin ≥ 150 mg/day for subjects with CLcr 30 to 
< 60 mL/min for at least 4 weeks, declared lack of effect 
13. Previous Administration of gabapentin ≥ 1200 mg/day for subjects with CLcr 
≥ 60 mL/min or gabapentin ≥ 600 mg/day for subjects with CLcr 30 to < 60, for at 
least 4 weeks, declared lack of effect 
14. Use of mirogabalin, pregabalin, or gabapentin within 28 days prior to screening 
15. Use of strong opioids for analgesic of CPSP within 3 months prior to screening 
16. CLcr (using the Cockcroft-Gault equation) < 30 mL/min at screening 
17. Malignancy other than basal cell carcinoma within the past 2 years prior to 
screening 
18. Clinically significant unstable endocrine (eg, diabetes mellitus), neurologic, 
ophthalmologic, hepatobiliary, respiratory, hematologic illness, or cardiovascular 
disease (eg, uncontrolled cardiac arrhythmia, or myocardial infarction) at 
screening or enrollment 
19. Clinically significant findings on ECG at screening 
20. History of pernicious anemia, untreated hypothyroidism, or human 
immunodeficiency virus infection 


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21. Pregnancy, potential pregnancy, breast feeding, or subject unwilling to take 
reliable contraceptive measures during the study or for 4 weeks after study 
completion 
22. Known hypersensitivity to mirogabalin, pregabalin or gabapentin 
23. Participation in another clinical study, either currently or within 30 days prior to 
providing of informed consent 
24. Experience of participating mirogabalin clinical study and receiving 
investigational product 
25. Abuse of illicit drugs or alcohol history 
26. Response of “yes” to any of the questions on the C-SSRS at screening or 
enrollment in relation to events occurring within the past 12 months 
27. At screening, clinical laboratory values exceeding limits listed in Table 4.1 . 
28. The subject who is considered inappropriate for the study at the discretion of the 
investigator or sub-investigator 
Rationale 
6., 7., 8., 9., 10.: These criteria were selected so that efficacy and safety could be 
appropriately assessed in subjects.   
11., 12., 13., 15.: These criteria were selected out of consideration for efficacy 
assessment in subjects.   
14., 16., 17., 18., 19., 20., 21., 22., 23., 24., 25. 26. 27. 28.: These criteria were 
selected out of consideration for the safety of subjects. 
4.2.3. 
Exclusion Criteria for Patients With Central Neuropathic Pain in 
Parkinson’s Disease 
29. Stage V of the Hoehn and Yahr scale at screening 
30. Other severe pain at screening or enrollment, unrelated to pain in Parkinson’s 
disease, that may confound the assessment of pain in Parkinson’s disease 
31. Neurologic disorders at screening or enrollment, unrelated to pain in Parkinson’s 
disease, that may confound the assessment of pain in Parkinson’s disease 
32. Major psychiatric disorders within 1 year prior to screening 
33. ≤ 23 points on Mini-Mental State Examination at screening 
34. Previous administration of pregabalin ≥ 300 mg/day for subjects with CLcr 
≥ 60 mL/min or pregabalin ≥ 150 mg/day for subjects with CLcr 30 to 
< 60 mL/min for at least 4 weeks, declared lack of effect 
35. Previous Administration of gabapentin ≥ 1200 mg/day for subjects with CLcr 
≥ 60 mL/min or gabapentin ≥ 600 mg/day for subjects with CLcr 30 to < 60, for at 
least 4 weeks, declared lack of effect 


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36. Use of mirogabalin, pregabalin, or gabapentin within 28 days prior to screening 
37. Use of strong opioids for analgesic of CNePPD within 3 months prior to 
screening 
38. CLcr (using the Cockcroft-Gault equation) < 30 mL/min at screening 
39. Malignancy other than basal cell carcinoma within the past 2 years prior to 
screening 
40. Clinically significant unstable endocrine (eg, diabetes mellitus), neurologic, 
ophthalmologic, hepatobiliary, respiratory, hematologic illness, or cardiovascular 
disease (eg, uncontrolled cardiac arrhythmia, or myocardial infarction) at 
screening or enrollment 
41. Clinically significant findings on ECG at screening 
42. History of pernicious anemia, untreated hypothyroidism, or human 
immunodeficiency virus infection 
43. Pregnancy, potential pregnancy, breast feeding, or subject unwilling to take 
reliable contraceptive measures during the study or for 4 weeks after study 
completion 
44. Known hypersensitivity to mirogabalin, pregabalin or gabapentin 
45. Participation in another clinical study, either currently or within 30 days prior to 
providing of informed consent 
46. Experience of participating mirogabalin clinical study and receiving 
investigational product 
47. Abuse of illicit drugs or alcohol history 
48. Response of “yes” to any of the questions on the C-SSRS at screening or 
enrollment in relation to events occurring within the past 12 months 
49. At screening, clinical laboratory values exceeding limits listed in Table 4.1 . 
50. The subject who is considered inappropriate for the study at the discretion of the 
investigator or sub-investigator 
Rationale 
29., 30., 31., 32., 33.: These criteria were selected so that efficacy and safety could 
be appropriately assessed in subjects.   
34., 35., 36., 38.: These criteria were selected out of consideration for efficacy 
assessment in subjects.   
37., 39., 40., 41., 42., 43., 44., 45., 46., 47., 48., 49., 50.: These criteria were selected 
out of consideration for the safety of subjects. 


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Table 4.1: 
Hematology/Blood Chemistry Limits 
Hematology 
Platelet Count 
< 100,000/mm3 
Blood Chemistry 
AST (GOT) 
> 2.0 × ULN 
ALT (GPT) 
> 2.0 × ULN 
ALP 
> 1.5 × ULN 
T-Bil 
> 1.5a × ULN 
a: If a subject has T-Bil 1.5 > ULN: unconjugated and conjugated bilirubin fractions should be analyzed 
and only subjects documented to have Gilbert’s syndrome may be enrolled.   
 


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5. 
STUDY TREATMENT(S) 
5.1. 
Assigning Subjects to Treatments and Blinding 
5.1.1. 
Treatment Group(s)/Sequences 
The duration of investigational product administration will be 52 weeks, consisting of a 
titration period (4 weeks), a maintenance dose period (47 weeks) and taper period (1 
week).  The schedule of events is provided in Section 17.1.  Additional information 
regarding study procedures is provided in Section 6.   
5.1.1.1. 
Treatment Group(s)/Sequences for Patients With CNePSCI 
After the treatment period of the double-blind phase study, the eligible patients will be 
enrolled.   
Patients with CLcr ≥ 60 mL/min at Visit 6 of double-blind phase, will start with 5 mg 
BID of mirogabalin at first 2 weeks.  From the third week, the investigational product is 
administered at a dosage of 10 mg BID.  From the fifth week, if there are no problems in 
safety, the patients will escalate the dose to 15 mg BID.  For the following visits, the 
dosage may be changed to either 10 mg BID or 15 mg BID depending on safety findings 
at the time of each visit.  At taper period (last week of treatment period), if the dosage is 
10 mg BID just before tapering, it will be changed to 10 mg QD, and if the dosage is 
15 mg BID just before tapering, it will be changed to 15 mg QD. 
Patients with CLcr 30 to < 60 mL at Visit 6 of double-blind phase, will start with 2.5 mg 
BID of mirogabalin at first 2 weeks.  From the third week, the investigational product is 
administered at a dosage of 5 mg BID.  From the fifth week, if there are no problems in 
safety, the patients will escalate the dose to 7.5 mg BID.  For the following visits, the 
dosage may be changed to either 5 mg BID or 7.5 mg BID depending on safety findings 
at the time of each visit.  At taper period (last week of treatment period), if the dosage is 
5 mg BID just before tapering, it will be changed to 5 mg QD, and if the dosage is 7.5 mg 
BID just before tapering, it will be changed to 7.5 mg QD. 
5.1.1.2. 
Treatment Group(s)/Sequences for Patients With Central Post Stroke 
pain and Central Neuropathic Pain in Parkinson’s Disease 
After completion of the observation period, the eligible patients will be enrolled.   
Patients with CLcr ≥ 60 mL/min at Visit 1, will start with 5 mg BID of mirogabalin at 
first 2 weeks.  From the third week, the investigational product is administered at a 
dosage of 10 mg BID.  From the fifth week, if there are no problems in safety, the 
patients will escalate the dose to 15 mg BID.  For the following visits, the dosage may be 
changed to either 10 mg BID or 15 mg BID depending on safety findings at the time of 
each visit.  At taper period (last week of treatment period), if the dosage is 10 mg BID 
just before tapering, it will be changed to 10 mg QD, and if the dosage is 15 mg BID just 
before tapering, it will be changed to 15 mg QD. 
Patients with CLcr 30 to < 60 mL/min at Visit 1, will start with 2.5 mg BID of 
mirogabalin at first 2 weeks.  From the third week, the investigational product is 


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administered at a dosage of 5 mg BID.  From the fifth week, if there are no problems in 
safety, the patients will escalate the dose to 7.5 mg BID.  For the following visits, the 
dosage may be changed to either 5 mg BID or 7.5 mg BID depending on safety findings 
at the time of each visit.  At taper period (last week of treatment period), if the dosage is 
5 mg BID just before tapering, it will be changed to 5 mg QD, and if the dosage is 7.5 mg 
BID just before tapering, it will be changed to 7.5 mg QD. 
5.1.2. 
Method of Treatment Allocation 
5.1.2.1. 
Enrollment 
Subjects are to be enrolled in this study using the Interactive Response Technology (IRT) 
in accordance with the procedures specified below.  IRT will assign each consenting 
subject a unique subject identification code, and that identification code will be recorded 
in a subject identification log.  For patients with CNePSCI, a unique identification code 
assigned at double-blind phase are used.   
5.1.2.2. 
Procedures for Subject Enrollment 
The investigator or sub-investigator will perform a mandatory interview to assess the 
eligibility of subjects for the study, after obtaining each subject’s written informed 
consent, and will make necessary entries in the IRT.   
5.1.3. 
Blinding 
This is an open-label study.   
5.1.4. 
Emergency Unblinding Procedure 
No specify the emergency unblinding procedure because this study is an open-label.   
5.2. 
Study Drug(s) 
5.2.1. 
Description 
The investigator must ensure that the investigational product will be used only in 
accordance with the protocol. 
The investigational products for this study are:   
• Mirogabalin 2.5 mg, 5 mg, 7.5 mg, 10 mg, and 15 mg tablets 
5.2.2. 
Labeling and Packaging 
Mirogabalin will be packaged in aluminum blister packs.  Packages for treatment period 
will be prepared for the combinations shown in Table 5.1, Table 5.2, and Table 5.3.  The 
packaging will be clearly labeled "For Clinical Study Use Only," and will show the 
display name of the investigational product, the investigational-product-manufacturing 
code, the study drug identifier, the name and address of the sponsor, and the expired date 
of the investigational product in accordance with local regulations.  Each wallet card of 


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the investigational product will contain sufficient extra doses to cover the permitted visit 
window for each subject.   
Table 5.1: 
Drug Combinations During the Treatment Period (Week LT_1-2) 
Treatment group 
Investigational product combination 
Morning 
Bedtime 
Mirogabalin  group 
CLcr ≥ 60 mL/min 
5 
5 
Mirogabalin  group 
CLcr 30 to < 60 mL/min 
2.5 
2.5 
5: mirogabalin 5 mg tablet 
2.5: mirogabalin 2.5 mg tablet 
 
Table 5.2: 
Drug Combinations During the Treatment Period (Week LT_3-4) 
Treatment group 
Investigational product combination 
Morning 
Bedtime 
Mirogabalin  group 
CLcr ≥ 60 mL/min 
10 
10 
Mirogabalin  group 
CLcr 30 to < 60 mL/min 
5 
5 
10: mirogabalin 10 mg tablet 
5: mirogabalin 5 mg tablet 
 
Table 5.3: 
Drug Combinations During the Treatment Period (Week LT_5 to 
Week 52 ) 
Treatment group 
Investigational product combination 
Morning 
Bedtime 
Mirogabalin  group 
CLcr ≥ 60 mL/min 
10 or 15 
10 or 15 
Mirogabalin  group 
CLcr 30 to < 60 mL/min 
5 or 7.5 
5 or 7.5 
10: mirogabalin 10 mg tablet, 15: mirogabalin 15 mg tablet 
5: mirogabalin 5 mg tablet, 7.5: mirogabalin 7.5 mg tablet 
Bedtime only at the last week of treatment period 
5.2.3. 
Preparation 
Preparation of the study drug is detailed in the Pharmacy Manual.   


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5.2.4. 
Administration 
During the treatment period, basically 1 tablet of either mirogabalin will be administered 
orally BID (in the morning and at bedtime), and then 1 tablet of mirogabalin will be 
administered orally QD (at bedtime) at the last week of treatment period as shown in 
Table 5.4.   
 


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Table 5.4: 
Method of Administration During the Treatment Period 
Group 
LT_Day 1 
LT_Day 2 to 14 
LT_Day 15 
LT_Day 16 to 28 
LT_Day 29 
LT_Day 30 to 357 LT_Day 358 to 364 
Mornin
g 
Bedtime Mornin
g 
Bedtime Mornin
g 
Bedtime Morning Bedtime Morning Bedtime Morning Bedtime Morning Bedtime 
Mirogabalin 
CLcr 
≥ 60 mL/min 
- 
5 
5 
5 
5 
10 
10 
10 
10 
10 or 15 10 or 15 10 or 15 
- 
10 or 15 
Mirogabalin 
CLcr 30 to 
< 60 mL/min 
- 
2.5 
2.5 
2.5 
2.5 
5 
5 
5 
5 
5 or 7.5 5 or 7.5 5 or 7.5 
- 
5 or 7.5 
 


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5.2.5. 
Storage 
Up to 25°C; do not freeze (excursion permitted up to 30°C).   
Drug supplies must be stored appropriately in a locked cabinet in a room with limited and 
controlled access under the recommended storage conditions.   
Note: If storage conditions go outside of the recommended storage conditions, the site 
must not dispense the affected supplies (affected supplies should be placed in quarantine) 
and must contact Daiichi Sankyo Clinical Supply Operations personnel or designee to 
determine if the affected supplies can be used.   
5.2.6. 
Drug Accountability 
When a drug shipment is received, the Investigator or designee will check the amount 
and condition of the drug, check for appropriate local language in the label, drug 
expiration date, and sign the Receipt of Shipment Form provided.   
In addition, the Investigator or designee shall contact Sponsor as soon as possible if there 
is a problem with the shipment.   
A Drug Accountability Record will be provided for the study drug.  The record must be 
kept current and should contain the dates and quantities of study drug received, subject’s 
(identification number or supply number as applicable), for whom the study drug was 
dispensed, the date and quantity of study drug dispensed and remaining, as well as the 
initials of the dispenser.   
At the end of the study, or as directed, all mirogabalin with all discrepancy resolved, 
including unused, partially used, or empty containers, will be returned to a designee as 
instructed by Sponsor.  Study drug will be returned only after the study monitor has 
completed a final inventory to verify the quantity to be returned.  The return of study 
drug must be documented and the documentation included in the shipment.  At the end of 
the study, a final study drug reconciliation statement must be completed by the 
Investigator or designee and provided to the Sponsor.   
5.3. 
Control Treatment 
Not Applicable.   
5.4. 
Dose Interruptions and Reductions 
Dose interruption will be occurred only if investigators or sub-investigators decide 
administration should be interrupted due to safety concerns.  During a maintenance dose 
period, dose will be reduced from 15 mg BID to 10 mg BID or from 7.5 mg BID to 5 mg 
BID in patients with CLcr ≥ 60 mL/min or CLcr 30 to < 60 mL/min respectively, only if 
drug related adverse events occur and investigators or sub-investigators judge 
continuation of 15 mg BID or 7.5 mg BID dosing is difficult due to the adverse events. 


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5.5. 
Method of Assessing Treatment Compliance 
All subjects in this study will commence therapy as outpatients or inpatients, and the 
investigational product will be self-administered orally.  Subjects will be sent home with 
the investigational product.  Each subject is to return the investigational product at every 
visit.  Compliance will be assessed by returned tablet count.  Administration of the 
investigational product will be recorded in the electronic case report form (eCRF)/Drug 
Accountability Record (number of tablets taken) at all treatment visits.  If no tablets are 
returned, the subject will be asked whether any were discarded or thrown away, or if all 
of the tablets were taken orally.   
5.6. 
Concomitant Medications 
Patients with CNePSCI 
Any concomitant medications and any concomitant treatments used by a subject during 
the period from his/her Visit 7 until his/her post-treatment follow-up (Visit 22) will be 
documented in the CRF.  The route of administration, the total daily dose, the duration of 
use, the indication for use, and the classification of therapies will also be documented in 
the CRF.   
Patients with CPSP and CNePPD 
Any concomitant medications and any concomitant treatments used by a subject during 
the period from the time of obtaining informed consent until his/her post-treatment 
follow-up (Visit 22) will be documented in the CRF.  The route of administration, the 
total daily dose, the duration of use, the indication for use, and the classification of 
therapies will also be documented in the CRF. 
5.6.1. 
Prohibited Concomitant Medications 
5.6.1.1. 
Prohibited Concomitant Medication for Patients With Central 
Neuropathic Pain After Spinal Cord Injury 
The following drugs are prohibited for concomitant use from the titration period (Visit 7) 
through the post-treatment follow-up (Visit 22).   
1. Mirogabalin, Pregabalin, and Gabapentin 
2. Other investigational products 
5.6.1.2. 
Prohibited Concomitant Medication for Patients With Central Post 
Stroke Pain and Central Neuropathic Pain in Parkinson’s Disease 
The following drugs are prohibited for concomitant use from the screening (Visit 1) 
through the post-treatment follow-up (Visit 22).  After informed consent is obtained, 
subjects who are under treatment with Mirogabalin, Pregabalin, and Gabapentin will 
undergo for 28 days as a minimum washout period.  Visit 1 will occur after completion of 
this washout period.   
1. Mirogabalin, Pregabalin, and Gabapentin 


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2. Other investigational products 
5.6.2. 
Restricted Concomitant Medications 
Not Applicable.   
5.6.3. 
Rescue Medications 
Not Applicable.  
5.6.4. 
Prohibited Concomitant Therapies 
Not Applicable.   
5.6.5. 
Restricted Concomitant Therapies 
Not Applicable.   
5.6.6. 
Other 
Subjects should be instructed to avoid excessive consumption of alcohol during the 
treatment period as combination with investigational drugs and alcohol may enhance 
impaired attention and impaired equilibrium function.   
5.7. 
Subject Withdrawal/Discontinuation 
5.7.1. 
Withdrawal Criteria 
If a subject meets the following withdrawal criteria, that subject should be withdrawn 
from the study.   
• Difficulty of continuing the study due to adverse event (AE) 
• AE related to suicide (if there are any “yes” responses to any of the questions 
in the C-SSRS) 
• Subjects with any of the following elevations in clinical laboratory values 
− Increase in alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) ≥ 5 × upper limit of normal (ULN) 
− ALT or AST rises to ≥ 3 × ULN and persists for more than 2 weeks 
− Concurrent increases in ALT or AST ≥ 3 × ULN and total bilirubin 
(T-Bil) ≥ 2 × ULN 
− ALT or AST ≥ 3 × ULN associated with a clinical presentation suggestive 
of liver injury (ie, including the appearance of fatigue, nausea, vomiting, 
jaundice, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia) 
• Withdrawal by subject (ie, withdrawal of consent) 


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• Major protocol deviation (difficulty of continuing the study in terms of 
ensuring safety) 
5.7.2. 
Reasons for Withdrawal 
If a subject is withdrawn from the study, the date and the reason for withdrawal must be 
recorded on the eCRF using the following options.  If the subject receiving at least one 
study medication and withdrew/was withdrawn from the study treatment, the reason for 
the withdrawal of study treatment must be recorded on the eCRF. 
For subjects withdrawn prior to enrollment but after signing informed consent   
• Screen Failure 
• Withdrawal by Subject (eg, AE, lack of efficacy [LOE], Other) 
• Physician Decision 
• Other 
For subjects withdrawn after enrollment but before completing the study as per protocol   
• AE 
• Death 
• LOE 
• Lost to Follow-up 
• Protocol violation 
• Pregnancy 
• Study Terminated by Sponsor 
• Withdrawal by Subject (eg, AE, LOE, Other)  
• Other 
If a subject is withdrawn due to need for a prohibited medication, the reason may be 
recorded as LOE, as appropriate.  Reasons recorded under “Protocol violation” may 
include failure to comply with protocol requirements or study procedures.   
For all subjects who withdraw from the study, the investigator must complete and report 
pertinent observations as thoroughly as possible up to the date of withdrawal, including 
the date of last treatment and the reason for withdrawal.   
If a subject is withdrawn due to an AE, the investigator should follow the subject until the 
AE has resolved or stabilized.   
All subjects who are withdrawn from the study should complete protocol-specified 
withdrawal procedures (see Section 5.7.3 and Section 6.6).   


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5.7.3. 
Withdrawal Procedures 
If the subject withdraws or is withdrawn from the study before the completion of 
investigational product administration, appropriate measures will be implemented.  In 
addition, to the extent that the subject’s cooperation can be obtained, all observations and 
tests scheduled for the End of Treatment/Early Termination Visit (Visit 21) will be 
conducted, assessments will be made at that time point, all observations and tests 
scheduled for the Post-treatment Follow-up Visit (Visit 22) will be conducted, and 
assessments will be made after 5 to 14 days after the last dose.  This will be done for all 
subjects who were treated with even one dose of the investigational product.  If the 
withdrawal was due to AEs, the outcome for that subject will be recorded to the extent 
possible in the case report form (CRF).  If the withdrawal was due to suicidal behavior 
and/or suicidal ideation, appropriate measures will be implemented such as referring the 
subject to a specialist.  To the extent that the subject’s cooperation can be obtained, taper 
will be conducted before withdrawal of study treatment as necessary: After Visit 8, the 
dosage of the study drug taking until just before the withdrawal will be changed from 
twice a daily to once a daily (see Section 5.1.1). 
5.7.4. 
Subject Replacement 
Subjects removed from the study for any reason will not be replaced.   
5.7.5. 
Subject Re-screening Procedures 
Patients with CNePSCI 
Re-screening is not permitted for any subjects.   
Patients with CPSP and CNePPD 
Re-screening is allowed to only subjects who violate Exclusion Criteria 14, 16, 23, 27, 
36, 38, 45 and 49.  The rescreening is permitted only once.   
 


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6. 
STUDY PROCEDURES 
A study visit schedule in tabular format is provided in Table 17.1:  and Table 17.2.   
In principle, all of the activities and/or examinations will be recorded with the date in the 
CRF.   
Missing visits are strongly discouraged in this study.  It is expected that investigator site 
staff strongly explain the visit schedule with the potential subjects.  If it is felt that a 
subject is not able to adhere to the visit schedule, then that subjects should not be enrolled 
into the study.  Any missed visit that occurs during the open-label treatment period must 
be rescheduled within 1 week. 
6.1. 
Screening (Visit 1) 
This screening visit is applied to only patients with CPSP and CNePPD.   
Written informed consent should be obtained before starting any examination and 
observations to be performed at Visit 1.  After informed consent is obtained, patients who 
are under treatment with mirogabalin, pregabalin, and gabapentin will undergo a washout 
period of 28 days or more (Section 5.6.1).  The following activities and/or examinations 
will be performed at screening.   
• Evaluate inclusion criteria and exclusion criteria 
• Record demographics  
CPSP; birth date, sex, disease duration, duration of CNeP, reason of stroke 
(bleeding or infarction), presence or absence of paralysis, site of stroke (basal 
ganglia, thalamus, putamen, brainstem, or other), medical/surgical history 
related to exclusion criteria 
CNePPD; birth date, sex, disease duration, duration of CNeP, presence or 
absence of wearing-off, presence or absence of DOPA-induced dyskinesia, 
presence or absence of dystonia, medical/surgical history related to exclusion 
criteria 
• Complete SF-MPQ 
• Complete HADS 
• Measure body height and weight 
• Perform medical interview 
• Perform evaluation of edema 
• Measure blood pressure and pulse rate 
• Perform 12-lead ECG 
• Collect blood and urine samples for laboratory tests 
• Evaluate SAEs 
• Complete C-SSRS 


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• Perform pregnancy test (only in women of childbearing potential) 
• Evaluate prior drug treatment, concomitant drugs, and concomitant therapy 
6.2. 
Visit 7 
At the beginning of the titration period, the following activities and/or examinations will 
be performed and 5 mg BID of new investigational product (patients with CLcr 
≥ 60 mL/min) or 2.5 mg BID of new investigational product (patients with CLcr 30 to 
< 60 mL/min) will be issued to the patient.   
If the same examinations are already performed at Visit 7 of the double-blind study in 
patients with CNePSCI, those data will be used. 
• Obtain written informed consent (only for patients with CNePSCI) 
• Evaluate inclusion criteria and exclusion criteria 
• Complete SF-MPQ 
• Complete HADS 
• Perform medical interview 
• Measure body weight 
• Perform evaluation of edema (only for patients with CNePSCI) 
• Measure blood pressure and pulse rate 
• Perform 12-lead ECG (only for patients with CNePSCI) 
• Collect blood and urine samples for laboratory tests 
• Evaluate AEs 
• Complete C-SSRS 
• Perform pregnancy test (only in women of childbearing potential with 
CNePSCI) 
• Evaluate concomitant drugs, and concomitant therapy 
• Issue the investigational product 
6.3. 
Visit 8 
After the first 2 weeks of the titration period (starting at Visit 7), the subject will come to 
the study site (Visit 8).  At Visit 8, the following activities and/or examinations will be 
performed and 10 mg BID of new investigational product (patients with CLcr 
≥ 60 mL/min) or 5 mg BID of new investigational product (patients with CLcr 30 to 
< 60 mL/min) will be issued to the patient after the investigator or sub-investigator 
confirms tolerability and reviews continuation of the treatment. 
• Complete SF-MPQ 


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• Complete HADS 
• Perform medical interview 
• Measure body weight 
• Measure blood pressure and pulse rate 
• Perform evaluation of edema 
• Collect blood and urine samples for laboratory tests 
• Evaluate AEs 
• Complete C-SSRS 
• Record and evaluate concomitant drugs and concomitant therapy 
• Collect unused investigational product, and record the date of the first dose 
taken and review drug-taking compliance 
• Issue the investigational product 
6.4. 
Visit 9 
Two weeks after Visit 8, the subject will come to the study site (Visit 9).  The following 
activities and/or examinations will be performed at Visit 9.  At this point, “10 mg BID or 
15 mg BID” of new investigational product (patients with CLcr ≥ 60 mL/min) or “5 mg 
BID or 7.5 mg BID” of new investigational product (patients with CLcr 30 to 
< 60 mL/min) will be issued to the patient after the investigator or sub-investigator 
confirms tolerability and reviews continuation of the treatment. 
• Complete SF-MPQ 
• Complete HADS 
• Perform medical interview 
• Measure body weight 
• Measure blood pressure and pulse rate 
• Perform evaluation of edema 
• Collect blood and urine samples for laboratory tests 
• Evaluate AEs 
• Complete C-SSRS 
• Record and evaluate concomitant drugs and concomitant therapy 
• Collect unused investigational product, and record and review drug-taking 
compliance 
• Issue the investigational product 


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6.5. 
Visit 10 to Visit 20 
After Visit 9, the subject will come to the study site every 4 weeks (Visit 10 to Visit 20).  
The following activities and/or examinations will be performed at each visit, and “10 mg 
BID or 15 mg BID” of new investigational product (patients with CLcr ≥ 60 mL/min) or 
“5 mg BID or 7.5 mg BID” of new investigational product (patients with CLcr 30 to 
< 60 mL/min) will be issued to the patient after the investigator or sub-investigator 
confirms tolerability and reviews continuation of the treatment.  Taper will be conducted 
at the last week from Visit 20 to Visit 21 (see Section 5.1.1).   
• Complete SF-MPQ 
• Complete HADS 
• Perform medical interview 
• Measure body weight 
• Measure blood pressure and pulse rate 
• Perform evaluation of edema 
• Collect blood and urine samples for laboratory tests 
• Evaluate AEs 
• Complete C-SSRS 
• Record and evaluate concomitant drugs and concomitant therapy 
• Collect unused investigational product, and record and review drug-taking 
compliance 
• Issue the investigational product 
6.6. 
End of Treatment/Early Termination (Visit 21) 
The treatment period will be completed after 52 weeks of administration (Visit 21).  The 
following activities and/or examinations will be performed at the end of treatment/early 
termination. 
• Complete SF-MPQ 
• Complete HADS 
• Perform medical interview 
• Measure body weight 
• Measure blood pressure and pulse rate 
• Perform 12-lead ECG 
• Perform evaluation of edema 
• Collect blood and urine samples for laboratory tests 


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• Perform pregnancy test (only in women of childbearing potential) 
• Evaluate AEs 
• Complete C-SSRS 
• Record and evaluate concomitant drugs and concomitant therapy 
• Collect unused investigational product, record the date of the last dose taken 
and review drug-taking compliance 
6.7. 
Post-treatment Follow-up (Visit 22, 7 Days After the 
Completion of Administration) 
Follow-up observations will be conducted 7 days after the completion of administration 
(Visit 22).  The following activities and/or examinations will be performed at follow-up. 
• Complete HADS 
• Measure body weight 
• Perform medical interview 
• Measure blood pressure and pulse rate 
• Collect blood and urine samples for laboratory tests 
• Evaluate AEs 
• Complete C-SSRS 
• Record and evaluate concomitant drugs and concomitant therapy 
 


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7. 
EFFICACY ASSESSMENTS 
7.1. 
Assessments for Efficacy Endpoint(s) 
At every visit except for Visit 22, subjects will provide a self-assessment using SF-MPQ. 
The SF-MPQ consists of 3 parts.   
• Fifteen pain descriptors that are given a score of 0 (none) to 3 (severe) based 
on intensity.  The scores are summarized as a sensory score of 11 descriptors, 
an affective score of 4 descriptors, and a total score of 15 descriptors.   
• A VAS, in which the subject rates pain intensity on a 100 mm-long horizontal 
line, where 0 mm = no pain and 100 mm = worst possible pain.   
• A Present Pain Intensity index that provides a score of 0 to 5 based on 
intensity.  . 
7.2. 
Appropriateness of Selected Efficacy Assessment(s) 
The efficacy endpoint were selected for this study because this endpoint was suitable for 
assessing the main symptom of CNeP. 
 


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8. 
PHARMACOKINETIC/PHARMACODYNAMIC 
ASSESSMENTS 
8.1. 
Pharmacokinetic Assessment(s) 
Not Applicable.   
8.2. 
Pharmacodynamic Assessment(s) 
Not Applicable.   
8.3. 
Biomarker Assessment(s) 
Not Applicable.   
8.4. 
Immunogenicity 
Not Applicable.   
8.5. 
Pharmacogenomic Analysis 
Not Applicable. 
 


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9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Assessment of Safety Endpoint(s) 
Safety endpoints will be body weight, TEAEs, laboratory values, vital signs, 12-lead 
ECG, C-SSRS, HADS, edema. 
9.2. 
Adverse Event Collection and Reporting 
All serious AEs (SAEs) (see Section 9.4.1 and 9.4.2 for definitions) occurring after the 
subject signs the ICF and up to 7 days after the last dose of study medication (ie, the 
follow-up period), whether observed by the Investigator or reported by the subject, will 
be recorded on the AE section in CRF.  All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up. 
All non-serious AEs occurring after the subject has taken the first dose of study 
medication until 7 days after the last dose of study medication will be recorded on the AE 
section in CRF.  
When an AE occurs, the investigator or sub-investigator will provide appropriate 
treatment and to the extent possible will monitor progress until the AE is resolved or 
resolving.  However, the investigator or sub-investigator can terminate the monitoring as 
the clinical trial after explaining it to the subject that he/she deems medically impossible 
to resolve it at the end of the study (although the treatment for the AE will be continued). 
In addition, the investigator or sub-investigator can also terminate it, if he/she decides 
further follow-up is unnecessary because of an AE for which a causal relationship with 
the investigational product can be ruled out, or if the subject refuses further follow-up. 
For patients with CPSP and CNePPD, any symptom that the investigator or sub-
investigator considers associated with CPSP and CNePPD will be evaluated as an 
efficacy variable and will not be regarded as an AE.  However, if the symptom is 
considered potentially related to the investigational product, such symptom will be 
regarded as an AE.  Medical conditions (including clinically significant laboratory values 
that are not symptoms of CPSP and CNePPD /vital signs that are out of range) that were 
diagnosed or known to exist prior to the first dose of study medication will be recorded as 
a medical history, not the AE section.  For any medical occurrence ongoing on the date of 
the first dose of study medication, the CRF Medical History module will record the start 
date of the medical occurrence even if the onset date is before the first dose.   
For patients with CNePSCI, any symptom that the investigator or sub-investigator 
considers associated with primary disease will be evaluated as an efficacy variable and 
will not be regarded as an AE.  However, if the symptom is considered potentially related 
to the investigational product, such symptom will be regarded as an AE.  Medical 
conditions (including clinically significant laboratory values that are not symptoms of 
CNePSCI /vital signs that are out of range) that were diagnosed or known to exist prior to 
the first dose of study medication will be recorded as AE in double-blind phase. 


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Exacerbation of a pre-existing medical occurrence and symptom after the first dose of 
study medication including increase in severity of the symptom will be recorded as an AE 
on the AE section, unless it is the condition of CNePSCI, CPSP, and CNePPD. 
All AEs, SAEs, and AEs of special interest (AESI) are to be reported according to the 
procedures in Section 9.5.   
All clinical laboratory results, vital signs, and ECG results or findings should be 
appraised by the Investigator to determine their clinical significance.  Isolated abnormal 
laboratory results, vital sign findings, or ECG findings (ie, not part of a reported 
diagnosis) should be reported as AEs if they are symptomatic, lead to study drug 
discontinuation, dose reduction, require corrective treatment, or constitute an AE in the 
Investigator’s clinical judgment. 
At each visit, the Investigator will determine whether any AEs have occurred by 
evaluating the subject.  AEs may be directly observed, reported spontaneously by the 
subject or by questioning the subject at each study visit.  Subjects should be questioned in 
a general way, without asking about the occurrence of any specific symptoms.  The 
Investigator must assess all AEs to determine seriousness, severity, and causality, in 
accordance with the definitions in Section 9.4.  The Investigator’s assessment must be 
clearly documented in the site’s source documentation with the Investigator’s signature.   
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, 
report the primary sign or symptom as the AE or SAE term with additional details 
included in the narrative until the diagnosis becomes available.  If the signs and 
symptoms are distinct and do not suggest a common diagnosis, report them as individual 
entries of AE or SAE.   
For events that are serious due to hospitalization, the reason for hospitalization must be 
reported as the SAE (diagnosis or symptom requiring hospitalization).  A procedure is not 
an AE or SAE, but the reason for the procedure may be an AE or SAE.  Pre-planned 
(prior to signing the ICF) procedures or treatments requiring hospitalization for pre-
existing conditions that do not worsen in severity should not be reported as SAEs (see 
Section 9.4.2 for Definitions).   
For deaths, the underlying or immediate cause of death should always be reported as an 
SAE.   
Any serious, untoward event that may occur subsequent to the reporting period that the 
Investigator assesses as related to study drug should also be reported and managed as an 
SAE. 
9.3. 
Adverse Events of Special Interest 
All antiepileptic drugs carry a risk of increased suicidal behavior and ideation.  
Furthermore, increased hepatic transaminases have been observed in the mirogabalin 
development program.  Therefore, the following “suicidal behavior and ideation” and 
“liver enzyme elevations/liver dysfunction” will be treated as AESI.   
• Increase in ALT or AST ≥ 5 × ULN 


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• ALT or AST rises to ≥ 3 × ULN and persists for more than 2 weeks 
• Concurrent increases in ALT or AST ≥ 3 × ULN and T-Bil ≥ 2 × ULN 
• ALT or AST ≥ 3 × ULN associated with a clinical presentation suggestive of 
liver injury (ie, including the appearance of fatigue, nausea, vomiting, 
jaundice, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia) 
• Serious hepatobiliary AE 
• Severe hepatobiliary AE 
• Hepatobiliary AE leading to discontinuation 
• Any transaminase elevation associated with a clinical presentation suggestive 
of liver injury 
• As elevation of ALT or AST ≥ 3 × ULN (without clinical presentation 
suggestive of liver injury) 
• AE related to suicide (if there are any “yes” responses to any of the questions 
in the C-SSRS) 
9.4. 
Adverse Event 
9.4.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical 
product and that does not necessarily have to have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal 
product (ICH E2A Guideline.  Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting, Oct 1994). 
Dizziness, somnolence, edema, and weight gain are defined as significant AE.  Any other 
significant AEs to be added will be specified in the statistical analysis plan (SAP). 
It is the responsibility of Investigators, based on their knowledge and experience, to 
determine those circumstances or abnormal laboratory findings which should be 
considered AEs. 
9.4.2. 
Serious Adverse Event 
A SAE is any untoward medical occurrence that at any dose: 
• Results in death, 
• Is life-threatening, 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability/incapacity, 


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• Is a congenital anomaly/birth defect, or 
• Is an important medical event. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe (ICH E2A Guideline.  
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, 
Oct 1994). 
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.  Examples include allergic bronchospasm, convulsions, and blood 
dyscrasias or development of drug dependency or drug abuse. 
Note:  
• Procedures are not AEs or SAEs, but the reason for the procedure may be an 
AE or SAE.   
• Pre-planned (prior to signing the ICF) procedures or treatments requiring 
hospitalizations for pre-existing conditions that do not worsen in severity are 
not SAEs. 
9.4.3. 
Severity Assessment 
The following definitions should be used to assess intensity of AEs: 
• Mild: Awareness of sign or symptom, but easily tolerated, ie, does not 
interfere with subject’s usual function. 
• Moderate: Discomfort enough to cause interference with usual activity. 
• Severe: Incapacitating with inability to work or do usual activity, ie, interferes 
significantly with subject’s usual function. 
Severity vs. Seriousness: Severity is used to describe the intensity of a specific event 
while the event itself, however, may be of relatively minor medical significance (such as 
severe headache).  This is not the same as "seriousness," which is based on patient/event 
outcome at the time of the event. 
9.4.4. 
Causality Assessment 
The Investigator should assess causal relationship between an AE and the study drug on 
the basis of his/her clinical judgment and the following definitions.  The causality 
assessment must be made based on the available information and can be updated as new 
information becomes available. 
• Related: 


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− The AE follows a reasonable temporal sequence from study drug 
administration, and cannot be reasonably explained by the subject’s 
clinical state or other factors (eg, disease under study, concurrent diseases, 
and concomitant medications). 
or 
− The AE follows a reasonable temporal sequence from study drug 
administration, and is a known reaction to the drug under study or its 
chemical group, or is predicted by known pharmacology. 
• Not Related: 
− The AE does not follow a reasonable sequence from study drug 
administration, or can be reasonably explained by the subject’s clinical 
state or other factors (eg, disease under study, concurrent diseases, and 
concomitant medications).  
9.4.5. 
Action Taken Regarding Study Drug(s) 
• Dose Not Changed: No change in study drug dosage was made. 
• Drug Withdrawn: The study drug was permanently stopped. 
• Dose Reduced: The dosage of study drug was reduced. 
• Drug Interrupted: The study drug was temporarily stopped. 
• Not Applicable: Subject died, study treatment had been completed prior to 
reaction/event, or reaction/event occurred prior to start of treatment 
9.4.6. 
Other Action Taken for Event 
• None. 
− No treatment was required. 
• Medication required. 
− Prescription and/or OTC medication was required to treat the AE. 
• Hospitalization or prolongation of hospitalization required. 
− Hospitalization was required or prolonged due to the AE, whether or not 
medication was required. 
• Other. 
9.4.7. 
Adverse Event Outcome 
• Recovered/Resolved 
− The subject fully recovered from the AE with no residual effect observed. 
• Recovering/Resolving 


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− The AE improved but has not fully resolved. 
• Not Recovered/Not Resolved 
− The AE itself is still present and observable. 
• Recovered/Resolved with Sequelae 
− The residual effects of the AE are still present and observable. 
− Include sequelae/residual effects. 
• Fatal 
− Fatal should be used when death is a direct outcome of the AE. 
• Unknown 
9.4.8. 
Definition of Adverse Drug Reaction 
Those AEs for which the relationship to the investigational product is considered 
“Related” will be handled as adverse drug reactions (ADRs). 
9.5. 
Serious Adverse Events and Adverse Event of Special Interest 
Reporting–Procedure for Investigators 
All AEs, and SAEs, and events of special interest, will be reported in the CRF. 
The following types of events should be reported to the sponsor within 24 hours after 
becoming aware of the event in the designated form to the eCRF: 
• SAEs (see Section 9.4.2 for definition) 
• Increase in ALT or AST ≥ 5 × ULN 
• ALT or AST rises to ≥ 3 × ULN and persists for more than 2 weeks 
• Concurrent increases in ALT or AST ≥ 3 × ULN and T-Bil ≥ 2 × ULN 
• ALT or AST ≥ 3 × ULN associated with a clinical presentation suggestive of 
liver injury (ie, including the appearance of fatigue, nausea, vomiting, 
jaundice, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia) 
• AE related to suicide (if there are any “yes” responses to any of the questions 
in the C-SSRS) 
The following types of events should be reported to the sponsor as promptly as possible 
after becoming awareness of the event in the designated form to the eCRF: 
• Severe hepatobiliary AE 
• Hepatobiliary AE leading to discontinuation 
• Any transaminase elevation associated with a clinical presentation suggestive 
of liver injury 


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• As elevation of ALT or AST ≥ 3 × ULN (without clinical presentation 
suggestive of liver injury) 
All events (serious and non-serious) must be reported with Investigator’s assessment of 
the event’s seriousness, severity, and causality to the study drug.  A detailed narrative 
summarizing the course of the event, including its evaluation, treatment, and outcome 
should be provided.  Specific or estimated dates of event onset, treatment, and resolution 
should be included when available.  Medical history, concomitant medications, and 
laboratory data that are relevant to the event should also be summarized in the narrative.  
For fatal events, the narrative should state whether an autopsy was or will be performed, 
and include the results if available.  Source documents (including medical reports) will be 
retained at the study site and should not be submitted to the Sponsor for SAE reporting 
purposes. 
Urgent safety queries must be followed up and addressed promptly.  Follow-up 
information and response to non-urgent safety queries should be combined for reporting 
to provide the most complete data possible within each follow-up.  
In the event that eCRF is unavailable, report SAEs/AESIs on a Serious Adverse Event 
Report (SAVER) form.  All completed SAVER forms must be signed by the Investigator, 
and e-mailed to CMIC. 
9.6. 
Notifying Regulatory Authorities, Investigators, and 
Institutional Review Board/Ethics Committee 
Daiichi Sankyo and/or CMIC will inform Investigators, Institutional Review 
Boards/Ethics Committees, and regulatory authorities of any Suspected Unexpected 
Serious Adverse Reactions (SUSARs) occurring in other study sites or other  studies of 
the investigational drug, as appropriate per local reporting requirements.  Daiichi Sankyo 
and/or CMIC will comply with any additional local safety reporting requirements.  The 
section of “Reference Safety Information” in the updated investigator's brochure should 
be referred to judge “Unexpected”  
9.7. 
Exposure In Utero During Clinical Studies 
Daiichi Sankyo must be notified of any subject who becomes pregnant while receiving or 
at the time of discontinuing the study drug.  
Although pregnancy is not technically an AE, all pregnancies must be followed to 
conclusion to determine their outcome.  This information is important for both drug 
safety and public health concerns.  It is the responsibility of the Investigator, or designee, 
to report any pregnancy in a female subject or a male subject’s female partner using the 
exposure in utero (EIU) reporting form.  Please contact your study monitor to receive the 
EIU Reporting Form upon learning of a pregnancy.  The Investigator should make every 
effort to follow the subject until completion of the pregnancy and complete the EIU 
Reporting Form with complete pregnancy outcome information, including normal 
delivery and induced abortion.  The adverse pregnancy outcome, either serious or non-
serious, should be reported in accordance with study procedures.  If the outcome of the 
pregnancy meets the criteria for immediate classification as a SAE (ie, post-partum 


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complications, spontaneous or induced abortion, stillbirth, neonatal death, or congenital 
anomaly, including that in an aborted fetus), the Investigator should follow the 
procedures for reporting SAEs outlined in Section 9.5.  
9.8. 
Clinical Laboratory Evaluations 
The study site staff will collect blood and urine specimens for routine laboratory tests at 
specified times.  Specimens will be stored under conditions stipulated in the Sample 
Handling Manual until they are transported for measurement.  Specimens will be 
transported and measured by a central laboratory. Table 9.1 and Table 9.2 summarize the 
laboratory parameters to be assessed and the times of assessment. 
Results of all laboratory tests will be reported from the central laboratory to the site. 
A value or finding that represents a clinically significant abnormal change should be 
regarded as an AE, and should be described (diagnosed) appropriately in the CRF. 


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Table 9.1: 
Laboratory Parameters to be Assessed, and Time of Assessment for 
Patients With Central Neuropathic Pain After Spinal Cord Injury 
 
Parameters 
Time of assessment 
Hematology 
WBC, RBC, hemoglobin, hematocrit, platelet count, 
differential leukocyte (neutrophil, eosinophil, 
basophil, monocyte, lymphocyte) counts, 
reticulocyte count 
Visit 7 to Visit 22, 
Early termination 
Blood 
chemistry 
Total protein, albumin, A/G ratio, T-Bil, AST 
(GOT), ALT (GPT), ALP, γ-GT (γ-GTP), LDH, 
BUN, creatinine, uric acid, creatine kinase, total 
cholesterol, triglycerides, Na, K, Cl, Ca, Mg, 
inorganic phosphorus, bicarbonate, CRP 
Urinalysis 
Standard urinalysis, including microscopic 
examination   
Specific gravity, pH, protein, glucose, ketones, 
urobilinogen, occult blood, RBC, WBC, bilirubin 
HbA1c 
HbA1c 
Visit 7, Visit 12, 
Visit 15, Visit 18, 
Visit 21, Early 
Termination   
Pregnancy 
Qualitative test (urine) 
Visit 7, Visit 21, 
Early termination  
 
 
 


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Table 9.2: 
Laboratory Parameters to be Assessed, and Time of Assessment for 
Patients With Central Post Stroke Pain and CNePPD Central 
Neuropathic Pain in Parkinson’s Disease 
 
Parameters 
Time of assessment 
Hematology 
WBC, RBC, hemoglobin, hematocrit, platelet count, 
differential leukocyte (neutrophil, eosinophil, 
basophil, monocyte, lymphocyte) counts, reticulocyte 
count 
Visit 1,  
Visit 7 to Visit 22, 
Early termination 
Blood chemistry Total protein, albumin, A/G ratio, T-Bil, AST (GOT), 
ALT (GPT), ALP, γ-GT (γ-GTP), LDH, BUN, 
creatinine, uric acid, creatine kinase, total cholesterol, 
triglycerides, Na, K, Cl, Ca, Mg, inorganic 
phosphorus, bicarbonate, CRP 
Urinalysis 
Standard urinalysis, including microscopic 
examination   
Specific gravity, pH, protein, glucose, ketones, 
urobilinogen, occult blood, RBC, WBC, bilirubin 
HbA1c 
HbA1c 
Visit 7, Visit 12, 
Visit 15, Visit 18, 
Visit 21, Early 
Termination   
Pregnancy 
Qualitative test (urine) 
Visit 1, Visit 21, Early 
termination  
 
In cases of liver laboratory abnormalities, it is important to ensure that the nature and the 
extent of liver injury is identified and study subjects are monitored until the liver 
laboratory assessments return to normal.  Subjects who have any transaminase elevation 
associated with a clinical presentation suggestive of liver injury (ie, including the 
appearance of fatigue, nausea, vomiting, jaundice, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia) or an elevation of ALT or AST ≥ 3 × ULN 
(without clinical presentation suggestive of liver injury) at any visit should be monitored 
closely, according to the following: 
• Repeat liver tests of at least all four of the usual serum measures (ALT, AST, 
alkaline phosphatase (ALP), and T-Bil at least 2 times weekly (the first repeat 
should be within 48 to 72 hours of initial abnormality) until values have 
decreased to < 2 × ULN, then at least every 1 or 2 weeks until resolution or 
return to baseline.  An additional serum separating tube of blood will be 
collected at time of event and until values return to baseline.  Samples will be 
stored for further analysis, as required. 
• Review or obtain a detailed history of symptoms and prior or concurrent 
diseases. 


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• Review or obtain a history of the use of concomitant drugs, including 
nonprescription medications, herbal and dietary supplements, alcohol, 
recreational drugs, and special diets. 
• Rule out alcoholic hepatitis; non-alcoholic steatohepatitis; hypoxic/ischemic 
hepatopathy; and biliary tract disease. 
• Obtain a history of exposure to environmental chemical agents. 
• Perform additional liver function tests (eg, serum lactate dehydrogenase, ALP, 
gamma-glutamyl transpeptidase, prothrombin time), evaluations for potential 
viral etiologies (including hepatitis A, B, C, E; cytomegalovirus; Epstein-Barr 
virus) and autoimmune etiologies (anti-nuclear antibody, anti-smooth muscle 
antibody, anti-mitochondrial antibody). 
Combined elevations of aminotransferases and bilirubin meeting the criteria of a potential 
Hy’s Law case [ALT or AST ≥ 3 × ULN with simultaneous T-Bil ≥ 2 × ULN], either 
serious or non-serious and whether or not causally related, should always be reported to 
the sponsor within 24 hours (refer to Section 9.2), with the investigator’s assessment of 
seriousness, causality, and a detailed narrative. (Food Drug Administration’s Guidance 
for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation; July 2009; 
http://www.fda.gov/downloads/Drugs/Guidance/UCM174090.pdf).  These events should 
be reported as soon as possible following the procedures outlined in Section 9.5 for SAE 
reporting.  Criteria for discontinuing subjects based on transaminase increases are 
provided in Section 5.7.1.   
For subjects discontinued from the study due to any transaminase increase or hepatic 
event, the following should be performed: 
• Gastroenterology or hepatology consultation  
• Hepatobiliary ultrasound 
 


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9.9. 
Vital Signs 
Vital signs will be recorded at all visits and will include pulse rate and blood pressure in a 
supine position in principle.  For measurement of supine blood pressure, subjects should 
be in a supine or semirecumbent position for a minimum of 5 minutes before the blood 
pressure measurement.  Measurement of blood pressure should be conducted using a 
calibrated manometer or automatic inflatable cuff monitor.  Results will be recorded in 
the CRF. 
9.10. 
Electrocardiograms 
Patients with CNePSCI 
At the stipulated times (Visit 7 and Visit 21), 12-lead ECG will be performed.  Results 
(Normal/Abnormal, not clinically significant/Abnormal, clinically significant) will be 
recorded in the CRF.   
Patients with CPSP and CNePPD 
At the stipulated times (Visit 1 and Visit 21), 12-lead ECG will be performed.  Results 
(Normal/Abnormal, not clinically significant/Abnormal, clinically significant) will be 
recorded in the CRF.   
9.11. 
Physical Findings 
9.11.1. 
Body Height and Weight 
Patients with CNePSCI 
Body weight will be measured at each visit.  Results will be recorded in the CRF.   
Patients with CPSP and CNePPD 
At Screening (Visit 1), body height will be measured.  Body weight will be measured at 
each visit.  Results will be recorded in the CRF.   
9.11.2. 
Medical Interview 
Medical interview will be performed at each visit.   
9.11.3. 
Evaluation of Edema 
Patients with CNePSCI 
Evaluation of edema will be performed, including medical interview and pitting, at each 
visit excepting Visit 22.  Results (presence or absence of edema and expression site) will 
be recorded in the CRF.   
Patients with CPSP and CNePPD 
Evaluation of edema will be performed, including medical interview and pitting, at each 
visit excepting Visit 7 and Visit 22.  Results (presence or absence of edema and 
expression site) will be recorded in the CRF.   


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9.12. 
Other Examinations 
9.12.1. 
Columbia-Suicide Severity Rating Scale 
The C-SSRS is a tool designed to systematically assess and track suicidal AEs (behavior 
and ideation).  The C-SSRS assesses lifetime suicidality during an initial baseline 
evaluation using standardized questions, and then prospectively monitors ideations and 
behaviors at subsequent follow-up assessments throughout the trial.  The reviewer is an 
investigator, sub-investigator or clinical study coordinator who has completed training 
prior to the study using the training material.  The C-SSRS will be administered by the 
reviewer at each visit.  Answers to all relevant questions will be recorded in the CRF.  If 
the subject is judged to have suicidal behavior and/or suicidal ideation, appropriate 
measures will be implemented such as referring the subject to a specialist as described in 
the withdrawal procedures (see Section 5.7.3).   
9.12.2. 
Hospital Anxiety and Depression Scale 
At each visit, subjects will provide a self-assessment using the HADS.  The HADS 
consists of 7 items to score depression (4-point scale) and 7 items to score anxiety 
(4-point scale).  The subject will respond to each item on the questionnaire.  Based on the 
results, the investigator will check for the presence or absence of depression and/or 
anxiety.  If the subject is judged to have an AE, appropriate measures will be 
implemented such as referring the subject to a specialist.  Result will be recorded in the 
CRF. 
9.12.3. 
Pregnancy Test 
Patients with CNePSCI 
Pregnancy tests (urine tests) will be conducted at the stipulated times (Visit 7 and Visit 
21), for women of child-bearing potential only.  All female subjects will be considered as 
women of child-bearing potential unless they have undergone surgical sterilization (with 
documented bilateral oophorectomy) or are postmenopausal and have experienced no 
menses within the previous 6 months.  The subject is considered to be postmenopausal 
when 12 consecutive months of absence of menstruation is confirmed with no 
pathological or physiological factors.  Results will be recorded in the CRF.   
Patients with CPSP and CNePPD 
Pregnancy tests (urine tests) will be conducted at the stipulated times (Visit 1 and Visit 
21), for women of child-bearing potential only.  All female subjects will be considered as 
women of child-bearing potential unless they have undergone surgical sterilization (with 
documented bilateral oophorectomy) or are postmenopausal and have experienced no 
menses within the previous 6 months.  The subject is considered to be postmenopausal 
when 12 consecutive months of absence of menstruation is confirmed with no 
pathological or physiological factors.  Results will be recorded in the CRF. 
 


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10. 
OTHER ASSESSMENTS 
Not Applicable. 
 


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11. 
STATISTICAL METHODS  
11.1. 
General Statistical Considerations 
The efficacy and safety analysis sets will be used for all efficacy and all safety analyses, 
respectively.   
No imputation will be done for the missing data of safety valuables.  For the efficacy 
endpoint of SF-MPQ, missing data will be handled using the standard scoring 
instructions of the SF-MPQ questionnaire.  The SAP will provide the details on the 
handling of missing data.   
Continuous variables will be summarized by the number of observations, mean, standard 
deviation, median, and minimum, and maximum values.  Categorical variables will be 
summarized using frequency counts and percentages.   
No interim analyses are planned.   
Subgroup analyses will be pre-specified in the SAP.   
The detailed SAP describing the methodology to be used in the final analysis will be 
prepared before a database lock.  A change in the planned statistical analysis will require 
a protocol amendment only if it substantively alters the principal features of the protocol.  
Any deviations from the planned statistical analyses in the protocol will be fully 
described in the SAP.   
11.2. 
Analysis Sets 
The safety analysis set will include all subjects who signed the ICF and received at least 
one dose of study medication.   
The efficacy analysis set will include all subjects who signed the ICF and received at 
least one dose of study medication, which is the same as the safety analysis set.   
11.3. 
Study Population Data 
The number of enrolled subjects who signed the ICF will be summarized.  The number 
and percentage will be tabulated for subjects who completed the study, prematurely 
discontinued from the study, and the reason for the study discontinuation.  In addition, 
the number and percentage of subjects for each analysis set will be tabulated.   
Demographic and baseline characteristics will be summarized for the safety analysis set 
and efficacy analysis set.   
Treatment compliance for each subject will be summarized.   
11.4. 
Efficacy Analyses 
Summary statistics will be calculated for the measured value and the change from 
baseline in the sensory score, affective score, total score, VAS, and the present pain 
intensity index at each scheduled visit for the efficacy analysis set. 


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Summary statistics will be calculated for the measured value and the change from 
baseline in severity of pain and impact on daily functions at each scheduled visit using 
the efficacy analysis set.   
11.4.1. 
Safety Analyses 
All safety analyses will be performed using the safety analysis set.   
11.4.1.1. Adverse Event Analyses 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
TEAEs are defined as AEs that newly emerges or worsen in severity after the first 
administration of the study drug for the open-label extension study until the following 
dates: 
• Follow-up visit or 14 days after the last dose of the study drug whichever is 
earlier.   
The number and percentage of subjects reporting TEAE and treatment-emergent ADR 
(TEADR) will be calculated overall, by system organ class (SOC), and by preferred term 
(PT).  TEAE and TEADR will be further summarized by SOC, PT, and severity and by 
SOC, PT, and relationship to study drug.  Similarly, the number and percentage of 
subjects with serious TEAE, serious TEADR, significant TEAE, significant TEADR, 
TEAE leading to treatment discontinuation, and TEADR leading to treatment 
discontinuation will be tabulated. 
Time to first dizziness, somnolence edema and weight gain, defined as the duration from 
first administration of investigational product to the first TEAE, will be summarized 
based on the Kaplan-Meier product limit method.   
11.4.1.2. Clinical Laboratory Evaluation Analyses 
Summary statistics will be provided for the clinical laboratory tests results by scheduled 
visit of evaluation, as well as for the change from baseline.  A shift table will be created 
for the categorical data (eg, abnormal low, normal, abnormal high”) between baseline and 
each scheduled visit of evaluation.   
Additionally, for ALT, AST, T-Bil, and ALP, the number and percentage of subjects who 
meet the criteria specified in FDA Drug-Induced Liver Injury guideline will be tabulated 
and evaluation of drug-induced serious hepatotoxicity plot will also be provided.   
11.4.1.3. Vital Sign Analyses 
Summary statistics will be provided for the measured value and change from baseline in 
vital sign parameters by scheduled visit.   
11.4.1.4. Electrocardiogram Analyses 
Shift table will be provided for ECG parameters between baseline and visit of End of 
Treatment/Early Termination.   


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11.4.1.5. Medical Interview 
Summary statistics will be calculated for the measured value and change from baseline in 
body weight measurements by scheduled.  The number and percentage of subjects who 
increased their body weight by 5% or 10% from the baseline will be also tabulated.   
For the evaluation of edema, the results (presence or absence) will be tabulated for each 
expression site.   
11.4.1.6. Columbia-Suicide Severity Rating Scale 
The results from C-SSRS will be tabulated.   
11.4.1.7. Hospital Anxiety and Depression Scale 
The subscales of Anxiety and Depression for HADS will be summarized by scheduled 
visit of evaluation.   
11.4.2. 
Other Endpoint Analysis 
Not Applicable.   
11.5. 
Interim Analyses 
Interim analysis will be performed when all subjects other than withdrawal subjects have 
completed study drug treatment at least for 6 months. 
11.6. 
Sample Size Determination 
The open-label extension phase is expected to enroll up to approximately 180 subjects.  
Of those subjects enrolled, over 100 are expected to complete 1-year treatment with 
mirogabalin.  This meets the recommendations generally agreed upon in the ICH E1 
guideline (100 subjects exposed for a minimum of 1 year).    
11.7. 
Statistical Analysis Process 
The SAP will provide the statistical methods and definitions for the analysis of the 
efficacy and safety data, as well as describe the approaches to be taken for summarizing 
other clinical study information such as subject disposition, demographic and baseline 
characteristics, study drug exposure, and prior and concomitant medications.  The SAP 
will also include a description of how missing, unused, and spurious data will be 
addressed.   
The SAP will be finalized prior to database lock.   
All statistical analyses will be performed using SAS® Version 9.3 or higher (SAS 
Institute, Cary, NC 27513).   


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12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
Refer to Section 12 of double-blind study in the protocol (DS5565-A-J314). 
12.1. 
Monitoring and Inspections 
Refer to Section 12.1 of double-blind study in the protocol (DS5565-A-J314). 
12.2. 
Data Collection 
Refer to Section 12.2 of double-blind study in the protocol (DS5565-A-J314). 
12.3. 
Data Management 
Refer to Section 12.3 of double-blind study in the protocol (DS5565-A-J314). 
12.4. 
Study Documentation and Storage 
Refer to Section 12.4 of double-blind study in the protocol (DS5565-A-J314). 
12.5. 
Record Keeping 
Refer to Section 12.5 of double-blind study in the protocol (DS5565-A-J314). 
 


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13. 
FINANCING AND INSURANCE 
13.1. 
Finances 
Refer to Section 13.1 of double-blind study in the protocol (DS5565-A-J314). 
13.2. 
Reimbursement, Indemnity, and Insurance 
Refer to Section 13.2 of double-blind study in the protocol (DS5565-A-J314). 
 


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14. 
PUBLICATION POLICY AND PUBLIC DISCLOSURE OF 
CLINICAL TRIAL INFORMATION 
Refer to Section 14 of double-blind study in the protocol (DS5565-A-J314). 
 


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15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance 
Refer to Section 15.1 of double-blind study in the protocol (DS5565-A-J314).   
15.2. 
Subject Confidentiality 
Refer to Section 15.2 of double-blind study in the protocol (DS5565-A-J314).   
15.3. 
Informed Consent  
Refer to Section 15.3 of double-blind study in the protocol (DS5565-A-J314).   
15.4. 
Regulatory Compliance 
Refer to Section 15.4 of double-blind study in the protocol (DS5565-A-J314).   
15.5. 
Protocol Deviations 
Refer to Section 15.5 of double-blind study in the protocol (DS5565-A-J314).   
15.6. 
Supply of New Information Affecting the Conduct of the Study 
Refer to Section 15.6 of double-blind study in the protocol (DS5565-A-J314).   
15.7. 
Protocol Amendments 
Refer to Section 15.7 of double-blind study in the protocol (DS5565-A-J314). 
15.8. 
Study Termination 
Refer to Section 15.8 of double-blind study in the protocol (DS5565-A-J314).   
15.9. 
Data and Safety Monitoring Board 
Not Applicable.   
15.10. 
Address List 
Refer to Section 15.10 of double-blind study in the protocol (DS5565-A-J314).   
 


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16. 
REFERENCES 
Refer to Section 16 of double-blind study in the protocol (DS5565-A-J314). 
1. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for 
Parkinson's disease. Movement Disord. 2015;30(12):1591-601 
2. Ford B. Pain in Parkinson’s disease. Movement Disord. 2010;25 Suppl 1:S98-103 
 


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17. 
APPENDICES 
17.1. 
Schedule of Events 
 


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Table 17.1: 
Study Visits for Patients with Central Neuropathic Pain After Spinal Cord Injury 
 
Screening and 
Enrollment 
Treatment period 
End of Treatment 
Post-treatment 
follow-up 
Early Termination 
Visit 
7 
8 
9 
10 to 20 
21 
22 
 
Week 
LT_0 
LT_2 
LT_4 
Every 4 weeks 
LT_52 
LT_53 
 
Day 
LT_1 
LT_15 
LT_29 
LT_57 to LT 337 
LT_365 
LT_372 
 
Visit window (days) 
 
±3 
±3 
±7 
±7 
Day 5 to 14  
post-last dose 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Body weight 
Xa 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
Medical interviewb 
Xa 
X 
X 
X 
X 
X 
X 
Evaluation of edema 
Xa 
X 
X 
X 
X 
 
X 
Vital signs 
Xa 
X 
X 
X 
X 
X 
X 
12-lead ECG 
Xa 
 
 
 
X 
 
X 
Clinical safety laboratory tests 
Xa 
X 
X 
X 
X 
X 
X 
C-SSRS 
Xa 
X 
X 
X 
X 
X 
X 
HADS 
Xa 
X 
X 
X 
X 
X 
X 
SF-MPQ 
Xa 
X 
X 
X 
X 
 
X 
Pregnancy test 
Xa 
 
 
 
X 
 
X 
AE reporting 
Non-serious AE 
 
 
 
 
 
 
 
SAE 
 
 
 
 
 
 
 
Prior and concomitant medication 
Xa 
X 
X 
X 
X 
X 
X 
Investigational product dispensing 
X 
X 
X 
Xc 
 
 
 
Investigational product compliance 
 
X 
X 
X 
X 
 
X 
a: The result at Visit 7 in the double-blind study will be applied. 
b: Check subject’s health condition through verbal communication. Additional tests may be performed based on any signs or symptoms exhibited by subject. 
c: Taper will be conducted at the last week (approximately 1 week) from Visit 20 to Visit 21 (see Section 5 1.1). 


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Table 17.2: 
Study Visits for Patients with Central Post Stroke Pain and Central Neuropathic Pain in Parkinson’s Disease 
 
Screening 
Enrollment 
Treatment period 
End of Treatment 
Post-treatment 
follow-up 
Early Termination 
Visit 
1 
7 
8 
9 
10 to 20 
21 
22 
 
Week 
LT_-1 
LT_0 
LT_2 
LT_4 
Every 4 weeks 
LT_52 
LT_53 
 
Day 
< LT_−7 
LT_1 
LT_15 
LT_29 
LT_57 to LT_337 
LT_365 
LT_372 
 
Visit window (days) 
−7 to −14 
- 
±3 
±3 
±7 
±7 
Day 5 to 14  
post-last dose 
 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
Medical / surgical history 
X 
 
 
 
 
 
 
 
Body height and weight 
X 
Xa 
X a 
X a 
X a 
X a 
X a 
X a 
Medical interviewb 
X 
X 
X 
X 
X 
X 
X 
X 
Evaluation of edema 
X 
 
X 
X 
X 
X 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
X 
 
X 
Clinical safety laboratory tests 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
HADS 
X 
X 
X 
X 
X 
X 
X 
X 
SF-MPQ 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy test 
X 
 
 
 
 
X 
 
X 
AE reporting 
Non-serious AE 
 
 
 
 
 
 
 
 
SAE 
 
 
 
 
 
 
 
 
Prior and concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
Investigational product dispensing 
 
X 
X 
X 
Xc 
 
 
 
Investigational product compliance 
 
 
X 
X 
X 
X 
 
X 
a: Body weight only 
b: Check subject’s health condition through verbal communication. Additional tests may be performed based on any signs or symptoms exhibited by subject. 
c: Taper will be conducted at the last week (approximately 1 week) from Visit 20 to Visit 21 (see Section 5.1.1).