Conditions: Alcohol Dependence
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 405
Healthy volunteers: no

Brief summary:
The long-term safety and efficacy of nalmefene hydrochloride at 20 mg in patients with alcohol dependence will be evaluated in a multicenter, open-label, uncontrolled trial.

Detailed description:

Arms:
arm 1: As-needed; tablets, orally

Interventions: intervention 1: Nalmefene hydrochloride
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
Protocol No. 339-14-002 
 
 
 
 
 
CLINICAL  STUDY  PROTOCOL 
 
 
A Long-term Extension Study for the Phase 3 Study of Nalmefene 
(339-14-001) in Patients With Alcohol Dependence 
(Phase 3 Trial) 
 
 
NCT Number:  02382276 
PRT NO. 339-14-002 
PRT Version Date: 20 Nov 2014 （Version 2）


Protocol No. 339-14-002 
 
 
 
 
 
A Long-term Extension Study for the Phase 3 Study of Nalmefene 
(339-14-001) in Patients With Alcohol Dependence 
(Phase 3 Trial) 
 
 
Clinical Protocol 
Protocol No.:  339-14-002 
(Translated Version) 
 
Confidential 
 
 
 
 
 
 
Otsuka Pharmaceutical Co., Ltd. 
2-9 Kanda-Tsukasamachi, Chiyoda-ku, Tokyo 101-8535, Japan 
 
Version 1:  31 Oct 2014 
Version 2: 20 Nov 2014 
 


Protocol No. 339-14-002 
 
 
 
Statement of Confidentiality 
The trial protocol is to be treated as confidential information and is to be made available 
only to persons involved in the trial.  The content of the protocol is not to be disclosed to 
any third party without the prior written consent of Otsuka Pharmaceutical Co., Ltd., 
except in the case of its being explained to a candidate trial subject.  Disclosure of the 
results of the trial to academic societies or journals, etc, in part or in whole, will require 
the prior written approval of Otsuka Pharmaceutical Co., Ltd. 
 


Protocol No. 339-14-002 
 
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Trial Protocol Synopsis 
Name of Test Product 
Lu AA36143 (international nonproprietary name [INN]:  
nalmefene; hereinafter referred to as “nalmefene”) 
Trial Title 
A long-term extension study for the phase 3 study of nalmefene 
(339-14-001) in patients with alcohol dependence 
Trial Objectives 
The long-term safety and efficacy of nalmefene hydrochloride at 
20 mg in patients with alcohol dependence will be evaluated in a 
multicenter, open-label, uncontrolled trial. 
Phase of Development 
Phase:  3 
Type of trial:  long-term safety trial 
Trial Design 
This trial will consist of a 24-week treatment period (open-label, 
uncontrolled), a 4-week run-out period (double-blind, placebo-
controlled), and a 4-week posttreatment observation period.  In 
the treatment period, subjects will receive nalmefene 
hydrochloride 20 mg.  In the run-out period, subjects will be 
randomized to either nalmefene hydrochloride 20 mg group or 
placebo group at the ratio of 1:1, and will receive the 
corresponding investigational medicinal product (IMP). 
Target Disease 
Alcohol dependent patients 
Target Number of 
Subjects 
Approximately 400 subjects proceeding on from Study 399-14-
001 
Inclusion Criteria 
1) Patients who have completed Study 339-14-001. 
2) Patients who have signed the informed consent form (ICF) 
for Study 339-14-002. 
Exclusion Criteria 
Patients who fall under any of the following exclusion criteria at 
the examination at the end of the treatment period of Study 339-
14-001 will be excluded from the trial. 
1) The patient has a clinically significant unstable illness (eg, 
complication of New York Heart Association [NYHA] 
class III or IV heart failure or angina pectoris, renal 
function disorder with estimated glomerular filtration rate 
[eGFR] of < 30 mL/min/1.73 m2, hepatic failure, and 
neoplastic disorder). 


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2) The patient has a clinically significant abnormal 
electrocardiogram (ECG) which is inappropriate for the 
participation in the trial in the opinion of the investigator 
or subinvestigator. 
3) The patient satisfies at least one of the following suicide 
risk criteria: 
 Answers “Yes” on the Columbia-Suicide Severity Rating 
Scale (C-SSRS) Suicidal Ideation Item 4 (Active 
Suicidal Ideation with Some Intent to Act, without 
Specific Plan) or the C-SSRS Suicidal Ideation Item 5 
(Active Suicidal Ideation with Specific Plan and Intent) 
and whose episode meeting criteria for any of these 2 
C-SSRS Ideation Items occurred within the last 6 
months, OR 
 Answers “Yes” on any of the 5 C-SSRS Suicidal 
Behavior Items (Actual Attempt [non-fatal], Interrupted 
Attempt, Aborted Attempt, Preparatory Acts or 
Behavior, Completed Suicide) and whose most recent 
episode meeting criteria for any of these 5 C-SSRS 
Suicidal Behavior Items occurred within the last 2 years, 
OR 
 The patient is, in the opinion of the investigator or 
subinvestigator, at significant risk of suicide. 
4) The patient has at least one of the following laboratory 
findings: 
 Red blood cell count:  < 3,000,000/mm3, hemoglobin:  
< 9.5 g/dL, white blood cell count:  < 3,000/mm3, 
platelet count:  < 75,000/mm3 
 Alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) > 3 times the upper limit of 
normal (ULN) 
5) The patient is mainly engaged in driving or those engaged 
in potentially hazardous activities, such as operating 
machinery or working in high place. 
6) Women who are pregnant or breast-feeding, who may be 
pregnant, or who wish to become pregnant during the trial 
and within 4 weeks after the final IMP administration.  
Men whose partners wish to become pregnant during the 
trial and within 4 weeks after the final IMP 
administration.  Also, patients who or whose partners 
cannot use birth control. 
7) Patients otherwise judged by the investigator or 


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subinvestigator to be inappropriate for inclusion in the 
trial for any reason. 
Discontinuation Criteria 
1) The subject requests to be withdrawn from the trial. 
2) The subject experiences an adverse event (AE) making 
continuation of the trial difficult. 
3) Psychosocial therapy other than BRENDA approach is 
needed (except for the period after the end of the 
examination of the run-out period). 
4) The dose of the IMP needs to be changed. 
5) It has been found after the start of the trial that the subject 
does not meet the inclusion criteria or falls under any of 
the exclusion criteria. 
6) A female subject has become pregnant or been suspected 
of being pregnant. 
7) The investigator or subinvestigator judges that the subject 
should be withdrawn for other reasons. 
Investigational Medicinal 
Products, Dose and 
Regimen, and Treatment 
Period 
IMP:  White film-coated tablets containing 20 mg (as an 
anhydride of nalmefene hydrochloride) per tablet or placebo 
tablets. 
Dose and regimen:  All subjects will receive one tablet of 
nalmefene hydrochloride 20 mg in the treatment period and one 
tablet of either nalmefene hydrochloride 20 mg or placebo in the 
run-out period.  Each subject will be instructed to take one tablet 
(nalmefene hydrochloride 20 mg or placebo) on days when the 
subject perceives a risk of drinking alcohol, as needed 1 to 
2 hours before the anticipated risk of drinking.  If the subject has 
started drinking alcohol without taking the IMP, the subject 
should take one tablet as soon as possible.  The IMP can be taken 
up to one tablet a day (one day is defined as the period from 
0 AM of the day to 0 AM of the next day).  Tablets must not be 
divided. 
Treatment period:  28 weeks (treatment period for 24 weeks and 
run-out period for 4 weeks) 
Prohibited Concomitant 
Drugs and Restricted 
Concomitant Drugs 
 Agents used for treatment of alcohol dependence 
 IMPs and drugs not approved in Japan 
 Opioid analgesics 


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 Opioid antidiarrheal drugs 
 Antitussive drugs and cold medicines containing opioids 
 Antidepressants 
 Antipsychotics 
 Anticonvulsants 
 Anxiolytics 
 Hypnotics 
 Anorexics 
 Other psychotropic agents (including herbal agents used 
against mental disorder) 
 Antineoplastics 
 Muscle relaxants 
 Insulin 
 Anticoagulants 
 Antibiotics with possible interaction with alcohol 
(nitrofurantoin, metronidazole, and tinidazole) 
 Antifungal agents (systemic) 
 Steroids 
Variables 
Safety 
 Adverse events, clinical laboratory values, blood 
pressure and pulse rate, body weight, 12-lead ECG, 
physical examination, Profile of Mood States (POMS), 
C-SSRS, and dependency assessment 
Efficacy 
Baseline for the number of heavy drinking days (HDDs), total 
alcohol consumption (TAC), and drinking risk level (DRL) is 
defined as the data collected by the Timeline Followback (TLFB) 
method during the period of 4 weeks before the Screening Visit 
of Study 339-14-001.  One month is defined as 4 weeks (28 days) 
for this trial. 
 Change in the number of HDDs from baseline  
(The number of HDDs is defined as the number of days 
per month [days/month] with alcohol consumption per 
day of > 60 g for males and > 40 g for females) 
 Change in TAC from baseline 
(TAC is defined as mean alcohol consumption per day 


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[g/day] over a 1-month period) 
 Response Shift Drinking Risk Level (RSDRL):  The 
percentage of subjects with a downward shift in DRL of 
2 categories or more from baseline 
 Response Low Drinking Risk Level (RLDRL):  The 
percentage of subjects with a low DRL or below 
 70% TAC responder rate:  The percentage of subjects 
whose TAC is reduced by ≥ 70% 
 HDD responder rate:  The percentage of subjects in 
whom the number of HDDs is ≤ 4 
 Clinical Global Impression-Severity of Illness (CGI-S) 
 Clinical Global Impression-Global Improvement (CGI-I) 
 MOS 36-item Short-form Health Survey (SF-36) 
 EuroQol 5 Dimension (EQ-5D) 
 Alcohol Quality of Life Scale (AQoLS) 
 Resource Use Measurement Questionnaire-Alcohol 
Dependence (RUMQ-ADP) 
 Gamma-glutamyl transferase (GGT) 
 ALT 
Scheduled Duration of the 
Trial 
05 Dec 2014 to 31 Mar 2018 
 


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Table of Contents 
Trial Protocol Synopsis ................................................................................. 4 
Table of Contents........................................................................................... 9 
List of Abbreviations and Definition of Terms ........................................ 16 
1 
Introduction ........................................................................................ 18 
1.1 
Background of Trial Plan .................................................................................. 18 
1.2 
Study Results and Trial Rationale ..................................................................... 19 
1.2.1 
Nonclinical Study Results .............................................................................. 19 
1.2.2 
Clinical Study Results .................................................................................... 20 
1.2.2.1 
Results of PET Study in Healthy Caucasian Subjects (Study CPH-
101-0902) .................................................................................................... 20 
1.2.2.2 
Results of Phase 1 Study in Healthy Japanese Subjects (Study 
13505A) ...................................................................................................... 21 
1.2.2.3 
Results of Phase 3 Studies in Patients With Alcohol Dependence ............. 22 
1.2.2.3.1 
Results of Foreign Phase 3 Confirmatory Studies (Studies 12014A 
and 12023A) ............................................................................................ 22 
1.2.2.3.2 
Results of Foreign Phase 3 Extension Study (Study 12013A) ................ 24 
1.2.3 
Trial Rationale ................................................................................................ 25 
2 
Trial Objectives .................................................................................. 25 
3 
Trial Plan............................................................................................. 26 
3.1 
Trial Design ...................................................................................................... 26 
3.2 
Rationale for Trial Design................................................................................. 27 
3.2.1 
Rationale for Dose and Dosage Regimen ....................................................... 27 
3.2.2 
Rationale for Trial Duration ........................................................................... 27 
3.2.3 
Rationale for Run-out Period ......................................................................... 28 
3.2.4 
Rationale for Posttreatment Observation Period ............................................ 28 
3.3 
Variables ........................................................................................................... 28 
3.3.1 
Safety .............................................................................................................. 28 
3.3.2 
Efficacy........................................................................................................... 28 
3.4 
Number of Patients Planned .............................................................................. 29 
4 
Investigational Medicinal Products .................................................. 30 


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4.1 
Test Product and Comparator ........................................................................... 30 
4.1.1 
Test Product .................................................................................................... 30 
4.1.2 
Comparator:  Placebo ..................................................................................... 30 
4.2 
Packaging and Labeling .................................................................................... 30 
4.2.1 
Packaging ....................................................................................................... 30 
4.2.2 
Contents of Label ........................................................................................... 30 
5 
Trial Population ................................................................................. 31 
5.1 
Target Disease ................................................................................................... 31 
5.2 
Inclusion Criteria............................................................................................... 31 
5.3 
Exclusion Criteria ............................................................................................. 31 
6 
Trial Design ......................................................................................... 33 
6.1 
Dose, Regimen, and Treatment Period ............................................................. 33 
6.1.1 
Dose and Regimen.......................................................................................... 33 
6.1.2 
Treatment Period ............................................................................................ 33 
6.2 
Prior and Concomitant Treatment ..................................................................... 33 
6.2.1 
Prohibited Concomitant Drugs and Restricted Concomitant Drugs .............. 34 
6.2.2 
Concomitant Therapies .................................................................................. 35 
6.3 
Method of Minimizing or Avoiding Bias ......................................................... 36 
7 
Trial Procedures ................................................................................. 36 
7.1 
Schedule and Procedures .................................................................................. 36 
7.1.1 
Acquisition of Informed Consent ................................................................... 38 
7.1.2 
Subject Registration ....................................................................................... 38 
7.1.3 
Eligibility Confirmation (Examinations at the End of the Treatment 
Period of Study 339-14-001) .......................................................................... 38 
7.1.4 
Observations, Examinations, and Evaluations During the Treatment 
Period ............................................................................................................. 39 
7.1.4.1 
Week 0 (Start Date of the Treatment Period, Visit 2), Week 1 (Visit 
3), Week 2 (Visit 4), Week 4 (Visit 5), Week 8 (Visit 6), Week 12 
(Visit 7), Week 16 (Visit 8), and Week 20 (Visit 9) ................................... 39 
7.1.4.2 
Week 24 (End of the Treatment Period, Visit 10) ...................................... 40 
7.1.5 
Week 28 (Run-out Period, Visit 11) ............................................................... 41 
7.1.6 
Week 32 (Posttreatment Observation, Visit 12) ............................................. 41 


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7.1.7 
Time of Withdrawal ....................................................................................... 42 
7.1.8 
Follow-up Investigation ................................................................................. 43 
7.2 
Method of Evaluation ....................................................................................... 43 
7.2.1 
Safety .............................................................................................................. 43 
7.2.1.1 
Clinical Laboratory Values ......................................................................... 43 
7.2.1.2 
Blood Pressure and Pulse Rate, and Body Weight ..................................... 44 
7.2.1.3 
Twelve-lead Electrocardiogram .................................................................. 44 
7.2.1.4 
Physical Examination ................................................................................. 45 
7.2.1.5 
Profile of Mood States ................................................................................ 45 
7.2.1.6 
Columbia-Suicide Severity Rating Scale .................................................... 45 
7.2.1.7 
Dependency Assessment ............................................................................. 45 
7.2.2 
Efficacy Evaluation ........................................................................................ 46 
7.2.2.1 
Timeline Followback .................................................................................. 46 
7.2.2.2 
Clinical Global Impression-Severity of Illness and Clinical Global 
Impression-Global Improvement ................................................................ 46 
7.2.2.3 
MOS 36-item Short-form Health Survey .................................................... 47 
7.2.2.4 
EuroQol 5 Dimension ................................................................................. 47 
7.2.2.5 
Alcohol Quality of Life Scale ..................................................................... 48 
7.2.2.6 
Resource Use Measurement Questionnaire-Alcohol Dependence ............. 48 
7.2.3 
Others ............................................................................................................. 48 
7.2.3.1 
Breath Alcohol Concentration .................................................................... 48 
7.2.3.2 
Pregnancy Test ............................................................................................ 48 
7.2.4 
Investigational Medicinal Product Compliance ............................................. 49 
7.3 
Measures to Be Taken for Subjects Visiting or Planning to Visit Other 
Hospitals or Departments .................................................................................. 49 
8 
Adverse Events ................................................................................... 50 
8.1 
Definitions......................................................................................................... 50 
8.1.1 
Adverse Event ................................................................................................ 50 
8.1.2 
Serious Adverse Event ................................................................................... 50 
8.2 
Response to Occurrence of Adverse Events ..................................................... 51 
8.2.1 
Actions to Be Taken for Subjects ................................................................... 51 
8.2.2 
Expedited Reporting of Serious Adverse Events ........................................... 51 


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8.2.3 
Emergency Code Breaking (Procedure for Unblinding During the Trial 
Period) ............................................................................................................ 52 
8.3 
Assessment of Adverse Events ......................................................................... 52 
8.3.1 
Terms for Adverse Events .............................................................................. 53 
8.3.2 
Date of Onset and Recovery ........................................................................... 53 
8.3.3 
Severity ........................................................................................................... 53 
8.3.4 
Causal Relationship With Investigational Medicinal Product ....................... 53 
8.3.5 
Actions to Be Taken Regarding IMP Administration .................................... 54 
8.3.6 
Actions to Be Taken for Adverse Events ....................................................... 55 
8.3.7 
Outcome ......................................................................................................... 55 
8.4 
Follow-up Investigation of Adverse Events ...................................................... 55 
8.5 
Pregnancy .......................................................................................................... 56 
8.5.1 
Guidance to Subjects Including Contraceptive Methods ............................... 56 
8.5.2 
Actions to Be Taken by the Investigator or Subinvestigator When 
Pregnancy Is Suspected .................................................................................. 57 
8.5.3 
Actions to Be Taken by the Investigator or Subinvestigator When a 
Subject Is Discovered to Be Pregnant ............................................................ 57 
8.5.4 
Expedited Reporting of Pregnancy ................................................................. 57 
8.5.5 
Follow-up Investigation of Pregnancy ........................................................... 58 
9 
Withdrawal of Individual Subjects From the Trial ....................... 58 
9.1 
Screen Failure ................................................................................................... 58 
9.2 
Criteria and Procedures for Withdrawal of Individual Subjects ....................... 58 
9.3 
Follow-up Investigation of Subjects Who Do not Visit the Trial Site .............. 59 
10 
Collection of Case Report Form Data and Specification of 
Source Data ......................................................................................... 59 
10.1 
Collection of Case Report Form Data ............................................................... 59 
10.2 
Source Documents ............................................................................................ 60 
10.3 
Case Report Form Items to Be Treated as Source Data .................................... 61 
10.4 
Data to Be Collected by the Sponsor ................................................................ 61 
11 
Statistical Analysis ............................................................................. 61 
11.1 
Analysis Sets ..................................................................................................... 61 
11.2 
Handling of Data ............................................................................................... 61 


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11.2.1 
Baseline and Baseline II ................................................................................. 61 
11.2.2 
Timepoint of Evaluation and Timepoint of Case Report Form Entry 
(Nominal Timepoint) ...................................................................................... 62 
11.2.3 
Endpoints Derived by Timeline Followback .................................................. 62 
11.3 
Analysis Items and Method ............................................................................... 62 
11.3.1 
Safety Analysis ............................................................................................... 62 
11.3.1.1 
Extent of Exposure ..................................................................................... 62 
11.3.1.2 
Adverse Events ........................................................................................... 63 
11.3.1.3 
Death, Other Serious Adverse Events and Other Significant Adverse 
Events ......................................................................................................... 64 
11.3.1.4 
Clinical Laboratory Tests ............................................................................ 65 
11.3.1.5 
Vital Signs and Body Weight ..................................................................... 66 
11.3.1.6 
Twelve-lead Electrocardiogram .................................................................. 66 
11.3.1.7 
Physical Examination ................................................................................. 66 
11.3.1.8 
Profile of Mood States ................................................................................ 67 
11.3.1.9 
Columbia-Suicide Severity Rating Scale .................................................... 67 
11.3.1.10 
Dependence Survey .................................................................................... 69 
11.3.2 
Efficacy Analysis ............................................................................................ 69 
11.3.2.1 
Number of Heavy Drinking Days ............................................................... 69 
11.3.2.2 
Total Alcohol Consumption ....................................................................... 70 
11.3.2.3 
Response Shift Drinking Risk Level .......................................................... 70 
11.3.2.4 
Response Low Drinking Risk Level ........................................................... 70 
11.3.2.5 
70% Total Alcohol Consumption Responder Rate ..................................... 70 
11.3.2.6 
Heavy Drinking Day Responder Rate ......................................................... 71 
11.3.2.7 
Clinical Global Impression-Severity of Illness ........................................... 71 
11.3.2.8 
Clinical Global Impression-Global Improvement ...................................... 71 
11.3.2.9 
SF-36 Subscales (Physical Functioning, Physical Role Functioning, 
Bodily Pain, General Health Perceptions, Vitality, Mental Health, 
Emotional Role Functioning, and Social Role Functioning), Physical 
Component Summary, and Mental Component Summary ......................... 71 
11.3.2.10 
EuroQol 5 Dimension Utility Score and EuroQol 5 Dimension Visual 
Analog Scale ............................................................................................... 71 
11.3.2.11 
Alcohol Quality of Life Scale ..................................................................... 71 


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11.3.2.12 
Resource Use Measurement Questionnaire-Alcohol Dependence ............. 71 
11.3.2.13 
Gamma-glutamyl Transferase ..................................................................... 72 
11.3.2.14 
Alanine Aminotransferase .......................................................................... 72 
11.3.3 
Disposition of Subjects................................................................................... 72 
11.3.4 
Demographic and Other Baseline Characteristics .......................................... 72 
11.4 
Procedures for Reporting Deviations From the Original Statistical 
Analysis Plan..................................................................................................... 73 
11.5 
Rationale for Sample Size Determination ......................................................... 73 
12 
Quality Control and Quality Assurance for the Trial .................... 73 
13 
General Items of Caution Pertaining to the Trial ........................... 74 
13.1 
Ethics and GCP Compliance ............................................................................. 74 
13.2 
Institutional Review Board ............................................................................... 74 
13.3 
Subject Consent ................................................................................................ 74 
13.3.1 
Procedures for Obtaining Consent ................................................................. 74 
13.3.2 
Contents of Informed Consent Form .............................................................. 75 
13.3.3 
Amendments to the Informed Consent Form ................................................. 76 
13.4 
Management of Investigational Medicinal Products ......................................... 76 
13.5 
Direct Access to Source Documents and Monitoring ....................................... 76 
13.5.1 
Direct Access to Source Documents .............................................................. 76 
13.5.2 
Monitoring ...................................................................................................... 77 
13.5.3 
Documents to Be Retained by the Investigator .............................................. 77 
13.6 
Deviations From and Changes or Amendments to the Trial Protocol .............. 77 
13.6.1 
Deviations From the Trial Protocol ................................................................ 77 
13.6.2 
Amendments to the Trial Protocol ................................................................. 77 
13.7 
Archiving of Records ........................................................................................ 78 
13.8 
Termination or Interruption of Part or All of the Trial ..................................... 78 
13.8.1 
Termination or Interruption of the Trial at Individual Trial Sites .................. 78 
13.8.2 
Termination or Interruption of the Entire Trial .............................................. 78 
13.9 
Protection of Subjects’ Personal Information ................................................... 79 
13.10 
Compensation for Injury to Health ................................................................... 79 
13.11 
Agreement on Publication ................................................................................. 79 
14 
Trial Administrative Structure ......................................................... 80 


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15 
Scheduled Duration of the Trial ....................................................... 80 
16 
References ........................................................................................... 80 
 
Appendix 1: 
Timeline Followback (TLFB) 
Appendix 2: 
Clinical Global Impression (CGI) 
Appendix 3: 
MOS 36-item Short-form Health Survey (SF-36) 
Appendix 4: 
EuroQol 5 Dimension (EQ-5D) 
Appendix 5: 
Alcohol Quality of Life Scale (AQoLS) 
Appendix 6: 
Resource Use Measurement Questionnaire-Alcohol 
Dependence (RUMQ-ADP) 
Appendix 7: 
Profile of Mood States (POMS) 
Appendix 8: 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Appendix 9: 
Dependence Survey 
 
Annex 1: 
Emergency Contact 
Annex 2: 
Trial Organization 
Annex 3: 
Lists of Trial Sites and Investigators Participating in the Trial 
 


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List of Abbreviations and Definition of Terms 
List of Abbreviations 
Abbreviation 
Expansion 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AQoLS 
Alcohol Quality of Life Scale 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC24h 
Area under the concentration-time curve from time zero to 24 hours 
AUC∞ 
Area under the concentration-time curve from time zero to infinity 
BAC 
Breath alcohol concentration 
BRENDA 
Biopsychosocial evaluation, Report to the patient on assessment, Empathic 
understanding of the patient's situation, Needs collaboratively identified by 
the patient and treatment provider, Direct advice to the patient on how to 
meet those needs, Assess reaction of the patient to advice and adjust as 
necessary for best care 
BUN 
Blood urea nitrogen 
CGI 
Clinical Global Impression 
CGI-I 
Clinical Global Impression-Global Improvement 
CGI-S 
Clinical Global Impression-Severity of Illness 
CRF 
Case report form 
CRP 
C-reactive protein 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DNA 
Deoxyribonucleic acid 
DRL 
Drinking risk level 
ECG 
Electrocardiogram, electrocardiography 
EDC 
Electronic Data Capture 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EQ-5D 
EuroQol 5 Dimension 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HCG 
Human chorionic gonadotropin 
HDD 
Heavy drinking day 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IMP 
Investigational medicinal product 
INN 
International nonproprietary name 
INR 
International normalized ratio 


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Abbreviation 
Expansion 
IRB 
Institutional review board 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
MCV 
Mean corpuscular volume 
MMRM 
Mixed model for repeated measures 
NYHA 
New York Heart Association 
PCS 
Potentially clinically significant 
PET 
Positron emission tomography 
PK 
Pharmacokinetic, pharmacokinetics 
PMDA 
Pharmaceuticals and Medical Devices Agency 
POMS 
Profile of Mood States 
PT 
Preferred term 
QTcB 
QT interval as corrected by Bazett’s formula 
QTcF 
QT interval as corrected by Fridericia’s formula 
RLDRL 
Response Low Drinking Risk Level 
RSDRL 
Response Shift Drinking Risk Level 
RUMQ-ADP 
Resource Use Measurement Questionnaire-Alcohol Dependence 
SF-36 
MOS 36-item Short-form Health Survey 
SOC 
System organ class 
SS 
Safety set 
TAC 
Total alcohol consumption 
TEAE 
Treatment-emergent adverse event 
TLFB 
Timeline Followback 
TMD 
Total mood disturbance 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
 
Definitions of Terms 
Term 
Definition 
Screen failure 
A screen failure is a subject from whom written informed consent was 
obtained, but who did not advance to the treatment period of this trial. 
Individual subject 
trial start date 
The day of obtaining the subject’s written informed consent 
Individual subject 
trial discontinuation 
date 
The day when the investigator or subinvestigator determined that the 
subject was to be withdrawn from the trial or the day of the 
withdrawal examination, whichever is later 
Individual subject 
trial completion date 
The day of posttreatment observation examination (final observation 
day) or the date of trial discontinuation for the subject 
Individual subject 
trial period 
Period from the day of obtaining the subject’s informed consent to the 
day of trial completion.  Does not include the period of follow-up 
investigation of adverse events (AEs). 


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1 
Introduction  
1.1 
Background of Trial Plan 
Alcohol dependence is a psychiatric disorder characterized by cognitive, behavioral, and 
physiological symptoms in addition to continued alcohol consumption despite serious 
alcohol-related problems.  The major symptoms of alcohol dependence include 
compulsive drinking behaviors, an increased tolerance to alcohol, and withdrawal 
symptoms associated with an elimination of alcohol in the body.1  Many patients with 
alcohol dependence also suffer from physical complications such as liver disorders and 
cardiovascular disorders as well as psychiatric disorders such as depression and 
anxiety.2,3  In addition, alcohol dependence is a serious social problem as it can be a 
cause of violent behaviors and traffic accidents by drinking driving.  It has been reported 
that the number of the patients with alcohol dependence who are receiving any treatment 
in Japan is around 50,000 by the survey of Ministry of Health, Labour and Welfare in 
2008.4  On the other hand, the number of the patients with alcohol dependence was 
estimated to be 800,000 in accordance with International Classification of Diseases and 
Related Health Problems 10th Revision criteria by the survey conducted in 2003, 
indicating that large number of patients is dependent on alcohol.5 
General treatment process for the patients with alcohol dependence in Japan consists of 1) 
introduction period to educate and motivate patients for disorder and treatment, 2) 
detoxification period to develop an appropriate response to acute intoxication and 
withdrawal symptoms, and 3) rehabilitation period to help continued abstinence.6  In this 
process, the principal goal in the treatment of alcohol dependence was abstinence.  In 
contrast, a new treatment strategy which incorporates the means of harm reduction7 has 
been proposed in order to alleviate physical and psychological complications by the 
reduction of alcohol consumption in addition to abstinence-oriented therapy in foreign 
countries.8  Like other countries, when abstinence is set as the sole goal, some alcohol-
dependent patients refuse treatment and some cannot continue the treatment before 
achieving abstinence, which is a clinical problem in Japan.  Thus, a new treatment 
strategy aiming at a reduction of alcohol consumption has recently been proposed in 
Japan.9,10 
Nalmefene (clinical trial ingredient code:  Lu AA36143; international nonproprietary 
name [INN]:  nalmefene) is an opioid receptor antagonist synthesized at Rockefeller 
University, USA in the 1960s.  Nalmefene selectively binds to opioid receptors, exerting 


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antagonist activity at the μ-opioid and δ-opioid receptors but partial agonist activity at the 
κ-opioid receptor.  It is known that endorphin, an intrinsic opioid, is associated with the 
reinforcing effects of alcohol.  Nalmefene is considered to decrease the reinforcing effects 
by counteracting the intrinsic opioid and reduce the alcohol consumption.11,12  Nalmefene 
showed a reduction in voluntary alcohol consumption in pharmacological studies using 
rodents.  H. Lundbeck A/S conducted clinical development of nalmefene in the EU and 
gained approval for marketing nalmefene hydrochloride 20 mg as a drug to be taken as 
needed for reducing alcohol consumption in alcohol-dependent patients in February 
2013.13 
Currently, alcohol-deterrent drugs (cyanamide and disulfiram) and a drug to help 
maintain alcohol abstinence (acamprosate calcium) are approved in Japan for the 
treatment of alcohol dependence.  However, there are no drugs approved with an 
indication of a reduction of alcohol consumption.  Based on the above background, 
Otsuka Pharmaceutical concluded that nalmefene, which possesses a new mechanism of 
action and is expected to be effective in reducing alcohol consumption, could 
significantly contribute to the medical treatment of alcohol dependence and began clinical 
development of nalmefene in Japan by entering into a contract for co-development with H. 
Lundbeck A/S in October 2013. 
1.2 
Study Results and Trial Rationale   
1.2.1 
Nonclinical Study Results 
Nalmefene had high affinity to all opioid receptor subtypes in vitro, exerting antagonist 
activity at the μ-opioid and δ-opioid receptors but partial agonist activity at the κ-opioid 
receptor.  No significant binding to other receptors, ion-channels and enzymes was 
observed.  Nalmefene had opioid antagonistic properties in the rat tail flick test and tail 
skin temperature response in rats.  In alcohol-preferring rats, concomitant administration 
of nalmefene reduces voluntary ethanol drinking. 
Single and repeated-dose toxicity studies, mutagenicity tests and carcinogenicity 
bioassays, reproduction and developmental toxicology, local tolerance studies and 
dependence tests were conducted. 
Safety pharmacological studies in animals showed no potential for interaction with the 
respiratory or cardiovascular systems, including the electrical conduction in the heart, at 
clinically relevant exposure levels.  There were behavioral changes with dose-related 
effect in rats at doses above 50 mg/kg (passivity, dispersion in cage, increased touch 


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response and catalepsy).  In single-dose acute toxicity studies in mice, rats, and rabbits 
severe toxicity (ataxia, convulsions) and deaths was induced in each species.  The 
minimal lethal dose after single oral dosing was 200 mg/kg in mice, 250 mg/kg in rats, 
and 225 mg/kg in rabbits.  Repeated-dose toxicity studies induced central nervous system 
toxicity (tremors, convulsions) and deaths in rats and dogs.  No other definable 
toxicological findings were seen in either species although multiple hematological, 
clinical pathological, and organ weight changes were recorded.  There were no 
histopathological findings considered to be treatment-related in rats and dogs. 
Nalmefene did not affect male or female fertility in rats and was not associated with fetal 
malformations or affected fetal viability in rats or rabbits and post natal development in 
rats.  A slight retardation in fetal development was noted in rabbit litters in terms of 
decreased ossification of the distal femur and reduced fetal weight at 200 mg/kg/day.  
Nalmefene has no genotoxic potential in a battery of in vitro and in vivo mutagenicity 
tests.  No carcinogenic potential was observed in the 104-week rat study.  The 80-week 
mouse carcinogenicity study was also negative.  In dependence study, nalmefene has been 
found to be free of any actions likely to result in drug abuse in primates. 
1.2.2 
Clinical Study Results 
Several clinical studies have been conducted overseas until now.  This section reports 
results of a positron emission tomography (PET) study in healthy Caucasian subjects 
(Study CPH-101-0902), pharmacokinetics (PK) and safety results of a phase 1 study in 
healthy Japanese subjects (Study 13505A), and the results of 3 phase 3 studies in patients 
with alcohol dependence (Studies 12014A, 12023A, and 12013A). 
1.2.2.1 
Results of PET Study in Healthy Caucasian Subjects (Study 
CPH-101-0902) 
A PET study in healthy Caucasian male subjects was conducted to investigate μ-opioid 
receptor occupancy in the brain region following single and once-daily 7-day repeated 
administration of nalmefene hydrochloride 20 mg.  As a result, μ-opioid receptor 
occupancy by nalmefene hydrochloride 20 mg reached 94% to 100% at 3 hours after 
administration and remained at 83% to 100% until 26 hours after administration.  Thus, it 
was shown that the maximal μ-opioid receptor occupancy rate (100%) can be achieved at 
20 mg. 


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1.2.2.2 
Results of Phase 1 Study in Healthy Japanese Subjects (Study 
13505A) 
Study 13505A consisted of Parts A and B.  In Part A conducted in a randomized, open-
label, 2-period crossover manner, 13 healthy Japanese males received a single oral dose 
of nalmefene hydrochloride at 20 mg under a fasted or fed condition to investigate food 
effect, safety, and tolerability.  In Part B conducted in a randomized, double-blind, 
placebo-controlled, parallel-group manner, 81 healthy subjects consisting of 21 male and 
20 female Japanese and 20 male and 20 female Caucasians received 5-day repeated oral 
doses of nalmefene hydrochloride at 20 and 40 mg to investigate PK, safety, and 
tolerability. 
In Part A, when nalmefene hydrochloride 20 mg was orally administered under a fasted 
condition, the plasma nalmefene concentration reached the highest (27.0 ng/mL) 
approximately 1.5 hours after the administration, with a mean area under the 
concentration-time curve from time zero to infinity (AUC∞) of 159 ng∙h/mL and half-life 
of 12.2 hours.  Under a fed condition, the plasma concentration reached the highest 
(25.4 ng/mL) approximately 1 hour after the administration, with a mean AUC∞ of 
156 ng∙h/mL and half-life of 12.3 hours.  No influence of food on the PK of nalmefene 
hydrochloride was found.  In Part B, in which when 20 mg was administered to Japanese 
male and female subjects, the plasma concentration reached the highest (30.8 ng/mL and 
37.6 ng/mL) approximately 1 hour and 0.5 hour after the administration on Day 1, 
respectively, with a mean area under the concentration-time curve from time zero to 
24 hours (AUC24h) of 137 ng∙h/mL and 140 ng∙h/mL, respectively.  On Day 5, the plasma 
concentration reached the highest (44.1 ng/mL and 53.4 ng/mL) approximately 0.5 hour 
after the administration both in male and female subjects, with a mean AUC24h of 
187 ng∙h/mL and 186 ng∙h/mL, respectively, and half-life of 11.2 hours and 11.1 hours, 
respectively.  The maximum (peak) plasma concentration of the drug (Cmax) and AUC24h 
were slightly higher on Day 5 than on Day 1, but clinically significant accumulation was 
not observed.  Exposure (area under the concentration-time curve [AUC] and Cmax) was 
slightly higher in Japanese subjects than in Caucasian subjects, but there were no 
clinically significant differences between the races. 
Major adverse events (AEs) (reported in at least 2 subjects) were fatigue, dizziness, and 
back pain in Part A and fatigue, dizziness, nausea, headache, back pain, euphoric mood, 
decreased appetite, nasopharyngitis, oropharyngeal pain, apathy, and hyperhidrosis in Part 
B.  In both parts, most of these AEs were mild in severity.  In Part A, one Japanese male 


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subject withdrew from the trial due to bacterial infection, whereas in Part B, one Japanese 
male subject withdrew from the trial due to dizziness, fatigue, and nausea that occurred 
after the administration of nalmefene hydrochloride 20 mg, and one Caucasian male 
withdrew due to anemia (prior to investigational medicinal product [IMP] administration).  
No serious AEs were reported in either part.  In addition, there were no clinically 
significant changes in blood pressure, pulse rate, electrocardiogram (ECG) parameters, 
physical examinations, or clinical laboratory safety assessments.  The safety and 
tolerability profiles in Japanese subjects were similar to those in Caucasian subjects. 
Based on the results of the phase 1 study in healthy Japanese subjects mentioned above, 
nalmefene hydrochloride at 20 mg and 40 mg is considered to have no major safety 
concerns in Japanese subjects. 
1.2.2.3 
Results of Phase 3 Studies in Patients With Alcohol 
Dependence 
Among three phase 3 studies, Study 12014A and Study 12023A were conducted to 
evaluate the efficacy of nalmefene hydrochloride 20 mg as-needed use for 24 weeks 
(hereinafter referred to as foreign phase 3 confirmatory studies) and Study 12013A was 
conducted to evaluate the safety of nalmefene hydrochloride 20 mg as-needed use for one 
year (hereinafter referred to as foreign phase 3 extension study).  One-year efficacy results 
were described for Study 12013A. 
1.2.2.3.1 
Results of Foreign Phase 3 Confirmatory Studies (Studies 
12014A and 12023A) 
Two foreign phase 3 confirmatory studies with the same design were conducted by H. 
Lundbeck A/S in separate areas in EU.  These foreign phase 3 confirmatory studies were 
conducted in patients with alcohol dependencea who had at least medium drinking risk 
level3 (DRL) as randomized, double-blind, placebo-controlled, parallel-group 
comparative study to evaluate the efficacy and safety of oral nalmefene hydrochloride 
20 mg as-needed use for 24 weeks. 
In both studies, the number of heavy drinking days (HDDs) and total alcohol 
consumption (TAC) were the co-primary efficacy endpoints.  In Study 12014A, 
nalmefene hydrochloride 20 mg was significantly superior to placebo in change in the 
number of HDDs and change in TAC from baseline until 24 weeks after start of 
                                                 
aIn the foreign phase 3 studies, Diagnostic and Statistical Manual of Mental Disorders, 4th 
Edition, Text Revision was adopted for diagnostic criteria for alcohol dependence. 


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administration.  In Study 12023A, nalmefene was superior to placebo in the change in the 
number of HDDs, but the reduction in TAC by nalmefene was not statistically significant 
compared with placebo. 
These two studies were conducted in patients including those who had medium DRL.  
According to the European Medicines Agency (EMA) guideline on the development of 
medicinal products for the treatment of alcohol dependence,14  patients enrolled in 
alcohol reduction studies should have a high or very high DRL.  Furthermore, since a 
large reduction in alcohol consumption was observed in the observation period before 
randomization, there were many patients with improved DRL prior to therapeutic 
intervention in these studies.  Thus, H. Lundbeck A/S conducted a post hoc analysis of 
the primary efficacy outcome in patient population in accordance with above-mentioned 
EMA guideline and whose alcohol consumption was not improved before the therapeutic 
intervention (ie, who had high or very high DRL at both screening and randomization).  
As a result, a statistically significant difference in favor of nalmefene in the change of the 
number of HDDs and TAC compared to placebo was observed in both Studies 12014A 
and 12023A (p < 0.05). 
Nalmefene was administered to 302 and 341 subjects in Study 12014A and Study 
12023A (described in the same order hereinafter), respectively, and placebo to 296 and 
337 subjects, respectively.  The incidences of AEs in the nalmefene hydrochloride group 
were 81% and 68%, respectively, and those in the placebo group were 67% and 59%, 
respectively.  Most of AEs were either mild or moderate in severity.  Withdrawal from 
the study due to AEs occurred in 23% and 7% in the nalmefene hydrochloride group, 
respectively, and 7% and 6% in the placebo group, respectively.  Serious AEs occurred in 
6% and 2% in the nalmefene hydrochloride group, respectively, and 5% and 3% in the 
placebo group, respectively.  The most commonly reported treatment-emergent adverse 
events (TEAEs) in the nalmefene hydrochloride group that occurred with an incidence 
≥ 5% and more than twice higher than placebo during the treatment period were dizziness, 
nausea, fatigue, sleep disorder, insomnia, vomiting, and hyperhidrosis in Study 12014A 
and nausea, dizziness, insomnia, and vomiting in Study 12023A.  The changes in clinical 
laboratory values during the treatment period were similar between the nalmefene 
hydrochloride group and placebo group in both studies, and most of the values were 
within normal range.  No clinically significant changes were observed in blood pressure, 
pulse rate, body weight, 12-lead ECG parameters, and Profile of Mood States (POMS) 
score in either study. 


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1.2.2.3.2 
Results of Foreign Phase 3 Extension Study (Study 12013A) 
Study 12013A was conducted in patients with alcohol dependence who had at least low 
DRL as randomized, double-blind, placebo-controlled, parallel-group comparative study 
to evaluate the safety and efficacy of oral nalmefene hydrochloride 20 mg as-needed use 
for 1 year. 
In Study 12013A, statistically significant differences in the change in the number of 
HDDs and in TAC at 52 Week from baseline compared with placebo were seen 
(p < 0.05).  In addition, statistically significant differences were also observed in the 
patients with high or very high DRL at both baseline and randomization. 
Nalmefene was administered to 501 subjects, and placebo to 164 subjects.  The incidence 
of AEs was 75% in the nalmefene hydrochloride group and 63% in the placebo group.  
Withdrawal due to AEs occurred in 11% in the nalmefene hydrochloride group and 3% in 
the placebo group.  Serious AEs occurred in 7% in the nalmefene hydrochloride group 
and 5% in the placebo group.  The most commonly reported TEAEs (reported in ≥ 5% 
and more than twice higher than that in the placebo group) in the nalmefene 
hydrochloride group during the treatment period were nausea, insomnia, dizziness, 
vomiting, fatigue, and decreased appetite. 
Adverse events which occurred beyond 6 months after randomization were reviewed in 
order to evaluate AEs under long-term treatment.  The numbers of patients receiving 
treatment for 6 months or longer were 388 and 133 in the nalmefene hydrochloride group 
and placebo group, respectively.  The incidences of AEs under long-term treatment were 
43% and 40.5% in the nalmefene hydrochloride group and placebo group, respectively.  
The incidences of the most commonly reported AEs in the nalmefene hydrochloride 
group (nausea, insomnia, dizziness, vomiting, fatigue, and decreased appetite) were < 5% 
under long-term treatment.  The AEs which occurred with an incidence ≥ 5% in either 
nalmefene hydrochloride group or placebo group included nasopharyngitis (4.9% in the 
nalmefene hydrochloride group and 9.9% in the placebo group, described in the same 
order hereinafter), headache (5.9% and 5.3%), and insomnia (4.6% and 5.3%). 
In this study, changes in clinical laboratory values during the treatment period were 
similar between the nalmefene hydrochloride group and placebo group, and most of the 
values were within normal range.  No clinically significant changes were observed in 
blood pressure, pulse rate, weight, 12-lead ECG parameters, and POMS score in this 
study. 


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As mentioned above, no significant safety concerns with long-term administration of 
nalmefene hydrochloride were suggested in the clinical study conducted overseas. 
1.2.3 
Trial Rationale 
Nonclinical studies of nalmefene hydrochloride required for the conduct of the proposed 
clinical trial have already been completed overseas.  The efficacy of nalmefene 
hydrochloride 20 mg has been verified in multiple clinical trials in patients with alcohol 
dependence, and nalmefene hydrochloride 20 mg is approved in Europe.  Prior to this 
trial, Study 339-14-001 is planned in order to verify the efficacy of nalmefene 
hydrochloride 20 mg and to collect information on dose response.  While the treatment 
duration in Study 339-14-001 is 24 weeks, we deemed it necessary to accumulate safety 
data on 1-year treatment, considering the possibility that nalmefene is administered for a 
long term in the clinical settings.  The duration of IMP treatment of this trial will be 
28 weeks (treatment period plus run-out period).  When combined with the preceding 
Study 339-14-001, the maximum duration of IMP treatment will be 52 weeks.  Also, 
results of the phase 1 study in healthy Japanese subjects (Study 13505A) showed that the 
safety and tolerability profiles in Japanese subjects were similar to those in Caucasian 
subjects with no clinically significant difference between races although the exposure to 
nalmefene hydrochloride 20 mg tended to be slightly higher in Japanese subjects than 
Caucasian subjects.  The dose of nalmefene hydrochloride in this extension study is set at 
20 mg, the highest dose in the preceding Study 339-14-001.  Thus, this clinical trial was 
planned in order to investigate long-term safety of nalmefene hydrochloride 20 mg. 
Prior to the conduct of the present clinical trial, we had “Consultations after End of 
phase 2 study for drugs (other than orphan drug)” with the Pharmaceuticals and Medical 
Devices Agency (PMDA) on 16 May 2013 and 11 Jul 2014.  After receiving advice for 
this trial from the PMDA, we reflected it in the trial protocol. 
See the investigator’s brochure for further details of data mentioned in this protocol 
and other trial results. 
 
2 
Trial Objectives 
The long-term safety and efficacy of nalmefene hydrochloride at 20 mg in patients with 
alcohol dependence will be evaluated in a multicenter, open-label, uncontrolled trial. 
 


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3 
Trial Plan 
3.1 
Trial Design 
This trial is intended to evaluate the long-term safety of nalmefene hydrochloride at 
20 mg in patients with alcohol dependence who have completed Study 339-14-001.  The 
outline of the trial design is shown in Figure 3.1-1. 
This trial will consist of 1) a 24-week treatment period (open-label, uncontrolled), 2) a 
4-week run-out period (double-blind, placebo-controlled), and 3) a 4-week posttreatment 
observation period.  The duration of IMP treatment of this trial will be 28 weeks 
(treatment period plus run-out period).  When combined with the preceding Study 339-
14-001, the maximum duration of IMP treatment will be 52 weeks. 
The investigator or subinvestigator will fully explain the details of this trial and obtain 
written informed consent from each subject by the end of the treatment period of Study 
339-14-001. 
In the treatment period, nalmefene hydrochloride will be administered at 20 mg.  Each 
subject will be instructed to take the IMP orally on days when the subject perceives a risk 
of drinking alcohol, as needed 1 to 2 hours prior to the anticipated risk of drinking.  The 
IMP can be taken up to one tablet a day (one day is defined as the period from 0 AM of 
the day to 0 AM of the next day), and if a subject requires dose change during the 
treatment period, the subject will be withdrawn from the trial.  When a subject is 
withdrawn from the trial, the subject will be requested to visit the site and to undergo the 
specified assessments and examinations wherever possible. 
In the run-out period, subjects will be randomized to either nalmefene hydrochloride 
20 mg group or placebo group at 1:1 ratio.  Each subject will be instructed to take the 
IMP orally on days when the subject perceives a risk of drinking alcohol, as needed 1 to 
2 hours prior to the anticipated risk of drinking.  The IMP can be taken up to one tablet a 
day (one day is defined as the period from 0 AM of the day to 0 AM of the next day), and 
if a subject requires dose change during the run-out period, the subject will be withdrawn 
from the trial.  When a subject is withdrawn from the trial, the subject will be requested 
to visit the site and to undergo the specified assessments and examinations wherever 
possible. 
A posttreatment observation period will be scheduled after the end of the run-out period 
to evaluate safety after the end of treatment with nalmefene hydrochloride.  However, 


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posttreatment observation will be performed only in subjects who complete the run-out 
period. 
 
Figure 3.1-1 
Summary of Trial Design 
V = visit. 
Posttreatment observation will be performed only in subjects who complete the run-out period. 
 
3.2 
Rationale for Trial Design 
3.2.1 
Rationale for Dose and Dosage Regimen 
This trial is a long-term extension study subsequently conducted following a phase 3 
study (Study 339-14-001) to evaluate efficacy and safety of nalmefene hydrochloride at 
10 mg and 20 mg in Japanese patients with alcohol dependence.  As once-a-day as-
needed use at 1 to 2 hours before drinking is employed in the preceding phase 3 study 
(Study 339-14-001), the same dosage regimen will be used in this extension study.  The 
dose of nalmefene hydrochloride in this extension study is set at 20 mg, the highest dose 
in the preceding phase 3 study (Study 339-14-001). 
3.2.2 
Rationale for Trial Duration 
Considering the possibility that nalmefene is administered for a long term exceeding 
24 weeks in the clinical settings, we have set the treatment duration of this trial at 
24 weeks, making the total treatment duration 48 weeks when combined with the 
24-week treatment period of the preceding Study 339-14-001.  In addition, a 4-week run-


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out period has been employed to evaluate any withdrawal symptoms.  Based on the above, 
the duration of the administration in this trial is set at 28 weeks. 
3.2.3 
Rationale for Run-out Period 
In the foreign phase 3 confirmatory trials (Studies 12014A and 12023A), a 4-week run-
out period following a 24-week treatment period was adopted in order to evaluate any 
discontinuation effect of nalmefene hydrochloride.  In the present trial, a 4-week run-out 
period will be adopted with reference to the foreign phase 3 confirmatory trials (Studies 
12014A and 12023A), and the discontinuation effects of this drug will be evaluated after 
the re-randomization to nalmefene hydrochloride group or placebo group.  Dependency 
on this drug will be evaluated with Dependency Assessment Form A. 
3.2.4 
Rationale for Posttreatment Observation Period 
This period is scheduled to evaluate the effects after the long-term treatment with 
nalmefene hydrochloride.  Withdrawal symptoms from this drug will be evaluated with 
Dependency Assessment Form B. 
3.3 
Variables 
3.3.1 
Safety 
 Adverse events, clinical laboratory values, blood pressure and pulse rate, body 
weight, 12-lead ECG, physical examination, POMS, Columbia-Suicide Severity 
Rating Scale (C-SSRS), and dependence survey 
 
3.3.2 
Efficacy 
Baseline for the number of HDDs, TAC, and DRL is defined as the data collected by the 
Timeline Followback (TLFB) method during the period of 4 weeks before the Screening 
Visit of Study 339-14-001.  One month is defined as 4 weeks (28 days) for this trial. 
 Change in the number of HDDs from baseline 
(The number of HDDs is defined as the number of days per month [days/month] 
with alcohol consumption per day of > 60 g for males and > 40 g for females) 
 Change in TAC from baseline 
(TAC is defined as mean alcohol consumption per day [g/day] over a 1-month 
period) 


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 Response Shift Drinking Risk Level (RSDRL):  The percentage of subjects with 
a downward shift in DRL of 2 categories or moreb from baseline 
 Response Low Drinking Risk Level (RLDRL):  The percentage of subjects with 
a low DRL or below 
 70% TAC responder rate:  The percentage of subjects whose TAC is reduced by 
≥ 70% from baseline 
 HDD responder rate:  The percentage of subjects in whom the number of HDDs 
is ≤ 4 
 Clinical Global Impression-Severity of Illness (CGI-S) 
 Clinical Global Impression-Global Improvement (CGI-I) 
 MOS 36-item Short-form Health Survey (SF-36) 
 EuroQol 5 Dimension (EQ-5D) 
 Alcohol Quality of Life Scale (AQoLS) 
 Resource Use Measurement Questionnaire-Alcohol Dependence (RUMQ-ADP) 
 Gamma-glutamyl transferase (GGT) 
 Alanine aminotransferase (ALT) 
 
[Rationale for variable selection] 
  [Safety] 
Items necessary for safety evaluation have been selected. 
  [Efficacy] 
The number of HDDs and TAC are set as primary efficacy variables for IMPs aiming 
at harm reduction in the EMA guideline on the development of medicinal products 
for the treatment of alcohol dependence,14 and were used as the co-primary efficacy 
variables in foreign phase 3 studies of nalmefene hydrochloride.  In the present study, 
the variables were selected with reference to the guideline and the foreign clinical 
studies. 
 
3.4 
Number of Patients Planned 
Approximately 400 subjects who advance from Study 399-14-001 
 
                                                 
bA shift to medium DRL or lower for patients with a very high DRL at baseline; a shift to low 
DRL or below for patients with a high DRL at baseline 


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4 
Investigational Medicinal Products 
4.1 
Test Product and Comparator 
4.1.1 
Test Product 
Code Name 
Lu AA36143 
Generic Name 
INN:  Nalmefene 
Chemical Name 
17-(cyclopropylmethyl)-4,5α-epoxy-6-methylenemorphinan-3,14-
diol 
Content and Formulation White film-coated tablets containing 20 mg (as an anhydride of 
nalmefene hydrochloride) per tablet 
Storage Conditions 
Store at room temperature 
Supplier 
H. Lundbeck A/S 
 
4.1.2 
Comparator:  Placebo 
Content and Formulation Placebo tablets that are indistinguishable in appearance from 
nalmefene hydrochloride tablets 20 mg 
Storage Conditions 
Store at room temperature 
Supplier 
H. Lundbeck A/S 
 
4.2 
Packaging and Labeling 
4.2.1 
Packaging 
Fourteen tablets of nalmefene hydrochloride 20 mg or placebo are packaged in a blister 
card with a tamper-resistant seal. 
4.2.2 
Contents of Label 
The following information is written on the labels of IMP(s):  specification that the drug 
is for use in a clinical trial, the code name of the IMP, lot number, expiration date, storage 
conditions, name and address of the sponsor, etc. 
 


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5 
Trial Population 
5.1 
Target Disease 
Alcohol dependent patients 
5.2 
Inclusion Criteria 
Patients who meet all of the following inclusion criteria will be selected. 
1) Patients who have completed Study 339-14-001. 
2) Patients who have signed the informed consent form (ICF) for Study 339-14-002. 
 
[Rationale for Inclusion Criteria] 
1) 
This criterion was set to evaluate the safety of long-term treatment with 
nalmefene hydrochloride. 
2) 
For appropriate assessments of the IMP. 
 
5.3 
Exclusion Criteria 
Patients who fall under any of the following exclusion criteria at the examination at the 
end of the treatment period of Study 339-14-001 will be excluded from the trial. 
1) The patient has a clinically significant unstable illness (eg, complication of New 
York Heart Association [NYHA] class III or IV heart failure or angina pectoris, 
renal function disorder with estimated glomerular filtration rate [eGFR] of 
< 30 mL/min/1.73 m2, hepatic failure, and neoplastic disorder). 
2) The patient has a clinically significant abnormal ECG which is inappropriate for 
the participation in the trial in the opinion of the investigator or subinvestigator. 
3) The patient satisfies at least one of the following suicide risk criteria: 
 Answers “Yes” on the C-SSRS Suicidal Ideation Item 4 (Active Suicidal 
Ideation with Some Intent to Act, without Specific Plan) or the C-SSRS Suicidal 
Ideation Item 5 (Active Suicidal Ideation with Specific Plan and Intent) and 
whose episode meeting criteria for any of these 2 C-SSRS Ideation Items 
occurred within the last 6 months, OR 
 Answers “Yes” on any of the 5 C-SSRS Suicidal Behavior Items (Actual 
Attempt [non-fatal], Interrupted Attempt, Aborted Attempt, Preparatory Acts or 
Behavior, Completed Suicide) and whose most recent episode meeting criteria 
for any of these 5 C-SSRS Suicidal Behavior Items occurred within the last 
2 years, OR 
 The patient is, in the opinion of the investigator or subinvestigator, at significant 
risk of suicide. 


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4) The patient has at least one of the following laboratory findings: 
 Red blood cell count:  < 3,000,000/mm3, hemoglobin:  < 9.5 g/dL, white blood 
cell count:  < 3,000/mm3, platelet count:  < 75,000/mm3 
 Alanine aminotransferase or aspartate aminotransferase (AST) > 3 times the 
upper limit of normal (ULN) 
5) The patient is mainly engaged in driving or those engaged in potentially hazardous 
activities, such as operating machinery or working in high place. 
6) Women who are pregnant or breast-feeding, who may be pregnant, or who wish to 
become pregnant during the trial and within 4 weeks after the final IMP 
administration.  Men whose partners wish to become pregnant during the trial and 
within 4 weeks after the final IMP administration.  Also, patients who or whose 
partners cannot use birth control. 
7) Patients otherwise judged by the investigator or subinvestigator to be 
inappropriate for inclusion in the trial for any reason. 
 
[Rationale for Exclusion Criteria] 
1)-5) This criterion was set to ensure subject safety. 
6) 
The safety of nalmefene hydrochloride in fetuses has not been established. 
7) 
For appropriate assessments of the IMP. 
 
Reference:  NYHA Classification 
Class I 
Patients with cardiac disease but resulting in no limitation of physical activity.  
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or 
anginal pain. 
Class II 
Patients with cardiac disease resulting in slight limitation of physical activity.  They are 
comfortable at rest.  Ordinary physical activity results in fatigue, palpitation, dyspnea, 
or anginal pain. 
Class III 
Patients with cardiac disease resulting in marked limitation of physical activity.  They 
are comfortable at rest.  Less than ordinary activity causes fatigue, palpitation, dyspnea, 
or anginal pain. 
Class IV 
Patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort.  Symptoms of heart failure or the anginal syndrome may be present 
even at rest.  If any physical activity is undertaken, discomfort increases. 
 
Source:  Guidelines for Diagnosis and Treatment of Cardiovascular Diseases (2004-2005 Joint 
Working Group Report) 
 
[Digest version] Guidelines for Treatment of Acute Heart Failure (2006 revised version) 
 
Academic societies that participated in the joint working groups:  The Japanese Circulation Society, 
The Japanese Association for Thoracic Surgery, The Japanese Society for Cardiovascular Surgery, 
The Japanese College of Cardiology, and The Japanese Heart Failure Society 
 
http://www.j-circ.or.jp/guideline/pdf/JCS2006_maruyama_d.pdf 
 


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Risk Levels Defined by the World Health Organization Based on Average Volume of 
Alcohol Consumption per Day 
DRL 
Men 
Women 
Very high 
> 100 g 
> 60 g 
High 
> 60 g - ≤ 100 g 
> 40 g - ≤ 60 g 
Medium 
> 40 g - ≤ 60 g 
> 20 g - ≤ 40 g 
Low 
≥ 1 g - ≤ 40 g 
≥ 1 g - ≤ 20 g 
 
6 
Trial Design 
6.1 
Dose, Regimen, and Treatment Period 
6.1.1 
Dose and Regimen 
All subjects will receive a nalmefene hydrochloride tablet 20 mg in the treatment period 
and either a nalmefene hydrochloride tablet 20 mg or a placebo tablet in the run-out 
period.  Each subject will be instructed to take one tablet (nalmefene hydrochloride 20 mg 
or placebo) on days when the subject perceives a risk of drinking alcohol, as needed 1 to 
2 hours before the anticipated risk of drinking.  If the subject has started drinking alcohol 
without taking the IMP, the subject should take one tablet as soon as possible.  The IMP 
can be taken up to one tablet a day (one day is defined as the period from 0 AM of the day 
to 0 AM of the next day).  Tablets must not be divided. 
6.1.2 
Treatment Period 
28 weeks (24 weeks for a treatment period and 4 weeks for a run-out period) 
[Rationale for dose, regimen, and treatment period] 
Described in Section 3.2, Rationale for Trial Design. 
 
6.2 
Prior and Concomitant Treatment 
If a drug other than an IMP has been used during the period from the acquisition of 
consent to the end of the trial, the name of the drug, purpose of use, mode of 
administration, daily dose, route of administration, and dates of start and end of 
administration will be recorded in the case report form (CRF).  For a non-drug therapy, 
the name of therapy, purpose, and dates of start and end of treatment will be recorded in 
the CRF. 


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6.2.1 
Prohibited Concomitant Drugs and Restricted Concomitant 
Drugs 
Restriction on drugs to be used during the trial is set for each drug class.  The prohibited 
or restricted concomitant drugs (including over-the-counter drugs) in this trial are 
presented in Table 6.2.1-1.  The concomitant use of those drugs will be prohibited or 
restricted in the period from eligibility confirmation (Visit 1, at the end of the treatment 
period of Study 339-14-001) until the end of the run-out period (Visit 11) or withdrawal. 
Table 6.2.1-1 
Prohibited and Restricted Concomitant Therapy 
Drug Class 
Comments or Exceptions 
Agents used for treatment of 
alcohol dependence 
Including oral and injectable naltrexone, acamprosate calcium, 
topiramate, disulfiram, and cyanamide. 
IMPs for other trials and drugs not 
approved in Japan 
- 
Opioid analgesics 
Non-opioid analgesics are allowed to use. 
Opioid antidiarrheal drugs 
Non-opioid antidiarrheals are allowed to use. 
Antitussive drugs and cold 
medicines containing opioids 
Non-opioid antitussive drugs and cold medicines are allowed to use. 
Antidepressants 
- 
Antipsychotics 
- 
Anticonvulsants 
- 
Anxiolytics 
As-needed use is allowed. 
Hypnotics 
As-needed use is allowed. 
Anorexics 
- 
Psychotropic agents not otherwise 
specified (including herbal agents 
used against mental disorder) 
- 
Antineoplastics 
- 
Muscle relaxants 
As-needed use is allowed. 
Insulin 
- 
Anticoagulants 
- 
Antibiotics with possible 
interaction with alcohol 
(nitrofurantoin, metronidazole, and 
tinidazole) 
- 
Antifungal agents (systemic) 
Local antifungal agents are allowed to use. 
Steroids 
Local and inhalation steroids, oral contraceptives, and hormone 
replacement therapy are allowed. 
 
[Rationale for prohibited prior drugs, prohibited concomitant drugs, and restricted 
concomitant drugs] 
Those drugs are prohibited or restricted because they may significantly affect the 
efficacy and safety of the IMP. 
 


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6.2.2 
Concomitant Therapies 
All subjects will receive BRENDA approach as a psychosocial therapy.  It comprises six 
components covering the most important aspects of a psychosocial therapy for patients 
with alcohol dependence in a concise manner.  In addition, it is a strategy to manage an 
appropriate treatment for a patient by the collaboration between the treatment provider 
and the patient.  It is used to provide psychosocial support to patients and to ensure and 
enhance treatment compliance and is particularly well suited in conjunction with 
pharmacotherapy.  In this trial, trained personnel such as the investigator, subinvestigator, 
and clinical psychologist will perform BRENDA approach at each visit after Week 0 
(Visit 2). 
At each visit, BRENDA approach will be conducted according to its manual by the 
investigator, subinvestigator, or other personnel such as clinical psychologist.  The 
investigator or subinvestigator will document the results of BRENDA approach in the 
medical record and the date of the conduct in the CRF.  Psychosocial therapy other than 
BRENDA approach is not permitted in the period from eligibility confirmation (Visit 1) 
until the completion of the examination of the run-out period (Visit 11).  BRENDA 
approach comprises the following six components: 
 Biopsychosocial evaluation 
 Report to the patient on assessment 
 Empathic understanding of the patient’s situation 
 Needs collaboratively identified by the patient and treatment provider 
 Direct advice to the patient on how to meet those needs 
 Assess reaction of the patient to advice and adjust as necessary for best care 
 
All BRENDA providers are required to be trained and certified to ensure that BRENDA 
approach is applied according to the manual.  Before starting the trial, the sponsor will 
plan and provide the training for BRENDA approach.  Only providers who have received 
BRENDA training and met the criteria for certification will be authorized to perform 
BRENDA approach during the trial.  Training certificates will be issued to the trained 
personnel such as the investigator, subinvestigator, and clinical psychologist, and kept by 
the investigator. 
When a new BRENDA provider is added during the trial period, the provider will be 
certified in accordance with the same procedure. 


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6.3 
Method of Minimizing or Avoiding Bias 
An interactive web response system (IWRS) and interactive voice response system 
(IVRS) will be used in this trial. 
The run-out period of this trial is a randomized double-blind phase.  The investigator, 
subinvestigator, and subjects are blind to the IMP randomization code.  The sponsor’s 
trial staff, including personnel of contract research organizations, are also unable to 
access the IMP randomization code during the trial period. 
The randomization table will be kept under strict control by the IMP allocation manager 
until unblinding after fixation of all CRFs and the database. 
The emergency code list will be controlled by the IWRS and IVRS until the end of the 
trial, and, if a medical emergency occurs in a subject and knowledge of his or her IMP 
randomization code is considered important for treatment, the emergency code will be 
broken according to Section 8.2.3, Emergency Code Breaking (Procedure for Unblinding 
During the Trial Period). 
When IMPs are recovered by the sponsor prior to unblinding, they are to be recovered 
sealed by the study drug manager. 
 
7 
Trial Procedures 
7.1 
Schedule and Procedures  
The schedule of observations, examinations, and evaluations is shown in Table 7.1-1.  
The investigator or subinvestigator will perform observations, examinations, and 
evaluations in accordance with this schedule.  Items that trial associates are capable of 
performing, such as the subject demographic survey and clinical laboratory tests, may be 
performed by trial associates under the supervision of the investigator. 


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Table 7.1-1 
Trial Schedule 
 
 
Treatment Period 
Run-
out 
Period 
Post- 
treatment 
Observation 
Withdrawalb 
Visit 
V1a 
(Eligibility) 
V2 V3 V4 V5 V6 V7 V8 V9 
V10 
(Randomized) 
V11 
V12 
 
Week 
 
0 
1 
2 
4 
8 12 16 
20 
24 
28 
32 
 
Day 
 
1 
8 15 29 57 85 113 141 
169 
197 
225 
 
Acceptable time window 
for visit (Day)c 
−7 
0 ± 3 ± 3 ± 7 ± 7 ± 7 ± 7 ± 7 
± 7 
± 7 
± 7 
 
Signed informed consentd 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
■ 
 
 
 
 
 
 
 
 
 
 
 
 
BACe 
 
● ● ● ● ● ● 
● 
● 
● 
● 
● 
● 
Inclusion/exclusion criteria 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
● 
 
 
 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
TLFBf,g 
 
● ● ● ● ● ● 
● 
● 
● 
● 
 
● 
CGI-Sg 
 
● ● ● ● ● ● 
● 
● 
● 
● 
 
● 
CGI-I 
 
● ● ● ● ● ● 
● 
● 
● 
● 
 
● 
SF-36g 
 
 
 
 
 
 
● 
 
 
● 
● 
 
● 
EQ-5Dg 
 
 
 
 
 
 
● 
 
 
● 
● 
 
● 
AQoLSg 
 
 
 
 
 
 
● 
 
 
● 
● 
 
● 
RUMQ-ADPg 
 
 
 
 
 
 
● 
 
 
● 
● 
 
● 
GGTg 
■ 
 
 
 
 
 
● 
 
 
● 
● 
 
● 
ALTg 
■ 
 
 
 
 
 
● 
 
 
● 
● 
 
● 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory testsg 
■ 
 
 
 
 
 
● 
 
 
● 
● 
● 
● 
Vital signs and body weightg 
 
● ● ● ● ● ● 
● 
● 
● 
● 
● 
● 
12-lead ECGg 
■ 
 
 
 
 
 
● 
 
 
● 
● 
● 
● 
Examinations (physical)g 
 
 
 
 
 
 
● 
 
 
● 
● 
● 
● 
POMSg 
 
 
 
 
 
 
● 
 
 
● 
● 
● 
● 
C-SSRSg 
■ 
● 
● 
● ● ● ● 
● 
● 
● 
● 
● 
● 
Assessment of dependency A 
 
 
 
 
 
 
 
 
 
 
● 
 
 
Assessment of dependency B 
 
 
 
 
 
 
 
 
 
 
 
● 
 
Others 
 
 
 
 
 
 
 
 
 
 
 
 
 
BRENDA approach 
 
● ● ● ● ● ● 
● 
● 
● 
● 
● 
● 
IMP dispensed 
 
● ● ● ● ● ● 
● 
● 
● 
 
 
 
IMP returned and IMP 
accountability 
 
 
● ● ● ● ● 
● 
● 
● 
● 
 
● 
Concomitant drugs and 
therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of the newly 
started treatment for alcohol 
dependence 
 
 
 
 
 
 
 
 
 
 
 
● 
● 
Pregnancy testh 
■ 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
BAC = breath alcohol concentration; V = visit 
■ The data at the visit at the end of the treatment period (Visit 10) of Study 339-14-001 will be used. 


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aVisit 1 of Study 339-14-002 and the visit at the end of the treatment period (Visit 10) of Study 339-14-
001 will be performed at the same time. 
bThis visit should take place as soon as possible after the withdrawal is decided.  If a subject drops out 
before the start of the treatment period, the withdrawal examination will not be conducted, but the 
follow-up will be performed at 4 weeks after the completion of the treatment period of Study 339-14-
001.  If a subject is withdrawn after the completion of the run-out period, efficacy evaluation (TLFB, 
CGI-S, CGI-I, SF-36, EQ-5D, AQoLS, and RUMQ-ADP) will be unnecessary. 
cIf a date of a subject visit does not conform to the acceptable time window for the visit, subsequent 
visits should be planned to maintain the visit schedule relative to Week 0 (the start date of the 
treatment period, Visit 2). 
dInformed consent for this trial will be obtained before the completion of Study 339-14-001. 
eA breath alcohol concentration (BAC) will be obtained at each visit with a breath analyzer.  A BAC will 
be the first procedure at the visits.  If the BAC is ≥ 0.1 mg/L, the subject should visit the site again at a 
later date within the acceptable time window to undergo observations, examinations, and evaluations. 
fWith TLFB, alcohol consumption data in the period between the current visit and last visit will be 
collected at each visit.  Subjects may use supplementary materials for TLFB such as their personal 
calendars or a calendar provided by the site to help in recalling their drinking behaviors.  
Supplementary materials will be used as a memory aid to support subjects’ input to TLFB but not as 
source documents.  NB:  The TLFB may only be completed by a trained and certified rater. 
gThe data at the Screening Visit (Visit 1) of Study 339-14-001 will be used as baseline data for these 
endpoints. 
hPregnancy test will be performed only in female subjects of childbearing potential.  It is not necessary 
to perform pregnancy test in subjects without childbearing potential due to surgery such as 
hysterectomy and bilateral oophorectomy or subjects who have had menopause for at least 12 months. 
 
7.1.1 
Acquisition of Informed Consent  
The investigator or subinvestigator will obtain written consent directly from subjects 
before the completion of Study 339-14-001.  The date of informed consent acquisition 
will be recorded in the CRF. 
7.1.2 
Subject Registration 
A subject number (3-digit trial site number + S + 5-digit in-site serial number) for each 
subject will be used continuously in Study 339-14-001 and this trial.  After obtaining 
informed consent from a subject, the investigator, subinvestigator, or trial associate will 
access the IWRS or IVRS to receive a subject number for the subject who has signed the 
written information/ICF. 
7.1.3 
Eligibility Confirmation (Examinations at the End of the 
Treatment Period of Study 339-14-001) 
1) For eligibility confirmation for this trial, the results of the following examinations 
at the end of the treatment period of Study 339-14-001 will be used.  Eligibility 
will be confirmed within 1 week after the examinations at the end of the treatment 
period of Study 339-14-001. 


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 Clinical laboratory tests 
 12-lead ECG 
 C-SSRS 
 Pregnancy test (only in female subjects of childbearing potential) 
2) From the results of the examinations at the end of the treatment period of Study 
339-14-001, the investigator or subinvestigator will verify that each subject meets 
the inclusion criteria and does not fall under any of the exclusion criteria and will 
start the treatment period after registering the subject according to Section 7.1.2, 
Subject Registration.  The data on the efficacy endpoints of Study 339-14-001 will 
be recorded in the CRF before the start of the treatment period (Visit 2). 
 
7.1.4 
Observations, Examinations, and Evaluations During the 
Treatment Period 
7.1.4.1 
Week 0 (Start Date of the Treatment Period, Visit 2), Week 1 
(Visit 3), Week 2 (Visit 4), Week 4 (Visit 5), Week 8 (Visit 6), 
Week 12 (Visit 7), Week 16 (Visit 8), and Week 20 (Visit 9) 
According to the procedures shown in Section 7.2, Method of Evaluation, the following 
will be performed within the acceptable time window of ± 3 days until Week 2 (Visit 4) 
and within the acceptable time window of ± 7 days at Week 4 (Visit 5) to Week 20 
(Visit 9). 
 Measurement of BAC* (it will be the first procedure at each visit) 
 TLFB (alcohol consumption data after last visit will be collected) 
 CGI-S 
 CGI-I 
 SF-36 (Week 12 [Visit 7]) 
 EQ-5D (Week 12 [Visit 7]) 
 AQoLS (Week 12 [Visit 7]) 
 RUMQ-ADP (Week 12 [Visit 7]) 
 AEs 
 Clinical laboratory tests (Week 12 [Visit 7]) 
 Blood pressure and pulse rate, and body weight 
 12-lead ECG (Week 12 [Visit 7]) 
 Physical examination (Week 12 [Visit 7]) 
 POMS (Week 12 [Visit 7]) 
 C-SSRS 
 Concomitant drugs and therapies 


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 Pregnancy test (only in female subjects of childbearing potential) 
 Evaluation of treatment compliance (except for Week 0 [Visit 2]) 
*:  If the BAC is ≥ 0.1 mg/L, the subject should visit the site again at a later date 
within the acceptable time window to undergo observations, examinations, and 
evaluations. 
7.1.4.2 
Week 24 (End of the Treatment Period, Visit 10) 
1) According to the procedures shown in Section 7.2, Method of Evaluation, the 
following will be performed within the acceptable time window of ± 7 days. 
 Measurement of BAC* (it will be the first procedure at the visit) 
 TLFB (alcohol consumption data after last visit will be collected) 
 CGI-S 
 CGI-I 
 SF-36 
 EQ-5D 
 AQoLS 
 RUMQ-ADP 
 AEs 
 Clinical laboratory tests 
 Blood pressure and pulse rate, and body weight 
 12-lead ECG 
 Physical examination 
 POMS 
 C-SSRS 
 Concomitant drugs and therapies 
 Pregnancy test (only in female subjects of childbearing potential) 
 Evaluation of treatment compliance 
*:  If the BAC is ≥ 0.1 mg/L, the subject should visit the site again at a later date 
within the acceptable time window to undergo observations, examinations, and 
evaluations. 
2) Randomization (allocation of IMPs to subjects) 
The investigator or subinvestigator will enter information on subjects who have 
completed the treatment period in the IWRS or IVRS for randomization.  The 
IWRS or IVRS will randomize each subject to one of the treatment groups and 
allocate an IMP number to the subject. 
 


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7.1.5 
Week 28 (Run-out Period, Visit 11) 
According to the procedures shown in Section 7.2, Method of Evaluation, the following 
will be performed within the acceptable time window of ± 7 days. 
 Measurement of BAC* (it will be the first procedure at the visit) 
 TLFB (alcohol consumption data after last visit will be collected) 
 CGI-S 
 CGI-I 
 SF-36 
 EQ-5D 
 AQoLS 
 RUMQ-ADP 
 AEs 
 Clinical laboratory tests 
 Blood pressure and pulse rate, and body weight 
 12-lead ECG 
 Physical examination 
 POMS 
 C-SSRS 
 Assessment of dependency A 
 Concomitant drugs and therapies 
 Pregnancy test (only in female subjects of childbearing potential) 
 Evaluation of treatment compliance 
*:  If the BAC is ≥ 0.1 mg/L, the subject should visit the site again at a later date 
within the acceptable time window to undergo observations, examinations, and 
evaluations. 
7.1.6 
Week 32 (Posttreatment Observation, Visit 12) 
Only in subjects who have completed the run-out period, the following will be performed 
within the acceptable time window of ± 7 days at 4 weeks after the end of the run-out 
period according to the procedures shown in Section 7.2, Method of Evaluation. 
 Measurement of BAC* (it will be the first procedure at the visit) 
 AEs 
 Clinical laboratory tests 
 Blood pressure and pulse rate, and body weight 
 12-lead ECG 


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 Physical examination 
 POMS 
 C-SSRS 
 Assessment of dependency B 
 Concomitant drugs and therapies 
 Assessment of the newly started treatment for alcohol dependence 
 Pregnancy test (only in female subjects of childbearing potential) 
*:  If the BAC is ≥ 0.1 mg/L, the subject should visit the site again at a later date 
within the acceptable time window to undergo observations, examinations, and 
evaluations. 
7.1.7 
Time of Withdrawal 
Examinations, observations, and evaluations will be performed as soon as possible after 
the withdrawn is decided.  If a subject drops out before the start of the treatment period, 
the withdrawal examination will not be conducted, but the follow-up will be performed at 
4 weeks after the completion of the treatment period of Study 339-14-001.  If a subject is 
withdrawn after the completion of the run-out period, efficacy evaluation (TLFB, CGI-S, 
CGI-I, SF-36, EQ-5D, AQoLS, and RUMQ-ADP) will be unnecessary.  If the subject 
refuses to undergo any examinations at the time of withdrawal, or if the investigator or 
subinvestigator judges that any examinations cannot be performed due to an emergency 
or other circumstances, of the examination items specified for the time of withdrawal, 
only those items that can be performed will be performed. 
 Measurement of BAC* (it will be the first procedure at the visit) 
 TLFB (alcohol consumption data after last visit will be collected) 
 CGI-S 
 CGI-I 
 SF-36 
 EQ-5D 
 AQoLS 
 RUMQ-ADP 
 AEs 
 Clinical laboratory tests 
 Blood pressure and pulse rate, and body weight 
 12-lead ECG 
 Physical examination 


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 POMS 
 C-SSRS 
 Concomitant drugs and therapies 
 Assessment of the newly started treatment for alcohol dependence 
 Pregnancy test (only in female subjects of childbearing potential) 
 Evaluation of treatment compliance 
*:  If the BAC is ≥ 0.1 mg/L, the subject should visit the site again at a later date 
within the acceptable time window to undergo observations, examinations, and 
evaluations. 
7.1.8 
Follow-up Investigation 
If an AE has not resolved on the day of posttreatment observation examination or on the 
day of withdrawal, the AE will be followed up in accordance with Section 8.4, Follow-up 
Investigation of Adverse Events. 
7.2 
Method of Evaluation 
7.2.1 
Safety 
7.2.1.1 
Clinical Laboratory Values 
Blood samples for hematology and blood chemistry and urine samples for urinalysis 
listed in Table 7.2.1.1-1 will be taken.  These samples will be analyzed at the central 
clinical laboratory.  The laboratory test results at the end of the treatment period of Study 
339-14-001 will be used for eligibility confirmation for this trial (Visit 1). 
The sponsor will collect test results from the central clinical laboratory.  The investigator 
or subinvestigator will record the dates of blood and urine collection in the CRF.  The 
procedures for sampling, processing, storage, shipping, and measurement will be in 
accordance with the standard operating procedures. 


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Table 7.2.1.1-1 
Clinical Laboratory Tests 
Hematology 
Red blood cell count 
Hematocrit 
Hemoglobin 
MCV 
Total white blood cell 
count 
Neutrophils (% of total 
leucocytes) 
Eosinophils (% of total 
leucocytes) 
Basophils (% of total 
leucocytes) 
Lymphocytes (% of total 
leucocytes) 
Monocytes (% of total 
leucocytes) 
Platelet count 
Liver 
Total bilirubin 
Alkaline phosphatase 
ALTa,b 
ASTb 
GGTa 
P-INR/prothrombin time 
Albumin 
Cholinesterase 
Kidney 
Creatinine 
BUN 
Infection 
CRP 
Electrolytes 
Sodium 
Potassium 
Bicarbonate (HCO3-) 
Calcium 
Urine 
Protein 
Glucose 
Occult blood 
Ketones 
HCGc 
Urinary sediment 
Lipids 
Total cholesterol 
Triglycerides 
Nutritional 
Albumin 
Glucose 
Others 
Prolactin 
BUN = blood urea nitrogen; CRP = C-reactive protein; HCG =human chorionic gonadotropin; INR = 
international normalized ratio; MCV = mean corpuscular volume. 
aThese tests will be used for secondary efficacy analysis as well as safety analysis. 
bIf ALT or AST is > 5 times the ULN, it should be monitored more frequently. 
cThis test will be performed only in female subjects of childbearing potential. 
 
7.2.1.2 
Blood Pressure and Pulse Rate, and Body Weight 
Systolic and diastolic blood pressures will be measured in a sitting position after a 
5-minute rest.  Pulse rate will be recorded after blood pressure measurement. 
Subjects will be weighed while wearing light clothing and no shoes. 
The investigator or subinvestigator will record the dates and results of the measurement 
of blood pressure, pulse rate, and body weight in the CRF.  Those measurements will be 
performed before collecting blood in principle when blood sampling is scheduled. 
7.2.1.3 
Twelve-lead Electrocardiogram 
The results of 12-lead ECG at the end of the treatment period of Study 339-14-001 will 
be used for eligibility confirmation for this trial (Visit 1). 
A 12-lead ECG will be recorded with an ECG equipment provided by the sponsor.  The 
ECG will be transferred electronically to the central ECG laboratory.  The sponsor will 
collect the results of evaluation (heart rate, RR interval, PR interval, QRS interval, QT 
interval, QT interval as corrected by Bazett’s formula [QTcB], QT interval as corrected 
by Fridericia’s formula [QTcF], and assessment based on the ECG abnormality criteria) 
from the central ECG laboratory. 


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The investigator or subinvestigator will record the dates of ECG recording in the CRF. 
7.2.1.4 
Physical Examination 
In physical examination, the investigator or subinvestigator will examine the appearance, 
extremities, skin, head, neck, eyes, ears, nose, throat, lungs, chest, heart, abdomen, 
genitourinary system, and musculoskeletal system at a minimum.  The investigator or 
subinvestigator will record the dates and results of physical examination in the CRF. 
7.2.1.5 
Profile of Mood States 
Profile of Mood States has been developed to assess transient distinct mood states.  This 
scale is a self-report inventory.  The scale measures the following 6 factors:  tension-
anxiety, depression-dejection, anger-hostility, vigor-activity, fatigue-inertia, and 
confusion-bewilderment.  It allows calculation of a total mood disturbance (TMD) score.  
Each item is rated on a 5-point scale ranging from 0 (not at all) to 4 (extremely) based on 
how well each item describes a subject’s mood in the past week. 
Subjects will complete POMS for themselves.  The investigator or subinvestigator will 
record the dates and results of POMS assessment in the CRF. 
7.2.1.6 
Columbia-Suicide Severity Rating Scale 
The results of C-SSRS at the end of the treatment period of Study 339-14-001 will be 
used for eligibility confirmation for this trial (Visit 1). 
The investigator or subinvestigator will perform post-baseline assessment to focus on 
suicidality after last trial visit (suicidality after the end of the treatment period of Study 
339-14-001 for Week 0 [start of the treatment period, Visit 2]).  The investigator or 
subinvestigator will record the dates and results of these assessments in the CRF. 
7.2.1.7 
Dependency Assessment 
Dependency assessment is an index to assess dependency on nalmefene hydrochloride.  
Dependency Assessment Form A and Form B comprise 10 items and 6 items, 
respectively, and each item will be rated on a 4-point scale ranging from 1 (very much) to 
4 (no). 
The investigator or subinvestigator will perform the dependency assessment and record 
the dates and results of assessment in the CRF. 


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7.2.2 
Efficacy Evaluation 
7.2.2.1 
Timeline Followback 
Timeline Followback is a method to estimate alcohol consumption per day.  Subjects will 
be instructed to recall their drinking behaviors retrospectively and provide their estimated 
alcohol consumption per day using a standard unit of drinks.  One day is defined as a 
24-hour period starting at 6 AM and ending at 6 AM of the next morning.  Alcohol 
consumption data between last visit and the current visit will be collected at each visit.  If 
a visit is missed, the data that should have been provided at the missed visit will be 
collected at the next visit.  Subjects may use supplementary materials for TLFB such as 
their personal calendars or a calendar provided by the site to help in recalling their 
drinking behaviors.  Supplementary materials will be used as a memory aid to support 
subjects’ input to TLFB but not as source documents.  The dates of TLFB and alcohol 
consumption data collected at visits will be recorded in the CRF. 
Timeline Followback will be administered by site personnel such as the investigator, 
subinvestigator, and clinical psychologist according to the manual at each visit.  To be 
certified as a TLFB rater before the trial, it is not necessary to have previous experience 
with TLFB.  Before starting the trial, the sponsor will plan and provide the training for 
TLFB.  Only raters who have received TLFB training and met the criteria for certification 
will be authorized to perform TLFB during the trial.  Training certificates will be issued 
to the certified personnel such as the investigator, subinvestigator, and clinical 
psychologist, and kept by the investigator. 
When a new rater is added during the trial, the rater will be certified in accordance with 
the same procedure. 
Each subject must be assessed by the same rater throughout the trial period wherever 
possible. 
7.2.2.2 
Clinical Global Impression-Severity of Illness and Clinical 
Global Impression-Global Improvement 
The Clinical Global Impression (CGI) scale comprises 2 subscales of CGI-S and CGI-I. 
The CGI-S scale is used by clinicians when assessing their global impression of a 
patient’s current clinical condition.  The investigator or subinvestigator will use his/her 
clinical experience with this patient population to rate the severity of a subject’s clinical 
condition on a 7-point scale. 


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The CGI-I scale is used to assess a patient’s improvement (or worsening).  The 
investigator or subinvestigator is required to assess a subject’s condition relative to 
baseline at the Screening Visit of Study 339-14-001 on a 7-point scale.  In all cases, the 
rater should assess a subject’s condition independent of whether the subject’s 
improvement is related to the IMP or not. 
The investigator or subinvestigator will record the dates and results of CGI-S and CGI-I 
assessments in the CRF. 
Only trained raters will administer CGI-S and CGI-I.  To be certified, the investigator or 
subinvestigator will be required to receive training.  When a new rater is added during the 
trial, the rater will be certified in accordance with the same procedure. 
The CGI scale will be used to assess the mental condition of alcohol dependence.  Mental 
conditions other than alcohol dependence should not be considered in the CGI assessment. 
7.2.2.3 
MOS 36-item Short-form Health Survey 
MOS 36-item Short-form Health Survey has been developed as a general measure of 
subjective health condition perceived by patients.  It is a self-rating questionnaire 
comprising 36 questions, and can measure 8 health concepts:  physical functioning, 
physical role functioning, bodily pain, general health perceptions, vitality, mental health, 
emotional role functioning, and social role functioning.  It can also measure 2 summary 
scores as the comprehensive scales for the quality of life related to health:  Physical 
Component Summary which is focused on physical conditions and Mental Component 
Summary which is focused on mental conditions.  The SF-36 has been demonstrated to 
be useful in monitoring general and specific populations, comparing the burdens of 
different diseases, differentiating the health benefits by treatment, and screening 
individual patients. 
Subjects will complete SF-36 for themselves.  The investigator or subinvestigator will 
record the dates and results of SF-36 assessment in the CRF. 
7.2.2.4 
EuroQol 5 Dimension 
EuroQol 5 Dimension is a measure of health outcome.  It comprises 5 items (mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression) and a visual analog 
scale (VAS).  The 5 items allow the calculation of a utility index ranging between 0 (the 
worst) and 1 (the best).  The VAS ranges between 0 (the worst imaginable health state) 
and 100 (the best imaginable health state). 


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Subjects will complete EQ-5D for themselves.  The investigator or subinvestigator will 
record the dates and results of EQ-5D assessment in the CRF. 
7.2.2.5 
Alcohol Quality of Life Scale 
Alcohol Quality of Life Scale is an index to assess the consequences of alcohol drinking 
in a patient over the past 4 weeks, and is a self-rating questionnaire comprising 
34 questions. 
Subjects will complete AQoLS for themselves.  The investigator or subinvestigator will 
record the dates and results of AQoLS assessment in the CRF. 
7.2.2.6 
Resource Use Measurement Questionnaire-Alcohol 
Dependence 
Resource Use Measurement Questionnaire-Alcohol Dependence has been developed to 
collect information on resources used by a patient with alcohol dependence during the last 
3 months.  Information collected includes the following: 
 Health care related to the management of alcohol intoxication including 
hospitalization, consultations, and home-visit nursing 
 Health care related to the management of comorbidities including hospitalization, 
consultations, physiotherapy/kinesitherapy, and home-visit nursing 
 Sick leaves:  frequency and duration 
 
The investigator or subinvestigator will administer RUMQ-ADP and record the dates and 
results of assessment in the CRF. 
7.2.3 
Others 
7.2.3.1 
Breath Alcohol Concentration 
At each visit, BAC will be measured with a breath analyzer.  The BAC measurement will 
be the first procedure at each visit, and the observations, examinations, and evaluations 
specified in the trial will be performed only when the BAC is < 0.1 mg/L.  If the BAC is 
≥ 0.1 mg/L, the subject should visit the site again at a later date within the acceptable time 
window to undergo the observations, examinations, and evaluations.  The dates and 
results of the BAC measurement will be recorded in the CRF. 
7.2.3.2 
Pregnancy Test 
Pregnancy test will be performed only in female subjects of childbearing potential.  It is 
not necessary to perform pregnancy test in subjects without childbearing potential due to 
surgery such as hysterectomy and bilateral oophorectomy or subjects who have had 


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menopause for at least 12 months.  Serum pregnancy test will be performed only if 
pregnancy is suspected according to the result of urine pregnancy test.  The dates and 
results of pregnancy test will be recorded in the CRF. 
7.2.4 
Investigational Medicinal Product Compliance 
Based on the report from each subject, the dates of IMP administration, the number of 
taken tablets, and the timing of IMP administration (before/after drinking) will be 
recorded in the CRF.  Subjects may make a note of the dates of IMP administration in the 
margin of the IMP blister card as a memory aid.  For IMP compliance, the reports from 
subjects at visits will be regarded as source documents.  The notes used as a memory aid 
will not be source documents. 
7.3 
Measures to Be Taken for Subjects Visiting or Planning to Visit 
Other Hospitals or Departments 
At the time of obtaining informed consent, the investigator or subinvestigator will 
confirm whether or not the subject is receiving treatment at another hospital or 
department.  If the subject is receiving treatment at another hospital or department, the 
investigator or subinvestigator will inform the attending physician of that hospital or 
department about the subject’s participation in the clinical trial and the IMP being used, 
with the subject’s consent.  The investigator or subinvestigator will also obtain and record 
in the CRF information on the treatment that the subject is receiving at the other hospital 
or department (name of disease being treated and information on the type of treatment or 
measures being implemented) and judge whether or not the subject should participate in 
the trial. 
If a subject visits another hospital or department during the trial period, the investigator or 
subinvestigator will inform the attending physician of that hospital or department about 
the subject’s participation in the clinical trial and the IMP being used, with the subject’s 
consent.  The investigator or subinvestigator will also obtain and record in the CRF 
information on the treatment that the subject receives at the other hospital or department 
(name of disease treated and information on the type of treatment or measures 
implemented) and judge whether or not the subject should continue to participate in the 
trial. 
 


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8 
Adverse Events 
8.1 
Definitions 
8.1.1 
Adverse Event 
[International Conference on Harmonisation (ICH) E2A guideline:  Definition] 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which 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.c 
 
For this trial, the term “medical product” is regarded as “IMP,” and to secure the safety of 
subjects, AEs occurring from consent and from the end of the treatment period in Study 
339-14-001 (Visit 10) to the start of IMP administration are included in the definition of 
AEs in addition to the definition given by ICH. 
If an event, symptom, or sign existing at the time of acquisition of informed consent in 
the trial and at the end of the treatment period in Study 339-14-001 (Visit 10) worsens, 
the exacerbation will be treated as a new AE. 
8.1.2 
Serious Adverse Event 
A serious AE is defined as an AE corresponding to one of the events listed in 1) to 6) 
below.c 
The seriousness of AEs occurring during the period from consent and from the end of the 
treatment period in Study 339-14-001 (Visit 10) to the start of IMP administration will 
also be judged. 
1) An event resulting in death 
2) A life-threatening event 
                                                 
c“Clinical Safety Data Management,” Notification No. 227 of the Examination Division, 
Pharmaceutical Affairs Bureau dated 20 Mar 1995 (ICH E2A). 


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The term “life-threatening” refers to an event in which the patient was at a risk of 
death at the time of the event.  It does not refer to an event which hypothetically 
might have caused death, had it been more severe. 
3) An event requiring in-patient hospitalization or prolongation of existing 
hospitalization for treatment 
4) An event resulting in persistent or significant disability/incapacity 
5) An event causing a congenital anomaly/birth defect 
6) A major event resulting in other situations, such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization, but 
which may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in 1) to 5) above.  Examples of such events are intensive 
treatment in an emergency room for bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 
 
Explanation of hospitalization for treatment of a serious AE: 
Hospitalization for treatment means that the subject must be hospitalized at a medical 
institution for treatment of an AE, typically for at least one night.  This includes 
hospitalization for treatment of the AE in which no particular medical procedures are 
carried out (rest therapy).  However, it does not include hospitalization for undergoing 
tests or treatment for an underlying disease or complication that has not worsened since 
the subject’s entry into the trial, hospitalization for social reasons or convenience not 
intended for treatment of the AE, or hospitalization for treatment or tests scheduled prior 
to participation in the trial. 
8.2 
Response to Occurrence of Adverse Events 
8.2.1 
Actions to Be Taken for Subjects 
The investigator or subinvestigator will provide adequate medical care for all clinically 
significant, trial-related AEs throughout the period of subject participation in the trial as 
well as thereafter.  If treatment for an AE is necessary, the subject will be informed of this. 
8.2.2 
Expedited Reporting of Serious Adverse Events 
(1) Serious AEs Requiring Expedited Reporting 
1) Any serious AEs occurring during the trial period regardless of causal relationship 
with the IMP 
2) Serious AEs occurring during the follow-up period (see 8.4, Follow-up 
Investigation of Adverse Events), if a follow-up investigation is performed, for 
which a causal relationship with the IMP cannot be ruled out, or AEs that become 


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serious during the follow-up period for which a causal relationship with the IMP 
cannot be ruled out 
3) Among serious AEs occurring after completion of the trial (after the follow-up 
investigation, if a follow-up investigation is performed) and reported by subjects 
to the investigator or subinvestigator, those for which the investigator or 
subinvestigator cannot rule out a causal relationship with the IMP 
 
(2) Procedures for Expedited Reporting 
1) When an AE falling under any of the above items 1) to 3) occurs, the investigator 
or subinvestigator will notify the sponsor promptly after becoming aware of the 
event (within 24 hours, in principle) orally or by telephone or e-mail (refer to 
Annex 1, Emergency Contact). 
2) The investigator will then promptly submit a detailed report on any serious AEs 
occurring after the start of IMP administration to the head of the trial site and the 
sponsor within 10 days after becoming aware of them using the report form of the 
trial site or sponsor.  Any additional information will also be promptly relayed to 
the sponsor (within 24 hours, in principle) orally or by telephone or e-mail, and 
additional reporting will be performed if necessary. 
3) When the investigator or subinvestigator is requested by the sponsor, the head of 
the trial site, or the institutional review board (IRB) to prepare additional 
information (autopsy report, terminal care report, or other required information) 
on a reported serious AE, the investigator or subinvestigator will respond to the 
request. 
 
8.2.3 
Emergency Code Breaking (Procedure for Unblinding During the 
Trial Period) 
In the event of a medical emergency such as the occurrence of a serious AE, if the 
investigator or subinvestigator judges that emergency code breaking is necessary to 
ensure the safety of the subject, he or she can obtain the emergency code of the subject 
from the IWRS or IVRS in accordance with the specified procedures (see the 
corresponding parts of the IWRS and IVRS manual provided separately).  Upon breaking 
of the emergency code, the investigator or subinvestigator will promptly inform the 
sponsor of it, make a record of the reason for code breaking and the process, and submit it 
to the sponsor.  The IMP cannot be administered again to the subject whose emergency 
code has been broken. 
8.3 
Assessment of Adverse Events 
The investigator or subinvestigator will assess AEs for the following items. 


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8.3.1 
Terms for Adverse Events 
If the disease responsible for an AE can be specified, the name of the diagnosed disease 
will be recorded in the CRF and not the individual symptoms. 
8.3.2 
Date of Onset and Recovery 
 Date of onset: 
The date of onset of an AE or date of confirmation of an AE will be recorded in 
the CRF.  If an event, symptom, or sign existing at the time of acquisition of 
informed consent worsens, the date of exacerbation will be recorded in the CRF 
as “date of onset of AE.”  Also, if an AE occurring between the acquisition of 
informed consent and start of IMP administration worsens after administration of 
the IMP, the exacerbation will be recorded in the CRF as a new AE with the date 
of exacerbation recorded as “date of onset of exacerbated AE.” 
 Date of recovery: 
The date of recovery of an AE or date of confirmation of recovery of an AE will 
be recorded in the CRF. 
 
8.3.3 
Severity 
Severity of AEs will be classified using the following three categories. 
1) Mild 
Discomfort noticed, but no disruption to daily activity 
2) Moderate 
Discomfort sufficient to limit or affect normal daily activity 
3) Severe 
Inability to work or perform normal daily activity 
 
8.3.4 
Causal Relationship With Investigational Medicinal Product 
The causal relationship between the IMP and AEs occurring after the start of IMP 
administration will be judged according to the following two categories. 
1) Relationship is ruled out 
For reasons such as the following, the possibility of a relationship between 
occurrence of an AE and the IMP is not reasonably conceivable. 
a) The event can be assumed to be caused by an underlying disease, 
complication(s), or previous disease(s). 
b) The event can be assumed to be associated with age, sex, or some other 
demographic factor. 
c) A temporal relationship between IMP administration and occurrence of the 
AE is unlikely. 


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Example:  An AE that occurs after a considerable lapse of time from the 
conclusion of IMP administration. 
d) Considering the time course of the AE and IMP administration, a relationship 
with the IMP is unlikely. 
Example:  Despite continuous administration of the IMP, the AE disappeared 
spontaneously without any treatment (except cases in which it is judged that 
the subject became habituated to the IMP during continued administration). 
e) The event can be assumed to be caused by concomitant drug(s). 
f) The event can be assumed to be incidental (such as an accident or incidental 
disease). 
Example:  “femoral bone fracture” occurring in a traffic accident. 
g) A relationship with the IMP can be ruled out for other reasons based on 
medical consideration. 
2) Relationship cannot be ruled out 
For reasons such as the following, the possibility of a relationship between 
occurrence of an AE and the IMP is reasonably conceivable. 
a) A relationship is predictable from the pharmacological and toxicological 
effects of the IMP. 
Examples:  Occurrence of “pancytopenia” when effects on the hematopoietic 
system have been observed in nonclinical studies, or the occurrence of 
“dehydration” when the drug has a diuretic effect. 
b) The event has been observed in previous nonclinical studies and/or clinical 
studies. 
c) A temporal relationship is suspected between IMP administration and onset of 
the AE. 
Example:  “Allergic dermatitis” occurring several days after the start of IMP 
administration. 
d) A relationship is suspected based on the outcome of an AE after 
discontinuation or dose reduction of the IMP. 
Example:  Prompt disappearance of “nausea” after discontinuation of the IMP. 
e) A relationship with the IMP cannot be ruled out for other reasons based on 
medical consideration. 
 
8.3.5 
Actions to Be Taken Regarding IMP Administration 
Actions to be taken regarding IMP administration following the occurrence of an AE after 
initiation of IMP administration will be selected from among the following. 
 No change 
 Discontinuation of IMP administration 
 Unknown 


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 Not applicable 
Example:  Cases where the subject died or the AE occurred after the end of the 
treatment period. 
 
8.3.6 
Actions to Be Taken for Adverse Events 
The performance of medical treatments (medications and/or other treatments) for AEs 
and details of the treatments will be described in the CRF. 
8.3.7 
Outcome 
The outcome of an AE will be selected from the following six categories (one only). 
If the subject died, the date of death will be recorded in the CRF; if the subject’s 
condition was recovering/resolving, not recovered/not resolved, or unknown, the date of 
outcome confirmation will be recorded in the CRF. 
 Recovered/resolved 
 Recovering/resolving 
 Not recovered/not resolved 
 Recovered/resolved with sequelae 
 Fatal 
 Unknown (for some reason, a follow-up investigation could not be performed 
even once) 
 
8.4 
Follow-up Investigation of Adverse Events  
The term “recovered” used below means that a subject who had an AE prior to the start of 
IMP administration returned to his or her original condition, or a subject who had an AE 
after the start of IMP administration returned to his or her condition before the start of 
IMP administration. 
1) If an AE has not resolved by the day of the posttreatment observation examination 
(final observation day) or the day of withdrawal, the investigator or 
subinvestigator will explain to the subject the need for follow-up investigation 
after the completion of the posttreatment observation or withdrawal and request 
the subject’s cooperation.  The investigator or subinvestigator will conduct a 
follow-up investigation within 4 weeks after the end of the trial and record 
information regarding the AE in the subject’s medical records.  If an AE has not 
resolved by the day of the posttreatment observation examination (final 
observation day) or the day of withdrawal, the investigator or subinvestigator will 
record the outcome in the CRF as “recovering/resolving”, “not recovered/not 
resolved”, or as otherwise appropriate. 


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2) If an AE has not resolved by the day of the follow-up investigation and a causal 
relationship with the IMP cannot be ruled out, follow-up investigation will be 
continued until the event resolves or becomes stable and information regarding 
the AE will be recorded in the subject’s medical records.  If a causal relationship 
between the AE and the IMP can be ruled out, no further follow-up will be made 
beyond the day of the initial follow-up investigation. 
3) If, between the day of the posttreatment observation examination (final 
observation day) or the day of withdrawal and the day of the follow-up 
investigation, a new serious AE for which a causal relationship with the IMP 
cannot be ruled out occurs, or if an AE that has not resolved by the day of the 
posttreatment observation examination (final observation day) or the day of 
withdrawal and for which a causal relationship with the IMP cannot be ruled out 
becomes serious, follow-up investigation will be conducted until the AE resolves 
or becomes stable and information regarding the AE will be recorded in the 
subject’s medical records. 
4) If a serious AE for which a relationship with the IMP cannot be ruled out is 
discovered after the day of the posttreatment observation examination (final 
observation day) or the day of withdrawal, or after the day of the initial follow-up 
investigation (if performed), follow-up investigation will be conducted until the 
AE resolves or becomes stable or until follow-up of the subject becomes 
impossible and information regarding the AE will be recorded in the subject’s 
medical records. 
 
8.5 
Pregnancy  
If women of childbearing potential or male subjects whose partners are capable of 
becoming pregnant participate in the trial, the investigator or subinvestigator will attend 
to the following. 
 Information on reproductive and developmental toxicity of the IMP 
 Information regarding pregnancy in the ICF 
 Explanation of contraceptive methods 
 Reporting and follow-up of cases of pregnancy 
 
8.5.1 
Guidance to Subjects Including Contraceptive Methods 
1) Before the start of the trial, the investigator or subinvestigator will explain to the 
subjects the importance of using contraception and the risks associated with 
pregnancy of a female subject or partner of a male subject and, after subjects have 
read the written information for subjects and understood it, the investigator or 
subinvestigator will have subjects sign the ICF. 
2) If women of childbearing potential or male subjects whose partners are capable of 
becoming pregnant wish to participate in the trial, the investigator or 


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subinvestigator will instruct them to practice contraception during the period 
specified in the trial protocol. 
3) Contraceptive methods include condoms, pills, pessaries, intrauterine device, 
vasectomy, and tubal ligation.  However, if a female subject or male subject’s 
partner is without question unable to become pregnant (ie, has undergone bilateral 
ovariectomy or hysterectomy or has not experienced menses for at least 12 
consecutive months for whatever other medical reasons, or the male 
subject/partner has undergone bilateral orchidectomy), or if the subject and his/her 
partner remain abstinent, use of contraception is unnecessary. 
4) The investigator or subinvestigator will instruct the subjects that if the 
contraceptive measures fail and evidence of pregnancy of the female subject or 
male subject’s partner such as delay in menstruation is observed, this should be 
promptly reported to the investigator or subinvestigator. 
 
8.5.2 
Actions to Be Taken by the Investigator or Subinvestigator When 
Pregnancy Is Suspected 
If the investigator or subinvestigator or a subject suspects that the subject has become 
pregnant before initiation of IMP administration, initiation of IMP administration will be 
withheld and a pregnancy test will be performed.  If the test result is positive, the trial 
subject will be withdrawn without receiving IMP administration.  If a pregnancy is 
suspected after initiation of IMP administration, IMP administration will be discontinued 
(refer to Section 9.2, Criteria and Procedures for Withdrawal of Individual Subjects). 
8.5.3 
Actions to Be Taken by the Investigator or Subinvestigator When 
a Subject Is Discovered to Be Pregnant 
When a female subject is found to be pregnant, the investigator or subinvestigator will 
withdraw the subject from the trial and perform follow-up investigation until delivery or 
end of pregnancy, and report this in writing to the sponsor. 
After discontinuation of IMP administration, the investigator or subinvestigator will 
perform the withdrawal examinations and follow-up observation stipulated in the 
protocol, in so far as they do not affect the pregnancy. 
8.5.4 
Expedited Reporting of Pregnancy 
When a female subject or a partner of a male subject is found to be pregnant during the 
trial, the investigator or subinvestigator will promptly report this to the sponsor orally or 
by telephone or e-mail (refer to Annex 1, Emergency Contact).  The investigator or 
subinvestigator will then provide any additional information requested by the sponsor. 


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8.5.5 
Follow-up Investigation of Pregnancy 
If a female subject becomes pregnant, the investigator or subinvestigator will perform 
follow-up investigation of the pregnancy up to delivery or the end of pregnancy and 
report the results of follow-up in writing to the sponsor.  When a subject or subject’s 
partner has delivered, it is best that the neonate be observed for at least six months after 
delivery. 
 
9 
Withdrawal of Individual Subjects From the Trial 
Any subject may discontinue participation in the trial at any time without medical 
disadvantage.  The investigator or subinvestigator may withdraw a subject from the trial 
at any time if it is considered necessary for medical treatment of that subject. 
9.1 
Screen Failure 
If a subject is a screen failure, the following information should be recorded in the CRF 
for screen failure subjects. 
Date of investigation (eligibility confirmation), date of informed consent acquisition 
(from the subject), reason for screen failure. 
9.2 
Criteria and Procedures for Withdrawal of Individual Subjects 
In any of the events listed below, the investigator or subinvestigator will discontinue IMP 
administration, perform the tests to be performed at withdrawal stipulated in Section 7.1, 
Schedule and Procedures, and promptly inform the sponsor of the withdrawal (Annex 1, 
Emergency Contact).  The investigator or subinvestigator will record the date and reason 
for withdrawal in the CRF. 
If withdrawal is necessitated by problems with safety, such as the occurrence of an AE or 
aggravation of the underlying disease, the investigator or subinvestigator will promptly 
take appropriate measures and perform follow-up of subjects with AEs if necessary (refer 
to Section 8.4, Follow-up Investigation of Adverse Events. 
1) The subject requests to be withdrawn from the trial. 
2) The subject experiences an AE making continuation of the trial difficult. 
3) Psychosocial therapy other than BRENDA approach is needed (except for the 
period after the end of the examination of the run-out period). 
4) The dose of the IMP needs to be changed. 


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5) It has been found after the start of the trial that the subject does not meet the 
inclusion criteria or falls under any of the exclusion criteria. 
6) A female subject has become pregnant or been suspected of being pregnant. 
7) The investigator or subinvestigator judges that the subject should be withdrawn 
for other reasons. 
 
9.3 
Follow-up Investigation of Subjects Who Do not Visit the Trial Site 
If a subject does not visit the trial site for unknown reasons, the investigator or 
subinvestigator will promptly contact the subject or persons concerned such as the family 
by telephone or other means to confirm AEs and ask for visit. 
If the subject does not visit the trial site, the following will be investigated and recorded 
in the subject’s medical records, etc. 
1) The date of investigation 
2) The method of investigation 
3) Whether or not the subject was contacted 
4) Reason why the subject does not (or cannot) visit the trial site 
5) Details of IMP compliance 
6) Occurrence or non-occurrence of AEs.  If an AE has occurred:  name of the event, 
date (and time) of onset and date (and time) of recovery, severity, relationship to 
the IMP, measures taken regarding IMP administration, treatment of AE, outcome. 
7) If follow-up investigation is impossible:  the reason why 
 
10 
Collection of Case Report Form Data and Specification of 
Source Data  
10.1 
Collection of Case Report Form Data 
1) Electronic Data Capture (EDC) will be used in the trial. 
2) Subject data will be entered directly into the database from the trial site via a Web 
browser.  These data collected by EDC will constitute the CRF.  The results 
obtained from the clinical laboratory test performed by the central laboratory and 
the ECG analysis results obtained from the central ECG laboratory will be 
transferred from these facilities directly to the sponsor. 
3) Regarding quality assurance of CRFs, the guidelines specified in “Use of 
Electromagnetic Records and Electronic Signatures in Applications for Approval 
or Licensing of Drugs” (PFSB Notification No. 0401022, dated 01 Apr 2005) and 
“Guidance on Electronic Capture of Clinical Study Data” (Drug Evaluation 
Committee, Japan Pharmaceutical Manufacturers Association, dated 01 Nov 
2007) will be observed. 


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4) For every subject who provides consent to participate in the trial, a CRF will be 
created on an EDC data entry screen that conforms to the items of CRF data 
collection described in the trial protocol. 
5) The investigator, subinvestigator, or trial associate will create CRFs according to 
the manual provided by the sponsor.  If source documents are available and the 
objectivity of the data can be ensured, then the data may be recorded in a CRF by 
a trial associate. 
6) When entering data into CRFs from the trial site, a predetermined check will be 
automatically performed.  The investigator, subinvestigator, or a trial associate 
will make corrections as necessary. 
7) The sponsor will verify CRFs in comparison to source documents and conduct 
data reviews.  If additional query is necessary, the sponsor will issue an intra-
system query and the investigator, subinvestigator, or a trial associate will perform 
data correction or provide a response to the sponsor’s query as necessary. 
8) A history of all revisions made after the initial data entry is saved on the server 
will be automatically recorded within the system (date and time of revision, name 
of person making revision, pre- and post-revision data, reason for revision, date 
and time of query, name of person issuing query, details of query, etc). 
9) After completion of all CRF data entry and confirmation that the content is correct 
and complete, including confirmation of the audit trail, the investigator will attach 
an electronic signature. 
10) Details concerning data collection will be specified in a separate manual prepared 
in advance. 
 
10.2 
Source Documents 
1) Source documents are defined as those documents that are the source of data 
transcribed into CRFs as trial results.   
Medical records and other records (medical records, nursing records, prescription 
records), registration verification forms, subject screening list, ICFs, clinical 
laboratory test and other measurement reports, ECG charts, IMP management 
records, rating scales, and other documents 
2) The investigator or the trial site will retain all trial-related documents and records 
except CRFs in such a manner that enables the sponsor or the regulatory authority 
to have direct access to the documents and records. 
3) The original ICFs will be retained according to the method specified by each trial 
site. 
4) After completion of the trial, the sponsor will retain the original CRFs on CD-
ROM or some other appropriate electronic medium and the investigator or the 
trial site will retain copies. 
 


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10.3 
Case Report Form Items to Be Treated as Source Data 
Not applicable 
10.4 
Data to Be Collected by the Sponsor 
1) CRFs  
2) Clinical laboratory results and standard values 
3) Analysis results of 12-lead ECG obtained from the central ECG laboratory 
 
11 
Statistical Analysis 
Details of statistical analyses planned in this trial are described.  More detailed 
description of the statistical analyses will be contained in the statistical analysis plan to be 
separately prepared. 
11.1 
Analysis Sets 
Both of data from the preceding double-blind lead-in study and this extension study will 
be summarized and analyzed in the following analysis sets. 
 Safety set (SS): 
Subjects who received the IMP at least once in this trial 
 Full analysis set (FAS): 
Subjects in the SS who have data of the number of HDDsd at baseline in the 
lead-in study and at one timepoint or more after the initial IMP administration in 
this trial 
 
11.2 
Handling of Data 
11.2.1 
Baseline and Baseline II 
Unless otherwise specified, baseline for the treatment period will be the one in the lead-in 
study, and baseline in the run-out period and posttreatment observation period 
(hereinafter referred to as baseline II) will be Week 24 of the treatment period (Visit 10) 
in this trial. 
                                                 
dThe number of HDDs is defined as the number of days per month (days/month) with alcohol 
consumption per day of > 60 g for males and > 40 g for females.  One month is defined as 
4 weeks (28 days).  The number of HDDs is calculated as the number of days per month with 
alcohol consumption per day of > 60 g for males and > 40 g for females multiplied by 28 and 
then divided by the number of days per month without missing data.  Data will be considered as 
missing if the number of days per month without missing data is less than 7 days. 


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11.2.2 
Timepoint of Evaluation and Timepoint of Case Report Form 
Entry (Nominal Timepoint) 
Unless otherwise specified, nominal visits (an assessment is evaluated according to the 
visit it was intended to happen at with the exception of early withdrawals and 
unscheduled visits where windowing is used) will be used. 
11.2.3 
Endpoints Derived by Timeline Followback 
The baseline of the endpoints derived by TLFB (eg, number of HDDs and TAC) will be 
28 days before the Screening Visit in the lead-in study.  Week 4, Week 8, Week 12, Week 
16, Week 20, and Week 24 of the lead-in study will be 28 days each starting from the 
Randomization Visit of the lead-in study as Day 1 (eg, Days 1 to 28 for Week 4 and 
Days 29 to 56 for Week 8).  Week 4, Week 8, Week 12, Week 16, Week 20, and 
Week 24 of this trial will be 28 days each starting from Week 0 of this trial (Visit 2 of 
this trial) as Day 1. 
Baseline II will be 28 days before the start of the run-out period (Week 24 of the 
treatment period, Visit 10 of this trial).  The run-out period will be 28 days from the start 
of the run-out period.  However, if the Run-out Period Visit (Visit 11 of this trial) or the 
Withdrawal Visit after the run-out period comes before the start of the run-out period + 
28 days, the period will be from the start of the run-out period to the Run-out Period Visit 
or Withdrawal Visit. 
11.3 
Analysis Items and Method 
11.3.1 
Safety Analysis 
Unless otherwise specified, safety analysis will be performed in the SS with data from the 
lead-in study and this trial. 
11.3.1.1 
Extent of Exposure 
(1) Lead-in study and this trial 
Descriptive statistics (number of subjects, mean, standard deviation, minimum, median, 
maximum; the same statistics hereinafter) will be obtained for the number of days of IMP 
administration and the proportion of the number of days of IMP administration in the 
treatment period.  Frequency of days when alcohol was consumed without IMP 
administration will be calculated.  Pooled data from the treatment groups will be used for 
the tabulation regardless of the treatment groups in the lead-in study or treatment groups 
in the run-out period of this trial. 


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In subjects in the SS who received nalmefene hydrochloride 20 mg in the lead-in study 
and the run-out period of this trial, descriptive statistics will be obtained for the number 
of days of IMP administration and the proportion of the number of days of IMP 
administration in the treatment period.  Frequency of days when alcohol was consumed 
without IMP administration will be calculated. 
(2) Lead-in study and the treatment period of this trial 
Descriptive statistics will be obtained by treatment group in the lead-in study (nalmefene 
hydrochloride 10 mg, nalmefene hydrochloride 20 mg, and placebo groups) for the 
number of days of IMP administration in the lead-in study and the treatment period of this 
trial and the proportion of the number of days of IMP administration in the treatment 
periods.  Frequency of days when alcohol was consumed without IMP administration will 
be calculated. 
(3) Treatment period of this trial 
Descriptive statistics will be obtained by treatment group in the lead-in study for the 
number of days of IMP administration in the treatment period of this trial and the 
proportion of the number of days of IMP administration in the treatment period.  
Frequency of days when alcohol was consumed without IMP administration will be 
calculated. 
(4) Run-out period of this trial 
In subjects in the SS who advanced to the run-out period, descriptive statistics will be 
obtained by treatment group in the run-out period of this trial (nalmefene hydrochloride 
20 mg and placebo groups), for the number of days of IMP administration in the run-out 
period of this trial and the proportion of the number of days of IMP administration in the 
treatment period.  Frequency of days when alcohol was consumed without IMP 
administration will be calculated. 
11.3.1.2 
Adverse Events 
(1) AEs in the lead-in study and this trial 
Treatment-emergent adverse events will be summarized by system organ class (SOC) and 
preferred term (PT) as well as “any TEAEs,” and the summaries will provide the number 
of subjects with TEAEs and incidence of those.  Drug-related TEAEs will be summarized 
in the same manner.  Pooled data from the treatment groups will be used for the 
tabulation regardless of the treatment groups in the lead-in study or treatment groups in 
the run-out period of this trial. 


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In subjects in the SS who received nalmefene hydrochloride 20 mg in the lead-in study 
and the run-out period of this trial, TEAEs will be summarized by SOC and PT as well as 
“any TEAEs,” and the summaries will provide the number of subjects with TEAEs and 
incidence of those.  Tabulation by severity and tabulation by timepoint (lead-in study or 
this trial) will also be performed.  Drug-related TEAEs will be summarized in the same 
manner. 
(2) AEs in the lead-in study and the treatment period of this trial 
In each treatment group in the lead-in study, TEAEs will be summarized by SOC and PT 
as well as “any TEAEs,” and the summaries will provide the number of subjects with 
TEAEs and incidence of those.  Tabulation will also be performed by severity and 
timepoint (in the lead-in study and this trial).  Drug-related TEAEs will be summarized in 
the same manner. 
(3) AEs in the run-out period of this trial 
In subjects in the SS who advanced to the run-out period of this trial, TEAEs will be 
summarized by SOC and PT as well as “any TEAEs” for each treatment group in the run-
out period of this trial, and the summaries will provide the number of subjects with 
TEAEs and incidence of those.  Tabulation will also be performed by severity.  Drug-
related TEAEs will be summarized in the same manner. 
(4) AEs in the posttreatment observation period of this trial 
In subjects in the SS who advanced to the posttreatment observation of this trial, TEAEs 
will be summarized by SOC and PT as well as “any TEAEs” for each treatment group in 
the run-out period of this trial, and the summaries will provide the number of subjects 
with TEAEs and incidence of those.  Tabulation will also be performed by severity.  
Drug-related TEAEs will be summarized in the same manner. 
11.3.1.3 
Death, Other Serious Adverse Events and Other Significant 
Adverse Events 
In the same manner as AEs, the following AEs will be summarized by SOC and PT as 
well as “any AEs.” 
 Serious TEAEs, drug-related serious TEAEs, TEAEs leading to discontinuation, 
drug-related TEAEs leading to discontinuation in the lead-in study and this trial 
 Serious TEAEs, drug-related serious TEAEs, TEAEs leading to discontinuation, 
drug-related TEAEs leading to discontinuation in the lead-in study and the 
treatment period of this trial 


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 Serious TEAEs, drug-related serious TEAEs, TEAEs leading to discontinuation, 
drug-related TEAEs leading to discontinuation in the run-out period of this trial 
 Serious TEAEs, drug-related serious TEAEs, TEAEs leading to discontinuation, 
drug-related TEAEs leading to discontinuation in the posttreatment observation 
period of this trial 
 
11.3.1.4 
Clinical Laboratory Tests 
(1) Clinical laboratory tests in the lead-in study and this trial 
Hematology and chemistry at each timepoint will be summarized with descriptive 
statistics, as well as change from baseline.  Urinalysis at each timepoint will be 
summarized in shift tables from baseline.  Potentially clinically significant (PCS) values 
will also be summarized.  Pooled data from the treatment groups will be used for the 
tabulation regardless of the treatment groups in the lead-in study or treatment groups in 
the run-out period of this trial. 
In subjects in the SS who received nalmefene hydrochloride 20 mg in the lead-in study 
and the run-out period of this trial, hematology and chemistry at each timepoint will be 
summarized with descriptive statistics, as well as change from baseline.  Urinalysis at 
each timepoint will be summarized in shift tables from baseline.  Potentially clinically 
significant values will also be summarized. 
(2) Clinical laboratory tests in the lead-in study and the treatment period of this trial 
Hematology and chemistry at each timepoint will be summarized with descriptive 
statistics, as well as change from baseline by treatment group in the lead-in study.  
Urinalysis at each timepoint will be summarized in shift tables from baseline by treatment 
group in the lead-in study.  Potentially clinically significant values will also be 
summarized by treatment group in the lead-in study. 
(3) Clinical laboratory tests in the run-out period and posttreatment observation period of 
this trial 
In subjects in the SS who advanced to the run-out period of this trial, hematology and 
chemistry at each timepoint will be summarized by treatment group in the run-out period 
of this trial with descriptive statistics, as well as change from baseline II.  Urinalysis at 
each timepoint will be summarized by treatment group in the run-out period of this trial 
in shift tables from baseline II.  Potentially clinically significant values will also be 
summarized by treatment group in the run-out period of this trial. 


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11.3.1.5 
Vital Signs and Body Weight 
In the same manner as for clinical laboratory tests regarding “subjects, treatment group, 
and baseline,” vital signs (systolic blood pressure, diastolic blood pressure, and pulse 
rate) and body weight at each timepoint of the following periods will be summarized with 
descriptive statistics, as well as change from baseline. 
In the same manner, PCS values will be summarized in the following periods. 
 Vital signs and body weight in the lead-in study and this trial 
 Vital signs and body weight in the lead-in study and the treatment period of this 
trial 
 Vital signs and body weight in the run-out period and posttreatment observation 
period of this trial 
 
11.3.1.6 
Twelve-lead Electrocardiogram 
In the same manner as for clinical laboratory tests regarding “subjects, treatment group, 
and baseline,” heart rate, RR interval, PR interval, QRS interval, QT interval, QTcB, and 
QTcF at each timepoint of the following periods will be summarized with descriptive 
statistics, as well as change from baseline. 
In the same manner, a shift table of “Abnormal Significant,” “Abnormal Insignificant,” or 
“Normal” at each timepoint of the following periods from baseline will be provided. 
In the same manner, PCS values will be summarized in the following periods. 
In the same manner, QTcB/QTcF at each timepoint of the following periods and worst 
QTcB/QTcF will be categorically summarized.  Categories will be > 450 msec, 
> 480 msec, and > 500 msec.  Change in QTcB/QTcF from baseline at each timepoint 
and worst QTcB/QTcF will be categorically summarized.  Categories will be > 30 msec 
and > 60 msec. 
 12-lead ECG in the lead-in study and this trial 
 12-lead ECG in the lead-in study and the treatment period of this trial 
 12-lead ECG in the run-out period and posttreatment observation period of this 
trial 
 
11.3.1.7 
Physical Examination 
In the same manner as for clinical laboratory tests regarding “subjects, treatment group, 
and baseline,” the physical examinations will be categorically summarized by timepoint 


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of the following periods.  Categories will be “Abnormal Significant,” “Abnormal 
Insignificant,” and “Normal.” 
 Physical examinations in the lead-in study and this trial 
 Physical examinations in the lead-in study and the treatment period of this trial 
 Physical examinations in the run-out period and posttreatment observation 
period of this trial 
 
11.3.1.8 
Profile of Mood States 
In the same manner as for clinical laboratory tests regarding “subjects, treatment group, 
and baseline,” TMD score and factors (tension-anxiety, depression-dejection, anger-
hostility, vigor-activity, fatigue-inertia, and confusion-bewilderment) in the following 
periods will be summarized with descriptive statistics, as well as the changes from 
baseline. 
 POMS in the lead-in study and this trial 
 POMS in the lead-in study and the treatment period of this trial 
 POMS in the run-out period and posttreatment observation period of this trial 
 
For TMD score in the lead-in study and the treatment period of this trial, mixed model for 
repeated measures (MMRM) analysis will be performed for the changes from baseline in 
the same manner as the analysis of the number of HDDs. 
11.3.1.9 
Columbia-Suicide Severity Rating Scale 
(1) Subjects, treatment group, and period 
In the same manner as for clinical laboratory tests regarding “subjects, treatment group, 
and baseline,” C-SSRS in the following periods will be summarized as shown in (2) 
below. 
 C-SSRS in the lead-in study and this trial 
 C-SSRS in the lead-in study and the treatment period of this trial 
 C-SSRS in the run-out period and posttreatment observation period of this trial 
 
(2) Items and method of tabulation 
The following outcomes are C-SSRS categories and have binary responses (yes/no).  The 
Category 1 to 10 will be summarized in each treatment group at each timepoint. 
 Category 1 − Wish to be Dead 
 Category 2 − Non-specific Active Suicidal Thoughts 


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 Category 3 − Active Suicidal Ideation with Any Methods (Not Plan) without 
Intent to Act 
 Category 4 − Active Suicidal Ideation with Some Intent to Act, without Specific 
Plan 
 Category 5 − Active Suicidal Ideation with Specific Plan and Intent 
 Category 6 − Preparatory Acts or Behavior 
 Category 7 − Aborted Attempt 
 Category 8 − Interrupted Attempt 
 Category 9 − Actual Attempt (non-fatal) 
 Category 10 − Completed Suicide 
 
The following is also a C-SSRS outcome (although not suicide-related) and has a binary 
response (yes/no).  This outcome will also be summarized in each treatment group at each 
timepoint. 
 Self-injurious behavior without suicidal intent 
The following variables will be derived using the above categories.  These variables will 
also be summarized in each treatment group. 
 Suicidal ideation (1 to 5) 
A “yes” answer at any post-baseline visit to any one of the five suicidal ideation 
questions (Categories 1 to 5) on the C-SSRS. 
 Suicidal behavior (6 to 10) 
A “yes” answer at any post-baseline visits to any one of the five suicidal 
behavior questions (Categories 6 to 10) on the C-SSRS. 
 Suicidal ideation or behavior (1 to 10) 
A “yes” answer at any post-baseline visits to any one of the ten suicidal ideation 
and behavior questions (Categories 1 to 10) on the C-SSRS. 
 Treatment-emergent suicidal ideation 
An increase in the maximum suicidal ideation scoree at post-baseline visits from 
the suicidal ideation category at baseline. 
 Treatment-emergent serious suicidal ideation 
An increase in the maximum suicidal ideation score to 4 or 5 on the C-SSRS at 
                                                 
eSuicidal ideation score:  The maximum suicidal ideation category (1-5 on the C-SSRS) present 
at the assessment.  Assign a score of 0 if no ideation is present. 
0 = No Suicidal Ideation, 1 = Wish to be Dead, 2 = Non-specific Active Suicidal Thoughts, 
3 = Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act, 4 = Active 
Suicidal Ideation with Some Intent to Act, without Specific Plan, 5 = Active Suicidal Ideation 
with Specific Plan and Intent 


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post-baseline visits from not having serious suicidal ideation (scores of 0 to 3) at 
baseline. 
 Emergence of serious suicidal ideation 
An increase in the maximum suicidal ideation score to 4 or 5 on the C-SSRS at 
post-baseline visits from no suicidal ideation (scores of 0) at baseline. 
 Emergence of suicidal behavior 
The occurrence of suicidal behavior at post-baseline visits from not having 
suicidal behavior at screening or baseline in the lead-in study. 
 
In each treatment group, Maximum Suicidal ideation score at post-baseline visits will be 
summarized in shift tables from Suicidal ideation score at baseline. 
The following C-SSRS category will be derived and it will be summarized in shift tables 
from baseline in each treatment group at each timepoint. 
 C-SSRS category 
“No suicidal ideation or behavior,” “suicidal ideation,” and “suicidal behavior” 
 
11.3.1.10 
Dependence Survey 
Answers to questions of dependence survey A at the end of the run-out period and 
questions of dependence survey B at the end of the posttreatment observation will be 
summarized by treatment group in the run-out period of this trial. 
11.3.2 
Efficacy Analysis 
The following efficacy analyses will be performed in the FAS. 
11.3.2.1 
Number of Heavy Drinking Days 
The number of HDDs at each timepoint of the lead-in study and the treatment period of 
this trial will be summarized with descriptive statistics, as well as change from baseline 
by treatment group in the lead-in study (nalmefene hydrochloride 10 mg, nalmefene 
hydrochloride 20 mg, and placebo groups). 
In subjects in the FAS who advanced to the run-out period of this trial, the number of 
HDDs in the run-out period of this trial will be summarized with descriptive statistics by 
treatment group in the run-out period of this trial (nalmefene hydrochloride 20 mg and 
placebo groups), as well as change from baseline II. 
As an exploratory analysis, MMRM analysis will be performed for the changes in the 
number of HDDs from baseline at each timepoint of the lead-in study and the treatment 
period of this trial.  The baseline will be the one in the lead-in study.  Analyses will 


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include the fixed, categorical effects of treatment in the lead-in study, sex, timepoint 
(Weeks 4, 8, 12, 16, 20, and 24 of the lead-in study and Weeks 4, 8, 12, 16, 20, and 24 of 
this trial), and treatment-by-timepoint interaction as well as the continuous, fixed 
covariates of baseline number of HDDs, and baseline number of HDDs-by-timepoint 
interaction.  An unstructured (co)variance structure will be used to model the within-
patient errors.  The Kenward-Roger approximation will be used to estimate denominator 
degrees of freedom. 
As an exploratory analysis, in subjects in the FAS who advanced to the run-out period of 
this trial, changes in the number of HDDs from baseline II in the run-out period of this 
trial will be analyzed by using an analysis of covariance (ANCOVA) model with 
treatment and sex in the run-out period of this trial as fixed, categorical effect and number 
of HDDs at baseline II as covariance. 
11.3.2.2 
Total Alcohol Consumption 
Total alcohol consumption will be summarized with descriptive statistics, and exploratory 
MMRM analysis and ANCOVA will be performed in the same manner as with the 
number of HDDs. 
11.3.2.3 
Response Shift Drinking Risk Level 
Frequency of RSDRL at each timepoint of the lead-in study and the treatment period of 
this trial will be calculated by treatment group in the lead-in study. 
In subjects in the FAS who advanced to the run-out period of this trial, frequency of 
RSDRL in the run-out period of this trial will be calculated by treatment group in the run-
out period of this trial. 
Observed case data will be analyzed without imputation of missing values.  Furthermore, 
analyses will be performed in the entire FAS and all subjects in the FAS who advanced to 
the run-out period, where missing values will be handled as non-responders. 
11.3.2.4 
Response Low Drinking Risk Level 
In the same manner as with RSDRL, frequency of RLDRL at each timepoint will be 
calculated. 
11.3.2.5 
70% Total Alcohol Consumption Responder Rate 
In the same manner as with RSDRL, frequency of 70% TAC responder rate at each 
timepoint will be calculated. 


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11.3.2.6 
Heavy Drinking Day Responder Rate 
In the same manner as with RSDRL, frequency of HDD responder rate at each timepoint 
will be calculated. 
11.3.2.7 
Clinical Global Impression-Severity of Illness 
In the same manner as the number of HDDs, CGI-S will be summarized with descriptive 
statistics, and exploratory MMRM analysis will be performed. 
11.3.2.8 
Clinical Global Impression-Global Improvement 
In the same manner as the number of HDDs, CGI-I will be summarized with descriptive 
statistics, and exploratory MMRM analysis will be performed.  However, the scores at 
each timepoint will be analyzed as opposed to change from baseline since the score itself 
is an assessment of change from baseline.  The CGI-S at baseline will be included for 
covariate adjustment. 
11.3.2.9 
SF-36 Subscales (Physical Functioning, Physical Role 
Functioning, Bodily Pain, General Health Perceptions, Vitality, 
Mental Health, Emotional Role Functioning, and Social Role 
Functioning), Physical Component Summary, and Mental 
Component Summary 
For SF-36 subscales and each Component Summary, descriptive statistics will be 
obtained in the same manner as the number of HDDs, and exploratory MMRM analysis 
will be performed. 
11.3.2.10 
EuroQol 5 Dimension Utility Score and EuroQol 5 Dimension 
Visual Analog Scale 
For EQ-5D Utility score and EQ-5D VAS, descriptive statistics will be obtained in the 
same manner as the number of HDDs, and exploratory MMRM analysis will be 
performed. 
11.3.2.11 
Alcohol Quality of Life Scale 
For each domain and item of AQoLS, descriptive statistics will be obtained in the same 
manner as the number of HDDs, and exploratory MMRM analysis will be performed. 
11.3.2.12 
Resource Use Measurement Questionnaire-Alcohol 
Dependence 
Frequency will be calculated for each item in sociodemographic, resource consumption, 
and sick leaves at each timepoint of the lead-in study and the treatment period of this trial 
by treatment group in the lead-in study. 


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In subjects in the FAS who advanced to the run-out period of this trial, frequency will be 
calculated for each item in sociodemographic, resource consumption, and sick leaves in 
the run-out period of this trial by treatment group in the run-out period of this trial. 
11.3.2.13 
Gamma-glutamyl Transferase 
Log-transformed GGT will be summarized with descriptive statistics, and exploratory 
MMRM analysis will be performed in the same manner as the number of HDDs.  The 
model includes the fixed, categorical effects of treatment, sex, timepoint, and treatment-
by-timepoint interaction as well as the continuous, fixed covariates of log-transformed 
baseline values, and log-transformed baseline values-by-timepoint interaction. 
11.3.2.14 
Alanine Aminotransferase 
For log-transformed ALT, descriptive statistics will be obtained, and exploratory MMRM 
analysis will be performed in the same manner as the analysis of GGT. 
11.3.3 
Disposition of Subjects 
Disposition of subjects will be summarized.  The disposition includes the number of 
subjects who advanced to this trial, the number of subjects who advanced to the run-out 
period, the number of subjects who completed the trial, and the number of subjects who 
withdrew from the trial. 
The number of subjects who withdrew from the trial will be obtained by primary reason 
for withdrawal. 
11.3.4 
Demographic and Other Baseline Characteristics 
The following demographic and other baseline characteristics will be summarized by 
treatment group in the lead-in study for the FAS and SS. 
In subjects in the FAS and SS who advanced to the run-out period of this trial, the 
following demographic and other baseline characteristics will be summarized by 
treatment group in the run-out period of this trial. 
 Age 
 Sex 
 Height 
 Body weight 
 Body mass index 
 Medical history and complications 
 Alcohol drinking history 


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 Smoking history 
 Drug abuse history 
 Prior drugs and therapies 
 Concomitant drugs 
 Revised Clinical Institute Withdrawal Assessment for Alcohol 
 
11.4 
Procedures for Reporting Deviations From the Original Statistical 
Analysis Plan 
If any change is made to the analysis method planned in the protocol when the statistical 
analysis plan is finalized, the content and the reason for the change will be described in 
the statistical analysis plan and the clinical study report. 
11.5 
Rationale for Sample Size Determination 
The targeted subjects in this trial are the subjects who complete the preceding Study 339-
14-001 and wish to participate in this trial.  The estimate number of subjects is 
approximately 400. 
Based on the completion rate (nalmefene 20 mg group:  0.53 and placebo group:  0.67) in 
patients with a high or very high DRL at baseline and at randomization in Study 12013A 
(the duration of treatment:  52 weeks), the continuation rate of the completers in the 
preceding Study 339-14-001 to this trial was estimated to be 0.8. 
 
12 
Quality Control and Quality Assurance for the Trial 
To ensure quality of the trial, trial sites, contract research organizations, laboratories 
performing clinical tests, the DNA storage facility, and the sponsor will perform quality 
control for the trial according to their respective Standard Operating Procedures. 
The audit division of the sponsor company will carry out audits within the company and, 
as necessary, at the trial site and contract research organizations or organizations 
entrusted to perform related activities, and check whether quality control of the trial is 
appropriately performed according to the Standard Operating Procedures. 
 


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13 
General Items of Caution Pertaining to the Trial 
13.1 
Ethics and GCP Compliance 
This clinical trial is to be conducted in compliance with the ethical principles of the 
Declaration of Helsinki, the Pharmaceutical Affairs Law, the Ordinance on Good Clinical 
Practice (GCP) (Ministry of Health and Welfare Ordinance No. 28 dated 27 Mar 1997), 
relevant notifications, and this trial protocol. 
13.2 
Institutional Review Board 
Prior to performance of this trial, the appropriateness of performance of this trial will be 
reviewed from ethical, scientific, and medical perspectives by the IRB designated by the 
trial site, and this trial will be commenced only after obtaining the approval of the IRB. 
13.3 
Subject Consent 
13.3.1 
Procedures for Obtaining Consent 
1) Prior to the start of IMP administration, the investigator or subinvestigator will 
fully explain the matters listed in Section 13.3.2 to each subject who will be 
included in the trial, using the ICF, and give the ICF to the subject.  The subject 
will be provided sufficient time to make a decision regarding participation.  After 
confirming that the subject has properly understood the explanation, the 
investigator or subinvestigator will obtain written voluntary consent for 
participation in the trial from the subject. 
2) The investigator or subinvestigator who has provided the explanation and the 
subject will each put their printed name and personal seal or signature on the ICF, 
and write the date on which they sign or stamp the form.  If a trial associate has 
provided a supplemental explanation of the trial, he/she will also put his/her 
printed name and personal seal or signature on the form and write the date on 
which he/she signs or stamps the form. 
3) The original of the ICF that was signed or stamped and dated will be retained by 
the investigator or subinvestigator according to the regulations of the trial site.  A 
copy of the original ICF will be given to the subject. 
4) After obtaining informed consent from a subject, the investigator or 
subinvestigator will write the date of informed consent acquisition and subject 
identification code in the documents for enrolled subjects (list of screened 
subjects and list of enrolled subjects). 
5) If new information becomes available that may influence the willingness of the 
subject to continue participation in the trial, the investigator or subinvestigator 
will promptly inform the subject of such information and confirm the willingness 
of the subject to continue participation in the trial, and then record the result in the 


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subject’s medical records.  If there is guidance regarding the recording of re-
consent stipulated by the trial site, it will be followed. 
 
13.3.2 
Contents of Informed Consent Form 
1) An explanation that the trial involves research 
2) The type of IRB that reviews the appropriateness of trial conduct, matters to be 
reviewed by the IRB, and other relevant descriptions of the activity of the IRB 
3) The objectives of the trial 
4) The trial procedures (including research-related aspects of the trial, inclusion 
criteria for subjects, and, if random allocation is performed, the probability of 
randomization to each treatment arm) 
5) The expected duration of the subject’s participation in the trial 
6) The planned number of subjects involved in the trial 
7) The foreseeable IMP-related physical and mental benefits (if no benefits are 
expected, this should be indicated) as well as risks or inconveniences to the 
subject 
8) The existence of alternative treatments for the subject, and their important 
potential benefits and risks 
9) The treatment and compensation available to the subject in the event of trial-
related injury to health 
10) An explanation that the subject’s participation in the trial is voluntary, and that the 
subject can refuse to participate or withdraw from the trial, at any time, without 
penalty or loss of benefits to which he or she would otherwise be entitled 
11) An explanation that the subject will be informed in a timely manner if information 
becomes available that may be relevant to his or her willingness to continue 
participation in the trial 
12) The circumstances or reasons under which the subject’s participation in the trial 
should be terminated 
13) An explanation that the monitors, the auditors, the IRB, and the regulatory 
authorities will be granted direct access to the subject’s original medical records 
without violating the confidentiality of the subject, and that by signing the ICF, 
the subject is authorizing such access 
14) An explanation that if the results of the trial are published, the subject's identity 
will remain confidential 
15) The anticipated expenses to the subject for participating in the trial 
16) The anticipated payment, if any, to the subject for participating in the trial 
(agreements on payment, etc) 
17) The name, position, and contact address of the investigator or subinvestigator 


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18) The persons at the trial site to contact for further information regarding the trial 
and the rights of trial subjects, and whom to contact in the event of trial-related 
injury to health 
19) Matters to be observed by subjects 
 
13.3.3 
Amendments to the Informed Consent Form  
If revision of the ICF becomes necessary due to newly obtained information, the 
investigator will promptly revise the ICF to include that information after conferring with 
the sponsor. 
The investigator, when revising the ICF, will report this to the head of the trial site and 
submit the revised document to the IRB designated by the trial site to obtain its approval. 
If new information becomes available that may influence the willingness of subjects to 
continue participation in the trial and the ICF has been revised according to the new 
information, the investigator or subinvestigator will again obtain subjects’ written 
informed consent to continue participation in the trial. 
13.4 
Management of Investigational Medicinal Products 
1) The sponsor will issue the “Procedures for Handling of Investigational Medicinal 
Products” to the persons designated by the trial site. 
2) The sponsor will issue the “Document on Investigational Medicinal Products 
Storage Conditions” to the investigator or subinvestigator, trial associates, and 
IMP manager. 
3) The sponsor will deliver the IMPs to the trial site following the start of the trial 
period contracted with the trial site. 
4) The IMP manager will manage the IMPs appropriately according to the 
“Procedures for Handling of Investigational Medicinal Products” prepared by the 
sponsor. 
5) The IMP manager will prepare and retain the “Record of Management and 
Storage of Investigational Medicinal Products.” 
 
13.5 
Direct Access to Source Documents and Monitoring  
13.5.1 
Direct Access to Source Documents  
The head of the trial site and the investigator must accept monitoring and audits to be 
performed by the sponsor and inspection by the IRB and Japanese and foreign regulatory 
authorities, and must make source documents and all other trial-related records available 


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to these agencies for direct access (including copying).  Subjects authorize such direct 
access by signing the written ICF. 
13.5.2 
Monitoring 
The sponsor bears responsibility for ethical, legal, and scientific conduct of the trial.  The 
sponsor will perform monitoring according to the “Procedures for monitoring” specified 
for this trial.  Monitoring includes periodic visits, phone calls, or other contact with the 
trial site for the provision, obtaining, and recording of updated trial-related information 
by monitors designated by the sponsor. 
The sponsor may entrust a portion of monitoring activity to a contract research 
organization. 
13.5.3 
Documents to Be Retained by the Investigator 
The trial-related documents to be retained by the investigator will be kept in the 
investigator’s file, which will be managed by the investigator. 
13.6 
Deviations From and Changes or Amendments to the Trial 
Protocol 
13.6.1 
Deviations From the Trial Protocol 
1) The investigator or subinvestigator should not deviate from the protocol or change 
it without prior written agreement between the investigator and the sponsor and 
the written approval of the IRB of the trial site based on prior review. 
2) In unavoidable medical circumstances such as the need to avoid emergent risk to a 
subject, the investigator or subinvestigator may deviate from the protocol or 
change the protocol without prior written agreement from the sponsor and prior 
approval of the IRB.  In such an event, the investigator will promptly submit a 
document providing the details of and reason for the deviation or change to the 
sponsor and the head of the trial site and obtain approval from the IRB.  In 
addition, the investigator will obtain written approval from the head of the trial 
site and the written agreement of the sponsor by way of the head of the trial site. 
3) The investigator or subinvestigator will record all deviations from the protocol. 
 
13.6.2 
Amendments to the Trial Protocol  
1) The investigator will promptly submit to the sponsor, the head of the trial site, and 
the IRB by way of the head of the trial site, a written report on any changes in the 
trial that may significantly affect conduct of the trial or increase risks to the trial 
subjects. 


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2) The sponsor, after conferring with the investigator, will agree with the investigator 
on the contents of the revised protocol and compliance with the revised protocol. 
3) The sponsor will promptly submit the revised protocol to the head of the trial site. 
 
13.7 
Archiving of Records 
1) The trial site will retain all the trial-related documents and records for the period 
of time indicated in a) or b) below, whichever is longer.  However, if the sponsor 
requires a longer period of archiving, the head of the trial site will consult with the 
sponsor on the period and procedures of record retention. 
a) The date an Application for Approval of a Pharmaceutical Product for the IMP 
is granted; or, if the head of the trial site receives notification from the sponsor 
that development has been terminated or that results of the trial will not be 
submitted with the approval application, the date 3 years after receipt of such 
notification. 
b) The date 3 years after termination or completion of the trial. 
2) The investigator will retain the trial-related documents and records as directed by 
the head of the trial site. 
3) If it becomes no longer necessary to retain the trial-related documents and records 
at the trial site, the sponsor will notify the head of the trial site. 
 
13.8 
Termination or Interruption of Part or All of the Trial 
13.8.1 
Termination or Interruption of the Trial at Individual Trial Sites 
1) In the event of termination or interruption of the trial, the investigator will 
promptly provide the head of the trial site with written notification and a written 
explanation of the details of the termination or interruption of the trial. 
2) When the sponsor has been informed by the head of a trial site that the 
investigator has terminated or interrupted the trial, the sponsor will obtain a 
detailed written explanation of the termination or interruption of the trial from the 
head of the trial site. 
 
13.8.2 
Termination or Interruption of the Entire Trial 
1) When the entire trial is to be terminated or interrupted by the sponsor, the sponsor 
will promptly provide the heads of all trial sites involved in the trial and the 
regulatory authority with written notification and a detailed written explanation of 
the reason for the termination or interruption of the trial. 
2) When the investigator has received notification of termination or interruption of 
the entire trial by the sponsor from the head of the trial site, the investigator will 
obtain a detailed written explanation of the termination or interruption of the trial 
from the head of the trial site, promptly notify the trial subjects currently receiving 


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IMP administration, and take necessary measures such as switching to appropriate 
alternative treatment(s). 
3) When development of the IMP is terminated by the sponsor, the sponsor will 
promptly provide the heads and the investigators of all trial sites involved in the 
trial and the regulatory authority with written notification and a detailed written 
explanation of the reason for the termination of development. 
 
13.9 
Protection of Subjects’ Personal Information 
In completion and handling of CRFs, the investigator and subinvestigator will take 
adequate care to ensure protection of the personal information of subjects.  Individual 
subjects will be identified by subject numbers and subject identification codes.  The 
sponsor will not provide the information obtained to any third party. 
13.10 
Compensation for Injury to Health 
Trial subjects will be compensated for health damages according to the criteria 
established by the trial sponsor with reference to the “Guidelines for Health Damage 
Compensation to Trial Subjects” (revised 25 Nov 2009) of the Japan Pharmaceutical 
Industry Legal Affairs Association. 
13.11 
Agreement on Publication 
The sponsor may use the findings obtained from this trial for purposes such as an 
“Application for Approval of a Pharmaceutical Product” for the IMP. 
When the results of this trial and relevant data are to be published in scientific journals or 
at academic meetings, the investigator will obtain prior written approval from the sponsor. 
 


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14 
Trial Administrative Structure 
The administrative structure of this trial is shown in Annex 1, Annex 2, and Annex 3. 
 
15 
Scheduled Duration of the Trial 
From 05 Dec 2014 to 31 Mar 2018 
 
16 
References 
1 
Takahashi S, Someya Y, Ohno H, translators. Diagnostic and statistical manual of 
mental disorders. Tokyo: Igaku-Shoin Ltd.; 2003. 
2 
Gastfriend DR, Garbutt JC, Pettinati HM, Forman RF. Reduction in heavy drinking as 
a treatment outcome in alcohol dependence. J Subst Abuse Treat. 2007 Jul;33(1):71-
80. 
3 
World Health Organization. International guide for monitoring alcohol consumption 
and related harm. 2000. 
4 
Ministry of Health, Labour and Welfare, 2008 Summary of patient survey, 2008. 
5 
Ozaki Y, Matsushita S, Shirasaka T, Hiro H, Higuchi S. Nationwide survey of alcohol 
drinking and alcoholism among Japanese adults. Japanese Journal of Alcohol Studies 
& Drug Dependence. 2005;40(5):455-70. 
6 
Shirakura K, Higuchi S, Wada K. Guideline for diagnosis/treatment of disorders 
associated with alcohol and drugs. Tokyo: Jiho Inc.; 2002. 
7 
Marlatt GA, editor. Harm reduction: pragmatic strategies for managing high-risk 
behaviors. New York, NY: Guilford Press; 1998. 
8 
Rehm J, Rehm M, Alho H, Allamani A, Aubin H-J, Bühringer G, et al. Alcohol 
dependence treatment in the EU: a literature search and expert consultation about the 
availability and use of guidelines in all EU countries plus Iceland, Norway, and 
Switzerland. The International Journal of Alcohol and Drug Research. 2013;2(2). 
9 
Higuchi S, Saito T. Reduction in alcohol consumption: therapeutic goal in alcohol 
dependence treatment. Nihon Arukoru Yakubutsu Igakkai Zasshi. 2013 Feb;48(1):17-
31. 
10 Maesato H, Sakuma H, Kimura M, Nakayama H, Takimura T, Yoshimura A, et al. 
Survey of physicians and alcohol-dependent patients in regard to the goals of 
treatment of alcohol dependence. Nihon Arukoru Yakubutsu Igakkai Zasshi. 2013 
Feb; 48 (1):64-75. 
11 Herz A. Endogenous opioid systems and alcohol addiction. Psychopharmacology. 
1997 Jan;129(2):99-111. 


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12 Koob GF, Roberts AJ, Schulteis G, Parsons LH, Heyser CJ, Hyytia P, et al. 
Neurocircuitry targets in ethanol reward and dependence. Alcohol Clin Exp Res. 1998 
Feb;22(1):3-9. 
13 Summary of Product Characteristics (SmPC). 
14 European Medicines Agency (EMA). Guideline on the development of medicinal 
products for the treatment of alcohol dependence. EMA/CHMP/EWP/20097/2008. 
2010. 
 

SAP_001.pdf: 
 
 
STATISTICAL  ANALYSIS  PLAN 
 
 
A Long-term Extension Study for the Phase 3 Study of Nalmefene 
 (339-14-001) in Patients With Alcohol Dependence (Phase 3 Trial) 
 
 
                                                               NCT Number: 02382276 
                                                               PRT NO. ：339-14-002 
                                                               Version 1: 27 Mar 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
A Long-term Extension Study for the Phase 3 Study of Nalmefene (339-14-
001) in Patients With Alcohol Dependence (Phase 3 Trial) 
 
 
 
 
 
Statistical Analysis Plan 
Protocol No.: 339-14-002 
 
Confidential 
(Translated Version) 
 
 
 
 
 
 
 
 
 
 
 
Otsuka Pharmaceutical Co., Ltd. 
 
 
 
 
 
Version 1: 27 Mar 2017 
 


 
2 
Table of Contents 
Table of Contents ......................................................................................................... 2 
List of Abbreviations and Definition of Terms ............................................................... 4 
1 
Introduction ........................................................................................................... 6 
2 
Trial Objectives ..................................................................................................... 7 
3 
Trial Design ........................................................................................................... 8 
4 
Implementation of Planned Analyses .................................................................... 9 
5 
Analysis Sets ...................................................................................................... 10 
5.1 
Analysis Sets ................................................................................................................................. 10 
6 
Data Analysis Considerations ............................................................................. 11 
6.1 
Software ........................................................................................................................................ 11 
6.2 
Dictionary ...................................................................................................................................... 11 
6.3 
Data Conversion and Calculation .................................................................................................. 11 
6.4 
Handling of Timepoint .................................................................................................................. 13 
6.5 
Handling of Missing Values and Outliers ...................................................................................... 15 
6.6 
Significance Level and Confidence Coefficient ............................................................................ 15 
7 
Disposition of Subjects ........................................................................................ 16 
7.1 
Details of Subject Disposition ....................................................................................................... 16 
7.2 
Analysis Sets ................................................................................................................................. 16 
8 
Description of Analysis Sets ................................................................................ 17 
8.1 
Demographic and Other Baseline Characteristics ......................................................................... 17 
8.2 
Implementation Status ................................................................................................................... 19 
9 
Safety Analysis ................................................................................................... 20 
9.1 
Extent of Exposure ........................................................................................................................ 20 
9.2 
Adverse Events ............................................................................................................................. 21 
9.3 
Death, Other Serious Adverse Events and Other Significant Adverse Events .............................. 23 
9.4 
Subgroup Analyses of Adverse Events .......................................................................................... 26 
9.5 
Clinical Laboratory Tests .............................................................................................................. 26 
9.6 
Vital Signs ..................................................................................................................................... 28 
9.7 
Twelve-lead Electrocardiogram (results obtained from the central ECG laboratory) ................... 28 
9.8 
Physical Examination .................................................................................................................... 29 
9.9 
POMS ............................................................................................................................................ 29 
9.10 C-SSRS ......................................................................................................................................... 30 
9.11 Dependence Survey ....................................................................................................................... 31 


 
3 
10 Efficacy Analysis ................................................................................................. 33 
10.1 Number of Heavy Drinking Days ................................................................................................. 33 
10.2 TAC ............................................................................................................................................... 33 
10.3 RSDRL .......................................................................................................................................... 34 
10.4 RLDRL.......................................................................................................................................... 34 
10.5 70% Total Alcohol Consumption Responder Rate ........................................................................ 34 
10.6 Heavy Drinking Day Responder Rate ........................................................................................... 34 
10.7 CGI-S ............................................................................................................................................ 34 
10.8 CGI-I ............................................................................................................................................. 34 
10.9 SF-36 ............................................................................................................................................. 35 
10.10 EQ-5D-3L ..................................................................................................................................... 35 
10.11 AQoLS .......................................................................................................................................... 35 
10.12 RUMQ-ADP ................................................................................................................................. 35 
10.13 Gamma-glutamyl Transferase ....................................................................................................... 36 
10.14 ALT ............................................................................................................................................... 36 
11 Rationale for Sample Size Determination ........................................................... 37 
12 Changes from the Analysis Method Planned in the Protocol ....................................... 38 
13 References ......................................................................................................... 39 
14 Revision History .................................................................................................. 40 
15 APPENDIX .......................................................................................................... 41 
15.1 PCS Criteria for Clinical Laboratory Tests ................................................................................... 41 
15.2 PCS Criteria for Vital Signs .......................................................................................................... 42 
15.3 PCS Criteria for 12-lead ECG ....................................................................................................... 42 
 


 
4 
List of Abbreviations and Definition of Terms 
List of Abbreviations 
Abbreviation 
Expansion or Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AQoLS 
Alcohol Quality of Life Scale 
BMI 
Body Mass Index 
BRENDA 
Biopsychosocial evaluation, Report to the patient on assessment, Empathic 
understanding of the patient's situation, Needs collaboratively identified by the patient 
and treatment provider, Direct advice to the patient on how to meet those needs, Assess 
reaction of the patient to advice and adjust as necessary for best care 
BUN 
Blood urea nitrogen 
CGI-I 
Clinical Global Impression-Global Improvement 
CGI-S 
Clinical Global Impression-Severity of Illness 
CIWA-Ar 
Revised Clinical Institute Withdrawal Assessment For Alcohol 
CRP 
C-reactive protein 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DRL 
Drinking Risk Level 
EQ-5D 
EuroQol 5 Dimension 
FAS 
Full Analysis Set 
γ-GTP 
Gamma-glutamyl transpeptidase 
HDD 
Heavy Drinking Day 
ICH 
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities ICH 
MMRM 
Mixed model for repeated measures approach 
OC 
Observed Case 
PCS 
Potentially clinically significant 
POMS 
Profile of Mood States 
QTc 
Corrected QT interval 
QTcB 
QT interval as corrected by Bazett’s formula 
QTcF 
QT interval as corrected by Fridericia’s formula 
RLDRL 
Response Low Drinking Risk Level 
RSDRL 
Response Shift Drinking Risk Level 
RUMQ-ADP 
Resource Use Measurement Questionnaire-Alcohol Dependence 
SAS 
Statistical Analysis System 
SD 
Standard deviation 
SE 
Standard Error 
SF-36  
MOS 36-item Short-form Health Survey 
SS 
Safety Set 
TAC 
Total Alcohol Consumption 
TEAE  
Treatment-emergent adverse event 
TLFB 
Timeline Followback 
TMD 
Total mood disturbance 


 
5 
Abbreviation 
Expansion or Definition 
VAS  
Visual analog scale 
WHO 
World Health Organization 
 
Definitions of Terms 
Term 
Definition 
Descriptive statistics 
Number of subjects, mean, standard deviation, minimum, median, maximum 
Frequency 
Number of subjects, proportion 
Percentile 
10th percentile, 25th percentile, 75th percentile, 90th percentile 
 
 


 
6 
1 Introduction 
This statistical analysis plan describes the detailed statistical analysis methods planned for Study 339-14-
002. 
This statistical analysis plan is prepared based on the protocol of the trial version 2 (prepared on 20 Nov 
2014) of the trial. 
 
 


 
7 
2 Trial Objectives 
The long-term safety and efficacy of nalmefene hydrochloride at 20 mg in patients with alcohol 
dependence will be evaluated in a multicenter, open-label, uncontrolled trial. 
 


 
8 
3 Trial Design 
This trial is intended to evaluate the long-term safety of nalmefene hydrochloride at 20 mg in patients 
with alcohol dependence who have completed Study 339-14-001. The outline of the trial design is shown in 
Figure 3-1. 
This trial will consist of a 24-week treatment period (open-label, uncontrolled), a 4-week run-out period 
(double-blind, placebo-controlled), and a 4-week post-treatment observation period. The duration of 
investigational medicinal product (IMP) treatment of this trial will be 28 weeks (treatment period plus run-
out period). When combined with the preceding Study 339-14-001, the maximum duration of IMP 
treatment will be 52 weeks. 
The investigator or sub-investigator will fully explain the details of this trial to, and obtain written 
informed consent from, each subject by the end of the treatment period of Study 339-14-001. 
In the treatment period, subjects will receive nalmefene hydrochloride 20 mg. Each subject will be 
instructed to take the IMP orally as needed on days when the subject perceives a risk of drinking alcohol, 1 
to 2 hours prior to the anticipated risk of drinking. The IMP can be taken up to one tablet a day (one day is 
defined as the period from 0 AM of the day to 0 AM of the next day), and if a subject requires dose change 
during the treatment period, the subject will be withdrawn from the trial. When a subject is withdrawn from 
the trial, the subject will be requested to visit the site and to undergo the specified assessments and 
examinations wherever possible. 
In the run-out period, subjects will be randomized to either nalmefene hydrochloride 20 mg group or 
placebo group at a ratio of 1:1. Each subject will be instructed to take the IMP orally as needed on days 
when the subject perceives a risk of drinking alcohol, 1 to 2 hours prior to the anticipated risk of drinking. 
The IMP can be taken up to one tablet a day (one day is defined as the period from 0 AM of the day to 0 
AM of the next day), and if a subject requires dose change during the run-out period, the subject will be 
withdrawn from the trial. When a subject is withdrawn from the trial, the subject will be requested to visit 
the site and to undergo the specified assessments and examinations wherever possible. 
A post-treatment observation period will be scheduled after the end of the run-out period to evaluate 
safety after the end of treatment with nalmefene hydrochloride. However, post-treatment observation will 
be performed only in the subjects who complete the run-out period. 
 
Figure 3-1 
Summary of Trial Design 
V = visit. Post-treatment observation will be performed only in the subjects who complete the run-out 
period. 
Nalmefene 
10 mg 
Nalmefene  
20 mg 
Placebo 
Study 339-
14-001 
Nalmefene 20 mg 
24-week treatment period 
Nalmefene  
20 mg 
Placebo 
Run-out period 
4 weeks 
Post-treatment 
observation  
4 weeks 
Eligibility 
Week 0 
Week 1 
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
(Randomized) 
Week 28 
Week 32 


 
9 
4 Implementation of Planned Analyses 
The final analysis will be performed using locked data after unblinding. 
 


 
10 
5 Analysis Sets 
5.1 
Analysis Sets 
The analysis sets in this trial consist of the "safety set" and the "full analysis set." 
5.1.1 
Safety Set (SS) 
Subjects who receive the IMP at least once in this trial 
5.1.2 
Full Analysis Set (FAS) 
Subjects in the SS who have data of the number of HDDsa at baseline of Study 339-14-001 (hereinafter 
referred to as the lead-in study), and at one timepoint or more after the initial IMP administration in this 
trial 
 
                                                        
a 
The number of HDDs is defined as the number of days per month (days/month) with alcohol consumption per day of > 
60 g for males and > 40 g for females. One month is defined as 4 weeks (28 days). The number of HDDs is calculated as 
the number of days per month with alcohol consumption per day of > 60 g for males and > 40 g for females multiplied by 
28, and divided by the number of days per month without missing data. Data will be considered as missing if the number 
of days per month without missing data is less than 7 days. 


 
11 
6 Data Analysis Considerations 
6.1 
Software 
Data will be tabulated and analyzed using SAS (SAS Institute Japan Ltd.). SAS released version 9.4 or 
later will be used. 
 
6.2 
Dictionary 
Adverse events and complications will be coded using MedDRA (Ver 19.0). Prior and concomitant 
drugs will be coded using the WHO Drug Dictionary (March 2015 version). 
 
6.3 
Data Conversion and Calculation 
6.3.1 
Baseline and Baseline II 
Unless otherwise specified, the baseline of the treatment period will be the one in the lead-in study, and 
the baseline of the run-out period and post-treatment observation period (hereinafter referred to as baseline 
II) will be Week 24 of the treatment period (Visit 10) in this trial. 
6.3.2 
Endpoints Derived by Timeline Followback (TLFB) 
The number of HDDs and TAC will be derived based on the alcohol consumption data collected with 
TLFB. Alcohol consumption data will be collected in units of drinks. One drink is defined as consumption 
of approximately 10 g of pure alcohol, and alcohol consumption will be calculated by multiplying the 
number of drinks by 10. 
The baseline for the endpoints will be the 28-day period before the Screening Visit in the lead-in study. 
Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 of the lead-in study will be 28 days each, 
starting from the Randomization Visit of the lead-in study as Day 1 (e.g., Days 1 to 28 for Week 4 and 
Days 29 to 56 for Week 8). Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 of this trial will 
be 28 days each, starting from the day of the Week 0 visit (Visit 2) of this trial as Day 1. 
Baseline II will be the 28-day period before the start of the run-out period. The run-out period will be 28 
days from the start of the run-out period. However, if the Run-out Period Visit or the Withdrawal Visit after 
the run-out period comes before the start of the run-out period + 28 days, the period will be from the start 
of the run-out period to the day before the Run-out Period Visit, or the day before the Withdrawal Visit. 
The number of HDDs and TAC at the relevant timepoint will be considered as missing, if the number of 
days per month without missing data is less than 7 days. 
When alcohol consumption data on the day of TLFB is collected at the withdrawal examination, the data 
on the day of withdrawal examination will be handled as missing. 
6.3.2.1 
Number of Heavy Drinking Days (HDDs) 
The number of HDDs is calculated as the number of days per month with alcohol consumption per day 
of > 60 g for males and > 40 g for females multiplied by 28, and divided by the number of days per month 
without missing data. 


 
12 
6.3.2.2 
TAC 
TAC is calculated as the total of daily alcohol consumption per month divided by the number of days per 
month without missing data. 
6.3.3 
DRL 
DRL at each timepoint will be determined based on risk levels defined by the WHO based on average 
volume of alcohol consumption per day (criteria for risk of acute problems) using TAC. 
DRL 
Men 
Women 
Very high 
> 100 g 
> 60 g 
High 
> 60 g - ≤ 100 g 
> 40 g - ≤ 60 g 
Medium 
> 40 g - ≤ 60 g 
> 20 g - ≤ 40 g 
Low 
≥ 1 g - ≤ 40 g 
≥ 1 g - ≤ 20 g 
6.3.4 
RSDRL 
A downward shift in DRL of 2 categories or moreb 
6.3.5 
RLDRL 
A low DRL or below 
6.3.6 
70% TAC Responder Rate 
The percentage of subjects whose TAC is reduced by ≥ 70% from baseline 
6.3.7 
HDD Responder Rate 
The percentage of subjects in whom the number of HDDs is ≤ 4 
6.3.8 
CGI-I and CGI-S 
An assessment of "0. Not assessed” will be handled as missing. 
6.3.9 
SF-36 Subscales and Summary Scores 
The data will be calculated according to the method described in Manual of SF-36v2 Japanese version 
(2004)1. However, when an item included in any of the subscales is missing, the missing value will not be 
imputed and the subscale including the missing item will not be calculated. Component summaries will be 
calculated using the "factor coefficient based on the 1995 Japanese survey.” If at least one of the 8 
subscales is missing, component summaries will not be calculated. 
6.3.10 
Derivation of EQ-5D Utility Score 
EQ-5D Utility score will be obtained based on Estimating an EQ-5D population value set: The case of 
Japan (2002)2. The plain main effects model will be used. 
                                                        
b 
A shift to medium DRL or lower for patients with a very high DRL at baseline; a shift to low DRL or below for patients 
with a high DRL at baseline 


 
13 
6.3.11 
AQoLS Total Score 
Each AQoLS item will be scored as “not at all: 0”, “a little: 1”, “quite a lot: 2, or “very much: 3” and the 
AQoLS total score will be calculated. If at least one item is missing, the total score will not be calculated. 
Total Mood Disturbance (TMD) Score and Each Factor in POMS 
The TMD score and each factor will be calculated based on Protocol Appendix 7. The TMD score will 
be obtained by adding the values for each factor (except for the "vigor-activity" value, which will be 
subtracted). 
 
6.4 
Handling of Timepoint 
Unless otherwise specified, the timepoint of case report form entry (nominal timepoint) will be used. 
6.4.1 
Baseline 
The periods are described in 6.3.1 Baseline and Baseline II. 
6.4.2 
Final Assessment 
The last data of the assessment in the treatment period after the day of Week 0 visit of this trial (the day 
of the measurement of the breath alcohol concentration at Visit 2 of this trial), including early withdrawals 
and unscheduled visits. 
6.4.3 
Withdrawal Examination 
For the efficacy endpoints and POMS, if the day of the withdrawal examination in the treatment period is 
included in the time window in Table 6.4-1, and there is no data for the timepoint of case report form entry, 
the data at withdrawal examination will be used as the data at the timepoint of assessment. For the 
withdrawal examination in the run-out period, the data will be used as the data at Week 28, regardless of 
the examination day. For the withdrawal examination in the post-treatment observation period, the data will 
be used as the data at Week 32, regardless of the examination day. 
Table 6.4-1 
Time Window 
Week 
Day 
Time Window 
CGI-S, CGI-I 
 
SF-36, EQ-5D, AQoLS, RUMQ-
ADP and POMS 
Week 0 
1 
- 
- 
Week 1 
8 
2 - 11 
- 
Week 2 
15 
12 - 22 
- 
Week 4 
29 
23 - 43 
- 
Week 8 
57 
44 - 71 
 
Week 12 
85 
72 - 99 
2 - 127 
Week 16 
113 
100 - 127 
 
Week 20 
141 
128 - 155 
 
Week 24 
169 
156 - 183 
128 - 183 
Day 1 (reference day) is the day of Week 0 visit of this trial (the day of the measurement of the breath alcohol concentration at Visit 2 of 
this trial). 


 
14 
6.4.4 
Reference Day of Visit and Timepoints 
6.4.4.1 
Reference Day of Visit 
The day of the Randomization Visit of the lead-in study is the day of inclusion/exclusion assessment at 
Week 0 of the lead-in study. 
The day of Week 0 visit of this trial is the day of the measurement of the breath alcohol concentration at 
Week 0 (Visit 2 of this trial). 
The day of the start of the run-out period is the day of the randomization at Week 24 (Visit 10 of this 
trial). 
The day of the Run-out Period Visit is the day of the measurement of the breath alcohol concentration at 
Week 28 (Visit 11 of this trial). 
The day of the post-treatment observation period visit is the day of the measurement of the breath 
alcohol concentration at Week 32 (Visit 12 of this trial). 
6.4.4.2 
Treatment Period 
The treatment period of this trial will be from Week 0 visit of this trial to the day before the start of the 
run-out period. 
The lead-in study and the treatment period of this trial will be from the Randomization Visit of the lead-
in study to the day before the start of the run-out period. However, the examination data entered at the 
timepoint of case report form entry at Week 24 (Visit 10 of this trial) will be used as the data in the 
treatment period. 
In case of withdrawal prior to the start of the run-out period (withdrawal in the treatment period, 
withdrawal prior to the randomization of this trial), the treatment period will be up to the final day of the 
withdrawal examination. If no withdrawal examination is performed, it will be up to the day of decision of 
the withdrawal. 
6.4.4.3 
Run-out Period 
The run-out period is defined only for the subjects who complete the treatment period of this trial (those 
who advance to the run-out period). 
The run-out period of this trial will be from the start of the run-out period to the day before the Run-out 
Period Visit. 
However, the examination data entered at the timepoint of case report form entry at Week 28 (Visit 11 of 
this trial) will be used as the data in the run-out period. 
In case of withdrawal prior to the Run-out Period Visit (withdrawal in the run-out period, subjects who 
do not measure the breath alcohol concentration at Week 28 [Visit 11] of this trial), the run-out period will 
be up to the final day of the withdrawal examination. If no withdrawal examination is performed, it will be 
up to the day of decision of the withdrawal. 
6.4.4.4 
Post-treatment Observation Period 
The post-treatment observation period is defined only for the subjects who complete the run-out period 
of this trial (those who advance to the post-treatment observation period and made the scheduled Run-out 
Period Visit [Visit 11]). 
The post-treatment observation period will be from the Run-out Period Visit to the Post-treatment 
Observation Visit. 


 
15 
In case of withdrawal prior to the Post-treatment Observation Visit, the post-treatment observation 
period will be up to the final day of the withdrawal examination. If no withdrawal examination is 
performed, it will be up to the day of decision of the withdrawal. 
 
6.5 
Handling of Missing Values and Outliers 
Handling of missing values at the time of derivation of each endpoint is shown in "6.3 Data Conversion 
and Calculation.” Imputation of missing values at the time of analysis is described in the analysis section 
for each endpoint. 
 
6.6 
Significance Level and Confidence Coefficient 
The significance level will be 5% (two-sided), and the confidence coefficient will be 95% (two-sided). 
6.6.1 
Multiple Comparison/Multiplicity 
Efficacy endpoints will be tested but not adjusted for multiplicity due to the exploratory nature of the 
analysis. 
 


 
16 
7 Disposition of Subjects 
7.1 
Details of Subject Disposition  
For the subjects who provide informed consent to this trial, the number of subjects providing informed 
consent, the number of subjects advancing to this trial, the number of subjects withdrawing before 
advancing to this trial, and the number of subjects withdrawing after advancing to this trial but before the 
IMP administration will be obtained for the entire population and for each treatment group of the lead-in 
study (the entire groups receiving nalmefene hydrochloride and each treatment group). Subjects who 
withdraw prior to advancing to this trial and subjects who withdraw after advancing to this trial but before 
the IMP administration will be tabulated by reason for withdrawal. 
For the subjects who advance to this trial, the number of subjects advancing to this trial and the number 
of subjects receiving the IMP will be obtained for the entire population and for each treatment group of the 
lead-in study. 
For the subjects who receive the IMP (SS), the number of subjects advancing to the run-out period (the 
number of subjects completing the treatment period) and the number of subjects withdrawing during the 
treatment period, and their respective proportions will be obtained for the entire population and for each 
treatment group of the lead-in study. The number of subjects who withdraw during the treatment period and 
its proportion will be obtained by primary reason for withdrawal. In addition, frequency of the respective 
primary reasons for withdrawal will be tabulated by timepoint of withdrawal. The timepoints of withdrawal 
in frequency tabulation will be the same as the respective Weeks (Weeks 4, 8, 12, 16, 20 and 24) of this 
trial after baseline of the endpoints derived from TLFB. 
For the subjects in the SS who advance to the run-out period, the number of subjects receiving the IMP 
during the run-out period, the number of subjects withdrawing during the run-out period, the number of 
subjects advancing to the post-treatment observation period (the number of subjects completing the run-out 
period), the number of subjects withdrawing during the post-treatment observation period, and the number 
of subjects completing the post-treatment observation period (the number of subjects completing the trial), 
and their respective proportions will be obtained for the entire population and for each treatment group of 
the run-out period. The number of subjects who withdraw during the run-out period and the number of 
subjects who withdraw during the post-treatment observation period, and their respective proportions will 
be obtained by primary reason for withdrawal. 
 
7.2 
Analysis Sets 
For the subjects who advance to this trial, the number of subjects included in the SS and subjects 
included in the FAS, the number of subjects not included in the SS and subjects not included in the FAS, 
and their respective proportions will be obtained for the entire population and for each treatment group of 
the lead-in study (the entire groups receiving nalmefene hydrochloride and each treatment group). For the 
included subjects, the number of subjects advancing to the run-out period and its proportion, and the 
number of subjects advancing to the post-treatment observation period and its proportion will be obtained 
for the entire population and for each treatment group of the run-out period. 


 
17 
8 Description of Analysis Sets 
8.1 
Demographic and Other Baseline Characteristics 
For the SS and FAS, the demographic and other baseline characteristics shown in Table 8.1-1, Table 
8.1-2, and Table 8.1-3 will be summarized for the entire population and for each treatment group of the 
lead-in study (the entire groups receiving nalmefene hydrochloride and each treatment group). 
For the subjects in the SS and FAS who advance to the run-out period of this trial, the demographic and 
other baseline characteristics shown in Table 8.1-1, Table 8.1-2, and Table 8.1-3 will be summarized for 
the entire population and for each treatment group of the run-out period of this trial. 
For the SS, important medical history related to alcohol dependence and complications will be 
summarized by System Organ Class (SOC) and Preferred Term (PT) for the entire population and for each 
treatment group of the lead-in study. 
For the subjects in the SS who advance to the run-out period, important medical history related to 
alcohol dependence and complications will be tabulated by SOC and PT for the entire population and for 
each treatment group of the run-out period of this trial. 
 
Table 8.1-1 
Demographic and Other Baseline Characteristics 
Variables 
Method of tabulation 
Categories 
Age (years old) 
Descriptive statistics 
- 
Age (years old) 
Frequency 
< 65, 65 ≤ 
< 25, 25 ≤ - < 35, 35 ≤ - < 45, 45 ≤ - < 55, 
55 ≤ - < 65, 65 ≤ 
Sex 
Frequency 
Female, Male 
Body weight (kg) 
Descriptive statistics 
- 
Frequency 
< 65, 65 ≤ 
< 80, 80 ≤ 
Height (cm) 
Descriptive statistics 
- 
Body Mass Index (BMI) (kg/m2) a) 
Descriptive statistics 
- 
Frequency 
< 18.5, 18.5 ≤ - < 25, 25 ≤ - < 30, 30 ≤ - < 
40, 40 ≤ 
< 25, 25 ≤ - < 30, 30 ≤ 
Important medical history related to 
alcohol dependence 
Frequency 
Yes, No 
Complication 
Frequency 
Yes, No 
Smoking history 
Frequency 
"Now smokes every day,” "Now smokes 
some days (not every day),” "Has smoked,” 
"Never smoked" 
Drug abuse history 
Frequency 
Yes, No 
Prior drugs 
Frequency 
Yes, No 
Prior therapies other than BRENDA 
Frequency 
Yes, No 
Concomitant drugs 
Frequency 
Yes, No 
Prior concomitant therapy other than 
BRENDA 
Frequency 
Yes, No 
CIWA-Ar Total Score (at screening of 
the lead-in study) b) 
Descriptive statistics 
- 
CIWA-Ar Total Score (at 
randomization of the lead-in study) b) 
Descriptive statistics 
- 
a) To be calculated using the height at screening and the body weight at the Randomization Visit of the lead-in study. 
b) If at least one item is missing, the total score will not be calculated. 


 
18 
 
Table 8.1-2 
Alcohol Drinking History 
Variables 
Method of tabulation 
Categories 
Age when started drinking (years old) 
Descriptive statistics 
- 
Frequency 
< 15, 15 ≤ - < 18, 18 ≤ 
< 20, 20 ≤ 
Age when drinking problems detected 
(years old) 
Descriptive statistics 
- 
Frequency 
< 20, 20 ≤ 
Family history of problematic alcohol use 
Frequency 
Yes, No 
 
Table 8.1-3 
Treatment History for Drinking Problems 
Variables 
Method of tabulation 
Categories 
Age when started treatment for drinking 
problems (years old) 
Descriptive statistics 
- 
Treatments for alcohol dependence 
Frequency 
Yes, No 
 
Inpatient treatment  
Frequency 
Yes, No 
Inpatient treatment (number of 
times) 
Descriptive statistics 
- 
Inpatient treatment, psychiatrist 
Frequency 
Yes, No 
Inpatient treatment, psychiatrist 
(number of times) 
Descriptive statistics 
- 
Inpatient treatment, specialist 
other than psychiatrist 
Frequency 
Yes, No 
Inpatient treatment, specialist 
other than psychiatrist (number 
of times) 
Descriptive statistics 
- 
Outpatient treatment 
Frequency 
Yes, No 
Outpatient treatment (number of 
times) 
Descriptive statistics 
- 
Outpatient treatment, 
psychiatrist 
Frequency 
Yes, No 
Outpatient treatment, 
psychiatrist (number of times) 
Descriptive statistics 
- 
Outpatient therapy, specialist 
other than psychiatrist 
Frequency 
Yes, No 
Outpatient treatment, specialist 
other than psychiatrist (number 
of times) 
Descriptive statistics 
- 
Treatments for alcohol withdrawal 
Frequency 
Yes, No 
 
Inpatient treatment 
Frequency 
Yes, No 
Inpatient treatment (number of 
times) 
Descriptive statistics 
- 
Outpatient treatment 
Frequency 
Yes, No 
Outpatient treatment (number of 
times) 
Descriptive statistics 
- 
Treatments for alcohol dependence or 
withdrawal 
Frequency 
Yes, No 
Participation in Alcoholics Anonymous or 
other patient groups 
Frequency 
Never participated, Currently 
participating, Participated within the 
past 4 weeks, Participated more than 4 
weeks ago 
 


 
19 
8.2 
Implementation Status 
8.2.1 
Use of Drugs other than Investigational Medicinal Product 
For the SS, the number and proportion of subjects who use drugs other than the IMP or "newly initiated 
therapy for alcohol dependence" will be obtained using the data of the lead-in study and this trial in terms 
of the "periods and treatment groups" shown in 1), 2), 3). They will be obtained for all drugs by ACT 
classification (Level 2, Level 3 and Level 4) coded in the WHO Drug Dictionary Enhanced, and by 
Preferred name. 
1) Drugs used during the treatment period of the lead-in study 
For the drugs started by the day prior to Randomization Visit in the lead-in study and continued 
after the Randomization Visit, or for the drugs started during the treatment period of the lead-in study, 
the number and the proportion of each will be obtained for each treatment group of the lead-in study 
(the entire groups receiving nalmefene hydrochloride and each treatment group). 
2) Drugs started during the treatment period of this trial 
For the drugs started during the treatment period of this trial, the number and its proportion will be 
obtained for the entire population and for each treatment group of the lead-in study. 
3) Drugs started during the run-out period or the post-treatment observation period of this trial 
For the subjects in the SS who advance to the run-out period of this trial and for the drugs started 
during the run-out period, or the post-treatment observation period of this trial, the number and the 
proportion of each will be obtained for the entire population and for each treatment group of the run-
out period of this trial. 
8.2.2 
Status of Non-drug Therapy 
For the SS, the number of subjects who newly start a therapy for alcohol dependence and its proportion 
will be obtained for all non-drug therapies by ACT classification (Level 2, Level 3 and Level 4) coded in 
the WHO Drug Dictionary Enhanced, and by Preferred name. For prior therapies or concomitant therapies 
other than BRENDA, or BRENDA approach, tabulation will not be conducted. 


 
20 
9 Safety Analysis 
Unless otherwise specified, the following safety analyses will be performed for the SS as the analysis set 
using data from the lead-in study and this trial 
9.1 
Extent of Exposure 
The study treatment duration will be defined as the study treatment duration (number of days of TLFB 
during the treatment period) in the lead-in study and the number of TLFB days during the treatment period 
and the run-out period of this trial. 
9.1.1 
Duration of Treatment and Duration of Exposure to IMP 
The study treatment duration (person-years) and the duration of exposure to the IMP (person-years) in 
the lead-in study will be obtained for each treatment group of the lead-in study (the entire groups receiving 
nalmefene hydrochloride and each treatment group). The study treatment duration (person-years) and the 
duration of exposure to the IMP (person-years) during the treatment period of this trial will be obtained for 
the entire population and for each treatment group of the lead-in study. In addition, for the subjects who 
advance to the run-out period of this trial, the study treatment duration (person-years) and the duration of 
exposure to the IMP (person-years) during the run-out period of this trial will be obtained for each 
treatment group of the lead-in study and for each treatment group of the run-out period. 
9.1.2 
Investigational Medicinal Product Compliance 
1) Lead-in study and this trial 
Descriptive statistics and percentiles (10%, 25%, 75%, 90%) will be obtained for the number of 
days of IMP administration and the proportion of the number of days of IMP administration to the 
study treatment duration overall and monthly. Descriptive statistics and percentiles will also be 
obtained for “the number of days of drinking with IMP administration,” “the number of days of 
drinking without IMP administration,” “the number of days of not drinking with IMP administration,” 
“the number of days of not drinking without IMP administration,” and their respective proportions to 
the number of TLFB days in the study treatment duration. Frequency of days of drinking without IMP 
administration will also be tabulated. The categories for frequency are 0 day, 1 - 9 days, 10 - 19 days, 
20 - 29 days, 30 - 39 days, 40 - 59 days, 60 - 99 days, and ≥100 days. Pooled data from the treatment 
groups will be used for the tabulation regardless of the treatment groups of the lead-in study or 
treatment groups of the run-out period of this trial. 
For the subjects in the SS who receive nalmefene hydrochloride 20 mg in the lead-in study and the 
run-out period of this trial, descriptive statistics and percentiles will be obtained for the number of 
days of IMP administration and the proportion of the number of days of IMP administration to the 
study treatment duration. Descriptive statistics and percentiles will also be obtained for “the number of 
days of drinking with IMP administration,” “the number of days of drinking without IMP 
administration,” “the number of days of not drinking with IMP administration,” “the number of days 
of not drinking without IMP administration,” and their respective proportions to the number of TLFB 
days in the study treatment duration. Frequency of days of drinking without IMP administration will 
also be tabulated. The categories for frequency are 0 day, 1 - 9 days, 10 - 19 days, 20 - 29 days, 30 - 
39 days, 40 - 59 days, 60 - 99 days, and ≥100 days. 
2) Lead-in study and the treatment period of this trial 
Descriptive statistics and percentiles will be obtained for the number of days of IMP administration 


 
21 
in the lead-in study and the treatment period of this trial and the proportion of the number of days of 
IMP administration to the study treatment duration for the entire population and for each treatment 
group of the lead-in study. Descriptive statistics and percentiles will also be obtained for “the number 
of days of drinking with IMP administration,” “the number of days of drinking without IMP 
administration,” “the number of days of not drinking with IMP administration,” “the number of days 
of not drinking without IMP administration,” and their respective proportions to the number of TLFB 
days in the study treatment duration. Frequency of days of drinking without IMP administration will 
also be tabulated. The categories for frequency are 0 day, 1 - 9 days, 10 - 19 days, 20 - 29 days, 30 - 
39 days, 40 - 59 days, 60 - 99 days, and ≥100 days  
3) Treatment period of this trial 
Descriptive statistics and percentiles will be obtained for the number of days of IMP administration 
in the treatment period of this trial and the proportion of the number of days of IMP administration to 
the study treatment duration for the entire population and for each treatment group of the lead-in 
study. Descriptive statistics and percentiles will also be obtained for “the number of days of drinking 
with IMP administration,” “the number of days of drinking without IMP administration,” “the number 
of days of not drinking with IMP administration,” “the number of days of not drinking without IMP 
administration,” and their respective proportions to the number of TLFB days in the study treatment 
duration. Frequency of days of drinking without IMP administration will also be tabulated. The 
categories for frequency are 0 day, 1 - 9 days, 10 - 19 days, 20 - 29 days, 30 - 39 days, 40 - 59 days, 
60 - 99 days, and ≥100 days. 
4) Run-out period of this trial 
For the subjects in the SS who advance to the run-out period, descriptive statistics and percentiles 
will be obtained for the number of days of IMP administration in the run-out period of this trial and 
the proportion of the number of days of IMP administration to the study treatment duration for each 
treatment group of the run-out period of this trial. Descriptive statistics and percentiles will also be 
obtained for “the number of days of drinking with IMP administration,” “the number of days of 
drinking without IMP administration,” “the number of days of not drinking with IMP administration,” 
“the number of days of not drinking without IMP administration,” and their respective proportions to 
the number of TLFB days in the study treatment duration. Frequency of days of drinking without IMP 
administration will also be tabulated. The categories for frequency are 0 day, 1 - 9 days, 10 - 19 days, 
and ≥20 days. 
Data in which both alcohol consumption and IMP compliance in each study treatment duration are 
available and neither of them is unknown will be used for tabulation. 
 
9.2 
Adverse Events 
1) Lead-in study and this trial 
Treatment-emergent adverse events (TEAEs) will be summarized by SOC and PT as well as “any 
TEAEs,” and the summaries will provide the number of subjects with TEAEs and incidence of those. 
Tabulation will also be performed by severity. Drug-related TEAEs will be summarized in the same 
manner. Pooled data from the treatment groups will be used for the tabulation regardless of the 
treatment groups of the lead-in study or treatment groups of the run-out period of this trial. 
For the subjects in the SS who receive nalmefene hydrochloride 20 mg in the lead-in study and the 
run-out period of this trial, TEAEs will be summarized for the entire treatment period and for 
timepoint (lead-in study or this trial) by SOC and PT as well as “any TEAEs,” and the summaries will 


 
22 
provide the number of subjects with TEAEs and incidence of those. Tabulation will also be performed 
by severity. Drug-related TEAEs will be summarized in the same manner. 
2) Lead-in study and the treatment period of this trial 
For the subjects in the entire population and in each treatment group of the lead-in study (the entire 
groups receiving nalmefene hydrochloride and each treatment group), TEAEs will be summarized for 
the entire treatment period and for timepoint (lead-in study, this trial) by SOC and PT as well as “any 
TEAEs,” and the summaries will provide the number of subjects with TEAEs and incidence of those. 
Tabulation will also be performed by severity. TEAEs will also be summarized for the entire treatment 
period and for timepoint (lead-in study or this trial) by SOC as well as “any TEAEs,” and the 
summaries will provide the number of subjects with TEAEs and incidence of those. Drug-related 
TEAEs will be summarized in the same manner. TEAEs that occur in this trial but before the start of 
the treatment period are included and summarized in the treatment period of this trial. 
In addition, TEAEs with an incidence of ≥ 2% in any treatment group of the lead-in study will be 
summarized for the entire treatment period and for timepoint (lead-in study or this trial). 
3) Run-out period of this trial 
For the subjects in the SS who advance to the run-out period of this trial, TEAEs will be 
summarized for each treatment group of the run-out period of this trial by SOC and PT as well as “any 
TEAEs,” and the summaries will provide the number of subjects with TEAEs and incidence of those. 
Tabulation will also be performed by severity. TEAEs will also be summarized by SOC as well as 
“any TEAEs,” and the summaries will provide the number of subjects with TEAEs and incidence of 
those. Drug-related TEAEs will be summarized in the same manner. 
4) Post-treatment observation period of this trial 
For the subjects in the SS who advance to the post-treatment observation period of this trial, TEAEs 
will be summarized for the entire population and for each treatment group of the run-out period of this 
trial by SOC and PT as well as “any TEAEs,” and the summaries will provide the number of subjects 
with TEAEs and incidence of those. Tabulation will also be performed by severity. Drug-related 
TEAEs will be summarized in the same manner. 
5) Treatment period with nalmefene hydrochloride 
The following summaries will be provided for the entire population and for each treatment group of the 
lead-in study. For the subjects who receive nalmefene hydrochloride 10 mg or nalmefene hydrochloride 20 
mg in the lead-in study, TEAEs occurring in the lead-in study and TEAEs occurring before or during the 
treatment period of this trial; For the subjects who receive placebo in the lead-in study, TEAEs occurring 
during the treatment period of this trial after the start of IMP administration; For the subjects who receive 
nalmefene hydrochloride 20 mg in the run-out period, TEAEs occurring during the run-out period. 
For the number of days to the onset of TEAE, the day of initial administration of nalmefene 
hydrochloride is defined as Day 0. The duration will be from the day of the onset as Day 1 until the day of 
resolution or confirmation of the outcome. 
 
TEAEs by time of the first onset after the initial IMP administration 
 
The categories of time of the first onset (days) are 0 ≤ - ≤ 84, 85 ≤ - ≤ 168, 169 ≤ - ≤ 252, 253 
≤ - ≤ 336, and 337 ≤. The incidence will be calculated based on the number of subjects who 
are treated at least 1 day at the relevant timepoint. 
 
Median, minimum, and maximum of the time of the first onset (days) will be provided. 
 
TEAEs by outcome 


 
23 
 
If the same event occurs more than once in the same subject, the last confirmed outcome will 
be used. 
 
TEAEs by duration 
 
The categories of duration (days) are 1 ≤ - ≤ 7, 8 ≤ - ≤ 14, 15 ≤ - ≤ 21, 22 ≤ - ≤ 28, 29 ≤ - ≤ 56, 
57 ≤ - ≤ 84, 85 ≤ - ≤ 112, 113 ≤ - ≤ 140, 141 ≤. 
 
Median, minimum, and maximum of the duration (days) will be provided. 
 
If the same event occurs more than once in the same subject, the longest duration will be used. 
Non-serious TEAEs with an incidence of 5% or higher in this trial will be summarized by SOC and PT 
as well as “any TEAEs” and the summaries will provide the number of subjects with TEAEs and incidence 
of those. 
 
9.3 
Death, Other Serious Adverse Events and Other Significant Adverse Events 
The following TEAEs will be summarized by SOC and PT as well as “any TEAEs” in terms of the 
“periods, subjects, treatment groups” shown in 1), 2), 3), 4). The summaries will provide the number of 
subjects with TEAEs and incidence of those. 
 
Serious Adverse Event 
 
Drug-related serious TEAEs 
The following TEAEs will be summarized by SOC and PT as well as “any TEAEs” in terms of the 
“periods, subjects, treatment groups” shown in 1), 2), 3), 4). The summaries will provide the number of 
subjects with TEAEs and incidence of those. However, for 2), tabulation for timepoint (lead-in study or this 
trial) will not be performed. 
 
TEAEs resulting in discontinuation of IMP administration 
 
Drug-related TEAEs resulting in discontinuation of IMP administration 
The following TEAEs will be summarized in terms of the “periods, subjects, treatment groups” shown in 
2), 3), 4). The summaries will provide the number of subjects with TEAEs and incidence of those. 
 
TEAEs leading to death 
 
Drug-related TEAEs leading to death 
 
Severe TEAEs 
 
Drug-related severe TEAEs 
1) Lead-in study and this trial 
a) Pooled data from the treatment groups will be used for the tabulation regardless of the treatment 
groups of the lead-in study or treatment groups in the run-out period of this trial. 
b) Tabulation will be conducted for the subjects in the SS who receive nalmefene hydrochloride 20 
mg in the lead-in study and the run-out period of this trial by timepoint (lead-in study or this 
trial). 
2) Lead-in study and the treatment period of this trial 
The TEAEs will be summarized for the entire population and for each treatment group of the lead-
in study (the entire groups receiving nalmefene hydrochloride and each treatment group). They will be 
summarized for timepoint (lead-in study or this trial). TEAEs that occur in this trial but before the start 


 
24 
of the treatment period are included and summarized in the treatment period of this trial. 
3) Run-out period of this trial 
Tabulation will be performed for the subjects in the SS who advance to the run-out period of this 
trial for each treatment group of the run-out period of this trial. 
4) Post-treatment observation period of this trial 
Tabulation will be performed for the subjects in the SS who advance to the post-treatment 
observation period of this trial for the entire population and for each treatment group of the run-out 
period of this trial. 
By defining the following notable AEs, regarding the TEAEs occurring in the treatment period of the 
lead-in study and the TEAEs occurring before or during the treatment period of this trial, the number of 
subjects with TEAEs, the incidence of those, the number of withdrawals, and the percentage of those will 
be obtained by PT and “any TEAEs” for the entire period and for timepoint (lead-in study or this trial) for 
the entire population and for each treatment group (the entire groups receiving nalmefene hydrochloride 
and each treatment group). However, the number of withdrawals and its percentage will be summarized 
only for this trial. 
 
Adverse events related to accident or injury 
AEs retrieved from [SMQ] 20000135/Accidents and Injuries 
 
Adverse events related to convulsion 
AEs retrieved from [SMQ] 20000079/Convulsions 
 
Adverse events related to depression 
AEs retrieved from [SMQ] 20000167/Depression (excl. suicide and self injury) using narrow 
search 
 
Adverse events related to drug abuse 
AEs retrieved from [SMQ] 20000100/Drug abuse, dependence and withdrawal 
 
Drug-related hepatic disorder 
AEs retrieved from [SMQ] 20000006/Drug related hepatic disorders - comprehensive search 
 
Alcohol-related hepatic disorder 
AEs retrieved from [SMQ] 20000017/Hepatic disorders specifically reported as alcohol-related 
 
AEs related to rhabdomyolysis or myopathy 
AEs retrieved from [SMQ] 20000002/Rhabdomyolysis/myopathy 
 
Psychiatric adverse events 
The following preferred terms will be used. 
10010305 Confusional state 
10063033 
Depressive delusion 
10012245 
Delusion of replacement 
10012244 
Delusion of reference 
10012241 
Delusion of grandeur 
10015134 
Erotomanic delusion 
10023164 
Jealous delusion 
10041317 
Somatic delusion 
10034702 
Persecutory delusion 
10012239 
Delusion 
10012250 
Delusional disorder, grandiose type 
10012252 
Delusional disorder, mixed type 


 
25 
10012249 
Delusional disorder, erotomanic type 
10012251 
Delusional disorder, jealous type 
10012255 
Delusional disorder, unspecified type 
10012254 
Delusional disorder, somatic type 
10053195 
Delusional disorder, persecutory type 
10012258 
Delusional perception 
10012295 
Dementia of the Alzheimer's type, with delusions 
10076429 
Mixed delusion 
10077805 
Depersonalisation/derealisation disorder 
10012422 
Derealisation 
10013395 
Disorientation 
10013457 
Dissociation 
10062824 
Hallucination, synaesthetic 
10020928 
Hypnopompic hallucination 
10019063 
Hallucination 
10019072 
Hallucination, olfactory 
10019075 
Hallucination, visual 
10019070 
Hallucination, auditory 
10019071 
Hallucination, gustatory 
10019074 
Hallucination, tactile 
10062684 
Somatic hallucination 
10020927 
Hypnagogic hallucination 
10019079 
Hallucinations, mixed 
10021403 
Illusion 
10048294 
Mental status changes 
10049986 
Mental status changes postoperative 
10033864 
Paranoia 
10012355 
Dependent personality disorder 
10020155 
Histrionic personality disorder 
10003865 
Avoidant personality disorder 
10006034 
Borderline personality disorder 
10029901 
Obsessive-compulsive personality disorder 
10028712 
Narcissistic personality disorder 
10034723 
Personality disorder of childhood 
10034721 
Personality disorder 
10039651 
Schizotypal personality disorder 
10039624 
Schizoid personality disorder 
10002822 
Antisocial personality disorder 
10033869 
Paranoid personality disorder 
10040535 
Shared psychotic disorder 
10061921 
Psychotic disorder due to a general medical condition 
10061920 
Psychotic disorder 
10006362 
Brief psychotic disorder, with postpartum onset 
10048549 
Brief psychotic disorder with marked stressors 
10056395 
Brief psychotic disorder without marked stressors 
10043431 
Thinking abnormal 
 
Adverse events related to psychosis or psychotic disorder 
AEs retrieved from [SMQ] 20000117/Psychosis and psychotic disorders using narrow search and 
AEs defined in the psychiatric adverse events 
 
Adverse events related to suicide 
AEs retrieved from [SMQ] 20000037/Suicide/self injury 
 
Nighttime symptoms related to sleep disorder 


 
26 
The following preferred terms will be used. 
10022035 Initial insomnia 
10022437 
Insomnia 
10027590 
Middle insomnia 
10040984 
Sleep disorder 
10061827 
Dyssomnia 
10062519 
Poor quality sleep 
10068932 
Terminal insomnia 
 
Daytime symptoms related to sleep disorder 
The following preferred terms will be used. 
10002942 
Apathy 
10003549 
Asthenia 
10016256 
Fatigue 
10020765 
Hypersomnia 
10024264 
Lethargy 
10039897 
Sedation 
10041349 
Somnolence 
A list of subjects with overdose will be prepared. Overdose is defined by the following preferred terms. 
 
<PT> 10000381/Accidental overdose 
 
<PT> 10022523/Intentional overdose 
 
9.4 
Subgroup Analyses of Adverse Events 
For the following subgroups, regarding the TEAEs occurring in the treatment period of the lead-in study 
and the TEAEs occurring before or during the treatment period of this trial, the number of subjects with 
TEAEs and the incidence of those will be obtained by SOC and PT as well as “any TEAEs” for the entire 
period and for timepoint (lead-in study or this trial) for the entire population and for each treatment group 
of the lead-in study (the entire groups receiving nalmefene hydrochloride and each treatment group). 
 
Sex [female, male] 
 
Age (years old) [< 65, 65 ≤] 
 
Body Mass Index (BMI) (kg/m2) [< 25, 25 ≤ - < 30, 30 ≤] 
 
9.5 
Clinical Laboratory Tests 
For clinical laboratory tests, the following summarization will be performed in terms of the "periods, 
subjects, treatment groups, baseline, and timepoints" shown in 1), 2), 3). 
 
Descriptive statistics will be calculated for hematology and chemistry at each timepoint and their 
changes from baseline. 
 
Classification (low, normal, and high) based on reference values of hematology and blood 
chemistry at each timepoint will be summarized in shift tables from baseline. 
 
Urinalysis at each timepoint will be summarized in shift tables from baseline. Frequency 
distributions will be prepared for urinary sediment. No summarization will be performed for HCG. 
For changes in clinical laboratory values assesses as PCS or related to drug-induced liver injury, the 


 
27 
number and percentage of subjects meeting the criteria (with the number of subjects included in the 
assessment as a denominator) will be obtained for measured values after baseline in terms of the "periods, 
subjects, treatment groups, baseline, and timepoints" shown in 1), 2), 3). However, data at each timepoint 
will not be tabulated. For condition 1), data will be summarized for the lead-in study and this trial as a 
whole. For condition 2), data will be summarized for timepoint (lead-in study or this trial) in addition to the 
lead-in study and the treatment period of this trial as a whole. For condition 3), data will be summarized for 
the run-out period and for the post-treatment observation period. The subjects who meet the criteria for 
changes in clinical laboratory values assessed as PCS or related to drug-induced liver injury will be 
tabulated in their respective tables. The criteria for PCS values are shown in Appendix 15.1, and the criteria 
for changes in clinical laboratory values related to drug-induced hepatic disorder are shown below. For 
changes in clinical laboratory values related to drug-induced liver injury, when subjects meet any of the 
following criteria, they will be tabulated as change in clinical laboratory values related to drug-induced 
liver injury and tabulated by individual assessment criteria. 
 
AST or ALT ≥ 3 times the upper limit of normal 
 
AST or ALT ≥ 5 times the upper limit of normal 
 
AST or ALT ≥ 10 times the upper limit of normal 
 
AST or ALT ≥ 20 times the upper limit of normal 
 
Total bilirubin ≥ 2 times the upper limit of normal 
 
Alkaline phosphatase ≥ 1.5 times the upper limit of normal 
 
AST or ALT ≥ 3 times the upper limit of normal and total bilirubin ≥ 2 times the upper limit of 
normal 
 
AST or ALT ≥ 3 times the upper limit of normal and total bilirubin ≥ 2 times the upper limit of 
normal, and an alkaline phosphatase ≤ 1.5 times the upper limit of normal 
 
AST or ALT ≥ 3 times the upper limit of normal, total bilirubin ≥ 2 times the upper limit of 
normal or INR/prothrombin time ≥ 1.5 times the upper limit of normal, and alkaline 
phosphatase ≤ 1.5 times the upper limit of normal 
Classification (low, normal, and high) based on the PCS criteria of hematology, blood chemistry, and 
prolactin will be summarized in shift tables from baseline in terms of the "periods, subjects, treatment 
groups, baseline, and timepoints" shown in 1), 2), 3). However, data at each timepoint will not be tabulated. 
For condition 1), data will be summarized for the lead-in study and this trial as a whole. For condition 2), 
data will be summarized for timepoint (lead-in study or this trial) in addition to the lead-in study and the 
treatment period of this trial as a whole. For condition 3), data will be summarized only for the run-out 
period. 
1) Lead-in study and this trial 
a) The data in the SS will be summarized with baseline of the lead-in study. The timepoints are 
baseline, Weeks 12 and 24 of the lead-in study, and Week 12, Week 24, Week 28 (the run-out 
period), Week 32 (the post-treatment observation period) and the final evaluation point of this 
trial. Pooled data from the treatment groups will be used for the tabulation regardless of the 
treatment groups of the lead-in study or treatment groups in the run-out period of this trial.  
b) Tabulation will be conducted for the subjects in the SS who receive nalmefene hydrochloride 20 
mg in the lead-in study group and the run-out period of this trial. Baseline and timepoints are the 


 
28 
same as in a). 
2) Lead-in study and the treatment period of this trial 
The data in the SS will be summarized with baseline of the lead-in study. The timepoints are 
baseline, Weeks 12 and 24 of the lead-in study, Weeks 12 and 24, and the final evaluation of the 
treatment period of this trial. The data will be summarized for the entire population and for each 
treatment group of the lead-in study (the entire groups receiving nalmefene hydrochloride and each 
treatment group). 
3) The run-out period and the post-treatment observation period of this trial 
The data of the subjects in the SS who advance to the run-out period of this trial will be summarized 
with baseline II (baseline of the run-out period and the post-treatment observation period). The 
timepoints are baseline II, Week 28 (the run-out period), Week 32 (the post-treatment observation 
period) and the final evaluation after the run-out period of this trial. Data will be summarized for the 
entire population and for each treatment group of the run-out period of this trial. 
In addition, a scatter plot will be prepared for hematology and blood chemistry with the data at the 
baseline of the lead-in study (X-axis) and the final evaluation of the treatment period (Y-axis). 
 
9.6 
Vital Signs 
The following data will be tabulated in terms of the same "period, subjects, treatment groups, baseline, 
and timepoints" as for clinical laboratory tests. However, for the timepoints of the treatment period, the 
timepoints of tests planned in the protocol will also be included in the tabulation. 
 
Descriptive statistics will be calculated for systolic and diastolic blood pressures, pulse rate, and 
body weight at each timepoint and their changes from baseline. 
For PCS, frequency will be summarized and listed in the same manner as for clinical laboratory tests. 
The criteria for PCS are shown in Appendix 15.2. 
 
9.7 
Twelve-lead Electrocardiogram (results obtained from the central ECG 
laboratory) 
The following data will be tabulated in terms of the same "period, subjects, treatment groups, baseline, 
and timepoints" as for clinical laboratory tests. 
 
Descriptive statistics will be calculated for heart rate, RR interval, PR interval, QRS interval, QT 
interval, QTcB, and QTcF at each timepoint, and their changes from baseline. 
 
A shift table of “Abnormal Significant,” “Abnormal Insignificant,” or “Normal” at each timepoint 
from baseline will be provided. 
 
QTcB/QTcF at each timepoint and their changes from baseline will be categorically summarized 
for frequency. The categories of QTcB and QTcF frequency summary are > 450 msec, > 480 msec, 
and > 500 msec, and the categories of QTcB and QTcF change frequency summary are > 30 msec 
and > 60 msec. For the worst values, frequency tabulation will be performed using the same 
categories. For the worst values for 1) Lead-in study and this trial, the worst values in the lead-in 
study and this trial as a whole will be used. For 2) Lead-in study and the treatment period of this 
trial, the worst values in each timepoint (the lead-in study and this trial) in addition to the worst 


 
29 
values in the lead-in study and the treatment period of this study as a whole will be used. For 3) 
The run-out period and the post-treatment observation period of this trial, the worst values pooled 
from the run-out period and the post-treatment observation period will be used. 
For PCS, frequency will be summarized and listed in the same manner as for clinical laboratory tests. 
The criteria for PCS are shown in Appendix 15.3. 
In addition, in the same manner as for the clinical laboratory test, classification (low, normal, and high) 
shift tables for categorical values based on PCS criteria for RR intervals, PR intervals, QRS intervals, and 
QT intervals versus baseline will be provided. 
 
9.8 
Physical Examination 
The physical examinations (“Abnormal Significant,” “Abnormal Insignificant,” and “Normal”) will be 
categorically summarized for frequency at each timepoint in terms of the “periods, subjects, treatment 
groups, and timepoints” shown in 1), 2), 3). 
1) Lead-in study and this trial 
a) Tabulation will be conducted for the SS. The timepoints are screening, Weeks 12 and 24 of the 
lead-in study, and Weeks 12, 24, 28 (the run-out period), 32 (the post-treatment observation 
period), and the final evaluation point of this trial. Pooled data from the treatment groups will be 
used for the tabulation regardless of the treatment groups of the lead-in study or treatment 
groups in the run-out period of this trial.  
b) Tabulation will be conducted for the subjects in the SS who receive nalmefene hydrochloride 20 
mg in the lead-in study group and the run-out period of this trial. The timepoints are the same as 
in a). 
2) Lead-in study and the treatment period of this trial 
Tabulation will be conducted for the SS. The timepoints are screening, Weeks 12 and 24 of the 
lead-in study, Weeks 12 and 24, and the final evaluation of the treatment period of this trial. The data 
will be summarized for the entire population and for each treatment group of the lead-in study (the 
entire groups receiving nalmefene hydrochloride and each treatment group). 
3) The run-out period and the post-treatment observation period of this trial 
Tabulation will be conducted for the subjects in the SS who advance to the run-out period of this 
trial. The timepoints are Week 24, Week 28 (the run-out period), Week 32 (the post-treatment 
observation period) and the final evaluation after the run-out period of this trial. Data will be 
summarized for the entire population and for each treatment group of the run-out period of this trial. 
 
9.9 
POMS 
The following data will be tabulated in terms of the same "period, subjects, treatment groups, baseline, 
and timepoints" as for clinical laboratory tests. 
 
Descriptive statistics will be provided for total mood disturbance (TMD) score and each factor 
(tension-anxiety, depression-dejection, anger-hostility, vigor-activity, fatigue-inertia, and 
confusion-bewilderment) at each timepoint and their changes from baseline. 
For changes in the TMD score from baseline of the lead-in study and the treatment period of this trial, 
MMRM analysis will be performed in the same manner as for the number of HDDs. The timepoints are 
Weeks 12 and 24 of the lead-in study and Weeks 12 and 24 of this trial. 
 


 
30 
9.10 C-SSRS 
The following data will be tabulated in terms of the same "period, subjects, treatment groups, baseline, 
and timepoints" as for clinical laboratory tests. However, for the timepoints of the treatment period, the 
timepoints of tests planned in the protocol will also be included in the tabulation. Baseline of the treatment 
period will be the Randomization Visit (Visit 2) of the lead-in study, and baseline II of the run-out period 
and post-treatment observation period will be Week 24 of this trial (Visit 10). 
 
The frequency of Categories 1-10 shown below will be tabulated at each timepoint and any time 
after baseline. For 1) Lead-in study and this trial, "any time after baseline" is defined as any time 
after baseline of the lead-in study and this trial as a whole. For 2) Lead-in study and the treatment 
period of this trial, tabulation will be conducted at any time after baseline of the lead-in study and 
this trial as a whole as well as any time after baseline of each timepoint (lead-in study or this trial). 
For 3) The run-out period and the post-treatment observation period of this trial, tabulation will be 
conducted at any time with pooled data from the run-out period and the post-treatment observation 
period. 
 
Category 1 − Wish to be Dead 
 
Category 2 − Non-specific Active Suicidal Thoughts 
 
Category 3 − Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
 
Category 4 − Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
 
Category 5 − Active Suicidal Ideation with Specific Plan and Intent 
 
Category 6 − Preparatory Acts or Behavior 
 
Category 7 − Aborted Attempt 
 
Category 8 − Interrupted Attempt 
 
Category 9 − Actual Attempt (non-fatal) 
 
Category 10 − Completed Suicide 
 
Frequency of the following C-SSRS item will be tabulated at each timepoint and any time after 
baseline. Definition of "Any time after baseline" will be the same as in the frequency tabulation for 
Categories 1-10 above. 
 
Self-injurious behavior without suicidal intent 
 
The following variables will be derived using the above Categories 1-10. These variables will 
also be summarized in a frequency table. For 1) Lead-in study and this trial, tabulation will be 
conducted for the lead-in study and this trial as a whole. For 2) Lead-in study and the treatment 
period of this trial, tabulation will be conducted for the lead-in study and this trial as a whole as 
well as for each timepoint (lead-in study or this trial). For 3) The run-out period and the post-
treatment observation period of this trial, tabulation will be conducted separately for the run-out 
period and for the post-treatment observation period. 
 
Suicidal ideation (1-5) 
A “yes” answer at any post-baseline visit to any one of the five suicidal ideation questions 
(Categories 1 to 5) on the C-SSRS. 
 
Suicidal behavior (6-10) 
A “yes” answer at any post-baseline visits to any one of the five suicidal behavior questions 


 
31 
(Categories 6 to 10) on the C-SSRS. 
 
Suicidal ideation or behavior (1-10) 
A “yes” answer at any post-baseline visits to any one of the ten suicidal ideation and behavior 
questions (Categories 1 to 10) on the C-SSRS. 
 
Treatment-emergent suicidal ideation 
An increase in the maximum suicidal ideation scorec at post-baseline visits from the suicidal 
ideation category at baseline. 
 
Treatment-emergent serious suicidal ideation 
An increase in the maximum suicidal ideation score to 4 or 5 on the C-SSRS at post-baseline 
visits from not having serious suicidal ideation (scores of 0 to 3) at baseline. 
 
Emergence of serious suicidal ideation 
An increase in the maximum suicidal ideation score to 4 or 5 on the C-SSRS at post-baseline 
visits from no suicidal ideation (scores of 0) at baseline. 
 
Emergence of suicidal behavior 
The occurrence of suicidal behavior at post-baseline visits from not having suicidal behavior at 
any time at screening or pre-baseline in the lead-in study. 
 
Maximum Suicidal ideation score at post-baseline visits will be summarized in shift tables from 
Suicidal ideation score at baseline. For 1) Lead-in study and this trial, tabulation will be conducted 
for the lead-in study and this trial as a whole. For 2) Lead-in study and the treatment period of this 
trial, tabulation will be conducted for the lead-in study and the treatment period of this trial as a 
whole as well as for each timepoint (lead-in study or this trial). For 3) The run-out period and the 
post-treatment observation period of this trial, tabulation will be conducted separately for the run-
out period and for the post-treatment observation period. 
 
The following C-SSRS categories will be derived and they will be summarized in shift tables from 
baseline at each timepoint after baseline. 
 
C-SSRS Category 
"No suicidal ideation or behavior,” "Suicidal ideation,” "Suicidal behavior" 
In a case of both "Suicidal ideation" and "Suicidal behavior,” it is included in "Suicidal 
behavior.” 
 
9.11 Dependence Survey 
Answers to each question of dependence survey A at the end of the run-out period and their overall 
score, and answers to each questions of dependence survey B at the end of the post-treatment observation 
period and their overall score will be summarized as frequency for the treatment group of the run-out 
period of this trial. For the overall score, the worst value in each survey will be used. 
                                                        
c  Suicidal ideation score: The maximum suicidal ideation category (1-5 on the C-SSRS) present at the assessment. Assign a 
score of 0 if no ideation is present. 
0=No Suicidal Ideation, 1=Wish to be Dead, 2=Non-specific Active Suicidal Thoughts, 3=Active Suicidal Ideation with 
Any Methods (Not Plan) without Intent to Act, 4=Active Suicidal Ideation with Some Intent to Act, without Specific 
Plan, 5=Active Suicidal Ideation with Specific Plan and Intent 


 
32 
 


 
33 
10 Efficacy Analysis 
Unless otherwise specified, the following efficacy analyses will be performed for the FAS as the analysis 
set using data from the lead-in study and this trial. 
10.1 Number of Heavy Drinking Days 
The number of HDDs at each timepoint of the lead-in study and the treatment period of this trial will be 
summarized with descriptive statistics, as well as changes from baseline for each treatment group of the 
lead-in study (nalmefene hydrochloride 10 mg, nalmefene hydrochloride 20 mg, and placebo groups). The 
time course of the change from baseline (mean ± standard deviation) will be plotted for each treatment 
group. 
For the subjects in the FAS who advance to the run-out period of this trial, the number of HDDs in the 
run-out period of this trial and changes from baseline II will be summarized with descriptive statistics for 
each treatment group of the run-out period of this trial. 
As an exploratory analysis, MMRM analysis will be performed for changes in the number of HDDs from 
baseline at each timepoint of the lead-in study and the treatment period of this trial, and the time course of 
the change from baseline (least squares mean ± standard error) will be plotted. The baseline will be the one 
in the lead-in study. The model includes the fixed, categorical effects of treatment in the lead-in study, sex, 
timepoint (Weeks 4, 8, 12, 16, 20, and 24 of the lead-in study and Weeks 4, 8, 12, 16, 20, and 24 of this 
trial), and treatment-by-timepoint interaction as well as the continuous, fixed covariates of baseline number 
of HDDs, and baseline number of HDDs-by-timepoint interaction. An unstructured (co)variance structure 
will be used to model the within-patient errors. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. 
As an exploratory analysis, for the subjects in the FAS who advance to the run-out period of this trial, 
changes in the number of HDDs from baseline II of the run-out period of this trial will be analyzed by 
using an analysis of covariance (ANCOVA) model with treatment group of the run-out period of this trial 
and sex as fixed, categorical effect and the number of HDDs at baseline II as covariance. 
In addition, the number of HDDs at each timepoint of the lead-in study and the treatment period of this 
trial and changes from baseline will be summarized with descriptive statistics for each treatment group of 
the lead-in study with another grouping (the entire groups receiving nalmefene hydrochloride and placebo 
group) and their time course (mean ± standard deviation) will be plotted. MMRM analysis and the time-
course plot (least squares mean ± standard error) will also be prepared. 
 
10.2 TAC 
Total alcohol consumption will be summarized with descriptive statistics, and the time-course plot (mean 
± standard deviation) will be prepared in the same manner as with the number of HDDs. The MMRM 
analysis, the time-course plot (least squares mean ± standard error) and ANCOVA analysis will be 
performed in an exploratory manner. As with the number of HDDs, TAC will be summarized with 
descriptive statistics for each treatment group of the lead-in study with another grouping (the entire groups 
receiving nalmefene hydrochloride and placebo group), and their time course (mean ± standard deviation) 
will be plotted. MMRM analysis and the time-course plot (least squares mean ± standard error) will also be 
prepared. 


 
34 
 
10.3 RSDRL 
Frequency of RSDRL at each timepoint of the lead-in study and the treatment period of this trial will be 
summarized for each treatment group (nalmefene hydrochloride 10 mg, nalmefene hydrochloride 20 mg, 
and placebo) of the lead-in study. 
Observed case data will be analyzed without imputation of missing values. Furthermore, analyses will be 
performed for the entire FAS, where missing values will be handled as non-responders. 
 
10.4 RLDRL 
In the same manner as with RSDRL, frequency of RLDRL at each timepoint will be calculated. 
 
10.5 70% Total Alcohol Consumption Responder Rate 
In the same manner as with RSDRL, frequency of 70% TAC responder rate at each timepoint will be 
calculated. 
 
10.6 Heavy Drinking Day Responder Rate 
In the same manner as with RSDRL, frequency of HDDs responder rate at each timepoint will be 
calculated. 
 
10.7 CGI-S 
In the same manner as the number of HDDs, CGI-S will be summarized with descriptive statistics, and 
exploratory MMRM analysis will be performed. The timepoints of the lead-in study and the treatment 
period of this trial are Weeks 1, 2, 4, 8, 12, 16, 20, and 24 of the lead-in study and Weeks 0, 1, 2, 4, 8, 12, 
16, 20, and 24 of this trial. The number and proportion of subjects with each score at each timepoint will be 
obtained. However, if the assessment is "0. Not assessed,” the data will be handled as missing, and the 
proportion will be calculated excluding the subjects with the assessment of "0. Not assessed.” In addition, 
descriptive statistics will be calculated for the subgroup excluding the subject with the baseline assessment 
of "1. Normal, not at all ill" and the subgroup of the subjects with the baseline assessment of "1. Normal, 
not at all ill,” and MMRM analysis will be performed. 
 
10.8 CGI-I 
In the same manner as with the number of HDDs, CGI-I will be summarized with descriptive statistics, 
and exploratory MMRM analysis will be performed. The timepoints of the lead-in study and the treatment 
period of this trial are Weeks 1, 2, 4, 8, 12, 16, 20, and 24 of the lead-in study and Weeks 0, 1, 2, 4, 8, 12, 
16, 20, and 24 of this trial. However, the scores at each timepoint will be analyzed, as opposed to changes 
from baseline, since the score itself is an assessment of change from baseline. The CGI-S at baseline will 
be included for covariate adjustment. The number and proportion of subjects with each score at each 
timepoint will be obtained. However, if the assessment is "0. Not assessed,” the data will be handled as 


 
35 
missing, and the proportion will be calculated excluding the subjects with the assessment of "0. Not 
assessed.” 
 
10.9 SF-36 
For the 8 subscales of SF-36 (Physical Functioning, Physical Role Functioning, Bodily Pain, General 
Health Perceptions, Vitality, Mental Health, Emotional Role Functioning, and Social Role Functioning), 
Physical Component Summary, and Mental Component Summary, descriptive statistics will be calculated 
in the same manner as with the number of HDDs, and MMRM analysis will be performed in an exploratory 
manner. The timepoints of the lead-in study and the treatment period of this trial are Weeks 12 and 24 of 
the lead-in study, and Weeks 12 and 24 of this trial. 
 
10.10 EQ-5D-3L 
For EQ-5D Utility score and EQ-5D VAS, descriptive statistics will be calculated in the same manner as 
with the number of HDDs, and exploratory MMRM analysis will be performed. 
 
10.11 AQoLS 
In the same manner as with the number of HDDs, AQoLS total score will be summarized with 
descriptive statistics, and exploratory MMRM analysis will be performed. 
 
10.12 RUMQ-ADP 
Frequency will be calculated for each of the following items in sociodemographic, resource 
consumption, and sick leaves at each timepoint of the lead-in study and the treatment period of this trial 
(baseline, Weeks 12 and 24 of the lead-in study, and Weeks 12 and 24 of this trial) for each treatment 
group of the lead-in study (nalmefene hydrochloride 10 mg, nalmefene hydrochloride 20 mg, and placebo). 
For the subjects in the FAS who advance to the run-out period of this trial, frequencies of the same items 
will be calculated for each treatment group of the run-out period of this trial. 
 
Sociodemographic 
 
Marital status [single, married/living together, divorced/separated, widowed] 
 
Number of children per household [0, 1, 2, 3, 4 ≤] 
 
Residence [countryside, urban area] 
 
Resource consumption 
 
Use of at least one healthcare resource [yes, no] 
 
Number of consultations with general physicians [0, 1, 2, 3, 4, 5, 6 ≤] 
 
Number of consultations with psychiatrists [0, 1, 2, 3, 4, 5, 6 ≤] 
 
Number of consultations with other specialists [0, 1, 2, 3, 4, 5, 6 ≤] 
 
Number of consultations with psychologists [0, 1, 2, 3 ≤] 
 
Number of consultations with nurses [0, 1, 2, 3 ≤] 


 
36 
 
Number of consultations with social workers [0, 1, 2, 3 ≤] 
 
Number of consultations with self-help groups (Alcoholics Anonymous, etc.) [0, 1, 2, 3 ≤] 
 
Psychiatric hospitalization [yes, no] 
 
Emergency admission [yes, no] 
 
General hospitalization [yes, no] 
 
Hospitalization for surgery [yes, no] 
 
Other (other than psychiatry, emergency care, general practice, surgery) hospitalization [yes, 
no] 
 
Sick leaves 
 
Sick leaves [yes, no] 
 
10.13 Gamma-glutamyl Transferase 
GGT at each timepoint in the lead-in study and the treatment period of this trial (baseline, Weeks 12 and 
24 of the lead-in study, and Weeks 12 and 24 of this trial) will be summarized with descriptive statistics 
and geometric mean for each treatment group of the lead-in study. 
For log-transformed GGT, exploratory MMRM analysis will be performed in the same manner as the 
number of HDDs. The least squares mean for each treatment group at each timepoint will be estimated, and 
the estimate results will be inversely log-transformed to obtain the mean on the actual scale. The model 
includes the fixed, categorical effects of treatment, sex, timepoint, and treatment-by-timepoint interaction 
as well as the continuous, fixed covariates of log-transformed baseline values, and log-transformed baseline 
values-by-timepoint interaction. The timepoints are Weeks 12 and 24 of the lead-in study and Weeks 12 
and 24 of this trial. 
 
10.14 ALT 
For ALT, descriptive statistics and geometric mean will be obtained in the same manner as the analysis 
of GGT. 
For log-transformed ALT, MMRM analysis will be performed in the same manner as the analysis of 
GGT. 
 


 
37 
11 Rationale for Sample Size Determination 
The targeted subjects in this trial are the subjects who complete the preceding Study 339-14-001 and 
wish to participate in this trial. The estimate number of the subjects is approximately 400. 
In calculating the estimated number of subjects, with reference to the completion rate (nalmefene 20 mg 
group: 0.53 and placebo group: 0.67) in patients with a high or very high DRL both at baseline and at 
randomization in Study 12013A (duration of treatment: 52 weeks), the continuation rate of the completers 
of the preceding Study 339-14-001 to this trial was assumed to be 0.8. 
 


 
38 
12 Changes from the Analysis Method Planned in the 
Protocol 
Changes from the analysis method planned in the protocol are described below. 
 
Change in AQoLS endpoint from "each domain and item" to "total score" 
Reason: Revised based on Validation of a new patient-reported outcome instrument of health-
related quality of life specific to patients with alcohol use disorder: the Alcohol Quality of Life 
Scale (AQoLS) (2015)3. 
 
 
Deletion of frequency summary of RSDRL, RLDRL, TAC 70% response rate, and HDD response 
rate for the subjects advancing to the run-out period 
Reason: In the run-out period, rebound phenomena will be checked regarding the amount of 
alcohol consumption. However, since these endpoints evaluate decrease in alcohol consumption 
but cannot evaluate rebound phenomena, they were deleted. 
 
 
Deletion of descriptive statistics for log-transformed GGT and ALT 
Reason: For log-transformed GGT and ALT, MMRM analysis will be conducted in an 
exploratory manner. The least squares mean for each treatment group at each timepoint will be 
estimated, and the mean on the actual scale will be calculated by inversely log-converting the 
estimated results. 
 
 


 
39 
13 References 
1 
Shunichi Fukuhara, Yoshimi Suzukamo. Manual of SF-36v2 Japanese version: Institute for Health 
Outcomes and Process Evaluation Research; Kyoto, 2004. 
2 
Tsuchiya A, Ikeda S, Ikegami N, et al. Estimating an EQ-5D population value set: The case of Japan. 
Health Economics 2002; 11(4):341-353. 
3 
A. Luquiens, et al. Validation of a new patient-reported outcome instrument of health-related quality 
of life specific to patients with alcohol use disorder: the Alcohol Quality of Life Scale (AQoLS) 
Quality of Life Research 2015 
 


 
40 
14 Revision History 
Not applicable as this is the first version. 
 
Version 
No. 
Revision 
date 
Item 
Number/ 
Item Name 
Before revision 
After revision 
Reason for revision 
 
 
 
 
 
 
 
 
 


 
41 
15 APPENDIX 
15.1 PCS Criteria for Clinical Laboratory Tests  
Items with low and high criteria will be analyzed separately for low and high values. 
Variables 
Criteria 
Hematology 
 
 
Red blood cell count 
< 3,000,000/ mm3 
 
Hematocrit Female 
≤ 32 % 
 
Hematocrit Male 
≤ 37 % 
 
Hemoglobin Female 
≥ 16.5 g/dL 
 
≤ 9.5 g/dL 
 
Hemoglobin Male 
≥ 18.5 g/dL 
 
≤ 11.5 g/dL 
 
MCV 
≥ 1.2 × upper limit of normal 
 
≤ 0.8 × lower limit of normal 
 
Total white blood cell count 
≥ 16,000/uL 
 
< 2,800/uL 
 
Neutrophils 
≥ 85 % 
 
≤ 20 % 
 
Eosinophils 
≥ 10 % 
 
Basophils 
≥ 10 % 
 
Lymphocytes 
≥ 75 % 
 
≤ 10 % 
 
Monocytes 
≥ 15 % 
 
Platelet count 
≥ 700,000/mm3 
 
≤ 75,000/mm3 
Blood chemistry 
 
 
Total bilirubin 
≥ 2 × upper limit of normal 
 
Alkaline phosphatase 
≥ 3 × upper limit of normal 
 
ALT 
≥ 3 × upper limit of normal 
 
AST 
≥ 3 × upper limit of normal 
 
Gamma-glutamyl Transferase 
≥ 200 U/L 
 
INR/prothrombin time 
≥ 2.0 
 
Albumin 
≤ 2.7 g/dL 
 
Cholinesterase 
No reference range 
 
Total cholesterol 
≥ 302 mg/dL 
 
Triglycerides 
≥ 500 mg/dL 
 
Creatinine 
≥ 1.5 × upper limit of normal 
 
≤ 0.5 × lower limit of normal 
 
BUN 
> 30 mg/dL 
 
Sodium 
≥ 155 mEq/L 
 
≤ 125 mEq/L 
 
Potassium 
≥ 6.0 mEq/L 
 
≤ 3.0 mEq/L 
 
Bicarbonate (HCO3-) 
≥ 38 mmol/L 
 
≤ 12 mmol/L 
 
Calcium 
≥ 12.0 mg/dL 
 
≤ 7.2 mg/dL 
 
Glucose 
≥ 162 mg/dL 
 
≤ 63 mg/dL 
 
CRP 
No reference range 
Urinalysis 
 


 
42 
 
Protein 
Increase ≥ 2 levels from baseline 
 
Glucose 
Increase ≥ 2 levels from baseline 
 
Occult blood 
Increase ≥ 2 levels from baseline 
 
Ketones 
Increase ≥ 2 levels from baseline 
 
Urinary sediment 
No reference range 
Others 
 
 
Prolactin 
≥ 67.5 ug/L 
 
15.2 PCS Criteria for Vital Signs  
Analyses will be performed separately for increase and decrease. 
Variables 
Criteria  
Systolic blood pressure 
≥ 180 mmHg and change from baseline ≥ 20 mmHg 
≤ 90 mmHg and change from baseline ≤ -20 mmHg 
Diastolic blood pressure 
≥ 105 mmHg and change from baseline ≥ 15 mmHg 
≤ 50 mmHg and change from baseline ≤ -15 mmHg 
Pulse rate 
≥ 120 bpm and change from baseline ≥ 15 bpm 
≤ 50 bpm and change from baseline ≤ -15 bpm 
Body weight 
Change from baseline ≥ 7% 
Change from baseline ≤ -7% 
 
15.3 PCS Criteria for 12-lead ECG 
Analyses will be performed separately for increase and decrease. 
Variables 
Criteria 
Heart rate 
≥ 120 bpm and change from baseline ≥ 15 bpm 
≤ 50 bpm and change from baseline ≤ -15 bpm 
RR interval 
≥ 1200 msec 
< 500 msec 
PR interval 
≥ 260 msec 
QRS interval 
≥ 150 msec 
QT interval 
≥ 500 msec 
QTcB 
≥ 500 msec or change from baseline ≥ 60 msec 
QTcF 
≥ 500 msec or change from baseline ≥ 60 msec