Conditions: Atopic Dermatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 73
Healthy volunteers: no

Brief summary:
To evaluate the safety, efficacy (dose response) and pharmacokinetics of 0.3% and 1% OPA-15406 when applied twice daily for 4 weeks in pediatric patients with atopic dermatitis.

Detailed description:

Arms:
arm 1: Subjects were treated with assigned 0.3% OPA-15406 ointment twice daily. arm 2: Subjects were treated with assigned 1% OPA-15406 ointment twice daily. arm 3: Subjects were treated with assigned 0% OPA-15406 ointment twice daily.

Interventions: intervention 1: OPA-15406 intervention 2: Placebos
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
 
Confidential - Proprietary Information 
 
Version 1.0, 06 Oct 2016 
 
CLINICAL  STUDY  PROTOCOL 
 
 
 
A Multicenter, Randomized, Double-blind, Vehicle-controlled,Parallel-
group Trial to Assess the Safety and Efficacy of 0.3% and 1% OPA-15406 
Ointments When Administered for 4 Weeks in Pediatric Patients With 
Atopic Dermatitis 
 
NCT Number: 03018691 
 
Protocol No. 271-102-00002 
 
PRT Version Date: 14 Nov 2016（Version 2.0） 
 
 
 
 
 
 
 
 
 
 


 
 
Protocol 271-102-00002 
 
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Otsuka Pharmaceutical Co., Ltd 
 
Investigational Medicinal Product 
 
OPA- 15406 
 
CLINICAL PROTOCOL 
 
A Multicenter, Randomized, Double-blind, Vehicle-controlled, Parallel-group Trial to 
Assess the Safety and Efficacy of 0.3% and 1% OPA-15406 Ointments When 
Administered for 4 Weeks in Pediatric Patients With Atopic Dermatitis  
 
Protocol No. 271-102-00002 
(Translated Version) 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
Clinical Development Phase: 2 
 
Sponsor: 
 
 
 
 
Otsuka Pharmaceutical Co., Ltd 
 
 
 
 
 
 
2-9 Kanda-Tsukasamachi, Chiyoda-ku,  
 
 
 
 
 
 
Tokyo 101-8535, Japan 
 
Immediately Reportable Event  
Pharmacovigilance Operation Office, 
Pharmacovigilance Department, Otsuka 
Pharmaceutical Co., Ltd. 
 
3-2-27, Otedori, Chuo-ku, Osaka-shi, Osaka 
540-0021, Japan  
 
 
 
 
 
 
IRE_271-102-00002@otsuka.jp 
 
 
 
 
 
 
 
Issue Date: 
 
 
 
 
14 Nov 2016 
 
Version No.:  
 
 
 
2.0 
 
Date of Translation:  
 
 
23 Feb 2017 
 
 


 
 
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Protocol Synopsis  
Name of Sponsor:  Otsuka Pharmaceutical Co., Ltd 
Name of Investigational Medicinal Product:  Trade, 
Generic (OPA-15406) 
Protocol No.:  271-102-
00002 
Protocol Title: 
A Multicenter, Randomized, Double-blind, Vehicle-controlled, 
Parallel-group Trial to Assess the Safety and Efficacy of 0.3% 
and 1% OPA-15406 Ointments When Administered for 4 
Weeks in Pediatric Patients With Atopic Dermatitis 
Clinical Phase/Trial 
Type: 
Phase:  2 
Type of Trial:  Pediatric dose-finding trial 
Treatment Indication:  Atopic dermatitis (AD )  
Objective(s):  
Primary Objective:  To evaluate the safety of 0.3% and 1% 
OPA-15406 when applied twice daily for 4 weeks in pediatric 
patients with AD 
Secondary Objective:  To evaluate the efficacy (dose response) 
and pharmacokinetics of 0.3% and 1% OPA-15406 when 
applied twice daily for 4 weeks in pediatric patients with AD 
Trial Design: 
Multicenter, randomized, double-blind, vehicle-controlled, 
parallel-group 
Subject Population: 
Pediatric subjects with AD with an baseline Investigator’s 
Global Assessment (IGA) score of 2 (mild) or 3 (moderate)  
60 subjects in total (at least 8 subjects of age 2 to 6) 
Inclusion/Exclusion 
Criteria:  
Major inclusion Criteria: 
 Age:  2 to 14 years, inclusive (at time of obtaining 
informed consent) 
 Diagnosis of AD based on the criteria of Hanifin and 
Rajka1 (Appendix 1) 
 Subjects whose legal guardian is able to provide informed 
consent prior to participation in the trial 
 AD affecting ≥5% to ≤40% of body surface area (BSA) 
 IGA score of 2 (mild) or 3 (moderate) 
 
Major exclusion Criteria: 
 Subjects who are judged by the investigator or 
subinvestigator to be problematic in withdrawing blood 


 
 
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 Subjects who are unable to stop using topical 
corticosteroids, topical immunomodulators, topical 
retinoids and topical antihistamine from 7 days prior to the 
baseline examination until the Week 4 assessment.  Low or 
medium potency corticosteroids in the Guidelines for 
Management of Atopic Dermatitis may be used until 4 
days prior to the baseline examination in the judgment of 
the investigator or subinvestigator for the gradual decrease 
in the screening period before stopping. 
 Subjects who are unable to stop using systemic 
corticosteroids, systemic immunomodulators, systemic 
antimetabolites, systemic retinoids, and biologics from 28 
days prior to the baseline examination until the Week 4 
assessment.  Intra-ocular, intra-nasal and intra-auricular or 
inhaled corticosteroids may be considered if, in the opinion 
of the investigator or subinvestigator, their use will not 
impact assessment of the affected area 
 Subjects who are unable to stop treatment with ultraviolet 
A, narrowband ultraviolet B, and ultraviolet B from 28 
days prior to the baseline examination until the Week 4 
assessment 
 Subjects who are unable to continue in the trial without 
changing the dosage and administration of systemic 
antihistamines, sodium cromoglicate, tranilast, or suplatast 
tosilate from 7 days prior to baseline examination until the 
Week 4 assessment.  Intra-ocular, intra-nasal, or inhalant 
formulations may be considered if, in the opinion of the 
investigator or subinvestigator, their use will not impact 
assessment of the affected area 
Trial Sites:  
Approximately 8 sites in Japan 
Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration: 
Test Product:  0.3% and 1% OPA-15406 Ointment or vehicle 
Twice daily repeated administration for 4 weeks 
Trial Assessments: 
 
Safety Endpoints:  Adverse events (AEs), physical examination, 
vital signs (including body weight), clinical laboratory values, 
12-lead ECG (as much as possible for children aged 2 - 6 years 
old) 
Efficacy Endpoints:  IGA, Eczema Area and Severity Index 


 
 
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(EASI), Visual Analogue Scale (VAS) for pruritus (only for 7 
- 14 years of age), Verbal Rating Scale (VRS) for pruritus 
(only for 7 - 14 years of age), Patient-Oriented Eczema 
Measure (POEM), affected BSA 
Pharmacokinetics:  Blood sampling for plasma concentration 
of OPA-15406  
Screening/others:  Medical history, medication history, 
pregnancy test 
Criteria for 
Evaluation 
Primary Endpoint:  Primary Endpoint:  The number and 
percentage of subjects experiencing AEs 
Secondary Endpoints:  Incidence of success in IGA at Week 
4, change from baseline in EASI, VAS for pruritus, VRS for 
pruritus, POEM, affected BSA at Week 4, and plasma 
concentration of OPA-15406 (trough concentration at Week 1 
and Week 4) 
Statistical Methods: 
Primary Endpoint:   
 The number and percentage of subjects experiencing AEs 
will be calculated for each treatment group 
Secondary Endpoints:   
 For incidence of success in IGA at Week 4, incidence of 
success of each treatment group and its 95% confidence 
interval will be calculated.  The difference between vehicle 
group and each treatment group in the success rate and its 
95% confidence interval will be calculated.  Incidence of 
success is defined as the number of subjects whose IGA 
score is 0 (clear) or 1 (almost clear) and improved by at 
least 2 grades from baseline.  Based on the Cochran-
Mantel-haenszel method, the difference in success rate 
adjusted by the severity of IGA at baseline and its 
confidence interval will be calculated as primary analysis.   
 For change from baseline in IGA at Week 1,Week 2 and 
Week 4, mixed-model repeated measures (MMRM) 
analysis with factors of treatment (0.3% or 1% OPA-15406 
groups, vehicle group), timepoint, baseline IGA (mild or 
moderate), and interaction between treatment and 
timepoint will be applied with an unstructured variance 
covariance structure to the change from baseline up to 
Week 4 based on OC dataset.  Kenward-Roger will be used 
for the calculation of standard error of fixed effects and 
degree of freedom.  The least square mean of each 
treatment group will be calculated by timepoint.  Also, the 


 
 
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difference in the least square means between the vehicle 
group and each OPA-15406 group, and the two-sided 95% 
confidence interval will be calculated at Week 1, Week 2 
and Week 4. 
 For other secondary endpoints, analysis will be performed 
in the same way as for change from baseline in IGA.  
However, change from baseline until Day 7 of IMP 
administration in VRS for pruritus will be calculated. 
 Descriptive statistics (number of subjects, arithmetic mean, 
standard deviation, coefficient of variation, minimum 
value, median value, and maximum value) of plasma 
concentration of OPA-15406 by treatment group and by 
timepoint will be calculated. 
 Descriptive statistics (number of subjects, arithmetic mean, 
standard deviation, coefficient of variation, minimum 
value, median value, and maximum value) of plasma 
concentration of OPA-15406 by treatment group and by 
timepoint adjusted by affected area (%) per total BSA at 
baseline examination will be calculated. 
 Descriptive statistics (number of subjects, arithmetic mean, 
standard deviation, coefficient of variation, minimum value, 
median value, and maximum value) of plasma concentration 
of OPA-15406 by treatment group, by timepoint, and by 
affected area (%) per total BSA at baseline examination (5% 
to <10%, ≥10% to <30%, ≥30%). 
 Descriptive statistics (number of subjects, arithmetic mean, 
standard deviation, coefficient of variation, minimum 
value, median value, and maximum value) of age, affected 
area at baseline (%), and amount applied (g) by affected 
area will be calculated. 
Trial Duration: 
Duration of the trial:  Dec 2016 to Aug 2017 
Screening period:  2-30 days 
Assessment period:  4 weeks 
Follow up period: 2  weeks  
 
 


 
 
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Table of Contents  
Protocol Synopsis ........................................................................................... 3 
Table of Contents ........................................................................................... 7 
List of In-text Tables ................................................................................... 12 
List of In-text Figures .................................................................................. 13 
List of Appendices........................................................................................ 14 
List of Abbreviations and Definitions of Terms ....................................... 15 
1 
Introduction ........................................................................................ 17 
1.1 
Nonclinical Study Results .................................................................................18 
1.2 
Clinical Study Results .......................................................................................20 
1.2.1 
Phase 1 Trial in Healthy Adult Subjects in the United States (271-11-
202) .................................................................................................................20 
1.2.2 
Phase 1 Trial in Healthy Adult Male Subjects in Japan (271-14-001) ...........21 
1.2.3 
Phase 1 Trial in Atopic Dermatitis Patients in the United States (271-
12-204) ............................................................................................................21 
1.2.4 
Phase 2 Trial in Atopic Dermatitis Patients Outside Japan (271-12-205) ......22 
1.2.5 
Trial for Phototoxicity in Healthy Adult Subjects in the United States 
(271-12-212) ...................................................................................................23 
1.2.6 
Trial for Photoallergy in Healthy Adult Subjects in the United States 
(271-12-213) ...................................................................................................23 
1.3 
Known and Potential Risks and Benefits ..........................................................23 
2 
Trial Rationale and Objectives.......................................................... 25 
2.1 
Trial Rationale ...................................................................................................25 
2.2 
Dosing Rationale ...............................................................................................30 
2.3 
Severity Rationale .............................................................................................31 
2.4 
Trial Objectives .................................................................................................31 
3 
Trial Design ......................................................................................... 32 
3.1 
Type/Design of Trial .........................................................................................32 
3.2 
Methods of Administration ...............................................................................34 
3.2.1 
Dose, Regimen, and Treatment Period ...........................................................34 
3.2.2 
Treatment Area ...............................................................................................35 


 
 
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3.3 
Trial Population .................................................................................................35 
3.3.1 
Number of Subjects and Description of Population .......................................35 
3.3.2 
Subject Selection and Numbering ..................................................................35 
3.4 
Eligibility Criteria..............................................................................................36 
3.4.1 
Informed Consent ...........................................................................................36 
3.4.2 
Inclusion Criteria ............................................................................................37 
3.4.3 
Exclusion Criteria ...........................................................................................38 
3.5 
Endpoints ...........................................................................................................40 
3.5.1 
Primary Endpoint ............................................................................................40 
3.5.2 
Secondary Endpoints ......................................................................................40 
3.6 
Measures to Minimize/Avoid Bias ....................................................................41 
3.7 
Trial Procedures ................................................................................................42 
3.7.1 
Schedule of Assessments ................................................................................45 
3.7.1.1 
Screening Examination (From the Day of Obtaining Informed 
Consent to 2 Days Prior to the Baseline Examination) ...............................45 
3.7.1.1.1 
Subject Demographics .............................................................................45 
3.7.1.2 
Subject Registration ....................................................................................46 
3.7.1.3 
Baseline Examination (2 - 30 Days After the Screening Examination)......46 
3.7.1.4 
Allocation of Investigational Medicinal Products to Subjects ....................47 
3.7.1.5 
Between the Day of Baseline Examination and the Day of Week 1 
Examination ................................................................................................47 
3.7.1.6 
Week 1 Examination (±2 Days) ..................................................................47 
3.7.1.7 
Week 2 Examination (±3 Days) ..................................................................48 
3.7.1.8 
Week 4 Examination (±3 Days) or Withdrawal Examination ....................48 
3.7.1.9 
Examination 2 Weeks After Last IMP Administration (±7 Days) ..............49 
3.7.1.10 
Unscheduled Visits .....................................................................................49 
3.7.2 
Status of IMP Administration .........................................................................50 
3.7.3 
Severity ...........................................................................................................50 
3.7.4 
Efficacy Assessments .....................................................................................50 
3.7.4.1 
Investigator’s Global Assessment (IGA) ....................................................50 
3.7.4.2 
Eczema Area and Severity Index (EASI)....................................................51 
3.7.4.3 
Visual Analogue Scale (VAS) for Pruritus .................................................51 


 
 
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3.7.4.4 
Verbal Rating Scale (VRS) for Pruritus ......................................................51 
3.7.4.5 
Patient-Oriented Eczema Measure (POEM) ...............................................52 
3.7.4.6 
Affected BSA ..............................................................................................52 
3.7.5 
Safety Assessments .........................................................................................52 
3.7.5.1 
Adverse Events............................................................................................52 
3.7.5.2 
Clinical Laboratory Tests ............................................................................52 
3.7.5.3 
Physical Examination ..................................................................................53 
3.7.5.4 
Vital Signs (Including Body Weight) .........................................................53 
3.7.5.5 
12-Lead ECG ..............................................................................................53 
3.7.5.6 
Other Safety Assessments ...........................................................................54 
3.7.6 
Pharmacokinetic Assessments ........................................................................54 
3.7.6.1 
Blood Sampling Timepoints and the Rationale ..........................................54 
3.7.6.2 
Methods of Blood Sampling and Processing ..............................................55 
3.7.6.3 
Sending Plasma Samples ............................................................................55 
3.7.7 
End of Trial .....................................................................................................55 
3.8 
Stopping Rules, Withdrawal Criteria, and Procedures ......................................56 
3.8.1 
Termination or Interruption of the Entire Trial ..............................................56 
3.8.2 
Termination or Interruption of the Trial at Individual Trial Sites ..................56 
3.8.3 
Individual Subject Discontinuation ................................................................56 
3.8.3.1 
Treatment Discontinuation ..........................................................................56 
3.8.3.2 
Documenting Reasons for Treatment Discontinuation ...............................57 
3.8.3.3 
Withdrawal of Consent ...............................................................................58 
3.8.3.4 
Procedures to Encourage Continued Trial Participation .............................59 
3.9 
Screen Failures ..................................................................................................59 
3.10 
Definition of Completed Subjects .....................................................................60 
3.11 
Definition of Subjects Lost to Follow-up ..........................................................60 
3.12 
Subject and Subject’s Legal Guardian Compliance ..........................................61 
3.13 
Deviations From the Trial Protocol ...................................................................61 
4 
Restrictions .......................................................................................... 62 
4.1 
Prohibited Concomitant Drugs and Therapies ..................................................62 
5 
Reporting of Adverse Events ............................................................. 63 


 
 
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5.1 
Definitions .........................................................................................................63 
5.2 
Eliciting and Reporting Adverse Events ...........................................................65 
5.3 
Immediately Reportable Events (IRE) ..............................................................65 
5.4 
Potential Drug-Induced Liver Injury .................................................................66 
5.5 
Implementation of Patch Test............................................................................66 
5.6 
Pregnancy ..........................................................................................................67 
5.7 
Procedure for Breaking the Blind ......................................................................68 
5.8 
Follow-up of Adverse Events ............................................................................68 
5.8.1 
Follow-up of Non-serious Adverse Events .....................................................69 
5.8.2 
Follow-up of Serious Adverse Events ............................................................69 
5.8.3 
Follow-up and Reporting of Serious Adverse Events Occurring After 
Day of Trial Completion (Final Observation Day).........................................69 
6 
Pharmacokinetic Analysis .................................................................. 70 
7 
Statistical Analysis .............................................................................. 70 
7.1 
Sample Size .......................................................................................................70 
7.2 
Datasets for Analysis .........................................................................................70 
7.2.1 
Safety Analysis Set .........................................................................................70 
7.2.2 
Efficacy Analysis Set ......................................................................................70 
7.2.3 
Pharmacokinetic Analysis Set ........................................................................71 
7.3 
Handling of Missing Data .................................................................................71 
7.4 
Primary, Secondary, and Exploratory Endpoint Analyses ................................71 
7.4.1 
Primary Endpoint Analysis .............................................................................71 
7.4.2 
Secondary Endpoint Analysis .........................................................................71 
7.4.3 
Interim Analysis ..............................................................................................73 
7.5 
Analysis of Demographic and Baseline Characteristics....................................73 
7.6 
Safety Analysis ..................................................................................................73 
7.6.1 
Adverse Events ...............................................................................................73 
7.6.2 
Clinical Laboratory Tests ...............................................................................74 
7.6.3 
Vital Signs ......................................................................................................74 
7.6.4 
12-Lead ECG ..................................................................................................74 
7.6.5 
Other Safety Data ...........................................................................................74 


 
 
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8 
Management of Investigational Medicinal Products ...................... 75 
8.1 
Packaging and Labeling ....................................................................................75 
8.2 
Storage ...............................................................................................................75 
8.3 
Accountability ...................................................................................................75 
8.4 
Returns and Destruction ....................................................................................75 
8.5 
Reporting of Product Quality Complaints .........................................................76 
8.5.1 
Eliciting and Reporting Product Quality Complaints .....................................76 
8.5.2 
Information Required for Reporting Purposes ...............................................76 
8.5.3 
Return Process ................................................................................................77 
8.5.4 
Assessment/Evaluation ...................................................................................77 
9 
Records Management ......................................................................... 77 
9.1 
Source Documents .............................................................................................77 
9.2 
Data Collection ..................................................................................................77 
9.3 
File Management at the Trial Site .....................................................................78 
9.4 
Records Retention at the Trial Site....................................................................78 
10 
Quality Control and Quality Assurance ........................................... 79 
10.1 
Monitoring .........................................................................................................79 
10.2 
Auditing .............................................................................................................79 
11 
Ethics and Responsibility ................................................................... 80 
12 
Confidentiality .................................................................................... 80 
13 
Amendment Policy .............................................................................. 81 
14 
Publication Authorship Requirements ............................................. 81 
15 
References ............................................................................................ 82 
 


 
 
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List of In-text Tables 
Table 2.1-1 
Serious Adverse Events Reported in the OPA-15406 Group 
in the Clinical Trials in AD Patients ..............................................28 
Table 2.1-2 
Adverse Events Leading to Treatment Discontinuation in the 
OPA-15406 Group in the Clinical Trials in AD Patients ..............28 
Table 2.1-3 
Adverse Events Occurred in at Least 2 Subjects in the 
Clinical Trials in AD Patients ........................................................29 
Table 2.1-4 
Adverse Events Possibly Related to the Trial Treatment in 
the OPA-15406 Group in the Completed Trials of OPA-
15406 in AD Patients .....................................................................30 
Table 3.4.2-1 
Inclusion Criteria ...........................................................................37 
Table 3.4.3-1 
Exclusion Criteria ..........................................................................38 
Table 3.7-1 
Schedule of Assessments ...............................................................43 
Table 5.5-1 
Reading Criteria .............................................................................67 
 
 


 
 
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List of In-text Figures 
Figure 3.1-1 
Trial Design Schematic ..................................................................33 
 
 


 
 
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List of Appendices 
Appendix 1 
Diagnostic Criteria for Atopic Dermatitis (Hanifin & Rajka) .......84 
Appendix 2 
Visual Analogue Scale (VAS) Sheet for Pruritus ..........................85 
Appendix 3 
Patient-Oriented Eczema Measure (POEM) ..................................86 
Appendix 4 
Human Body Drawing for Children Aged 8 to 14 Years Old .......88 
Appendix 5 
Human Body Drawing for Children Aged 2 to 7 Years Old .........89 
 
 


 
 
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List of Abbreviations and Definitions of Terms 
List of Abbreviations 
Abbreviation Definition 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BSA 
Body Surface Area 
cAMP 
Cyclic adenosine 3', 5'-monophosphate 
CNS 
Central nervous system 
EASI 
Eczema Area and Severity Index 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IGA 
Investigator’s Global Assessment 
IRB 
Institutional review board 
IRE 
Immediately reportable event 
MedDRA 
Medical Dictionary for Regulatory Activities 
OC 
Observed Cases 
PDE 
Phosphodiesterase 
POEM 
Patient-Oriented Eczema Measure 
PQC 
Product Quality Complaint  
SAE 
Serious adverse event 
TEAE 
Treatment-emergent adverse event 
US 
United States 
VAS 
Visual Analogue Scale 
VRS 
Verbal Rating Scale 
 
 
 
 
 


 
 
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Definitions of Terms 
Term 
Definition 
Screen failure 
A screen failure is a subject whose legal guardian has provided 
written informed consent, but to whom an investigational 
medicinal product will not be allocated.  
Individual subject 
trial start date 
The day of obtaining written informed consent from the subject’s 
legal guardian. 
Individual subject 
trial discontinuation 
date 
The day of individual subject withdrawal from the trial before the 
Week 4 examination is the examination day 2 weeks after the last 
IMP administration.  For those who have missed the examination 2 
weeks after the last IMP administration, the day of withdrawal is 
the day the investigator or subinvestigator determined that the 
subject was to be withdrawn from the trial. 
Individual subject 
trial completion 
date 
For subjects who have undergone the Week 4 examination, the day 
of trial completion is the day of the examination 2 weeks after the 
last IMP administration. 
Individual subject 
trial period 
Period from the day of obtaining informed consent from the 
subject’s legal guardian to the day of trial discontinuation or 
completion.  Does not include the follow-up period. 
 
List of Pharmacokinetic Parameters 
Abbreviation and Term 
Unit 
Expansion or Definition 
AUC 
ng•h/mL 
Area under the plasma concentration-time curve  
AUC8h 
ng•h/mL 
Area under the plasma concentration-time curve 
from time zero to 8 hours 
AUC∞ 
ng•h/mL 
Area under the plasma concentration-time curve 
from time zero to infinity 
Cmax 
ng/mL 
Maximum plasma concentration of the drug 
 


 
 
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1 
Introduction 
Atopic dermatitis (AD) is defined as “a disease with repeated exacerbations/remissions of 
which the main lesion is eczema with pruritus, and most patients have atopic 
predisposition.  Atopic predisposition means (1) having a family history/medical 
history (one or more diseases of bronchial asthma, allergic rhinitis/conjunctivitis, or AD) 
or (2) predisposition to producing IgE antibody.”2  In some patients, atopic dermatitis 
that occurred in infancy may spontaneously resolve with age.  Some patients experience 
the onset or recurrence of the disease in adulthood, namely, refractory AD in adults.   
Diagnostic criteria for the disease were established by Hanifin and Rajka in 19801 and in 
Japan, Guidelines for Management of Atopic Dermatitis was published by the Japanese 
Dermatological Association.2  The therapeutic strategies of AD are common in the world.  
The universally accepted concept of the disease is that AD is chronic eczema 
accompanied by physiological dysfunction of the skin and inflammation caused by 
multiple nonspecific stimuli or specific allergens.   
Topical agents such as steroids and calcineurin inhibitors (immunosuppressors) are used 
for the treatment of inflammation, topical moisturizers and protective agents for skin care 
to treat abnormal physiological functions, and oral antihistamines and antiallergic agents 
for pruritus as adjuvant treatment.  Elimination of as many aggravating factors as possible 
has been established by current consensus as a basic therapy for AD.  Inflammation can 
generally be suppressed by topical steroids.  However, long-term use of steroids may 
induce adverse drug reactions (eg, skin atrophy, hairiness); therefore, drugs with long-
term safety have been anticipated.   
Phosphodiesterase (PDE) 4 is an enzyme that hydrolyzes cyclic adenosine 3', 5'-
monophosphate (cAMP) and exists in inflammatory cells, such as macrophages, 
lymphocytes, and neutrophils.  In AD patients, elevated PDE activity in peripheral blood 
leukocytes and reduced intracellular cAMP levels are observed.3  PDE4 inhibitors exert 
their antiinflammatory activity by increasing intracellular cAMP levels and suppressing 
production of inflammatory cytokines and chemical mediators.  Therefore, PDE4 
inhibitors have been considered effective for treatment of AD. 
OPA-15406 is a PDE4 inhibitor synthesized by Otsuka Pharmaceutical Co., Ltd.  In a 
mouse chronic contact hypersensitivity model, OPA-15406 ointment demonstrated its 
efficacy on dermatitis by improving the symptoms.  Therefore, development of OPA-
15406 ointment was started with the expectation of efficacy for AD. 


 
 
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Clinical development of OPA-15406 has preceded outside Japan, and the phase 2 trial in 
AD patients (aged 10 - 70 years old) has been completed.  In Japan, the phase 1 trial in 
healthy adult male subjects has been completed, and the phase 2 trial in adult AD patients 
(aged 15 - 70 years old) is ongoing.  In healthy adult subjects and AD patients (phase 1 
and phase 2 trials outside Japan), OPA-15406 ointment showed no clinical relevant safety 
issues but good tolerability.  Also, in the phase 2 trial outside Japan, 1% OPA-15406 
ointment demonstrated the efficacy on AD. 
As AD is common in children4 and based on the above clinical trial results, the present 
trial is designed to evaluate the safety, efficacy, and pharmacokinetics of OPA-15406 
ointment in pediatric AD patients (aged 2 - 14 years old). 
1.1 
Nonclinical Study Results 
OPA-15406 had potent and selective PDE4 inhibitory actions, especially against PDE4B, 
and its 50% inhibitory concentration against PDE4B was 0.0112 μM. 
Using a mouse chronic contact hypersensitivity model as an animal model of AD, the 
dose-dependent efficacy of the OPA-15406 ointment (0.03% to 3%) for chronic allergic 
dermatitis was assessed.  Four weeks of topical administration of the OPA-15406 
ointment showed dose-dependent efficacy in improving skin thickening at 0.03% to 3%.  
The effect was inferior to that of betamethasone valerate, a strong steroid, and superior to 
that of tacrolimus ointment, a calcineurin inhibitor.  Four weeks of multiple 
administrations of 3% OPA-15406 ointment significantly suppressed infiltration of 
inflammatory cells, such as CD3 positive cells, eosinophils, and neutrophils, in skin 
lesions. 
Using a mouse scratching-induced chronic dermatitis model, the efficacy of OPA-15406 
(1% and 3%) dissolved in a solvent (1:1 mixture of acetone and methanol) was assessed.  
Six weeks of topical administration of OPA-15406 (1% or 3%) significantly improved 
the skin symptoms, though no particular effect was observed on the frequency of 
scratching.  The efficacy was superior to those of betamethasone valerate (0.1%) and 
tacrolimus (0.1%) dissolved in the solvent. 
The efficacy of OPA-15406 ointment (3%) was assessed in a mouse acute contact 
hypersensitivity model.  Single administration of the OPA-15406 ointment (3%) 
significantly suppressed edema.  The efficacy was equivalent to betamethasone valerate 
(Rinderon®-V ointment 0.12%) and tacrolimus ointment (Protopic® ointment 0.1%). 


 
 
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OPA-15406 ointment (0.1%, 0.3%, 1%, and 3%) was administered percutaneously to rats 
at 0.3, 0.9, 3, or 9 mg/kg as a single-dose.  Cmax and AUC of OPA-15406 increased dose-
dependently at 0.3 to 3 mg/kg, and reached a plateau at 3 to 9 mg/kg.  Single 
percutaneous administration of the OPA-15406 1% ointment at 3 mg/kg was performed 
for abraded skin of male rats.  The Cmax and AUC∞ of OPA-15406 in the male rats with 
abraded skin were 2.0 and 1.6 times that in male rats with intact skin. 
With percutaneous administration of 14C-OPA-15406 1% ointment in rats, the amount of 
detected OPA-15406 on the skin of the administration site was the largest, and the 
metabolites of MAP-15484, MAP-15485, and MAP-15497 were also detected.  OPA-
15406, MAP-15484, and MAP-15485 were detected in the plasma of the rats treated 
percutaneously and subcutaneously with 14C-OPA-15406 1% ointment. 
In a 4-week repeated-dose percutaneous toxicity study in rats, white petrolatum, OPA-
15406 ointment 0% (vehicle), 0.1% (1.06 mg/kg for male, 1.25 mg/kg for female), 0.3% 
(3.27 mg/kg for male, 3.78 mg/kg for female), 1% (11.02 mg/kg for male, 12.74 mg/kg 
for female), or 3% (33.56 mg/kg for male, 38.56 mg/kg for female) was administered to 
intact skin (open cutaneous) approximately equivalent to 10% of total body surface area 
(BSA) once daily.  No changes associated with the test substance were observed at the 
administration sites in any treatment groups.  Body weight and/or food consumption were 
reduced in the male rats treated with 1% and 3% ointments, and in female rats treated 
with 0.1%, 0.3%, and 1% ointments.  These changes were reversible or likely to be 
reversible during the 4-week recovery period.  In a 13-week repeated-dose percutaneous 
toxicity study in rats, white petrolatum, OPA-15406 ointment 0% (vehicle), 0.1% (0.31 
mg/kg for male, 0.38 mg/kg for female), 0.3% (0.92 mg/kg for male, 1.13 mg/kg for 
female), 1% (3.08 mg/kg for male, 3.75 mg/kg for female), or 3% (9.39 mg/kg for male, 
11.47 mg/kg for female) was administered to intact skin (open cutaneous) approximately 
equivalent to 3% of total BSA once daily.  No changes associated with the test substance 
were observed at the administration sites in any treatment groups.  Increase in body 
weight was suppressed in the male and female rats treated with the 3% ointment.  The no 
observed adverse effect dose level of systemic toxicity was estimated to be 1% ointment 
(3.08 mg/kg) for males and 1% ointment (3.75 mg/kg) for females.   
In a 4-week repeated-dose percutaneous toxicity study in rabbits, white petrolatum, OPA-
15406 ointment 0% (vehicle), 0.1%, 0.3%, 1%, or 3% was administered to intact skin 
(open cutaneous) approximately equivalent to 10% of total BSA once daily.  The OPA-


 
 
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15406 ointment was classified as weak skin irritation at all concentrations according to 
the Draize scale for skin irritation. 
In an 8-week repeated-dose percutaneous toxicity study in juvenile rats (25 days old at 
the start of administration), white petrolatum 0% (vehicle), OPA-15406 ointment 0.3% 
(male: 3.76 mg/kg, female: 4.23 mg/kg), 1% (male: 12.56 mg/kg, female: 14.32 mg/kg), 
or 3% (male: 38.52 mg/kg, female: 43.83 mg/kg) was administered once daily to intact 
skin (open cutaneous) approximately equivalent to 10% of total BSA.  As a result, no 
changes associated with the test substance were observed on the administration sites in 
any of the treatment groups.  Although suppressed weight increase and reductions in food 
intake and grip strength were observed in female rats with 1% or 3% ointment, these 
changes were not developmental toxicity and they resolved with washout.  Also, there 
was no difference in the toxicity threshold between adult and juvenile rats.  As the profile 
of OPA-15406 is such that it reaches the central nervous system (CNS)and the brain is 
known to develop after birth, a 10-week repeated-dose percutaneous toxicity study was 
conducted in neonatal rats (4 days old at the start of administration) with a focus on CNS 
development, but no influence of OPA-15406 on the function or structure of the CNS 
was found. 
1.2 
Clinical Study Results 
Clinical development of OPA-15406 has preceded outside Japan, and the phase 2 trial in 
AD patients has been completed.  In Japan, the phase 1 trial in healthy adult 
male subjects has been completed. 
1.2.1 
Phase 1 Trial in Healthy Adult Subjects in the United States (271-
11-202) 
In the phase 1 trial in healthy adult subjects (aged 18 - 64 years old) in the United States 
(US), side-by-side comparison was performed on the back of the subject using the vehicle 
of OPA-15406 ointment (placebo) as the control.  The dose was escalated from 0.1% to 
0.3%, 1%, and 3% (8 subjects for each group).  The amount of administration was 0.5 g, 
and the treatment area was 10 cm2 in single or 2-week once daily multiple administration.  
The plasma concentrations of OPA-15406 and its metabolites were all below the lower 
limit of quantification (0.2 ng/mL) at all doses.  No serious adverse events were reported, 
and no subjects were withdrawn from the trial due to adverse events. 


 
 
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1.2.2 
Phase 1 Trial in Healthy Adult Male Subjects in Japan (271-14-
001) 
In the phase 1 trial in healthy adult male subjects (aged 20 - 40 years old) in Japan, a 
single administration or 2-week twice-daily multiple administrations of OPA-15406 
ointment 0.3%, 1%, or 3% formulation (8 subjects for each group) were given to a 1,000 
cm2 area (about 5% of BSA) on the back of the subject at 5 g per dose, using the vehicle 
of OPA-15406 ointment (placebo) as the control, to investigate the safety and 
pharmacokinetics in Japanese subjects.  In the 0.3%, 1%, and 3% OPA-15406 groups, the 
mean Cmax was 0.508, 0.838, and 1.61 ng/mL, respectively, after the single-dose, and it 
was 0.506, 0.795, and 1.65 ng/mL, respectively, after the multiple doses.  The Cmax 
increased with dose after both the single and multiple administrations; however, the level 
of increase was lower than the dose ratio, and no dose-proportional increase was 
observed.  In all multiple-dose groups, the plasma concentrations of OPA-15406 and all 
metabolites in plasma are considered to have reached an almost steady state on Day 7.  In 
both the OPA-15406 group and the vehicle group, no adverse events were reported, and 
no subjects were withdrawn from the trial.  In physical findings and subjective symptoms, 
vital signs, skin findings, standard 12-lead ECG, and clinical laboratory tests, no 
clinically relevant variations or changes were observed.  Also, no particular concerns 
were reported regarding the safety of OPA-15406 ointment up to concentrations of 3%. 
1.2.3 
Phase 1 Trial in Atopic Dermatitis Patients in the United States 
(271-12-204) 
In the phase 1 trial in AD patients (aged 18 - 64 years old) in the US, 1 g of the 0.3%, 1%, 
or 3% formulation of OPA-15406 ointment (15 subjects for each group) was 
administered to 5% of BSA (about 1,000 cm2) as 4-week twice daily multiple 
administrations, using the vehicle of OPA-15406 ointment (placebo) as the control.  Then, 
OPA-15406 ointment 1% formulation (7 subjects), OPA-15406 ointment 3% formulation 
(8 subjects), or 0.1% tacrolimus ointment (15 subjects) was administered to 10% or more 
of affected BSA at 1 g per 5% of BSA as 4-week twice daily multiple administrations. 
The mean Cmax of the plasma OPA-15406 concentration after administration of OPA-
15406 ointment 1% and 3% formulations to 10% or more of affected BSA as 4-week 
twice daily multiple administrations was 12.9 and 22.3 ng/mL, respectively, and the mean 
AUC8h was 73.5 and 115 ng•h/mL, respectively. 
For safety, 1 case of the serious adverse event of cholelithiasis occurred in the 1% OPA-
15406 group, but its causal relationship with the investigational medicinal product (IMP) 


 
 
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was ruled out.  Two subjects discontinued treatment with the IMP due to adverse events; 
one of the subjects was in the 3% OPA-15406 group (name of adverse event:  
hypersensitivity), and the other was in the 0.1% tacrolimus group (name of adverse event:  
dermatitis allergic).  Both events were judged to be IMP-related. 
For efficacy, the rate of subjects whose Investigator’s Global Assessment (IGA) score 
improved to 0 or 1 at Week 4 after twice daily administrations of IMP to 5% of BSA was 
53.3%, 66.7%, 40.0%, and 26.7% in the 0.3%, 1%, and 3% OPA-15406 groups and the 
vehicle group, respectively.  Also, the rate of subjects whose IGA score improved to 0 or 
1 at Week 4 after twice daily administrations of IMP to 10% or more of BSA was 57.1%, 
14.3%, and 57.1% in the 1% and 3% OPA-15406 groups and the 0.1% tacrolimus group, 
respectively.  Among all subjects, the rate of an Investigator’s Global Assessment (IGA) 
score that improved to 0 or 1 at Week 4 was 53.3%, 63.6%, 31.8%, 26.7%, and 53.3% in 
the 0.3%, 1%, and 3% OPA-15406 groups, the vehicle group, and the 0.1% tacrolimus 
group, respectively, which suggested the efficacy of the OPA-15406 ointment 0.3% and 
1% formulations for AD.  The reason why the efficacy of the 3% formulation of OPA-
15406 ointment was not demonstrated has not been clarified. 
1.2.4 
Phase 2 Trial in Atopic Dermatitis Patients Outside Japan (271-
12-205) 
In the phase 2 trial in AD patients (aged 10 - 70 years old) outside Japan, the efficacy, 
safety, and pharmacokinetics of an 8-week twice-daily multiple administrations of OPA-
15406 ointment were investigated by selecting 0.3% and 1% formulations (40 subjects 
for each group) for which the efficacy was suggested in the phase 1 trial in the US, using 
the vehicle of OPA-15406 ointment (placebo) as the control.  The primary efficacy 
endpoint was established as the incidence of success in IGA (rate of subjects with an IGA 
score of 0 or 1 with an improvement by at least 2 grades) at Week 4.  The incidence of 
success in IGA was 14.63%, 20.93%, and 2.70% in the 0.3% OPA-15406 group, the 1% 
OPA-15406 group, and the vehicle group, respectively.  The 0.3% OPA-15406 group 
showed a higher incidence of success in IGA than the vehicle group; however, no 
significant difference was observed between the groups (p = 0.0690, CMH test).  In the 
1% OPA-15406 group, a significant difference was observed in the incidence of success 
in IGA compared to the vehicle group (p = 0.0165, CMH test).  Discontinuations due to 
adverse events occurred with 4 subjects (9.8%), 3 subjects (7.0%), and 7 subjects (18.9%) 
in the 0.3% OPA-15406 group, the 1% OPA-15406 group, and the vehicle group, 
respectively.  In the 0.3% OPA-15406 group, erythema and pruritus that occurred in 1 
subject were judged as IMP-related, and cellulitis, dermatitis atopic, and multiple 


 
 
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sclerosis that occurred in 1 subject each were judged as not IMP-related.  In the 1% OPA-
15406 group, dermatitis atopic in 2 subjects and giardiasis in 1 subject were reported; 
however, all of these events were judged as not IMP-related.  In the vehicle group, 
dermatitis atopic and application site irritation in 1 subject each were judged as IMP-
related, and dermatitis atopic in 2 subjects and pruritus, papule, and excoriation in 1 
subject each were judged as not IMP-related.  Serious adverse events were reported as 
liver function test abnormal and multiple sclerosis in 1 subject each in the 0.3% OPA-
15406 group and giardiasis and depression in 1 subject each in the 1% OPA-15406 
group; however, all of these events were determined as not IMP-related.  In the results of 
clinical laboratory tests, vital signs, and 12-lead ECG, no marked difference was 
observed among the 3 groups.  The plasma OPA-15406 concentrations at 4 hours post-
administration at Week 4 were 0.236 to 7.26 ng/mL in 5 subjects in the 0.3% OPA-15406 
group and 0.469 to 1.22 ng/mL in 4 subjects in the 1% OPA-15406 group. 
1.2.5 
Trial for Phototoxicity in Healthy Adult Subjects in the United 
States (271-12-212) 
In the trial for phototoxicity in 40 healthy adult subjects in the US, the phototoxicity was 
evaluated by a single administration of 0.3%, 1%, or 3% formulation of OPA-15406 
ointment or the corresponding vehicle (placebo) on the back of the subject.  At the 
treatment area, no adverse events were observed.  Also, no serious adverse events were 
reported, and no subjects were withdrawn from the trial due to adverse events. 
1.2.6 
Trial for Photoallergy in Healthy Adult Subjects in the United 
States (271-12-213) 
In the trial for photoallergy in 62 healthy adult subjects in the US, photoallergy was 
evaluated by multiple administrations of 0.3%, 1%, or 3% formulation of OPA-15406 
ointment or the corresponding vehicle (placebo) on the back of the subject by 
establishing a 19-day sensitization period and a 5-day induction period.  At the treatment 
area, erythema was observed in 1 subject as an adverse event, which was moderate in 
severity and determined as IMP-related.  No serious adverse events were reported.  One 
subject discontinued the trial due to the onset of an adverse event, pneumonia; however, a 
causal relationship with the IMP was ruled out. 
1.3 
Known and Potential Risks and Benefits 
In the phase 1 trial in healthy adults in the US (271-11-202), the trial for phototoxicity in 
the US (271-12-212), the trial for photoallergy in the US (271-12-213), the phase 1 trial 
in healthy adult male subjects in Japan (271-14-001), the phase 1 trial in AD patients in 


 
 
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the US (271-12-204), and the phase 2 trial outside Japan (271-12-205), OPA-15406 was 
administered to 174 healthy adult subjects and 144 AD patients (including 16 patients 
aged 10 - 17 years old).  The longest duration of dosing was 8 weeks. 
Commonly reported adverse events in healthy adult subjects receiving OPA-15406 for 4 
weeks were application site dermatitis in 26 subjects (14.9%), application site erosion in 
13 subjects (7.5%), pruritus in 8 subjects (4.6%), erythema in 7 subjects (4.0%), 
application site pruritus in 6 subjects (3.4%), application site erythema in 4 subjects 
(2.3%), headache in 4 subjects (2.3%), abdominal pain in 2 subjects (1.1%), and nausea 
in 2 subjects (1.1%). 
Commonly reported adverse events in AD patients receiving OPA-15406 for 4 or 8 
weeks were dermatitis atopic in 19 subjects (13.2%), headache in 7 subjects (4.9%), 
upper respiratory tract infection in 6 subjects (4.2%), nasopharyngitis in 4 subjects 
(2.8%), diarrhoea in 3 subjects (2.1%), application site pain in 3 subjects (2.1%), urinary 
tract infection in 3 subjects (2.1%), pruritus in 3 subjects (2.1%), vomiting in 2 subjects 
(1.4%), chest discomfort in 2 subjects (1.4%), impetigo in 2 subjects (1.4%), sinusitis in 2 
subjects (1.4%), and post inflammatory pigmentation change in 2 subjects (1.4%). 
In 271-12-204, application site pain was reported using terms of “application site stinging 
(mild)” in 1 subject in the OPA-15406 3% group and “application site burning sensation 
(mild)” in 1 subject in the OPA-15406 1% group.  In 271-12-205, application site pain 
was reported using the term “mild burning sensation after IMP administration (mild)” in 
1 subject in the OPA-15406 0.3% group.  Regardless of these symptoms, the subjects 
continued the treatment with OPA-15406 for 8 weeks which was the longest duration of 
treatment. 
In AD patients treated with OPA-15406, 5 serious adverse events (cholelithiasis, 
giardiasis, liver function test abnormal, multiple sclerosis, and depression) were reported; 
however, all of these events were judged as not IMP-related by the investigator or the 
sponsor. 
Of the adverse events judged as possibly related or definitely related to OPA-15406 in the 
overall trials, commonly reported events (in order of incidence) were dermatitis atopic 
(dermatitis atopic aggravated) (2.8%) and application site pain (2.1%).  Other adverse 
events judged as possibly related or definitely related to OPA-15406 were 1 event (0.7%) 
each of erythema, pruritus, application site oedema, dry mouth, hypersensitivity, 
vulvovaginal mycotic infection, and sinusitis.  All of these events were mild in severity.  
Due to the small number of subjects who were enrolled in this trial and included in the 


 
 
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analysis, further evaluation will be required for events that occurred only once and were 
judged as possibly related to IMP.  Therefore, these events should be monitored in detail.  
The Investigator’s Brochure includes other detailed information. 
The benefits of participating in the trial include the fact that AD symptoms may improve, 
and that the subjects could receive more detailed tests and examinations by physicians 
than they could have with just general examinations.  At present, no PDE4 inhibitors to 
indicate AD have been approved in and outside Japan. 
 
2 
Trial Rationale and Objectives 
2.1 
Trial Rationale 
Based on preclinical study results, OPA-15406 is expected to be useful for the treatment 
of AD; therefore, Otsuka Pharmaceutical Co., Ltd. started development of OPA-15406 
ointment from 2011 in the US aiming to obtain approval for the indication of “AD.”  
After completion of the phase 1 trial in healthy adults in the US (271-11-202), the phase 
1 trial in AD patients aged 18 to 64 years old was performed in the US (271-12-204) as a 
proof-of-concept trial.  Then, the phase 2 trial in AD patients aged 10 to 70 years old was 
completed outside Japan (271-12-205) as a dose-finding trial.  Currently, a 
pharmacokinetic trial in AD patients aged 2 to 9 years old has been planned in the US.  In 
Japan, development started from 2014, and the phase 1 trial was performed in healthy 
adults in Japan (271-14-001).  After safety had been demonstrated in healthy Japanese 
adult subjects, the phase 2 trial in adult AD patients aged 15 to 70 years old to evaluate 
the safety, efficacy, and pharmacokinetics (271-15-001), and this trial in pediatric AD 
patients aged 2 to 14 years old to evaluate the safety, efficacy, and pharmacokinetics have 
both been planned. 
In both pediatric and adult patients with AD, abnormalities in the skin barrier function are 
observed, such as an increased loss of transepidermal water, a decreased content of 
natural moisturizing factors in the stratum corneum, and a decreased filaggrin content in 
the stratum corneum.2,5,6  Also, in both pediatric and adult patients, AD is diagnosed 
based on symptoms of “pruritus,” “characteristic rash and its distribution,” and “chronic 
and repeated courses,” with no particular difference being found in the pathological 
nature between pediatric and adult patients with AD.7  Due to the reduced skin barrier 
function, AD patients have increased skin irritability against nonspecific stimulants than 
healthy people, which causes the development of inflammation.2  Skin inflammation 


 
 
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results in a vicious cycle of further exacerbation of eczema by reduced skin barrier 
function, increased irritability, and stimulation by scratching.  It has been reported that, 
within a year of birth, infants develop a similar skin barrier function to that of 
adults.8,9,10,11  However, infants younger than 2 years old have an incomplete barrier 
function compared to adults due to physiological differences, such as transepidermal 
water loss and pH12 and are likely to develop skin inflammation.4 
As described above, the pathological conditions of AD do not generally differ depending 
on age, but infants are still likely to develop skin inflammation.  According to the 
International Conference on Harmonisation (ICH)-E11 (Guidance on Clinical 
Investigation of Medicinal Products in the Pediatric Population), babies up to 23 months 
after birth are defined as infants and toddlers, and those aged 2 to 11 years old are defined 
as children.13  Therefore, the lower age limit is established as 2 years old in this trial.  In 
the package insert in Japan, children are usually defined as being of an age less than 15 
years old.  Therefore, in the phase 2 trial (271-15-001) in adult AD patients, the lower 
age limit was set as 15 years old, and in this trial in pediatric AD patients, the upper age 
limit has been set as 14 years old. 
Prior to start of this trial, a toxicity study was performed using 25-day-old juvenile rats 
(corresponding to about 2 years old in humans).14  White petrolatum, OPA-15406 
ointment 0% (vehicle), 0.3%, 1%, or 3% was administered to intact skin (open 
cutaneous) approximately equivalent to 10% of total BSA once daily for 8 weeks in 
multiple administrations.  As a result, no changes associated with the test substance were 
observed at the application sites in any of the treatment groups.  For systemic symptoms, 
decreased body weight in females of the 1% group, and decreased body weight gain, 
reduced food consumption, reduced grip strength, and decreased thymus and spleen 
weights in females of the 3% group were observed; however, these changes resolved after 
washout.  Also in adult animals, decreased body weight gain, reduced food consumption, 
and decreased thymus and spleen weights were observed, suggesting that these changes 
were not associated with developmental toxicity specific to juvenile rats.  The no 
observed adverse effect dose level was 3.27 mg/kg/day for males and 1.25 mg/kg/day for 
females in adult rats (6 weeks old), and 38.52 mg/kg/day for males and 4.23 mg/kg/day 
for females in juvenile rats (25 days old), revealing that the threshold of toxicity did not 
decrease in juvenile animals. 
In addition, it is known that the brain develops after birth, and that the profile of OPA-
15406 is such that it reaches the CNS.  Therefore, a 10-week repeated-dose percutaneous 


 
 
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toxicity study was conducted in neonatal rats (4 days old at the start of administration) 
with a focus on CNS development.  No influence of OPA-15406 on the function or 
structure of the CNS was found. 
Based on the clinical trial results obtained so far, the safety of OPA-15406 was discussed 
by dividing the OPA-15406 group into two age groups of adults ≥18 years old and 
juveniles including children from 10 to <18 years old.  Table 2.1-1 shows the serious 
adverse events.  In the adult population, serious adverse events were reported in 4 
subjects in the 0.3% and 1% groups; however, its causal relationship with the IMP was 
ruled out.  In the juvenile population, a serious adverse event was reported in 1 subject, 
and its causal relationship with the IMP was also ruled out.   Table 2.1-2 shows the 
adverse events leading to treatment discontinuation.  Adverse events leading to treatment 
discontinuation are reported in 6 subjects in the 0.3% and 1% groups in the adult 
population, and 2 subjects in the juvenile population.  Table 2.1-3 shows adverse events 
occurred in at least 2 subjects in either group.  The incidence of dermatitis atopic was 
slightly higher in juvenile subjects of the 0.3% group.  Table 2.1-4 presents adverse 
events possibly related to the IMP.  These results showed no marked difference in the 
incidence between the groups.  Based on the above findings, none of the adverse events 
was specific to the juvenile subjects, and no particular concerns were raised over safety. 
Also, efficacy was demonstrated in both the phase 1 trial in AD patients aged 18 to 64 
years old in the US (271-12-204) and the phase 2 trial in AD patients aged 10 to 70 years 
old outside Japan (271-12-205).   
 
 


 
 
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Table 2.1-1 
Serious Adverse Events Reported in the OPA-15406 Group in 
the Clinical Trials in AD Patients 
 
Adult subjects  
(≥18 years old) 
Juvenile subjects 
(10 to <18 years old) 
System organ class 
Preferred term 
0.3% 
(N=49) 
n (%) 
1% 
(N=56) 
n (%) 
3% 
(N=23) 
n (%) 
0.3% 
(N=7) 
n (%) 
1% 
(N=9) 
n (%) 
Total 
2 (4.1) 
2 (3.6) 
0 (0.0) 
0 (0.0) 
1 (11.1) 
Hepatobiliary disorders 
Cholelithiasis  
0 (0.0) 
1 (1.8) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Infections and infestations 
Giardiasis 
0 (0.0) 
1 (1.8) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Investigations 
Liver function test 
abnormal 
1 (2.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Nervous system disorders 
Multiple sclerosisa 
1 (2.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Psychiatric disorders 
Depressionb 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (11.1) 
The trial results of 271-12-204 and 271-12-205 are combined. 
aReported as newly developed multiple sclerosis. 
bReported as aggravation of depression. 
 
Table 2.1-2 
Adverse Events Leading to Treatment Discontinuation in the 
OPA-15406 Group in the Clinical Trials in AD Patients 
 
Adult subjects  
(≥18 years old) 
Juvenile subjects 
(10 to <18 years old) 
System organ class 
Preferred term 
0.3% 
(N=49) 
n (%) 
1% 
(N=56) 
n (%) 
3% 
(N=23) 
n (%) 
0.3% 
(N=7) 
n (%) 
1% 
(N=9) 
n (%) 
Total 
3 (6.1) 
3 (5.4) 
1 (4.3) 
1 (14.3) 
1 (11.1) 
Immune system disorders 
Hypersensitivity 
0 (0.0) 
0 (0.0) 
1 (4.3) 
0 (0.0) 
0 (0.0) 
Infections and infestations 
Cellulitis  
1 (2.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Giardiasis 
0 (0.0) 
1 (1.8) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Nervous system disorders 
Multiple sclerosisa 
1 (2.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Psychiatric disorders 
Depressionb 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (11.1) 
Skin and subcutaneous tissue disorders 
Dermatitis atopic 
0 (0.0) 
2 (3.6) 
0 (0.0) 
1 (14.3) 
0 (0.0) 
Erythema 
1 (2.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Pruritus 
1 (2.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
The trial results of 271-12-204 and 271-12-205 are combined.  
aReported as newly developed multiple sclerosis.  
bReported as aggravation of depression. 


 
 
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Table 2.1-3 
Adverse Events Occurred in at Least 2 Subjects in the Clinical 
Trials in AD Patients  
 
Adult subjects  
(≥18 years old) 
Juvenile subjects 
(10 to <18 years old) 
System organ class 
Preferred term 
0.3% 
(N=49) 
n (%) 
1% 
(N=56) 
n (%) 
3% 
(N=23) 
n (%) 
0.3% 
(N=7) 
n (%) 
1% 
(N=9) 
n (%) 
Gastrointestinal disorders 
Dental caries 
1 (2.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Diarrhoea 
1 (2.0) 
2 (3.6) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Toothache 
0 (0.0) 
1 (1.8) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Vomiting 
0 (0.0) 
2 (3.6) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
General disorders and administration site conditions 
Application site pain 
1 (2.0)a 
1 (1.8)b 
1 (4.3)c 
0 (0.0) 
0 (0.0) 
Chest discomfort 
0 (0.0) 
2 (3.6) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Infections and infestations 
Cellulitis  
1 (2.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Impetigo 
0 (0.0) 
2 (3.6) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Nasopharyngitis 
2 (4.1) 
1 (1.8) 
0 (0.0) 
1 (14.3) 
0 (0.0) 
Sinusitis 
1 (2.0) 
1 (1.8) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Upper respiratory tract 
infection  
3 (6.1) 
1 (1.8) 
0 (0.0) 
2 (28.6) 
0 (0.0) 
Urinary tract infection  
2 (4.1) 
0 (0.0) 
1 (4.3) 
0 (0.0) 
0 (0.0) 
Nervous system disorders 
Headache  
2 (4.1) 
2 (3.6) 
1 (4.3) 
1 (14.3) 
1 (11.1) 
Skin and subcutaneous tissue disorders 
Dermatitis atopic 
8 (16.3) 
6 (10.7) 
1 (4.3) 
3 (42.9) 
1 (11.1) 
Erythema 
1 (2.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Post inflammatory  
pigmentation change 
1 (2.0) 
1 (1.8) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Pruritus 
3 (6.1) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
The trial results of 271-12-204 and 271-12-205 are combined.  Adverse events occurring in at least 2 
subjects in the OPA-15406 group, or adverse events occurring in 1 subject in the OPA-15406 group and in 
at least 2 subjects in a combined group of the tacrolimus group or vehicle group are shown. 
aTerm used by the reporter:  Mild burning sensation after IMP administration (mild) 
bTerm used by the reporter:  Application site burning sensation (mild) 
cTerm used by the reporter:  Application site stinging (mild) 
 
 
 


 
 
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Table 2.1-4 
Adverse Events Possibly Related to the Trial Treatment in the 
OPA-15406 Group in the Completed Trials of OPA-15406 in 
AD Patients 
 
Adult subjects  
(≥18 years old) 
Juvenile subjects 
(10 to <18 years old) 
System organ class 
Preferred term 
0.3% 
(N=49) 
n (%) 
1% 
(N=56) 
n (%) 
3% 
(N=23) 
n (%) 
0.3% 
(N=7) 
n (%) 
1% 
(N=9) 
n (%) 
Total 
4 (8.2) 
3 (5.4) 
4 (17.4) 
2 (28.6) 
0 (0.0) 
Gastrointestinal disorders 
Dry mouth 
0 (0.0) 
0 (0.0) 
1 (4.3) 
0 (0.0) 
0 (0.0) 
General disorders and administration site conditions 
Application site oedema 
0 (0.0) 
1 (1.8) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Application site pain 
1 (2.0)a 
1 (1.8)b 
1 (4.3)c 
0 (0.0) 
0 (0.0) 
Immune system disorders 
Hypersensitivity  
0 (0.0) 
0 (0.0) 
1 (4.3) 
0 (0.0) 
0 (0.0) 
Infections and infestations 
Sinusitis 
1 (2.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Vulvovaginal mycotic 
infection 
0 (0.0) 
1 (1.8) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Skin and subcutaneous tissue disorders 
Dermatitis atopic 
1 (2.0) 
0 (0.0) 
1 (4.3) 
2 (28.6) 
0 (0.0) 
Erythema 
1 (2.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
Pruritus 
1 (2.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
The trial results of 271-12-204 and 271-12-205 are combined.  
aTerm used by the reporter:  Mild burning sensation after IMP administration (mild) 
bTerm used by the reporter:  Application site burning sensation (mild) 
cTerm used by the reporter:  Application site stinging (mild) 
 
Based on the above findings, it was judged scientifically and ethically appropriate to 
conduct this trial in order to evaluate the safety, efficacy, and pharmacokinetics of OPA-
15406 in children aged 2 to 14 years old, in consideration of the standard age 
classification in ICH-E11 and the package insert, and that no particular concerns over 
safety in juvenile animals corresponding to newborns to 2-year-old human infants in the 
nonclinical studies, and no marked concerns over safety and suggested efficacy in the 
clinical trials in AD patients aged 10 to <18 years old including children were observed. 
 
2.2 
Dosing Rationale 
Skin preparations are always exposed to opportunities of being removed after 
administration to the skin, such opportunities as washing the face, bathing, adhesion to 
clothing, or sweating resulting in dilution.  To be sure that effective concentration on the 


 
 
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skin is maintained, it is desirable that the IMP be administered multiple times a day.  In 
consideration of the fact that people generally wash their face and hands after getting up 
and when bathing at night, twice-daily administration is considered highly convenient for 
patients, and it may contribute to achieving the best adherence.  Therefore, twice-daily 
administration is employed. 
In the phase 1 trial in AD patients in the US (271-12-204), efficacy of OPA-15406 was 
suggested in the 0.3% and 1% formulations among the 0.3%, 1%, and 3% formulations 
tested.  In the phase 2 trial in AD patients aged 10 years and older outside Japan (271-12-
205), the efficacy of OPA-15406 was investigated by selecting the 0.3% and 1% 
formulations.  The results showed that the 1% formulation had a significantly higher 
efficacy in the primary efficacy endpoint compared to the vehicle, and the 0.3% 
formulation also had a higher efficacy compared to the vehicle.  Also, in adults and 
juveniles including children, no particular concerns were raised over safety in both the 
0.3% and 1% formulations.  Therefore, in the ongoing phase 2 trial in adult AD patients 
(aged 15 - 70 years old) in Japan, the same doses of 0.3% and 1% were selected as in the 
phase 2 trial outside Japan (271-12-205).  Also in this trial, the same doses of 0.3% and 
1% as in adults are selected in order to evaluate the safety and efficacy of OPA-15406 in 
pediatric AD patients (aged 2 - 14 years old) in Japan. 
 
2.3 
Severity Rationale 
Atopic dermatitis is mainly treated with topical drugs.  However, for severe patients, oral 
agents and ultraviolet therapy are often combined due to an inadequate response to 
topical drugs alone.  Therefore, this trial is designed to include patients with an IGA 
score of 2 (mild) or 3 (moderate) whose symptoms are controllable only by topical drugs.  
In the phase 1 trial (271-12-204) and phase 2 trial (271-12-205) outside Japan, efficacy 
and safety were both demonstrated.  Also in Japan, the phase 2 trial (271-15-001) is now 
ongoing to evaluate efficacy and safety in adult AD patients with an IGA score of 2 
(mild) or 3 (moderate). 
 
2.4 
Trial Objectives 
Primary objective:  To evaluate the safety of 0.3% and 1% OPA-15406 ointments in 
pediatric patients with AD when administered twice daily for 4 weeks. 


 
 
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Secondary objective:  To evaluate the efficacy (dose response) and pharmacokinetics of 
0.3% and 1% OPA-15406 ointments in pediatric patients with AD when administered 
twice daily for 4 weeks. 
 
3 
Trial Design 
3.1 
Type/Design of Trial 
This is a multicenter, randomized, double-blind, vehicle-controlled, parallel-group 
comparison trial to evaluate the safety, efficacy, and pharmacokinetics of OPA-15406 
ointment in pediatric patients with AD.  This trial consists of the 0.3% OPA-15406 group, 
the 1% OPA-15406 group, and the vehicle group.  The trial design is shown in Figure 
3.1-1. 
(1) 
Screening period 
After obtaining written informed consent from the subject’s legal guardian (if possible, 
after also obtaining informed assent from the subject), the investigator or subinvestigator 
will perform a screening examination.  The period between the day of the screening 
examination and the end of the baseline examination is defined as the screening period 
(2-30 days).  The subjects who meet the inclusion criteria and do not meet any of the 
exclusion criteria at the baseline examination will shift to the assessment period and will 
be dynamically allocated to the test product (0.3% or 1% formulation of OPA-15406) or 
the vehicle (placebo). 
(2) 
Assessment period (treatment period) 
For subjects meeting the inclusion criteria and not meeting any of the exclusion criteria at 
the baseline examination, the period between the day of the starting baseline examination 
and the day of the Week 4 examination (or the day of discontinuation) is defined as the 
assessment period.  The IMP will be administered to the treatment area from the day of 
the baseline examination twice daily for 4 weeks.  After the baseline examination, the 
examination will be performed at Weeks 1, 2, and 4. 
If a subject discontinues the IMP administration between the day of the baseline 
examination and the Week 4 examination, a withdrawal examination will be performed 
for that subject. 
(3) 
Post-treatment observation period 


 
 
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The period from completion of the Week 4 examination to the day of the examination 2 
weeks after the last IMP administration is defined as the post-treatment observation 
period.  Examinations will be performed at 2 weeks after the last IMP administration.  If 
any adverse event remained not recovered at the examination 2 weeks after the last IMP 
administration (or by the day of the last examination if the examination 2 weeks after the 
last IMP administration was not performed), it should be followed up according to the 
specifications. 
(4) 
Trial period 
The trial period for individual subjects is from the day of obtaining informed consent 
from the subject’s legal guardian to the day of trial discontinuation or completion and 
does not include the follow-up period. 
 
 
Screening period 
(2-30 days) 
Assessment period 
Twice daily administration 
(4 weeks) 
Post-treatment 
observation 
period  
(2 weeks) 
0.3% OPA-15406 group 
 
 
 
1% OPA-15406 group 
 
 
 
Vehicle group 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
:  Treatment period 
Figure 3.1-1 
Trial Design Schematic 
Screening examination 
Informed consent 
Start of IMP administration 
Baseline examination 
Week 4 examination 
Week 2 examination 
Week 1 examination 
Examination 2 weeks after the last 
IMP administration 


 
 
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3.2 
Methods of Administration 
3.2.1 
Dose, Regimen, and Treatment Period 
The 0.3% or 1% formulation or the vehicle of OPA-15406 ointment will be administered 
twice daily (approximately 12 hours apart between morning and night administration) for 
4 weeks.  The amount of IMP (g) per dose is calculated as follows. 
1) The subject’s BSA (m2) will be calculated based on height and body weight at the 
screening examination, using the following equation.   
 
 
BSA = body surface area;  
Ht = height; Wt = body weight   
                                      (Mosteller 1987)15  
 
2) The treatment area will be specified (see “3.2.2 Treatment Area”).   
3) The amount of IMP (g) per dose will be calculated as “subject’s BSA (m2)” × 
“treatment area (%)” × “10 g/m2.”   
Example:  In case of a BSA of 0.7 m2 and an affected BSA of 32%:  0.7 m2 × 
0.32 × 10 g/m2 = 2.24 g 
 
[Rationale for treatment period] 
The Guidelines for Management of Atopic Dermatitis specify that “Patients should be 
evaluated for treatment effects about once every 1 to 2 weeks, especially to maximize the 
drug effects and to minimize any adverse drug reaction, and if necessary, the drugs and 
treatment methods should be adjusted.  If no particular improvements are observed, or if 
any abnormal change is detected in the symptoms during about a month of remission 
induction therapy, referral of the patient to a more specialized institution may be 
considered.”4  In consideration of this standard AD treatment policy, the treatment period 
of this trial is established as 4 weeks.  In the phase 2 trial outside Japan (271-12-205), 
while no significant difference was observed the incidence of success in IGA (rate of 
subjects with an IGA score of 0 or 1 with an improvement by at least 2 grades) at Week 4, 
which was the primary efficacy endpoint between the 0.3% OPA-15406 group and the 
vehicle group (p = 0.0690, CMH test), the 1% OPA-15406 group showed a significantly 
higher incidence of success in IGA compared to the vehicle group (p = 0.0165, CMH 
test), and no particular concerns were raised over safety up to Week 8. 


 
 
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3.2.2 
Treatment Area 
The treatment area with the IMP is defined as follows.   
 The treatment area selected at baseline examination will be affected area determined 
at baseline examination (see “3.7.4.6 Affected BSA”). 
 After the baseline examination, when the affected area has expanded or a new 
affected area is detected, the expanded or newly affected area will also be included in 
the treatment area.   
 Even when the affected area is relieved, the IMP administration should be continued 
there as the treatment area.   
The investigator or subinvestigator will instruct the subject regarding the method of 
administration by specifying the treatment area (%) and the amount of administration (g) 
for each treatment area using the human body drawing (Appendix 4 for children aged 8 to 
14 years old and Appendix 5 for children aged 2 to 7 years old), and will give the human 
body drawing (copy) to the subject or the subject’s legal guardian.  The investigator or 
subinvestigator will record the treatment area (%) of the 4 body regions (face, neck, and 
head; upper limbs; trunk; and lower limbs) in the source document and case report form 
(CRF). 
The method of IMP administration is specified in the separate procedure for IMP 
administration. 
 
3.3 
Trial Population 
3.3.1 
Number of Subjects and Description of Population 
The target population of this trial is pediatric patients with AD with an IGA score of 2 
(mild) or 3 (moderate).  Subjects will be included in the trial to reach the target number of 
60 subjects for IMP administration (at least 8 subjects aged 2 to 6 years old).  Any 
withdrawals will not be supplemented. 
3.3.2 
Subject Selection and Numbering 
For the subjects whose legal guardians have provided informed consent, the investigator 
or subinvestigator will assign the subject identification code and subject number (3 digit 
number of site ID + S + 5 digit serial number starting from 00001). 
 


 
 
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3.4 
Eligibility Criteria 
3.4.1 
Informed Consent 
Freely given written informed consent will be obtained from the subjects’ legal guardians 
(guardians or legal representatives, as applicable by law) instead of the subjects.  If 
possible, assent (consent not bound by the legal restrictions obtained from pediatric 
subjects) will be obtained from the subjects participating in the trial.  A signed informed 
consent form will be retained as a document, and a signed assent form will also be 
retained as a document.  The explanatory document, informed consent form, and assent 
form will be approved by the same institutional review board (IRB) responsible for 
approval of this protocol. 
Each explanatory document and informed consent form should include the elements 
required by the International Conference on Harmonization (ICH) Guidelines for Good 
Clinical Practice (GCP)16 and local regulatory requirements. 
The investigator or subinvestigator may discuss the availability of the trial and the 
possibility for entry with a potential subject and subject’s legal guardian before obtaining 
consent.  However, written informed consent must be obtained from the subject’s legal 
guardian prior to the initiation of any procedures that are performed solely for the 
purpose of determining eligibility for this trial, including withdrawal from current 
medications. 
The potential subject and subject’s legal guardian can refuse to participate in or withdraw 
from the trial at any time without any justifiable reason.  The refusal or withdrawal by the 
potential subject and subject’s legal guardian will not affect any future treatments. 
Once the appropriate essential information and a full explanation in layman’s language 
appropriate for the potential subject’s age have been provided by the investigator or 
subinvestigator, the IRB-approved informed consent form will be personally signed and 
dated by the subject’s legal guardian and the person obtaining informed consent 
(investigator or subinvestigator).  When assent is also obtained from the subject, the 
assent form will be personally signed and dated by the subject (if possible) and the person 
obtaining informed consent (investigator or subinvestigator), in the same manner.  When 
a supplemental explanation is given by a clinical trial associate, the clinical trial associate 
will also sign and date the form.  The subject’s legal guardian will be given the 
explanatory document and copies of the signed informed consent form and assent form, 
and the originals will be kept by the investigator or subinvestigator. 


 
 
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If an amendment to the protocol substantially increases or alters the trial procedures, the 
subject’s legal guardian may be asked for an additional consent and to again sign the 
form. 
3.4.2 
Inclusion Criteria 
Subjects are required to meet the following inclusion criteria #1 through #5 in Table 
3.4.2-1 at the screening examination, and #6 and #7 at the screening examination and the 
baseline examination. 
Table 3.4.2-1 
Inclusion Criteria 
1 
Sex:  Either male or female 
2 
Hospitalization status:  Outpatient  
3 
Age: 2 to 14 years, inclusive (at time of obtaining informed consent)  
4 
Diagnosis of AD based on the criteria of Hanifin and Rajka1 (Appendix 1) 
5 
Subjects whose legal guardian is able to provide informed consent prior to 
participation in the trial 
6 
AD affecting ≥5% to ≤40% of BSA 
7 
IGA score of 2 (mild) or 3 (moderate) 
 
[Rationale for Inclusion Criteria] 
1) AD occurs in both males and females. 
2) Most patients to be included in this trial are outpatients. 
3) The objective of this study is to evaluate the safety and efficacy of the OPA-
15406 ointment in pediatric patients.  In consideration of the standard age 
classification in ICH-E11 and the package insert, children aged 2 to 14 years old 
are selected.  In the toxicity study in juvenile animals, suppressed weight increase 
and reductions in food intake and grip strength were observed in female rats with 
1% or 3% ointment.  However, these changes were not developmental toxicity 
specific to juvenile rats, and there was no difference in the toxicity threshold 
between adult and juvenile rats.  In the phase 1 trial in Japanese healthy adult 
subjects (271-14-001) and in the phase 2 trial in patients aged 10 years and older 
outside Japan (271-12-205), no particular safety concerns were raised. 
4) The criteria of Hanifin and Rajka have been most commonly used worldwide 
and have the same major diagnostic criteria as those of the Japanese 
Dermatological Association; therefore, the criteria can be used also in Japan 
without problems. 
5) In consideration of ethical issues concerning patients who are minors. 
6), 7)  To appropriately evaluate the efficacy of the IMP on the target disease. 
 
 


 
 
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3.4.3 
Exclusion Criteria 
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1 at the 
screening examination and the baseline examination. 
Table 3.4.3-1 
Exclusion Criteria 
1 
Subjects who have an AD or contact dermatitis flare-up defined as a sudden 
intensification of AD, within 28 days prior to the baseline examination 
2 
Subjects who have a concurrent or history of skin disease other than AD (eg, 
acne, psoriasis, Netherton’s syndrome, ichthyosis, graft versus host disease, etc) 
and who are judged inappropriate for assessment of AD in the present trial 
3 
Subjects who have an active viral skin infection (eg, herpes simplex, herpes 
zoster, chicken pox) or a clinical sign of any of these 
4 
Subjects who have a concurrent or history of malignancy 
5 
Subjects with a history of recurrent bacterial infection resulting in hospitalization 
or requiring intravenous antibiotic treatment 
6 
Subjects with a clinically significant complication or history of any of the 
following disorders that the investigator or subinvestigator judges would prevent 
safe conduct of the trial or impact efficacy assessments: 
 
 Cardiac disease (eg, rheumatic fever or heart valve replacement) 
 Endocrinologic disease (eg, severe or uncontrolled diabetes) 
 Pulmonary disease 
 Neurologic disease 
 Psychiatric disease 
 Hepatic disease (eg, hepatitis B, hepatitis C) 
 Renal disease 
 Hematologic disease 
 Immunologic or immunocompromised disease (eg, lymphoma, acquired 
immunodeficiency syndrome, Wiskott-Aldrich syndrome, carriers of human 
immunodeficiency virus [HIV] antibodies) 
 Other major disease (eg, systemic fungal infection) or other severe 
uncontrolled condition (eg, drug or alcohol abuse) judged by the investigator 
or subinvestigator to pose a health risk to the subject or to have the potential 
to impact trial assessment 
7 
Based on the laboratory test results at the screening examination, subjects for 
whom it is deemed by the investigator or subinvestigator that the trial cannot be 
conducted safely. 
8 
Subjects who are judged by the investigator or subinvestigator to have a 
clinically significant electrocardiogram (ECG) findings at the screening 
examination.  (For children aged 2 - 6 years old, a 12-lead ECG will be recorded, 


 
 
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Table 3.4.3-1 
Exclusion Criteria 
as much as possible.) 
9 
Subjects who are judged by the investigator or subinvestigator to have a 
clinically abnormal blood pressure or pulse rate at the screening examination 
10 
Subjects who are judged by the investigator or subinvestigator to be problematic 
in withdrawing blood 
11 
Subjects who are unable to stop using topical corticosteroids, topical 
immunomodulators, topical retinoids and topical antihistamine from 7 days prior 
to the baseline examination until the Week 4 examination.  Low or medium 
potency corticosteroids in the Guidelines for Management of Atopic Dermatitis2 
may be used until 4 days prior to the baseline examination in the judgment of the 
investigator or subinvestigator for the gradual decrease in the screening period 
before stopping.  
12 
Subjects who are unable to stop using systemic corticosteroids, systemic 
immunomodulators, systemic antimetabolites, systemic retinoids, and biologics 
from 28 days prior to the baseline examination until the Week 4 examination.  
Intra-ocular, intra-nasal and intra-auricular or inhaled corticosteroids may be 
considered if, in the opinion of the investigator or subinvestigator, their use will 
not impact assessment of the affected area.  
13 
Subjects who are unable to stop treatment with ultraviolet A , narrowband 
ultraviolet B, and ultraviolet B from 28 days prior to the baseline examination 
until the Week 4 examination 
14 
Subjects who are unable to continue in the trial without changing the dosage and 
administration of systemic antihistamines, sodium cromogicate, tranilast, or 
suplatast tosilate from 7 days prior to the baseline examination until the Week 4 
examination.  Intra-ocular, intra-nasal, or inhalant formulations may be 
considered if, in the opinion of the investigator or subinvestigator, their use will 
not impact the assessment of the affected area. 
15 
Subjects with known hypersensitivity (including history) to any drugs 
(prescription, OTC, etc) or any ingredient of OPA-15406 ointment (eg, white 
petrolatum, mineral oil, paraffin, white wax, or propylene carbonate) 
16 
Subjects with known plans to receive any of the prohibited concomitant drugs or 
therapies during the trial period 
17 
Subjects who have used any other investigational drug within 4 months prior to 
the baseline examination or who are scheduled to participate in any other clinical 
trial during the trial period 
18 
Subjects who have never been treated with a prescription medication for AD or 
who are satisfied with their current AD treatment regimen 
19 
Female subjects aged 7 to 14 years old who are pregnant or suspected of being 
pregnant, or who cannot agree to abstain from any actions that have the 
possibility of resulting in pregnancy 
20 
Subjects who are judged by the investigator or subinvestigator to be 
inappropriate to participate in the trial for any other reason 
 


 
 
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[Rationale for Exclusion Criteria] 
1), 11)-13) Due to a possible impact on the efficacy evaluation of the IMP. 
2), 6), and 16) Due to a possible impact on the safety and efficacy evaluation of the IMP. 
3)-5) In consideration of safety. 
7)-10) In consideration of safety. 
14) Due to a possible impact on the efficacy evaluation of the IMP and in consideration 
of safety. 
15) In consideration of safety. 
17) In reference to the “Criteria for Period to Avoid Participation in Clinical Studies” 
of the Japan Association of Contract Institutes for Clinical Pharmacology. 
18) To exclude patients who are not in need of treatment and to prevent 
registering patients who are satisfied with their current treatment, because trials have 
aspects of research. 
19) To prevent unknown consequences of the IMP in pregnant women, fetuses, or 
infants, and in consideration of safety. 
20)  To allow the investigator or subinvestigator to judge in consideration of other 
factors. 
 
3.5 
Endpoints 
3.5.1 
Primary Endpoint 
The number and percentage of subjects experiencing AEs  
[Rationale] 
To properly evaluate the safety of OPA-15406. 
3.5.2 
Secondary Endpoints 
IGA, Eczema Area and Severity Index (EASI), Visual Analogue Scale (VAS) for pruritus 
(only for patients aged 7 - 14 years old), Visual Rating Scale (VRS) for pruritus (only for 
patients aged 7 - 14 years old), Patient-Oriented Eczema Measure (POEM), and affected 
BSA 
[Rationale] 


 
 
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IGA is selected because it is one of the reliable indicators to assess the severity of AD 
symptoms and to determine the efficacy of IMP.  IGA is evaluated based on the severity 
of overall symptoms (eg, erythema, infiltration, papules, effusion, and scab formation) at 
administration sites and does not include other factors (eg, excoriation, lichenification, 
severity at each part, subjective symptoms, and affected BSA).  For this reason, EASI, 
VAS for pruritus, VRS for pruritus, POEM, and affected BSA are also established to 
evaluate the efficacy from multiple points of view. 
 
Plasma concentration of OPA-15406 (the trough concentration at Week 1 and Week 4) 
[Rationale] 
To determine the internal exposure to OPA-15406 in pediatric AD patients. 
 
3.6 
Measures to Minimize/Avoid Bias 
This trial is a randomized, double-blind trial.   
The IMP allocation manager will prepare a master “random allocation table” 
hereinafter, “randomization table”) and conduct IMP coding according to the operating 
procedures for randomization.  Also, the IMP allocation manager will prepare an 
emergency code list for use in emergencies such as the occurrence of a serious adverse 
event. 
The investigator, subinvestigator, and subjects are blind to the IMP randomization code.  
Except for some designated personnel, the sponsor’s trial staff, including the personnel of 
contract research organizations, are also unable to access the IMP randomization code 
during the trial period. 
Prior to the trial start and unblinding, the IMP allocation manager will confirm that the 
IMPs are indistinguishable.  The randomization table is sealed by the IMP allocation 
manager just after completion of IMP randomization and it is kept under strict control 
until unblinding after fixation of all CRFs and the database. 
The emergency code list will be kept under strict control by the registration system until 
the end of the trial.  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 the “5.7 Procedure for Breaking the Blind.” 


 
 
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When IMPs are recovered by the sponsor prior to unblinding, they are to be recovered 
sealed by the IMP manager.   
The subject will be allocated using the dynamic allocation method (minimization 
method).  Details will be specified in a separate specification prepared in advance. 
The results of drug concentration measurements will not be revealed until unblinding at 
the end of the trial. 
 
3.7 
Trial Procedures 
The schedule of assessments is shown in Table 3.7-1.  Items that clinical trial associates 
are capable of performing may be performed by the clinical trial associates under the 
supervision of the investigator. 
 


 
 
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Table 3.7-1 
Schedule of Assessments 
Assessment 
Screening period 
(2-30 days) 
Assessment period 
(4 weeks) 
Post-treatment 
observation 
period  
(2 weeks) 
Screening examination 
 
Baseline 
examination  
Week 1 
examinationa 
(± 2 days) 
Week 2 
examinationb 
(± 3 days) 
Week 4 
examinationb 
(± 3 days) 
Withdrawal 
examinationd 
Unscheduled 
visit 
Examination 
2 weeks after the 
last IMP 
administrationc 
(± 7 days) 
Informed consent 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
 
 
Subject demographics 
 
 
 
 
 
 
 
Physical findings 
 
 
 
 
 
  e 
 
Vital signs (including body weight) 
 
 
 
 
 
  e 
 
12-lead ECGf 
 
 
 
 
 
  e 
 
Clinical laboratory tests 
 
 
 
 
 
  e 
 
Pregnancy testg 
 
 
 
 
 
  e 
 
IGA 
 
 
 
 
 
 
 
EASI 
 
 
 
 
 
 
 
VAS for pruritush 
 
 
 
 
 
 
 
VRS for pruritush 
 
 i 
 
 
 
 
 
POEM 
 
 
 
 
 
 
 
Affected BSA 
 
 
 
 
 
 
 
Treatment area 
 
 
 
 
 
 
 
Blood sampling for plasma drug 
concentration measurement 
 
 
 j 
 
  k 
 
 
Administration diary 
 
 l 
 
 
 
 
 
Severity of AD 
 
 
 
 
 
 
 
Status of IMP Administration  
 
 
 
 
 
 
 
Prescription and return of IMP  
 
  m 
  n 
 
  o 
  n 
 
IMP administration 
 
 p 
 
 
 


 
 
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Table 3.7-1 
Schedule of Assessments, Continued 
Assessment 
Screening period 
(2-30 days) 
Assessment period 
(4 weeks) 
Post-treatment 
observation 
period  
(2 weeks) 
Screening examination 
 
Baseline 
examination  
Week 1 
examinationa 
(± 2 days) 
Week 2 
examinationb 
(± 3 days) 
Week 4 
examinationb 
(± 3 days) 
Withdrawal 
examinationd 
Unscheduled 
visit 
Examination 
2 weeks after the 
last IMP 
administrationc 
(± 7 days) 
Adverse events 
 
Concomitant medications and therapies  
                                                                                            
 
Patch testq 
 
 
IGA = Investigator’s Global Assessment; EASI = Eczema Area and Severity Index; VAS = Visual Analogue Scale; VRS = Verbal Rating Scale; POEM = Patient-Oriented 
Eczema Measure 
aAllowable window of ± 2 days 
bAllowable window of ± 3 days 
cAllowable window of ± 7 days 
dWithdrawal examination should be conducted, as much as possible.  
eThe evaluations can be conducted, as necessary.  
fFor children aged 2-6 years old, should be conducted as much as possible.  If possible, it will be conducted prior to blood sampling.  
gOnly for female children aged 7 to 14 years old.  
hOnly for children aged 7 to 14 years old.  
iShould be evaluated during the baseline examination, 4 ± 2 hours, 8 ± 2 hours (if possible), and 12 ± 2 hours (if possible) after the first IMP administration, and then twice 
daily from the next day (before IMP administration in the morning and at night) until the morning of the Week 1 examination (without IMP administration) (up to the 
morning of Day 7 at the latest).  
jOn the day of blood sampling, the first IMP application should be after blood sampling at the trial site.  
kOn the day of examination, the IMP should not be applied.  
lSubjects should keep a diary every day from the baseline examination to the Week 4 examination (withdrawal examination).  
mOnly IMP prescription 
nIMP will be additionally prescribed, as necessary.  
oOnly IMP collection 
pAfter completing all evaluations on the day of the baseline examination, IMP administration will be started at the trial site, and date and time of the application will be 
recorded.  
qIf any adverse event of suspected hypersensitivity occurred at the treatment area, verbal consent should be obtained again from the subject to conduct a patch test, and the 
patch test should be conducted according to the procedure. 
 


 
 
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3.7.1 
Schedule of Assessments 
3.7.1.1 
Screening Examination (From the Day of Obtaining Informed 
Consent to 2 Days Prior to the Baseline Examination) 
After acquisition of written informed consent from the subject’s legal guardian, the 
investigator or subinvestigator will assign a subject identification code and subject 
number (3 digit number of site ID + S + 5 digit serial number starting from 00001). 
The investigator or subinvestigator will perform the following examinations, observations, 
and evaluations and select subjects who meet the inclusion criteria and do not meet any 
of the exclusion criteria. 
 Subject demographics 
 Physical examination 
 Vital signs (including body weight) 
 12-lead ECG (For children aged 2 - 6 years old, as much as possible.  If possible, it 
will be conducted prior to blood sampling.) 
 Clinical laboratory tests 
 Pregnancy test (only for female children aged 7 - 14 years old) 
 IGA 
 Affected BSA 
 Adverse events 
 Concomitant medications and therapies  
 
The investigator or subinvestigator will record the results of the eligibility of subjects on 
the list of screened subjects and the list of enrolled subjects. 
3.7.1.1.1 
Subject Demographics 
The investigator or subinvestigator will assess or measure the following items and record 
them in the source document and CRF. 
 Date of informed consent 
 Sex 
 Date of birth 
 Height (Measured as an integer value in unit of centimeter.  When it is measurable to 
one decimal place, the value is rounded to an integer value.) 
 Complications 
 Date of onset of AD  
 Medical history (within 6 months prior to the date of informed consent) 


 
 
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 In- or outpatient status (outpatient) 
 Subject number 
 Country where the trial is conducted (Japan) 
 Race  
 Ethnicity  
 Possibility of pregnancy 
 
3.7.1.2 
Subject Registration 
The investigator or subinvestigator will register all subjects in the Interactive Web 
Response System (IWRS).  
3.7.1.3 
Baseline Examination (2 - 30 Days After the Screening 
Examination) 
The investigator or subinvestigator will perform the following examinations, observations, 
and evaluations, and record the results in the source document and CRF. 
 Physical examination 
 Vital signs (including body weight) 
 IGA 
 EASI 
 VAS for pruritus (only for 7 - 14 years of age) 
 VRS for pruritus (only for 7 - 14 years of age) 
 POEM 
 Affected BSA 
 Severity of AD 
 Adverse events 
 Concomitant medications and therapies  
 
For the clinical laboratory tests and 12-lead ECG, the results of the baseline examination 
will be used as data for the screening examination.  The investigator or subinvestigator 
will select subjects who meet the inclusion criteria and do not meet any of the exclusion 
criteria based on results of the screening and baseline examinations.  Also, the 
investigator or subinvestigator will record the results of the subjects’ eligibility on the list 
of screened subjects and the list of enrolled subjects. 


 
 
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3.7.1.4 
Allocation of Investigational Medicinal Products to Subjects 
The investigator or subinvestigator will enter the necessary information for subject’s 
eligibility in the IWRS.  On the day of the baseline examination, the subjects 
confirmed to be registered in the IWRS will be allocated to the 0.3% OPA-15406 group, 
the 1% OPA-15406 group, or the vehicle group.  The investigator or subinvestigator will 
confirm the allocation result and the drug code of IMP to be prescribed for 2 weeks on 
the IWRS screen displaying the registration result and prescribe the IMP.  The weight of 
the dispensed IMP will be measured (to one decimal place in unit of gram).  (Hereinafter, 
when the weight of IMP is measured, it will be measured to one decimal place in the 
same manner.)  After completion of all evaluations on the day of baseline examination, 
the first application of IMP will be given at the trial site, and date and time of the 
application will be recorded.  The subjects will be instructed to visit the trial site without 
morning IMP administration on the day of the next visit. 
3.7.1.5 
Between the Day of Baseline Examination and the Day of Week 1 
Examination 
The investigator or subinvestigator will instruct the subject to evaluate the following item 
at 4 ± 2 hours, 8 ± 2 hours (if possible), 12 ± 2 hours (if possible) after the first IMP 
administration on the day of baseline examination, and then twice daily from the next day 
(before IMP administration in the morning and at night) up to the morning of Week 1 
examination (before administration) (up to the morning of Day 7 at the latest).  
 VRS for pruritus (only for 7 - 14 years of age) 
 
3.7.1.6 
Week 1 Examination (±2 Days) 
The investigator or subinvestigator will perform the following examinations, observations, 
and evaluations and record the results in the source document and CRF. 
 Physical examination 
 Vital signs (including body weight) 
 IGA 
 EASI 
 VAS for pruritus (only for 7 - 14 years of age) 
 POEM 
 Affected BSA 
 Blood sampling for plasma drug concentration measurement 
 Adverse events 


 
 
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 Concomitant medications and therapies  
 Status of IMP Administration  
 
The investigator or subinvestigator will determine the treatment area (%) and enter it in 
the IWRS.  Also, the investigator or subinvestigator will confirm the subject’s allocation 
status on the IWRS screen and, if necessary, prescribe additional IMP.  When the IMP is 
additionally prescribed, the weight of the dispensed IMP will be measured. 
3.7.1.7 
Week 2 Examination (±3 Days) 
The investigator or subinvestigator will perform the following examinations, observations, 
and evaluations and record the results in the source document and CRF. 
 Physical examination 
 Vital signs (including body weight) 
 IGA 
 EASI 
 VAS for pruritus (only for 7 - 14 years of age) 
 POEM 
 Affected BSA 
 Adverse events 
 Concomitant medications and therapies  
 Status of IMP Administration  
 
The investigator or subinvestigator will collect the IMP and measure the weight of the 
collected IMP.  The investigator or subinvestigator will determine the treatment area (%) 
and enter it in the IWRS.  The investigator or subinvestigator will confirm the amount of 
IMP to be prescribed for the next 2 weeks and prescribe it.  The weight of the dispensed 
IMP will be measured.  The subjects will be instructed to visit the trial site without 
morning IMP administration on the day of the next visit. 
3.7.1.8 
Week 4 Examination (±3 Days) or Withdrawal Examination 
The investigator or subinvestigator will perform the following examinations, observations, 
and evaluations and record the results in the source document and CRF. 
 Physical examination 
 Vital signs (including body weight) 
 12-lead ECG (For children aged 2 - 6 years old, as much as possible.  If possible, it 
will be conducted prior to blood sampling.) 


 
 
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 Clinical laboratory tests 
 Pregnancy test (only for female children aged 7 - 14 years old) 
 IGA 
 EASI 
 VAS for pruritus (only for 7 - 14 years of age) 
 POEM 
 Affected BSA 
 Blood sampling for plasma drug concentration measurement 
 Adverse events 
 Concomitant medications and therapies  
 Status of IMP Administration  
 
The investigator or subinvestigator will collect the IMP and measure the weight of the 
collected IMP. 
3.7.1.9 
Examination 2 Weeks After Last IMP Administration (±7 Days) 
The investigator or subinvestigator will perform the following examinations, observations, 
and evaluations and record the results in the source document and CRF. 
 Physical examination 
 Adverse events 
 
3.7.1.10 
Unscheduled Visits 
The investigator or subinvestigator will instruct the subjects to visit the trial site if the 
area of affected BSA markedly enlarges.  The investigator or subinvestigator will 
perform the following examinations, observations, and evaluations and record the results 
in the source document and CRF.   
 Affected BSA  
 Adverse events 
 Concomitant medications and therapies 
 
The followings can be evaluated, as necessary. 
 Physical examination 
 Vital signs (including body weight) 
 12-lead ECG  
 Clinical laboratory tests 


 
 
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 Pregnancy test 
 
The investigator or subinvestigator will determine the treatment area (%) and enter it in 
the IWRS.  Also, the investigator or subinvestigator will confirm the subject’s allocation 
status on the IWRS screen and, if necessary, prescribe additional IMP.  When the IMP is 
additionally prescribed, the weight of dispensed IMP will be measured. 
3.7.2 
Status of IMP Administration 
Details of the administration diary will be recorded in the CRF.  If the frequency of 
compliance with IMP administration is less than 80%, the status of IMP administration is 
judged as poor.  The investigator and subinvestigator will confirm the status of IMP 
administration based on records in the administration diary and instruct the subjects, as 
necessary. 
3.7.3 
Severity 
The investigator or subinvestigator will determine the severity7 (mild, moderate, severe, 
or very severe) and record the result in the source document and CRF.   
Definition 
Severity 
Just mild skin eruption regardless of the area 
Mild 
Skin eruption with severe inflammation on <10% of the BSA 
Moderate 
Skin eruption with severe inflammation on ≥10% to <30% of the BSA 
Severe 
Skin eruption with severe inflammation on ≥30% of the BSA  
Very severe 
Mild skin eruption:  lesions mainly consisting of mild erythema, dryness, or desquamation  
Skin eruption with severe inflammation: lesions consisting of erythema, papules, erosion, infiltration, or 
lichenification 
 
3.7.4 
Efficacy Assessments 
3.7.4.1 
Investigator’s Global Assessment (IGA) 
The investigator or subinvestigator will assess the skin symptoms using IGA.17  The 
investigator or subinvestigator will score the severity (0 = clear, 1 = almost clear, 2 = 
mild, 3 = moderate, 4 = severe/very severe) of the overall symptoms of the treatment 
area (erythema, infiltration, papules, effusion, and scab formation).  The result will be 
recorded in the source document and CRF.  The same subject will be evaluated by the 
same physician, as much as possible. 
Symptom 
Severity score 
No inflammatory signs of AD 
0 = Clear  
Just perceptible erythema and just perceptible papulation/infiltration 
1 = Almost clear  
Mild erythema and mild papulation/infiltration 
2 = Mild 


 
 
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Symptom 
Severity score 
Moderate erythema and moderate papulation/infiltration 
3 = Moderate  
Severe erythema and severe papulation/infiltration with oozing/crusting 
4 = Severe/very severe  
 
3.7.4.2 
Eczema Area and Severity Index (EASI) 
The investigator or subinvestigator will assess the skin symptoms using EASI.18  The 
investigator or subinvestigator will score the severity (0-3 points) and affected BSA (%) 
based on the 4 symptoms (erythema, infiltration/papules, excoriation, and lichenification) 
on the 4 body regions (face, neck, and head; upper limbs; trunk; and lower limbs) and 
record the results in the source document and CRF.  As shown in the table below, the 
score of each region will be calculated and totalized.  The maximum EASI score is 72 
points.  The same subject will be evaluated by the same physician, as much as possible.   
Body region 
Calculation of the score for each region  
Face, neck, and 
head  
(E＋I＋Ex＋L) × score of affected BSA ×0.1 (×0.2 for children aged 2-7 years old) 
Upper limbs 
(E＋I＋Ex＋L) × score of affected BSA ×0.2 
Trunk 
(E＋I＋Ex＋L) × score of affected BSA ×0.3 
Lower limbs 
(E＋I＋Ex＋L) × score of affected BSA ×0.4 (×0.3 for children aged 2-7 years old ) 
E = severity score of erythema; I = severity score of infiltration/papules; Ex = severity score of excoriation; 
L = severity score of lichenification  
Severity score:  clear = 0; slight = 0.5; mild = 1; mild-moderate = 1.5; moderate = 2; severe = 2.5; very 
severe = 3 
Score of affected BSA (for each region):  clear = 0; 1% to 9% = 1; 10% to 29% = 2; 30% to 49% = 3; 50% 
to 69% = 4; 70% to 89% = 5; 90% to 100% = 6 
 
3.7.4.3 
Visual Analogue Scale (VAS) for Pruritus 
The investigator or subinvestigator will evaluate the level of pruritus based on VAS.19 
The subjects aged 7 to 14 years old will mark the point of pruritus intensity during the 
last 24 hours on the line of a 100-mm VAS sheet (Appendix 2) between the left end (no 
pruritus) and the right end (very severe pruritus).  The investigator or subinvestigator will 
record the length from the left end to the mark (integer value with mm as unit) in the 
medical record and CRF.  The VAS sheet will be kept as the source document.  For 
subjects aged 2 to 6 years, this will not be evaluated. 
3.7.4.4 
Verbal Rating Scale (VRS) for Pruritus  
The investigator or subinvestigator will evaluate the pruritus intensity based on VRS.19  
The subjects aged 7 to 14 years old will evaluate the pruritus intensity according to the 
following criteria.  The subjects will record the level of pruritus and the time and date of 
evaluation in a pruritus diary.   


 
 
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0:  None 
1:  Mild  
2:  Moderate  
3:  Severe  
The investigator or subinvestigator will record details of the pruritus diary in the CRF.  
The pruritus diary will be kept as the source document.  For subjects aged 2 to 6 years, 
this will not be evaluated. 
3.7.4.5 
Patient-Oriented Eczema Measure (POEM) 
The investigator or subinvestigator will evaluate eczema according to the POEM 
(Appendix 3).20  The subjects will answer 7 questions about their eczema.  If it is difficult 
for subjects to answer the questions, their parents will answer them instead.  The 
investigator or subinvestigator will record the results in the source document and CRF.  
The total score of POEM is 28 points at the most. 
3.7.4.6 
Affected BSA 
The investigator or subinvestigator will draw the affected BSA (range of skin eruption at 
the time of examination) on the human body drawing (Appendix 4 for subjects aged 8 to 
14 years old, or Appendix 5 for subjects aged 2 to 7 years old) to determine the affected 
areas (%) on the respective 4 body regions (face, neck, and head; upper limbs; trunk; and 
lower limbs).  The respective affected areas (%) will be recorded in the source document 
and CRF.  One palm of the subject corresponds to 1% BSA. 
3.7.5 
Safety Assessments 
3.7.5.1 
Adverse Events 
Refer to “5 Reporting of Adverse Events. ”  
3.7.5.2 
Clinical Laboratory Tests 
The investigator or subinvestigator will perform clinical laboratory tests for the following 
items.  Date of blood and urine sampling will be recorded on the source document and 
CRF.  
 Hematology:  differential white blood cell count (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils), white blood cell count, red blood cell count, 
hemoglobin, hematocrit, platelets 


 
 
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 Serum chemistry:  total cholesterol, total protein, albumin, blood urea nitrogen, 
creatinine, total bilirubin, AST (GOT), ALT (GPT), gamma glutamyl transpeptidase, 
lactic dehydrogenase, alkaline phosphatase, serum electrolytes (Ca, Na, K, Cl) 
 Qualitative urinalysis:  glucose, protein 
 
The tests will be performed at the central laboratory.  The investigator or subinvestigator 
will confirm the test results from the central laboratory, put the date and his or her printed 
name and personal seal or signature on the report from the clinical laboratory, and retain 
it for each subject as the source document.  The central laboratory will send the test 
results to the sponsor (in the form of electronic data). 
The total blood volume to be drawn for the clinical laboratory tests is about 10 mL during 
the trial period (about 5 mL each for the screening examination and for the Week 4 
examination). 
For female children aged 7 to 14 years old, a pregnancy test will be performed, and the 
result must be obtained prior to the IMP administration. 
3.7.5.3 
Physical Examination 
The investigator or subinvestigator will assess the subject’s physical condition by 
interview, visual examination, auscultation, or palpation. 
3.7.5.4 
Vital Signs (Including Body Weight) 
After the subject has rested for 3 minutes or more in principle, body temperature 
(measured by 0.1°C in the armpit), blood pressure (systolic/diastolic), pulse rate, and 
body weight (measured to one decimal place in unit of kilogram) will be measured, and 
the results of measurement will be recorded in the source document and CRF. 
3.7.5.5 
12-Lead ECG 
After the subject has rested for 10 minutes or more in a supine position, 12-lead ECG will 
be recorded prior to blood sampling, as much as possible.  Also, for subjects aged 2 to 6 
years old, it will be conducted before blood sampling, if possible.  For the ECG 
measurement, heart rate, RR interval, PR interval, QRS interval, QT interval, and QTc 
interval will be measured, using a 12-lead electrocardiograph obtained from the central 
ECG reading facility.  The measurement results will be analyzed at the central ECG 
reading facility.  The investigator or subinvestigator will confirm the “12-lead 
ECG analysis report” from the central ECG reading facility, assess whether the ECG 
results are normal or abnormal, and record the time and date of the measurement, 
assessment result, and findings in the source document and CRF.  Then, the investigator 


 
 
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or subinvestigator will put the confirmation date and his or her printed name and personal 
seal or signature on the “12-lead ECG analysis report” from the central ECG reading 
facility and retain it for each subject as the source document.  
If IMP randomization is necessary before the results from the central ECG reading 
facility are available, the automated analysis results of the 12-lead electrocardiograph at 
baseline (same as the ECG data to be sent to the central ECG reading facility) may be 
used for judgment of subject’s eligibility.  In that case, the investigator or subinvestigator 
will put the confirmation date and his or her printed name, and personal seal or signature 
on the automated analysis results of the 12-lead electrocardiograph and retain it as the 
source document. 
The central ECG reading facility will send the 12-lead ECG analysis results (in electronic 
data format) to the sponsor. 
3.7.5.6 
Other Safety Assessments 
Other safety assessments than the above have not been established. 
3.7.6 
Pharmacokinetic Assessments 
The plasma concentration of OPA-15406 will be measured.  For the vehicle group, it will 
not be measured.  On the day of measurement, the subjects will visit the trial site without 
morning IMP administration. 
3.7.6.1 
Blood Sampling Timepoints and the Rationale 
Trough concentration at Week 1 and Week 4 
It has been expected that AD patients with inflammation and a reduced skin barrier 
function will have higher absorption of the applied OPA-15406 through the skin into the 
blood than in those with healthy skin.  Therefore, it is necessary to assess the internal 
exposure to OPA-15406 in pediatric AD patients.  Assuming that skin inflammation 
improves during the course of IMP administration in relation to the number of days 
elapsed from the start of IMP administration, it is considered appropriate to determine the 
plasma OPA-15406 concentration at Week 1 when the subjects are expected to be 
exposed to OPA-15406 at the highest level during the trial observation period and at 
Week 4 to confirm the long-term exposure.  In the phase 1 trial of OPA-15406 in healthy 
subjects (271-14-001), the plasma OPA-15406 concentrations reached an almost steady 
state on Day 7 after multiple administrations of OPA-15406. 


 
 
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3.7.6.2 
Methods of Blood Sampling and Processing 
Sufficient caution should be taken for the parts of sterilization and site of blood sampling 
to avoid the blood samples from contamination with any IMP remnant on the skin surface.  
Approximately 2 mL of blood will be collected per dose from arm vein using vacuum 
blood collection tube (with heparin Na contained) and sufficiently mixed.  The sample 
will be mixed by inversion and cooled in ice-water.  Within 30 minutes of collection, the 
sample will be centrifuged at approximately 3000 rpm for 10 minutes.  Then, the plasma 
will be promptly transferred to a polypropylene tube and stored frozen at –15°C or less.  
When a refrigerated centrifuge is available, the sample will be centrifuged at 4°C.  For 
each subject, the time and date of the latest IMP administration and blood sampling will 
be recorded on the source document and CRF. 
The total blood volume to be drawn for the pharmacokinetic evaluation is about 4 mL 
during the trial period (2 mL each at the Week 1 examination and the Week 4 
examination). 
3.7.6.3 
Sending Plasma Samples 
The contract research organization for clinical laboratory tests will send the frozen 
samples packed in dry ice to the bioanalytical laboratory. 
The plasma concentration of OPA-15406 will be determined at the bioanalytical 
laboratory by using the liquid chromatography with tandem mass spectrometry.  
The bioanalytical laboratory will measure samples of the OPA-15406 group according to 
the randomization table.  Residual plasma samples after measurement will be stored at 
−70°C or less by the bioanalytical laboratory until the sponsor allows their disposal.  The 
sponsor will report the completion of measurement to the bioanalytical laboratory.  The 
bioanalytical laboratory will submit the report on results of drug concentration 
measurement (copy) and the measurement results (electronic data) to the sponsor. 
3.7.7 
End of Trial 
The “End of Trial” is defined as the Completion or Discontinuation Date entered in the 
Completion Status Form of the CRF for the last subject completing or withdrawing from 
the trial. 
 


 
 
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3.8 
Stopping Rules, Withdrawal Criteria, and Procedures 
3.8.1 
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 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. 
 
3.8.2 
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 is 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. 
 
3.8.3 
Individual Subject Discontinuation 
Any subject may discontinue participation in the trial at any time without any 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. 
3.8.3.1 
Treatment Discontinuation 
After the start of IMP administration, the investigator or subinvestigator may discontinue 
IMP administration for many reasons.  These reasons for discontinuation include a 
request from the subject who is not satisfied with IMP administration or  occurrence of an 
adverse event, a condition requiring medication(s) or treatment(s) that has not been 
permitted, or some other condition that requires treatment to be discontinued at the 
discretion of the investigator or subinvestigator.  Under all circumstances, each 


 
 
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investigator or subinvestigator must confirm details of such circumstances and provides 
the subject with all possible choices to continue with the IMP administration according to 
“3.8.3.4 Procedures to Encourage Continued Trial Participation.” 
In any of the events listed below, the investigator or subinvestigator will discontinue IMP 
administration, perform the tests to be performed at withdrawal stipulated and promptly 
inform the sponsor of the withdrawal.  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 
adverse event or aggravation of an underlying disease, the investigator or subinvestigator 
will promptly take appropriate measures and perform follow-up if necessary. 
1) Request from the subject or subject’s legal guardian to discontinue participation in 
the trial 
2) Discovery that the subject was included in the trial despite violation of the 
inclusion or exclusion criteria 
3) Occurrence of any adverse event that makes it difficult for the subject to continue 
administration of IMP (including a suspected treatment-related adverse event of 
skin hypersensitivity on the treatment area) 
4) Increase in the total treatment area to more than 40% of BSA 
5) Discovery that the subject is pregnant or suspected to be pregnant 
6) Judgment by the investigator or subinvestigator that it is necessary to withdraw 
the subject from the trial 
 
3.8.3.2 
Documenting Reasons for Treatment Discontinuation 
The subjects may discontinue IMP administration due to the reasons shown below. 
 Reasons related to adverse events:   
 Request from the subject due to distress or discomfort associated with a non-
serious adverse event that does not place the subject at excessive risk in normal 
cases  
 Decision by the investigator or subinvestigator that continuing with IMP 
administration places the subject at excessive risk (eg, cases with IMP-related 
safety concerns, including hypersensitivity at the administration site) 
 Serious adverse event (SAE) 
 Other safety concerns or adverse events possibly related to IMP 
 Death 
 Reasons not related to medical conditions (the details will be documented, and the 
history of adverse events for the subject will be confirmed.) 


 
 
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 Withdrawal of consent (complete documented withdrawal of consent) 
 Lost to follow-up  
 Pregnancy (see “5.6 Pregnancy”) 
 Entire or partial discontinuation of the trial by the sponsor 
 
If the subject discontinued the IMP administration due to an adverse event, the 
investigator, subinvestigator, or other clinical trial associates will follow the adverse 
event until it resolves or stabilizes, as much as possible, according to the procedures 
specified in “3.8.3.1 Treatment Discontinuation.” 
3.8.3.3 
Withdrawal of Consent 
All subjects and subjects’ legal guardians have the right to withdraw their consent of trial 
participation at any time without any disadvantages.  The subjects and the subjects’ legal 
guardians can only withdraw their consent for future trial participation, but they cannot 
withdraw consent for the use of data that has already been collected as part of the trial.  
The investigator or subinvestigator can also discontinue a subject’s participation in the 
trial at any time if medically necessary.  Unless the subject’s legal guardian withdraws 
consent in written form, or unless the investigator or subinvestigator prepares a document 
which confirms the verbal consent for complete withdrawal from the trial by the subject 
or subject’s legal guardian, the subject will undergo as many of the evaluations specified 
in the protocol as possible. 
Complete withdrawal of consent means that the subject or the subject’s legal guardian 
refuses all of the following follow-up procedures.   
 All follow-up procedures specified in the protocol (in any form such as the subject 
visiting the trial site, by telephone, or visiting the subject’s home) 
 Part of the follow-up procedures specified in the protocol (among part of the follow-
up procedures refused by the subject or the subject’s legal guardian, those agreed 
between the subject’s legal guardian and the clinical trial associate) 
 Contact with the subject or the subject’s legal guardian by the clinical trial associate 
to assess the subject’s current condition or to obtain the necessary medical or 
laboratory information related to the trial objectives (including contact by phone 
alone) 
 Contact with persons other than the subject who can be determined by the source 
document and can also talk about the subject’s condition (eg, family members, legally 
acceptable representatives, friends, neighbors, and physicians) (including contact only 
by phone, mail, or e-mail) 
 Access to other medical information sources (eg, medical records of other hospitals or 
clinics, notes of a physician from whom the subject was referred, public records, 


 
 
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information on registration to dialysis, transplants, population dynamics, or social 
media)  
 
Withdrawal of consent is a significant event for these trials.  Therefore, care should be 
taken regarding the procedures in the same manner as when obtaining the initial informed 
consent.  To ensure the subjects’ rights and the integrity of the trial, the reasons for 
consent withdrawal by the subject and the subject’s legal guardian should be completely 
understood, documented, and managed.  The subject and the subject’s legal guardian may 
at first ask for an interruption or to withdraw from IMP administration.  This request does 
not equal the will of complete withdrawal of consent for continued participation in the 
trial, but it may indicate that the subject and the subject’s legal guardian have felt some 
burden of continued participation in the trial regarding their work or social activities.  
Therefore, in reference to “3.8.3.2 Documenting Reasons for Treatment Discontinuation,” 
the investigator or subinvestigator will confirm the reasons for withdrawal from IMP 
administration and determine whether continued participation in the trial is possible by 
adjusting the schedule of administration or evaluations.  Complete withdrawal of consent 
for trial participation is established only for those subjects and subjects’ legal guardians 
who have refused all of the above follow-up procedures. 
3.8.3.4 
Procedures to Encourage Continued Trial Participation 
If discontinuation of IMP administration or withdrawal of consent is expected, the 
investigator or subinvestigator will discuss with the subject and the subject’s legal 
guardian about the possible options for them to continue participating in the trial.  With 
full respect for the subjects’ rights, the investigator or subinvestigator will take 
appropriate steps to confirm the reason(s) for withdrawal of consent.  When the reason(s) 
has been confirmed, it will be documented. 
 
3.9 
Screen Failures 
A screen failure subject is a subject from whom consent for trial participation has been 
obtained and whose legal guardian signed the informed consent form, but to whom an 
IMP was not allocated on the day of the baseline examination. 
If a subject is a screen failure, the following information should be recorded in the source 
document and CRF for screen failure subjects. 


 
 
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Subject number, date of screening examination, date of informed consent, date of birth, 
sex, reason for screen failure, country where the trial was conducted (Japan), race, 
ethnicity, possibility of pregnancy 
 
3.10 
Definition of Completed Subjects 
The treatment period is defined as the time period during which subjects are evaluated for 
primary, secondary, and/or exploratory endpoints, irrespective of whether the subject 
actually administered all doses of IMP.  Subjects who are evaluated at the last scheduled 
visit during the treatment period will be defined as completed subjects.  Based on the trial 
objectives, subjects who complete the examinations at Week 4 and 2 weeks after the last 
IMP administration are defined as completed subjects. 
 
3.11 
Follow-up of Subjects who Have Stopped Visiting the Trial Site 
If a subject has stopped visiting the trial site for an unknown reason, the investigator or 
subinvestigator will promptly contact (by telephone, etc.) the subject or relevant party 
such as family members to confirm any adverse events and encourage the subject to visit 
the trial site.  If the subject does not visit the trial site, the follow-up result will be 
recorded for the following items: 
1) Date of follow-up 
2) Method of follow-up 
3) Whether or not the subject has been contacted 
4) Reason why the subject has not (or has not been able to) visited the site 
5) Details on status of IMP administration 
6) Whether or not an adverse event(s) has occurred: if yes, the name of adverse 
event(s), dates of onset/recovery, severity, relationship with IMP, measures taken 
for IMP administration, treatment for the adverse event(s), and outcome 
7) If lost to follow-up, the reason why 
 
3.12 
Definition of Subjects Lost to Follow-up 
Subjects who cannot be contacted on and before the examination 2 weeks after the last 
IMP administration during the treatment period, and subjects whose survival is unknown 
on the trial completion day will be classified as lost to follow-up as the reason for 
discontinuation.  The subject’s survival can be judged by various information sources by 


 
 
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obtaining the proper documents which indicate death (ie, death certificate, medical record, 
public record, or statement by a family member or their doctor in charge) or those which 
indicate survival (ie, meeting record with the subject, medical record, contact record with 
the subject by phone, statement by a family member or their doctor in charge, or public 
record). 
If the subject cannot be contacted even after calling 3 times (the phone calls should be 
documented), the investigator, subinvestigator, or designated person will try to get in 
contact with the subject by sending a letter via registered mail or by other substitute 
methods.  If these efforts are not successful, the subject is judged as “lost to follow-up.”   
 
3.13 
Subject and Subject’s Legal Guardian Compliance 
 To avoid using drugs that are not permitted by the investigator or subinvestigator. 
 To thoroughly understand the details of the administration guidance and follow it. 
 To keep an administration diary every day.   
 Subjects aged 7 to 14 years old should keep a pruritus diary until the morning of the 
Week 1 examination (Day 7 at the latest). 
 When bathing or taking a shower, to administer the IMP afterwards.   
 To visit the trial site on the specified visit days during the trial period.   
 To visit the trial site without morning IMP administration on the day of drug 
concentration measurement.   
 To bring the IMP, administration diary, and pruritus diary as instructed.   
 To avoid excessive exercises, getting a suntan, and excessive drinking and eating 
and to keep regular hours to prevent possible effects on safety.   
 Information obtained during participation in this trial must not be disclosed to any 
third party. 
 
3.14 
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 


 
 
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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. 
 
4 
Restrictions 
4.1 
Prohibited Concomitant Drugs and Therapies 
1) From 28 days prior to the baseline examination until the Week 4 examination, use 
of the following drugs and therapies is prohibited 
 Systemic corticosteroids, systemic immunomodulators, systemic 
antimetabolites, systemic retinoids, biologics  
Intra-ocular, intra-nasal, intra-auricular or inhaled corticosteroids may be 
considered if, in the opinion of the investigator or subinvestigator, their use 
will not impact evaluations of the affected area. 
 Ultraviolet light A, narrowband ultraviolet B, ultraviolet light B 
2) From 7 days prior to the baseline examination until the Week 4 examination, use 
of the following drugs and therapies is prohibited. 
 Topical corticosteroids, topical immunomodulators, topical retinoids, and 
topical antihistamine.   
Low or medium potency corticosteroids in the Guidelines for Management of 
Atopic Dermatitis2 may be used until 4 days prior to the baseline examination 
in the judgment of the investigator or subinvestigator for the gradual decrease 
in the screening period before stopping  
3) From 7 days prior to baseline examination until the Week 4 examination, change 
in the dose and frequency of use for the following drugs is prohibited. 
 Systemic antihistamines, sodium cromoglicate, tranilast, suplatast tosilate 
Intra-ocular, intra-nasal, or inhalant formulations may be considered if, in the 
opinion of the investigator or subinvestigator, their use will not impact 
evaluations of the affected area. 
4) From the baseline examination until the Week 4 examination, use of the following 
drugs and products on the treatment area is prohibited. 
 All topical drugs (including ethical drugs, over-the-counter products, herbal 
medicine, quasi-drugs, and cosmetic products) 
Continuous use of cosmetics used in the face, neck, and head area if any had 
been used before obtaining informed consent is permitted unless the type of 
cosmetics and frequency of use are maintained the same. 
 
All other drugs and therapies not specified in the prohibited concomitant drugs and 
therapies are allowed to be used; however, any regimen or dose change or use of a new 
drug or therapy should be avoided as much as possible between the screening 


 
 
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examination and the Week 4 examination.  If any drug other than the IMP (excluding 
cosmetics) is used between 30 days before the screening examination and the Week 4 
examination, the name of the drug, purpose of use, daily dose, dose frequency, route of 
administration, and dates of start and end of administration will be recorded in the source 
document and CRF, regardless of it being prohibited or allowed for concomitant use.  If 
any concomitant therapy is given between 30 days before the screening examination and 
the Week 4 examination, regardless of it being prohibited or allowed for concomitant use, 
the name of the therapy, purpose of use, and the dates of the start and end of the therapy 
will be recorded in the source document and CRF. 
 
5 
Reporting of Adverse Events 
5.1 
Definitions 
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  AEs would not include information recorded as medical 
history at screening for pre planned procedures for which the underlying condition was 
known and no worsening occurred.  An adverse reaction is any untoward and unintended 
response to an IMP related to any dose administered. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE.  For the purpose of Investigational New Drug safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between 
the IMP and the AE.  Suspected adverse reaction implies a lesser degree of certainty 
about causality. 
An SAE includes any event that results in any of the following outcomes: 
 Death 
 Life-threatening; ie, the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred.  It does not include an 
event that, had it occurred in a more severe form, might have caused death. 
 Persistent or significant incapacity/disability or substantial disruption of the 
ability to conduct normal life functions. 
 Requires in-patient hospitalization or prolongs hospitalization. 
 Hospitalization itself should not be reported as an SAE; whenever possible 
the reason for the hospitalization should be reported. 


 
 
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 Hospitalizations or prolonged hospitalizations for social admissions (ie, 
those required for reasons of convenience or other non-medical need) are 
not considered SAEs. 
 Congenital anomaly/birth defect. 
 Other medically significant events that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above; eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or home, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse. 
 
Nonserious adverse events are all AEs that do not meet the criteria for a "serious" AE. 
Immediately Reportable Event (IRE):   
 Any SAE. 
 Any AE related to occupational exposure. 
 Potential Drug Induced Liver Injury (DILI) case (see Section 5.4).  
 Pregnancies are also defined as IREs.  Although normal pregnancy is not an 
AE, it will mandate IMP discontinuation and must be reported on an IRE form 
to the sponsor.  Pregnancy will only be documented on the AE section of CRF 
if there is an abnormality or complication. 
 
Clinical Laboratory Test Value Changes:  It is the investigator’s responsibility to 
review the results of all laboratory tests as they become available.  This review will be 
documented by the investigator’s dated signature on the laboratory report.  For each 
abnormal laboratory test result, the investigator needs to ascertain if this is an abnormal 
(ie, clinically significant) change from baseline for that individual subject.  This 
determination, however, does not necessarily need to be made the first time an abnormal 
value is observed.  The investigator may repeat the laboratory test or request additional 
tests to verify the results of the original laboratory tests.  If this laboratory value is 
considered medically relevant by the investigator (subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, and/or fulfills a seriousness criterion, this is considered an AE.  
Severity:  Adverse events will be graded on a 3-point scale and reported as indicated on 
the CRF.  Skin and subcutaneous tissue disorders will be graded according to the 
Common Terminology Criteria for Adverse Events v4.0 Japanese JCOG edition. 
1 = Mild: 
Discomfort noticed, but no disruption to daily activity. 


 
 
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2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity. 
3 = Severe: 
Inability to work or perform normal daily activity. 
 
IMP Causality:  Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows: 
Related:  
There is a reasonable possibility of a temporal and causal relationship 
between the IMP and the AE. 
Not Related:  There is no temporal or causal relationship between the IMP and the AE. 
 
5.2 
Eliciting and Reporting Adverse Events 
The investigator will periodically assess subjects for the occurrence of AEs.  To avoid 
bias in eliciting AEs, subjects should be asked the non-leading question: “How have you 
felt since your last visit?”  All AEs (serious and nonserious) reported by the subject must 
be recorded on the source documents and CRFs provided by the sponsor.  If an AE has 
occurred on the application site, it will also be recorded.  Eliciting SAEs will be started 
after the subject’s legal guardian has signed an informed consent form. 
Use medical terminology in AE reporting.  Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms.  If an AE has occurred on the application site, it will also 
be recorded.  Exacerbation or disease progression should be reported as an AE only if 
there are unusual or severe clinical features that were not present, or experienced earlier 
or not expected based on the course of the condition. 
In addition, the sponsor must be notified immediately by telephone, fax, or e-mail of any 
IREs according to the procedure outlined below, in Section 5.3 Immediately Reportable 
Events (IRE).  Special attention should be paid to recording hospitalization and 
concomitant medications. 
 
5.3 
Immediately Reportable Events (IRE) 
After either the investigator, subinvestigator, or designated person becomes aware of any 
SAE or any AE related to occupational exposure in healthcare professionals, potential 
drug-induced liver injury, or confirmed pregnancy, the investigator or subinvestigator 
must immediately report the event to the sponsor (within 24 hours in principle) by e-mail 


 
 
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(IRE_271-102-00002@otsuka.jp) or by facsimile (FAX: 06-6942-3692) if e-mail is not 
available (see cover page of this protocol for contact information).  An immediately 
reportable event (IRE) form must be completed and sent by e-mail or facsimile to the 
sponsor. (Please note that the IRE form is NOT the AE section of CRF.) 
Subjects experiencing SAEs should be followed until the events are resolved or clinically 
stabilized, or until the subjects are lost to follow-up.  Recovery is defined as the subject’s 
health returning to baseline status, and stabilization is a condition determined by the 
investigator or subinvestigator that no further improvement or worsening is likely.  The 
investigator or subinvestigator should provide the subjects with appropriate treatments 
and the sponsor with prompt updates on the subjects’ status. 
 
5.4 
Potential Drug-Induced Liver Injury 
For a subject who experiences an elevation in AST or ALT that is ≥3 times the upper 
limit of the normal range, a total bilirubin level should also be evaluated.  If the total 
bilirubin level is ≥2 times the upper limit of the normal range, the investigator or 
subinvestigator should promptly (within 24 hours in principle) complete an IRE form 
with all values listed and send it to the sponsor by e-mail or facsimile, and report as an 
AE on the CRF. 
 
5.5 
Implementation of Patch Test 
If any adverse event suspected of hypersensitivity occurs in the treatment area, the 
subject will be withdrawn from the trial and given appropriate treatments.  According to 
the following procedures, a patch test will be performed.  After obtaining verbal consent 
to patch test from the subject’s legal guardian, the consent will be recorded in the source 
document and CRF.  Prior to conducting the patch test, the recovery of symptom(s) 
should be confirmed.  To avoid any drugs used in the treatment affecting the patch test 
result, an appropriate washout period will be provided.  In principle, the patch test will be 
performed after a 2-week washout period for those receiving oral steroids or after a 1-
week washout period for those receiving topical steroids or topical/oral antihistamines.  
Test substances for the patch test are to consist of the IMP that the subject had received, 
vehicle, and white petrolatum.  After 48 hours from application, the patch test unit will be 
removed.  The first reading will be made about 1.5 to 2 hours after the tape removal, the 
time at which the removal-associated irritant reaction disappears.  Then, subsequent 


 
 
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readings will be made at 72 or 96 hours after the application and at 1 week after the 
application (allowable window of 5-7 days after the application).  The time and date of 
the reading and the reading result will be recorded in the source document and CRF. 
Reading criteria for skin reaction are shown in Table 5.5-1 (refer to the Guidelines for 
Management of Contact Dermatitis21 issued by the Japanese Dermatological Association 
for procedures of the patch test). 
Table 5.5-1 
Reading Criteria 
ICDRG criteria 
Reaction 
− 
No reaction 
+? 
Erythema only 
+ 
Erythema + infiltration, papules 
++ 
Erythema + infiltration + papules + small blisters  
+++ 
Large blisters 
IR 
Irritant reaction  
NT 
Not tested 
 
5.6 
Pregnancy 
Before enrolling female children aged 7 to 14 years old, the investigator or 
subinvestigator must review the trial participation guidelines for female children aged 7 
to 14 years old.  The topics should generally include: 
 Informed consent form 
 Guidelines for the follow-up of a reported pregnancy 
 
Before trial enrollment, female (candidate) subjects aged 7 to 14 years old and subjects’ 
legal guardians must be advised of the importance of avoiding pregnancy during their 
trial participation and the potential risk factors of an unintentional pregnancy.  The 
subject’s legal guardian must sign an informed consent form stating that the above-
mentioned risk factors and consequences were discussed with him or her. 
At the screening examination, female children aged 7 to 14 years old will undergo a urine 
or serum pregnancy test (human chorionic gonadotropin test).  If a positive urine test 
result is obtained, the investigator or subinvestigator will follow up with a confirmation 
serum test. 
During the trial, all female subjects and subjects’ legal guardians should be instructed to 
contact the investigator or subinvestigator immediately if they suspect they might be 
pregnant. 


 
 
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If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of pregnancy tests are available.  If the pregnancy is 
confirmed, the subject must not receive the IMP and must not be enrolled in the trial.  If 
pregnancy is suspected while the subject is taking IMP, the IMP must be withheld 
immediately (if reasonable, taking into consideration any potential withdrawal risks) until 
the result of the pregnancy test is known.  If pregnancy is confirmed, the IMP will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety) and the subject will be withdrawn from the trial.  
The investigator or subinvestigator must immediately notify the sponsor of any 
pregnancy associated with IMP exposure during the trial and for 30 days after the last 
dose of IMP, and record the event on the IRE form and promptly forward it to the 
sponsor (within 24 hours in principle).  The sponsor will forward Pregnancy Surveillance 
Form(s) for monitoring the outcome of the pregnancy. 
Protocol-required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies).  Other appropriate 
pregnancy follow-up procedures should be considered, if indicated.  In addition, the 
investigator or subinvestigator must report to the sponsor, on appropriate Pregnancy 
Surveillance Form(s), follow-up information regarding the course of the pregnancy, 
including perinatal and neonatal outcome.  Infants will be followed for a minimum of 6 
months from the date of birth. 
 
5.7 
Procedure for Breaking the Blind 
If a medical emergency occurs in a subject, such as an SAE, and his or her IMP 
randomization code is considered important for treatment by the investigator or 
subinvestigator, the emergency code will be broken according to the “Procedure for 
Emergency Code Breaking.”  If the blind is broken, the investigator or subinvestigator 
must notify the sponsor within 24 hours of opening the code, prepare a record of the 
reasons and the courses of blind-breakage, and submit it to the sponsor. 
 
5.8 
Follow-up of Adverse Events  
In this trial, information on adverse events (AEs) will be followed up as described below. 


 
 
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5.8.1 
Follow-up of Non-serious Adverse Events 
Non-serious AEs that are identified during the trial must be recorded on the AE section of 
CRF with the current status noted.  Any subject with an AE or who has not recovered 
from an AE at the examination 2 weeks after the last IMP administration will be followed 
up once in at least 4 weeks after the end of the trial until the AE either resolves or 
clinically stabilizes, or until the subject is lost to follow-up.  All non-serious AEs that are 
ongoing at the examination 2 weeks after the last IMP administration will be recorded as 
“ongoing” on the CRF.  For evaluation of AEs that occurred during the trial, additional 
relevant medical history information may be requested to further ascertain causality 
(including but not limited to, information such as risk-related behavior, family history, 
and occupation).  Follow-up information obtained after the examination 2 weeks after the 
last IMP administration will be recorded in medical records. 
5.8.2 
Follow-up of Serious Adverse Events 
In this trial, subjects will be actively observed for occurrence of any SAEs between the 
completion day of IMP administration and the day of the examination 2 weeks after the 
last IMP administration. 
Serious AEs that are identified or ongoing at the day of trial completion (final 
observation day) must be recorded on the AE section of CRF and reported to the sponsor 
according to the procedures outlined in “5.3 Immediately Reportable Events (IRE).”  All 
SAEs persisting on the day of trial completion (final observation day) will recorded in the 
CRF as “ongoing.”  This may include unresolved previously reported SAEs or new SAEs.  
The investigator or subinvestigator must follow any SAEs until the events are either 
resolved or clinically stabilized, or the subject is lost to follow-up.  The investigator or 
subinvestigator should report important follow-up information of SAEs to the sponsor 
using the IRE form until the events are either resolved or clinically stabilized, or the 
subject is lost to follow-up. 
5.8.3 
Follow-up and Reporting of Serious Adverse Events Occurring 
After Day of Trial Completion (Final Observation Day) 
Any new SAEs reported by the subject to the investigator or subinvestigator after the day 
of trial completion (final observation day), and are determined by the investigator or 
subinvestigator to be IMP-related should be reported to the sponsor.  This may include 
SAEs that are captured on follow-up telephone contact or at any other timepoint after the 
defined trial period (day of trial completion).  The investigator or subinvestigator should 
follow any SAEs identified after the day of trial completion (final observation day) until 


 
 
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the events are either resolved or clinically stabilized, or the subject is lost to follow-up.  
The investigator or subinvestigator should report any significant follow-up information to 
the sponsor using the IRE form until the event has been resolved or clinically stabilized, 
or the subject is lost to follow-up. 
 
6 
Pharmacokinetic Analysis 
The plasma concentration of OPA-15406 (trough concentration at Week 1 and Week 4) 
will be measured. 
 
7 
Statistical Analysis 
7.1 
Sample Size 
60 subjects 
The sample size of 20 subjects for each group, a total of 60 subjects, has been established 
in consideration of the feasibility of the trial and the number of subjects needed to 
evaluate efficacy and safety.  Assuming that the probabilities of success in IGA for each 
group are the same as those in the phase 2 trial outside Japan (271-12-205), the expected 
incidence of success in the 1% OPA-15406 group, the 0.3% OPA-15406 group, and the 
vehicle group is 20.93%, 14.63%, and 2.7%, respectively.  In that case, the probability of 
the 1% group > the vehicle group, the 0.3% group > the vehicle group, and the 1% group 
minus the vehicle group > 10% in the point estimate of incidence of success is 96.2%, 
88.3%, and 71.5%, respectively.  Also, the probability of the 1% group > the 0.3% group 
≥ the vehicle group in point estimate of incidence of success is 60.6%. 
 
7.2 
Datasets for Analysis 
7.2.1 
Safety Analysis Set 
The safety analysis set consists of all subjects who have received the IMP at least once. 
7.2.2 
Efficacy Analysis Set 
The efficacy analysis set consists of all subjects who have received the IMP at least once 
and whose efficacy data has been obtained after the start of IMP administration. 


 
 
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7.2.3 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set consists of all subjects whose plasma drug 
concentration has been measured. 
7.3 
Handling of Missing Data 
In this trial, no data imputation will be made for missing pharmacokinetic data.  For the 
efficacy variable of IGA, missing value in IGA will be handled as follows. 
1) Primary analysis for incidence of success in IGA  
 Subjects with an IGA score of 0 (clear) or 1 (almost clear) with an 
improvement by at least 2 grades from baseline are defined as responders.  
Subjects with missing IGA data at the time of evaluation will be handled as 
non-responders.  
2) Sensitivity analysis  
 Subjects with an IGA score of 0 (clear) or 1 (almost clear) with an 
improvement by at least 2 grades from baseline are defined as responders.  For 
subjects with missing IGA data at the time of evaluation, the last observation 
carried forward (LOCF) will be used.  
 Subjects with an IGA score of 0 (clear) or 1 (almost clear) with an 
improvement by at least 2 grades from baseline are defined as responders.  
Observed cases (OC) will be used.  
 Subjects with an improvement in IGA score to 0 (clear) or 1 (almost clear) are 
defined as responders.  Subjects with missing IGA data at the time of 
evaluation will be handled as non-responders. 
 
7.4 
Primary, Secondary, and Exploratory Endpoint Analyses 
7.4.1 
Primary Endpoint Analysis 
Analysis of AEs is described in Section 7.6.1. 
7.4.2 
Secondary Endpoint Analysis 
1) For the incidence of success in IGA at Week 4, the incidence of success of each 
treatment group and its 95% confidence interval will be calculated.  The 
difference between the vehicle group and each treatment group in the incidence of 
success and its 95% confidence interval will be calculated.  Incidence of success 
in IGA is defined as the rate of subjects whose IGA score is 0 (clear) or 1 (almost 
clear) and has improved by at least 2 grades (responders) from baseline.  Based on 
the Cochran-Mantel-Haenszel method, the difference in incidence of success 
adjusted by the severity of IGA at baseline and its confidence interval will be 
calculated as the primary analysis.  For reference, the Cochran-Mantel-Haenszel 


 
 
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method will be performed using baseline IGA (mild or moderate) as a 
stratification factor, and the p-value will be calculated.  A multiplicity adjustment 
will not be conducted. 
2) The incidence of success in IGA at Week 1 and Week 2 will be calculated, in the 
same manner as the incidence of success in IGA at Week 4. 
3) For the change from baseline in IGA at Week 1, Week 2 and Week 4, mixed-
model repeated measures (MMRM) analysis with factors of treatment (0.3% or 
1% OPA-15406 groups, and vehicle group), timepoint, baseline IGA (mild or 
moderate), and interaction between treatment and timepoint will be applied with 
an unstructured variance covariance structure to the change from baseline up to 
Week 4 based on OC dataset.  Kenward-Roger will be used to calculate the 
standard error of fixed effects and degree of freedom.  The least square mean of 
each treatment group will be calculated by timepoint.  Also, the difference in the 
least square means between the vehicle group and each OPA-15406 group, and 
the two-sided 95% confidence interval and p-value will be calculated at Week 1, 
Week 2 and Week 4.  Analysis of covariance (ANCOVA) with factors of 
treatment (0.3% or 1% OPA-15406 groups, vehicle group), and baseline IGA 
(mild or moderate) will be applied to the change from baseline up to each 
timepoint based on OC and LOCF dataset.  The least square mean of each 
treatment group will be calculated by timepoint.  Also, the difference in the least 
square means between the vehicle group and each OPA-15406 group, and the 
two-sided 95% confidence interval and p-value will be calculated.  Using the OC 
and LOCF data sets, the descriptive statistics will be calculated for measured 
values and changes from baseline by treatment group for each timepoint. 
4) The change from baseline in EASI, VAS for pruritus, POEM, and affected BSA 
will be calculated in the same manner as the change from baseline in IGA.  
Except for baseline, the same MMRM and ANCOVA models as those used in the 
analysis of IGA will be used.  For baseline, the baseline values of the respective 
variables will be used. 
5) Change from baseline in VRS for pruritus up to Day 7 will be calculated.  Using 
the OC and LOCF data sets up to Day 7, ANCOVA with factors of treatment 
(0.3% or 1% OPA-15406 groups, vehicle group), and baseline value will be 
applied to the change from baseline up to each timepoint based on OC and LOCF 
dataset.  The least square mean of each treatment group will be calculated by 
timepoint.  Also, the difference in the least square means between the vehicle 
group and each OPA-15406 group, and the two-sided 95% confidence interval 
and p-value will be calculated.  Using the OC and LOCF data sets, the descriptive 
statistics will be calculated for measured values and changes from baseline by 
treatment group for each timepoint.  The data will be collected at 4, 8, and 12 
hours after the start of administration, 1 day after the start of administration 
(morning and night), and thereafter in the same manner up to Day 7 (morning). 
6) For time to response in IGA and VRS for pruritus, Kaplan-Meier plots will be 
generated for each treatment group and vehicle group.  For IGA, subjects with an 
IGA score is 0 (clear) or 1 (almost clear) with an improvement by at least 2 grades 


 
 
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from the baseline are defined as responders.  For VRS for pruritus, subjects with 
VRS score of 0 (none) or 1 (mild) with an improvement by at least 1 grade from 
the baseline are defined as responders. 
7) The descriptive statistics (number of subjects, arithmetic mean, standard deviation, 
coefficient of variation, minimum value, median value, and maximum value) of 
plasma OPA-15406 concentrations will be calculated by treatment group and by 
timepoint. 
8) The descriptive statistics (number of subjects, arithmetic mean, standard deviation, 
coefficient of variation, minimum value, median value, and maximum value) of 
plasma OPA-15406 concentrations adjusted for affected area (%) per total BSA at 
baseline evaluation will be calculated by treatment group and by timepoint. 
9) The descriptive statistics (number of subjects, arithmetic mean, standard deviation, 
coefficient of variation, minimum value, median value, and maximum value) of 
plasma OPA-15406 concentrations will be calculated by treatment group, by 
timepoint, and by affected area per total BSA at baseline examination (5% to 
<10%, ≥10% to <30%, and ≥30%). 
10) The descriptive statistics (number of subjects, arithmetic mean, standard deviation, 
coefficient of variation, minimum value, median value, and maximum value) of 
age, affected area at baseline (%), and amount of administration (g) by affected 
area will be calculated. 
 
7.4.3 
Interim Analysis 
In this trial, no interim analysis will be performed. 
 
7.5 
Analysis of Demographic and Baseline Characteristics 
For sex, age, complications, medical history, previous medications (for AD or other 
diseases), concomitant medications, severity of AD, and baseline values of IGA, EASI, 
VAS for pruritus, VRS for pruritus, POEM, and affected BSA, the descriptive statistics 
will be calculated by treatment group depending on the characteristics of each parameter. 
 
7.6 
Safety Analysis 
7.6.1 
Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
system organ class and preferred term.  The version of MedDRA will be specified in the 
statistical analysis plan.  The number and percentage of subjects experiencing the 
following AEs will be calculated for treatment group. 


 
 
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a) 
TEAEs by severity  
b) 
TEAEs potentially causally related to IMP 
c) 
TEAEs resulting in death 
d) 
Serious TEAEs 
e) 
TEAEs leading to discontinuation of IMP administration 
 
If a subject experiences the same AE multiple times in the same period, the highest 
severity will be used for tabulations. 
7.6.2 
Clinical Laboratory Tests 
For clinical laboratory values, descriptive statistics will be calculated for measured values 
at baseline and each timepoint, and changes from baseline by timepoint for each 
treatment group.  Based on the reference range, shift tables will be created for changes 
from baseline classified into normal, high, and low. 
7.6.3 
Vital Signs 
For vital signs, descriptive statistics will be calculated for measured values at baseline 
and each timepoint, and changes from baseline by timepoint for each treatment group. 
7.6.4 
12-Lead ECG  
For 12-lead ECG, descriptive statistics will be calculated for the measured values and 
changes from baseline by timepoint for each treatment group.  Absolute QTc interval 
prolongation will be classified into >450 msec, >480 msec, and >500 msec, and the 
frequency distribution will be displayed.  In the same manner, the change from baseline 
will also be classified into >30 msec and >60 msec, and the frequency distribution will be 
displayed. 
7.6.5 
Other Safety Data 
Not applicable 
 


 
 
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8 
Management of Investigational Medicinal Products 
8.1 
Packaging and Labeling 
The IMP will be provided to the persons designated by the IMP manager, by the sponsor 
or designated agent.  The IMP will be supplied in a packing box.  Each packing box used 
in the treatment period will be labeled with the subject number, code name of the IMP, 
protocol number, name and address of the sponsor, statement that the drug is for use in a 
clinical trial, lot number, expiration date, storage method, drug number, and other 
precautions. 
 
8.2 
Storage 
The IMP will be stored in a securely locked location.  Access will be limited to the IMP 
manager.  Neither the investigators nor any designees may provide IMP to any subject 
not participating in this trial. 
The IMP will be stored at room temperature.  The trial site staff will maintain a 
temperature log in the drug storage area by recording the temperature at least once each 
working day. 
 
8.3 
Accountability 
The IMP manager must maintain an inventory record of IMP received, dispensed, 
administered, and returned. 
 
8.4 
Returns and Destruction 
Upon completion or termination of the trial, all unused and partially used IMP must be 
returned to the sponsor or a designated agent. 
All IMPs returned must be accompanied by appropriate documentation, such as storage 
records.  Returned IMPs should be in the original containers (ie, subject kits).  The 
assigned trial monitor will facilitate the return of unused and partially used IMP. 
 


 
 
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8.5 
Reporting of Product Quality Complaints 
A Product Quality Complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness or performance of a drug 
product or medical device after it is released for distribution.  Examples include, but are 
not limited to, communications involving: 
 Failure/malfunction of a product to meet any of its specifications 
 Incorrect or missing labeling 
 Packaging issues (eg, damaged, dirty, crushed, missing product) 
 Blister defects (eg, missing, empty blisters) 
 Bottle defects (eg, under/over-fill, no safety seal) 
 Vial defects 
 Product defect (eg, odor, chipped, broken, embossing illegible) 
 Loss or theft of product 
 
8.5.1 
Eliciting and Reporting Product Quality Complaints 
The investigator, subinvestigator, or designee must record all PQCs identified from the 
receipt of the IMP from the sponsor, or the sponsor’s designee, up to final confirmation 
of destruction, including the treatment period.  The investigator, subinvestigator, or 
designee must notify the sponsor (or the sponsor’s designee) within 24 hours of 
becoming aware of the PQC by e-mail according to the procedure outlined below. 
Email address for PQC reporting (PQC_271-102-00002@otsuka.jp) 
Identification of a PQC by the subject should be reported to the investigator or 
subinvestigator, who should then follow the above reporting procedure. 
8.5.2 
Information Required for Reporting Purposes 
 Description of compliant 
 Reporter identification (eg, investigator, site, etc.) 
 Reporter contact information (eg, address, phone number, e-mail address) 
 ID of material (product/compound name, coding) 
 Clinical protocol reference (number and/or trial name) 
 Dosage form/strength (if known) 


 
 
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 Pictures (if available) 
 Availability for return 
 
8.5.3 
Return Process 
Indicate during the PQC report if the complaint sample is available for return.  If 
complaint sample is available for return, it should be discussed with the sponsor, and the 
sample should be returned. 
It must be documented in the site accountability record that a complaint sample has been 
forwarded to the sponsor for complaint investigation. 
8.5.4 
Assessment/Evaluation 
Assessment and evaluation of PQCs will be handled by the sponsor. 
 
9 
Records Management 
9.1 
Source Documents 
Source documents are defined as the results of original observations and activities of a 
clinical investigation.  Source documents will include but are not limited to progress 
notes, electronic data, screening logs, and recorded data from automated instruments.  All 
source documents pertaining to this trial will be maintained by the investigators and made 
available for direct inspection by authorized persons. 
Investigators/institutions will permit trial-related monitoring, audits, IRB review, and 
regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF.  In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements. 
9.2 
Data Collection 
During each subject’s visit to the clinic, a clinician participating in the trial will record 
progress notes to document all significant observations.  At a minimum, these notes will 
contain: 
 Documentation of the informed consent process, including any revised consents; 
 Documentation of the investigator’s decision to enroll the subject into the trial, the 
review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial; 


 
 
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 The date of the visit and the corresponding Visit or Day in the trial schedule; 
 General subject status remarks, including any significant medical findings.  The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator's assessment of relationship to IMP must also be recorded; 
 Any changes in concomitant medications or dosages; 
 A general reference to the procedures completed;  
 The signature (or initials) and date of each clinician (or designee) who made an entry 
in the progress notes. 
 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above.  Any changes to information in the trial progress notes and other source 
documents will be initialed and dated on the day the change is made by a site staff 
member authorized to make the change.  Changes will be made by striking a single line 
through erroneous data (so as not to obliterate the original data), and clearly entering the 
correct data (eg, wrong data  right data).  If the reason for the change is not apparent, a 
brief explanation for the change will be written in the source documentation by the 
clinician.  If electronic data systems are being utilized, a full audit trail of changes must 
be maintained. 
Information from the trial progress notes and other source documents will be entered by 
investigative site personnel directly onto electronic CRFs in the sponsor’s electronic data 
capture system.  Changes to the data will be captured by an automatic audit trail.  
 
9.3 
File Management at the Trial Site 
The heads of all trial sites will ensure that the trial site file is maintained in accordance 
with Section 8 of the ICH GCP Guideline and as required by the applicable local 
regulations.  The trial sites must take measures to prevent accidental or premature 
destruction of these documents during the retention period. 
 
9.4 
Records Retention at the Trial Site 
The trial site will retain all the trial-related documents and records for the longer of the 
following 2 periods.  If the sponsor requires a longer period of archiving, the trial site will 
consult with the sponsor on the period and procedures of record retention. 


 
 
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 A period of at least 2 years following the date on which approval to market the drug 
is obtained.  If IMP development is discontinued, or if it is notified that the trial 
results will not be attached to the application for approval, a period of at least 3 years 
following the date on which the development discontinuation is determined or the 
date on which the notification indicating that the results will not be attached to the 
application for approval is received. 
 A period of at least 3 years following the date on which the trial is discontinued or 
completed 
 
The trial site must not dispose of any records relevant to this trial without either (1) 
written permission from the sponsor or (2) provision of an opportunity for the sponsor to 
collect such records.  The trial site will be responsible to maintain adequate and accurate 
electronic or hard copy source documents of all observations and data generated during 
this trial including any data clarification forms received from the sponsor.  Such 
documentation is subject to inspection by the sponsor and the relevant regulatory 
authorities. 
 
10 
Quality Control and Quality Assurance  
10.1 
Monitoring 
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH E6 GCP: Consolidated Guidance, and 
applicable regulatory requirements and local laws.  As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor's monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications.  In addition, all investigators and 
clinical site personnel will undergo initial and ongoing training for this particular trial, 
and this training will be clearly documented. 
 
10.2 
Auditing 
The sponsor's Quality Assurance Unit (or representative) may conduct trial site audits.  
Audits will include, but are not limited to, IMP supply, presence of required documents, 
the informed consent process, and comparison of CRFs with source documents.  The 
investigator agrees to participate with audits. 


 
 
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Regulatory authorities may inspect the investigator site during or after the trial.  The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs. 
 
11 
Ethics and Responsibility 
This trial must be conducted in compliance with the protocol, ICH GCP Guideline (E6), 
international ethical principles derived from the Declaration of Helsinki and Council for 
International Organizations of Medical Science guidelines, and applicable local laws and 
regulations.  Each trial site will seek approval/favorable opinion by an IRB according to 
regional requirements, and the investigator will provide that documentation to the 
sponsor.  The IRB will evaluate the ethical, scientific and medical appropriateness of the 
trial.  Further, in preparing and handling CRFs, the investigator, sub-investigator and 
their staff will take measures to ensure adequate care in protecting subject privacy.  To 
this end, a subject number and subject identification code will be used to identify each 
subject.  Financial aspects, subject insurance and the publication policy for the trial will 
be documented in the agreement between the sponsor and the investigator. 
 
12 
Confidentiality 
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission.  Subject confidentiality requirements of the region where the trial is 
conducted will be met.  However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements.  All IMPs, subject bodily fluids, and/or other 
materials collected shall be used solely in accordance with this protocol, unless otherwise 
agreed to in writing by the sponsor. 
Subjects will be identified only by unique subject numbers in CRFs.  If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials if necessary, subject to local regulations. 
 


 
 
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13 
Amendment Policy 
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB.  Any permanent 
change to the protocol, whether an overall change or a change for specific trial site(s), 
must be handled as a protocol amendment.  Any amendment will be written by the 
sponsor.  Each amendment will be submitted to the IRB, as required by local regulations.  
Except for “administrative” or “non-substantial” amendments, investigators will wait for 
IRB approval/favorable opinion of the amended protocol before implementing the 
change(s).  Administrative amendments are defined as having no effect on the safety of 
subjects, conduct or management of the trial, trial design, or the quality or safety of IMP 
used in the trial.  A protocol change intended to eliminate an apparent immediate hazard 
to subjects should be implemented immediately after agreement by the sponsor and 
investigator, followed by IRB notification within local applicable timelines.  The sponsor 
will submit protocol amendments to the applicable regulatory agencies within local 
applicable timelines. 
When the IRB, investigators, and/or the sponsor conclude that the protocol amendment 
substantially alters the trial design and/or increases the potential risk to the subject, the 
currently approved written ICF will require similar modification.  In such cases, after 
approval/favorable opinion of the new ICF by the IRB, repeat written informed consent 
will be obtained from subjects’ legal guardians enrolled in the trial before expecting 
continued participation and before the amendment-specified changes in the trial are 
implemented. 
 
14 
Publication Authorship Requirements 
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations).  According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met: 
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND 
2) Drafting the work or revising it critically for important intellectual content; AND 
3) Final approval of the version to be published; AND 


 
 
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4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
 
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors. 
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial.  By agreeing to participate in the 
trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct. 
 
15 
References 
1 
Hanifin JM, Rajka G.  Diagnostic features of atopic dermatitis.  Acta 
Dermatol Suppl.1980;92:44-7. 
2 
Kato N, Saeki H, Nakahara T, Tanaka A, Kabashima K, Sugaya M, et al. 
Guidelines for Management of Atopic Dermatitis. The Japanese Journal of 
Dermatology. 2016;126(2):121-55. 
3 
Hanifin JM, Butler JM, Chan SC.  Immunopharmacology of the atopic diseases. 
J Invest Dermatol.  1985;85 (1 Suppl):161s-4s 
4 
Committee for Guidelines for the Management of Atopic Dermatitis of Japanese 
Dermatological Association, Japanese Society of Allergy.  Guidelines for 
Management of Atopic Dermatitis 2015. KYOWA KIKAKU Ltd. 
5 
Stamatas GN, Nikolovski J, Mack MC, Kollias, N. Infant skin physiology and 
development during the first years of life: A review of recent findings based on in 
vivo studies. Int J Cosmet Sci. 2011;33:17-24. 
6 
Telofki LS, Morello PA, Correa MCM, Stamatas GN. The infant skin barriers: Can 
we preserve, protect, and enhance the barrier? Dermatol Res Pract. 2012; 2012:1-18. 
7 
Kohno Y, supervised by Yamamoto S.  Guidelines for Management of 
Atopic Dermatitis 2008.  Available from:  
http://www.jaanet.org/pdf/guideline_skin02.pdf 
8 
Evans NJ, Rutter N. Development of the epidermis in the newborn. Biol Neonate. 
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9 
Fluhr JW, Darlenski R, Taieb A, Hachem JP, Baudouin C, Msika P, De Belilovsky C, 
Berardesca E. Functional skin adaptation in infancy -almost complete but not fully 
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10 Fluhr JW, Pfisterer S, Gloor M. Direct comparison of skin physiology in children and 
adults with bioengineering methods. Pediatr Dermatol. 2000;17:436-49. 
11 Loomis CA. Development and morphogenesis of the skin. In: Adv Dermatol. Eds: 
Yancey KB. Mosby Inc, 2001;17(Chapter 7):183-210. 
12 Giusti F，Martella A，Bertoni L，Seidenari S. Skin barrier, hydration, and pH of 
the skin of infants under 2 years of age. Pediatr Dermatol 2001;18(2):93-6. 
13 International Conference on Harmonisation (ICH) [homepage on the Internet]. E11: 
Clinical Investigation of Medicinal Products in the Pediatric Population [July 2000 ]. 
Available from: http://www.ich.org 
14 Buelke-Sam J. Comparative schedules of development in rats and humans: 
Implications of developmental neurotoxicity testing. SOT 2003 Annual Meeting. Salt 
Lake City, UT. Toxicologist, Abstract #820, p.169. 
15 Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 
1987;317:1098. 
16 International Conference on Harmonisation (ICH) [Internet].  Guideline for Good 
Clinical Practice E6(R1) [finalized 1996 May, updated 1996 Jun 10, cited 2015 Jan 8]. 
Available from: http://www.ich.org/products/guidelines/efficacy/article/efficacy-
guidelines.html. 
17 Leung DY, Hanifin JM, Pariser DM, Barber KA, Langley RG, Schlievert PM, et al. 
Effect of pimecrolimus cream 1% in the treatment of patients with atopic dermatitis 
who demonstrate a clinical insensitivity to topical corticosteroids: a randomized, 
multicentre vehicle-controlled trial. Br J Dermatol. 2009;161:435-43. 
18 Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. Exp Dermatol. 
2001;10:11-8. 
19 Phan NQ, Blome C, Fritz F, Gers J, Reich A, Toshi Ebata T, et al. Assessment of 
Pruritis Intensity Prospective Study on Validity and Reliability of the Visual 
Analogue Scale, Numerical Rating Scale and Verbal Rating Scale in 471 Patients 
with Chronic Pruritus. Acta Derm Venereol. 2011;92:Epub ahead of print 
20 Charman CR, Venn AJ, Ravenscroft JC, Williams HS. Translating Patient-Oriented 
Eczema Measure (POEM) scores into clinical practice by suggesting severity strata 
derived using anchor-based methods. Br J Dermatol. 2013;169:1326-32. 
21 Takayama K, Yokozeki H, Matsunaga K, Katayama I, Aiba S, Itoh M, et 
al.  Guidelines for Management of Contact Dermatitis. The Japanese Journal 
of Dermatology.  2009;119(9):1757-93. 
 
 


 
 
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Appendix 1 
Diagnostic Criteria for Atopic Dermatitis (Hanifin & Rajka) 
A. Must have 3 or more basic features described below 
1) 
Pruritus 
2) 
Typical morphology and distribution 
Flexural lichenification in adults 
Facial and extensor involvement in infants and children 
3) 
Chronic or chronically-relapsing dermatitis 
4) 
Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis) 
B. Must have 3 or more following minor features: 
1) 
Xerosis 
2) 
Ichthyosis, palmar hyperlinearity, keratosis pilaris 
3) 
Immediate (type 1) skin test reaction 
4) 
Elevated serum IgE 
5) 
Early age of onset 
6) 
Tendency toward cutaneous infections (especially Staph. aureus and Herpes simplex)/impaired 
cell-mediated immunity 
7) 
Tendency toward non-specific hand or foot dermatitis 
8) 
Nipple eczema 
9) 
Cheilitis 
10) Recurrent conjunctivitis 
11) Dennie-Morgan infraorbital fold 
12) Keratoconus 
13) Anterior subcapsular cataracts 
14) Orbital darkening 
15) Facial pallor, facial erythema 
16) Pityriasis alba 
17) Anterior neck folds 
18) Itch when sweating 
19) Intolerance to wool and lipid solvents 
20) Perifollicular accentuation 
21) Food intolerance 
22) Course influenced by environmental and emotional factors 
23) White dermographism, delayed blanch 
 
 
 
 


 
 
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Version 1.0, 06 Oct 2016 
Appendix 2 
Visual Analogue Scale (VAS) Sheet for Pruritus 
 
 
 
 
 
 
 
 
No Itching 
Maximum Itching 
0 
100 


 
 
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Version 1.0, 06 Oct 2016 
Appendix 3 
Patient-Oriented Eczema Measure (POEM) 
 
The POEM questionnaire is shown on the next page.  If it is difficult for subjects to 
answer the questions, their parents will answer them instead. 
 
© The University of Nottingham 
 
 


 
 
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87 
Version 1.0, 06 Oct 2016 
 


 
 
Protocol 271-102-00002 
 
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88 
Version 1.0, 06 Oct 2016 
Appendix 4 
Human Body Drawing for Children Aged 8 to 14 Years Old 
      
 
Total amount of administration      _______   g 
 
For hospital use only 
 
Affected site 
Affected area (%) 
Face, neck, and head 
% 
Upper limbs 
% 
Trunk 
% 
Lower limbs 
% 
 
Signature of the investigator/subinvestigator 
 
_________________________________________________Day/_________Month/20_______ 
 
 
Administration site 
Treatment area (%) 
Face, neck, and head 
% 
Upper limbs 
% 
Trunk 
% 
Lower limbs 
% 
Total 
% 


 
 
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Appendix 5 
Human Body Drawing for Children Aged 2 to 7 Years Old 
  
Total amount of administration      _______   g 
 
For hospital use only 
 
Affected site 
Affected area (%) 
Face, neck, and head 
% 
Upper limbs 
% 
Trunk 
% 
Lower limbs 
% 
 
Signature of the investigator/subinvestigator 
 
_________________________________________________Day/_________Month/20_______ 
 
Administration site 
Treatment area (%) 
Face, neck, and head 
% 
Upper limbs 
% 
Trunk 
% 
Lower limbs 
% 
Total 
% 

SAP_001.pdf: 
 
 
 
 
 
 
STATISTICAL  ANALYSIS  PLAN 
 
 
A Multicenter, Randomized, Double-blind, 
Vehicle-controlled, Parallel-group Trial to Assess the Safety and 
Efficacy of 0.3% and 1% OPA-15406 Ointments When 
Administered for 4 Weeks in Pediatric Patients With  
Atopic Dermatitis 
 
 
                                                                                                    NCT Number: 03018691 
                                                                                               PRT NO. ：271-102-00002 
                                                                     PRT Version Date: 9 Aug 2017（Version 1） 
 
 
 


 
 
 
 
 
A Multicenter, Randomized, Double-blind, 
Vehicle-controlled, Parallel-group Trial to Assess the Safety and 
Efficacy of 0.3% and 1% OPA-15406 Ointments When 
Administered for 4 Weeks in Pediatric Patients With  
Atopic Dermatitis 
Phase 2 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
for 
Protocol No. 271-102-00002 
(Translated Version) 
 
Confidential 
 
 
 
 
Otsuka Pharmaceutical Co., Ltd 
 
 
Version 1: 9 Aug 2017 
Date of Translation: 28 Nov 2017 


Protocol 271-102-00002 
 
 
3 
 
 
Table of Contents 
Table of Contents ........................................................................................... 3 
List of Abbreviations and Definition of Terms........................................... 5 
1 
Introduction .......................................................................................... 6 
2 
Trial Objectives .................................................................................... 6 
3 
Trial Design ........................................................................................... 6 
4 
Implementation of Planned Analyses ................................................. 8 
5 
Statistical Analysis Sets ........................................................................ 8 
5.1 
Definitions of Analysis Sets ............................................................................... 8 
6 
Considerations for Data Analysis ....................................................... 9 
6.1 
Software .............................................................................................................. 9 
6.2 
Dictionaries ......................................................................................................... 9 
6.3 
Data Conversion and Calculation ....................................................................... 9 
6.4 
Study Week Windows ...................................................................................... 11 
6.5 
Handling of Missing Values ............................................................................. 12 
6.6 
Significance Level and Confidence Coefficient ............................................... 12 
7 
Disposition of Subjects ....................................................................... 13 
7.1 
Disposition of Subjects ..................................................................................... 13 
7.2 
Statistical Analysis Sets .................................................................................... 13 
7.3 
Protocol Deviations ........................................................................................... 13 
8 
Description of Analysis Datasets ....................................................... 13 
8.1 
Demographics and Baseline Characteristics ..................................................... 13 
8.2 
Medical History/Complications ........................................................................ 14 
8.3 
Prior and Concomitant Medications ................................................................. 14 
8.4 
Concomitant Therapies ..................................................................................... 14 
9 
Safety Analysis .................................................................................... 14 
9.1 
Primary Endpoint .............................................................................................. 14 
9.2 
Exposure to the IMP (Number of Subjects, Duration, and Doses) ................... 14 
9.3 
Adverse Events ................................................................................................. 15 
9.4 
Potentially Drug-related TEAEs ....................................................................... 15 


Protocol 271-102-00002 
 
 
4 
 
9.5 
Clinical Laboratory Tests .................................................................................. 15 
9.6 
Vital Signs (Including Body Weight) ............................................................... 16 
9.7 
Electrocardiogram (12-Lead ECG) ................................................................... 16 
10 
Efficacy Analyses ................................................................................ 17 
10.1 
Secondary Endpoints ........................................................................................ 17 
10.2 
Other Efficacy Endpoints .................................................................................. 21 
10.3 
Adjustments for Covariates .............................................................................. 22 
10.4 
Subgroup Analysis ............................................................................................ 22 
11 
Pharmacokinetic Analyses ................................................................. 22 
11.1 
Pharmacokinetics Analysis Set ......................................................................... 22 
11.2 
Pharmacokinetic Endpoints .............................................................................. 22 
11.3 
Method of Calculation of Pharmacokinetic Endpoints ..................................... 22 
11.4 
Method of Display ............................................................................................ 23 
11.5 
Handling of Values ........................................................................................... 23 
12 
Rationale for Target Number of Subjects ........................................ 24 
12.1 
Target Number of Subjects ............................................................................... 24 
12.2 
Rationale for the Number of Subjects ............................................................... 24 
13 
Changes From Analysis Planned in the Protocol ............................ 24 
13.1 
Changes From the Efficacy Analyses Planned in the Protocol ........................ 24 
13.2 
Changes From the Pharmacokinetic Analyses Planned in the Protocol ........... 24 
14 
References ........................................................................................... 25 
15 
Revision History ................................................................................. 26 
16 
Appendix ............................................................................................. 27 
16.1 
Criteria for Potentially Clinically Significant ................................................... 27 
16.2 
Table of Contents .............................................................................................. 28 
 
 
 


Protocol 271-102-00002 
 
 
5 
 
List of Abbreviations and Definition of Terms 
List of Abbreviations 
Abbreviation 
Expansion 
AD 
Atopic Dermatitis 
BSA 
Body Surface Area 
EASI 
Eczema Area and Severity Index 
IGA 
Investigator’s Global Assessment 
IMP 
Investigational Medicinal Product 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
OC 
Observed Cases 
POEM 
Patient-Oriented Eczema Measure 
QTcB 
QT interval as correlated by Bazett’s formula 
QTcF 
QT interval as correlated by Fridericia’s formula 
SS 
Safety Set 
TEAE 
Treatment-emergent Adverse Event 
VAS 
Visual Analogue Scale 
VRS 
Verbal Rating Scale 
 
Definition of Terms 
Term 
Definition 
Descriptive statistics 
Number of subjects, mean, standard deviation, minimum, 
median, and maximum 
Descriptive statistics of 
plasma OPA-15406 
concentrations 
Number of subjects, arithmetic mean, coefficient of 
variation, standard deviation, minimum, median, and 
maximum 
Frequency distribution 
Number and percentage of subjects 
 
 
 


Protocol 271-102-00002 
 
 
6 
 
1 
Introduction 
This statistical analysis plan (SAP) documents the detailed methodology of 
summarization/analyses and evaluation to provide the trial data required for the 
preparation of a clinical study report of Trial 271-102-00002. This document has been 
created based on Protocol No. 271-102-00002, Version 2.0, issued on 14 Nov 2016. The 
pharmacokinetic analyses are detailed in Section 11. 
 
2 
Trial Objectives 
Primary Objective: To evaluate the safety of 0.3% and 1% OPA-15406 when applied 
twice daily for 4 weeks in pediatric patients with atopic dermatitis (AD) 
Secondary Objective: To evaluate the efficacy (dose response) and pharmacokinetics of 
0.3% and 1% OPA-15406 when applied twice daily for 4 weeks in pediatric patients with 
AD 
 
3 
Trial Design 
This is a multicenter, randomized, double-blind, vehicle-controlled, parallel-group 
comparison trial to evaluate the safety, efficacy, and pharmacokinetics of OPA-15406 
ointment in pediatric patients with AD. This trial consists of the 0.3% OPA-15406 group, 
the 1% OPA-15406 group, and the vehicle group. The trial design is shown in Figure 3-1. 
1) Screening period 
After obtaining written informed consent from the subject’s legal guardian (if 
possible, after also obtaining informed assent from the subject), the investigator or 
subinvestigator will perform a screening examination. The period between the day of 
the screening examination and the end of the baseline examination is defined as the 
screening period (2-30 days). The subjects who meet the inclusion criteria and do not 
meet any of the exclusion criteria at the baseline examination will shift to the 
assessment period and will be dynamically allocated to the test product (0.3% or 1% 
formulation of OPA-15406) or the vehicle (placebo). 
2) Assessment period (treatment period) 
For subjects meeting the inclusion criteria and not meeting any of the exclusion 
criteria at the baseline examination, the period between the day of the starting 
baseline examination and the day of the Week 4 examination (or the day of 
discontinuation) is defined as the assessment period. The investigational medicinal 


Protocol 271-102-00002 
 
 
7 
 
product (IMP) will be administered to the treatment area from the day of the baseline 
examination twice daily for 4 weeks. After the baseline examination, the examination 
will be performed at Weeks 1, 2, and 4. 
If a subject discontinues the IMP administration between the day of the baseline 
examination and the Week 4 examination, a withdrawal examination will be 
performed for that subject. 
3) Post-treatment observation period 
The period from completion of the Week 4 examination to the day of the examination 
2 weeks after the last IMP administration is defined as the post-treatment observation 
period. Examinations will be performed at 2 weeks after the last IMP administration. 
If any adverse event remained not recovered at the examination 2 weeks after the last 
IMP administration (or by the day of the last examination if the examination 2 weeks 
after the last IMP administration was not performed), it should be followed 
up according to the specifications. 
4) Trial period 
The trial period for individual subjects is from the day of obtaining informed consent 
from the subject’s legal guardian to the day of trial discontinuation or completion and 
does not include the follow-up period. 
 
 


Protocol 271-102-00002 
 
 
8 
 
 
 
Screening 
period 
(2-30 days) 
Assessment period 
Twice daily administration 
(4 weeks) 
Post-treatment 
observation period 
(2 weeks) 
0.3% OPA-15406 group 
 
 
 
1% OPA-15406 group 
 
 
 
Vehicle group 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
: Treatment period 
 
Figure 3-1 
Trial Design Schematic 
 
 
4 
Implementation of Planned Analyses 
The SAP will be finalized prior to database lock, and analyses will be performed using 
the final data. 
 
5 
Statistical Analysis Sets 
5.1 
Definitions of Analysis Sets 
5.1.1 
Efficacy Set  
The efficacy set consists of all subjects who have received the IMP at least once and 
whose efficacy data has been obtained after the start of IMP administration. 
Screening examination 
Informed consent 
Start of IMP administration 
Baseline examination 
Week 1 examination 
Week 2 examination 
Week 4 examination 
Examination 2 weeks after the last  
IMP administration 


Protocol 271-102-00002 
 
 
9 
 
 
5.1.2 
Safety Set 
The safety set (SS) consists of all subjects who have received the IMP at least once. 
 
6 
Considerations for Data Analysis 
6.1 
Software 
SAS ver.9.4 (SAS Institute Inc.) 
 
6.2 
Dictionaries 
Coding of adverse events and medical history/complications: Medical Dictionary for 
Regulatory Activities (MedDRA)/J Version 20.0 
Coding of prior and concomitant medications: WHO Drug Dictionary (dated 1 Mar 2016) 
 
6.3 
Data Conversion and Calculation 
6.3.1 
Response in Investigator’s Global Assessment 
Responders and non-responders in investigator’s global assessment (IGA) are defined as 
follows: 
1) Primary analysis for incidence of success in IGA 
 Subjects with an IGA score of 0 (clear) or 1 (almost clear) with an improvement 
by at least 2 grades from baseline are defined as responders. Subjects with 
missing IGA data at the time of evaluation will be handled as non-responders. 
 
2) Sensitivity analysis 
 Subjects with an IGA score of 0 (clear) or 1 (almost clear) with an improvement 
by at least 2 grades from baseline are defined as responders. For subjects with 
missing IGA data at the time of evaluation, the last observation carried forward 
(LOCF) will be used. 
 Subjects with an IGA score of 0 (clear) or 1 (almost clear) with an improvement 
by at least 2 grades from baseline are defined as responders. Observed cases (OC) 
will be used. 


Protocol 271-102-00002 
 
 
10 
 
 Subjects with an improvement in IGA score to 0 (clear) or 1 (almost clear) are 
defined as responders. Subjects with missing IGA data at the time of evaluation 
will be handled as non-responders. 
 
6.3.2 
Treatment Compliance 
Treatment compliance = (total amount of the IMP applied from the start of administration 
to the assessment point1)/(sum of the specified amounts of the IMP per dose from the 
start of administration to the assessment point2) × 100 
1 [Total amount of the IMP prescribed from the start of administration to the assessment 
point] − [total amount of the IMP returned from the start of administration to the 
assessment point] 
If the total amount of the IMP returned is missing, the total amount of the IMP applied 
from the start of administration to the assessment point will be handled as a missing 
value. 
2 Calculation of “amount of the IMP (g) per dose” 
1) The subject’s body surface area (BSA) (m2) will be calculated based on height 
and body weight at the screening examination, using the following equation.  
3600
)
(
)
(
)
(
2
kg
Wt
cm
Ht
m
BSA


 
2) [Amount of the IMP (g) per dose] at the assessment point will be calculated as 
[the subject’s BSA (m2)] × [treatment area (%) at the assessment point (including 
baseline)]/100 × 10 g/m2. 
 
Treatment compliance with the number of administrations will be calculated as follows: 
Treatment compliance with the number of administrations = (number of administrations 
from the start of administration to the assessment point)/(number of days from the start of 
administration to the assessment point × 2) × 100 
 
6.3.3 
Overall Eczema Area and Severity Index Score 
Overall Eczema Area and Severity Index (EASI) score is the sum of the scores for 4 body 
regions (face, neck, and head; upper limbs; trunk; and lower limbs). The score for each 
region will be calculated as shown in Table 6.3-1. 


Protocol 271-102-00002 
 
 
11 
 
 
Table 6.3-1 
EASI Score for Each Region 
Body region 
Calculation of the score for each region 
Face, neck, and head 
(E+I+Ex+L) × score of affected BSA × 0.1 (× 0.2 for children aged 2-
7 years old)  
Upper limbs 
(E+I+Ex+L) × score of affected BSA × 0.2 
Trunk 
(E+I+Ex+L) × score of affected BSA × 0.3 
Lower limbs 
(E+I+Ex+L) × score of affected BSA × 0.4 (× 0.3 for children aged 2-
7 years old)  
 
E = severity score of erythema; I = severity score of infiltration/papules; Ex = severity score of 
excoriation; L = severity score of lichenification 
 
Severity score: clear = 0; slight = 0.5; mild = 1; mild-moderate = 1.5; moderate = 2; severe = 2.5; very 
severe = 3 
 
Score of affected BSA (for each region): clear = 0; 1% to 9% = 1; 10% to 29% = 2; 30% to 49% = 3; 
50% to 69% = 4; 70% to 89 % = 5; 90% to 100% = 6 
 
6.3.4 
EASI Symptom Score 
Each EASI symptom score (erythema, infiltration/papules, excoriation, and 
lichenification) will be determined as the sum of the severity scores (Body Regions 
Scores) for 4 regions (face, neck, and head; upper limbs; trunk; and lower limbs) (The 
scores of affected BSA or multipliers will not be used in the calculation). 
 
6.4 
Study Week Windows 
The definitions of timepoints for analysis are described in Table 6.4-1 and Table 6.4-2. 
Timepoints, including unscheduled visits and visit at discontinuation, will be determined 
based on the number of days from the start of IMP administration. However, for Verbal 
Rating Scale (VRS), the timepoint will be determined based on the amount of time that 
has elapsed from the start of IMP administration. For efficacy variables, the data obtained 
between the day of the start of IMP administration and 7 days after the last IMP 
administration will be used in analyses. If multiple data exist within the allowable 
window of the timepoint, the data obtained last will be used for analyses. Data for the 
Last Visit will be defined as the last data obtained between the day of the start of 
IMP administration and 7 days after the last IMP administration (including data obtained 
at discontinuation) for efficacy valuables or as the last data obtained after the start of the 
IMP administration for safety variables. 
In analyses, baseline data will be defined as data obtained on the day or at the date and 
time before and nearest to the start of IMP administration, including the screening data. 


Protocol 271-102-00002 
 
 
12 
 
Table 6.4-1 
Timepoints and Allowable Windows for Efficacy Variables 
(Except VRS) and Safety Variables 
Timepoint 
Study Day 
Allowable Window (Days After the Start of IMP 
Administration) 
Week 1 
8 
1 
- 
10 
Week 2 
15 
11 
- 
21 
Week 4 
29 
22 
- 
43 
 
Table 6.4-2 
Timepoints and Allowable Windows for VRS 
Timepoint 
Allowable Window (Hours After the Start of 
IMP Administration) 
Hour 4 
1 
- 
< 6 
Hour 8 
6 
- 
< 10 
Hour 12  
10 
- 
< 18 
Hour 24  
18 
- 
< 30 
Hour 36  
30 
- 
< 42 
Hour 48  
42 
- 
< 54 
Hour 60  
54 
- 
< 66 
Hour 72  
66 
- 
< 78 
Hour 84  
78 
- 
< 90 
Hour 96  
90 
- 
< 102 
Hour 108 
102 
- 
< 114 
Hour 120 
114 
- 
< 126 
Hour 132 
126 
- 
< 138 
Hour 144 
138 
- 
< 150 
Hour 156 
150 
- 
< 162 
Hour 168 
162 
- 
< 174 
 
6.5 
Handling of Missing Values 
Missing data for incidence of success in IGA will be handled as described in 
“Section 6.3.1 Response in Investigator’s Global Assessment.” Other variables at each 
timepoint will be analyzed based on the OC and LOCF data sets. 
 
6.6 
Significance Level and Confidence Coefficient 
No significance tests will be used in this trial; therefore, no significance levels are set. 
The confidence coefficient is set at two-sided 95%. 
6.6.1 
Multiple Comparisons and Multiplicity 
Multiplicity adjustment will not be conducted. 
 


Protocol 271-102-00002 
 
 
13 
 
7 
Disposition of Subjects 
7.1 
Disposition of Subjects 
Data will be summarized for overall population and by age group (<7 or ≥7). The 
numbers of screened and randomized subjects will be provided. The following frequency 
distributions will be provided for overall population and by treatment group, unless 
otherwise specified. The frequency distribution (number and percentage relative to all 
subjects randomized) of subjects treated, those who completed the trial, and those who 
discontinued the trial will be calculated. For subjects who discontinue the trial, the 
frequency distribution will be calculated by reason for discontinuation. 
 
7.2 
Statistical Analysis Sets 
Data will be summarized for overall population and by age group (<7 or ≥7). For the 
randomized subjects, the number and percentage of subjects included in the efficacy set, 
safety set, and pharmacokinetic analysis set will be provided. 
 
7.3 
Protocol Deviations 
The number and percentage of subjects with major protocol deviations will be provided 
for overall population and by treatment group. The number and percentage of major 
protocol deviations occurring in each trial site will be provided for overall population and 
by treatment group. 
 
8 
Description of Analysis Datasets 
8.1 
Demographics and Baseline Characteristics 
Data will be summarized for overall population and by age group (<7 or ≥7). For the 
randomized subjects, age, gender, duration of AD, body weight, height, BMI, race, 
baseline IGA score, and nation will be summarized for overall population and by 
treatment group using descriptive statistics or frequency distribution. 
Affected BSA at baseline will be categorized as follows and summarized for overall 
population and by treatment group using frequency distribution. 
Affected BSA categories: ≥5% to <10%, ≥10% to <30%, and ≥30%  
 


Protocol 271-102-00002 
 
 
14 
 
8.2 
Medical History/Complications 
Medical history and complications will be coded by MedDRA/J system organ class 
(SOC) and preferred term (PT). The medical history and complications will be listed, but 
not summarized. 
 
8.3 
Prior and Concomitant Medications 
For the randomized subjects, the numbers and percentages of subjects who take any 
concomitant medication before the start of IMP administration, during the assessment 
period, and after the last IMP administration will be provided by medication for the 
overall population and by treatment group. The medications will be coded using the 
WHO Drug Dictionary, and summarized by ATC Classification Level 2 and Preferred 
Name. 
 
8.4 
Concomitant Therapies 
The concomitant therapies will be listed, but not summarized. 
 
9 
Safety Analysis 
The following safety endpoints will be analyzed in the safety set (SS). 
9.1 
Primary Endpoint 
The primary endpoint in this trial is the number and percentage of subjects experiencing 
adverse events (AEs). The analysis of AEs is described in Section 9.3. 
 
9.2 
Exposure to the IMP (Number of Subjects, Duration, and Doses) 
Treatment compliance with the amount of administration and the number of 
administrations, calculated as described in Section 6.3.2, will be classified into the 
following categories, and the number and percentage of subjects will be provided for the 
overall population and by treatment group. The treatment compliance from baseline to 
Week 4 will be provided. The number and percentage of subjects who received 
IMP administration during each week (Week 1, Week 2, Week 3, Week 4, and every 
week thereafter, if necessary; Any Exposure) will be provided. 


Protocol 271-102-00002 
 
 
15 
 
Categories of treatment compliance with the amount of administration and the number of 
administrations: <50%, ≥50% to <60%, ≥60% to <70%, ≥70% to <80%, ≥80% to <90%, 
≥90% to <100%, ≥100% to <110%, ≥110% to <120%, ≥120% 
 
9.3 
Adverse Events 
Data will be summarized for the overall population and by age group (<7 or ≥7). All AEs 
will be coded using the MedDRA/J SOC and PT. 
The number and percentage of subjects experiencing the following treatment-emergent 
adverse events (TEAEs) will be provided for the overall population and by treatment 
group. Skin and subcutaneous tissue disorders will also be summarized by the grade in 
the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 Japanese JCOG 
edition. 
1. TEAEs 
2. TEAEs resulting in death 
3. Serious TEAEs 
4. TEAEs leading to discontinuation of IMP administration 
5. TEAEs by severity 
6. TEAEs by CTCAE grade (only skin and subcutaneous tissue disorders) 
7. TEAEs at treatment areas 
For TEAEs and non-serious TEAEs reported in at least 5% of subjects in any treatment 
group, the number and percentage of subjects will be provided for the overall population 
and by treatment group. 
 
9.4 
Potentially Drug-related TEAEs 
Potentially drug-related TEAEs (AEs for which a causal relationship with the IMP cannot 
be ruled out) will be summarized in the same manner as AEs. Serious potentially 
drug-related TEAEs will also be summarized. 
 
9.5 
Clinical Laboratory Tests 
For laboratory parameters (except qualitative urinalysis), measured values and changes 
from baseline at each timepoint will be summarized for the overall population and by 


Protocol 271-102-00002 
 
 
16 
 
treatment group using descriptive statistics. Shift tables (except qualitative urinalysis) 
will be created for predose and postdose values classified into normal, high, or low based 
on the reference range by treatment group. For qualitative urinalysis, shift tables will be 
created for predose and postdose values by each parameter. The number and percentage 
of potential Hy’s Law Cases will be provided for the overall population and by treatment 
group. A listing of the potential Hy’s Law Cases will be provided. Potential Hy’s Law 
Cases will be defined as follows: 
 
Potential Hy’s Law Cases are defined as subjects with AST or ALT ≥ 3 times the 
upper normal limit or whose levels increase ≥ 3 times the initial screening value, and 
with an increase in total bilirubin level ≥ 2 times the upper normal limit or initial 
screening value. 
 
9.6 
Vital Signs (Including Body Weight) 
Measured values and changes from baseline in body weight, body temperature, blood 
pressure (systolic/diastolic), and pulse rate at each timepoint will be summarized for the 
overall population and by treatment group using descriptive statistics. For body 
temperature, blood pressure (systolic/diastolic), and pulse rate, the number and 
percentage of subjects with potentially clinically significant vital sign 
abnormalities (Table 16.1-1) will be computed for the overall population and by 
treatment group. A listing of subjects with potentially clinically significant abnormalities 
will be provided. 
 
9.7 
Electrocardiogram (12-Lead ECG) 
Measured values and changes from baseline in heart rate, PR, QRS, QT, QTc (QT 
interval as correlated by Bazett’s formula [QTcB] and QT interval as correlated by 
Fridericia’s formula [QTcF]), and RR intervals at each timepoint will be summarized for 
the overall population and by treatment group using descriptive statistics. Criteria for 
potentially clinically significant ECG abnormalities in heart rate, PR, QRS, QT, QTcB, 
and QTcF intervals will be set (Table 16.1-2), and the number and percentage of 
subjects who meet the criteria will be provided for the overall population and by 
treatment group. 
 


Protocol 271-102-00002 
 
 
17 
 
10 
Efficacy Analyses 
Efficacy analyses will be performed in the efficacy set. 
10.1 
Secondary Endpoints 
10.1.1 
IGA 
 Incidence of success in IGA 
Incidence of success in IGA at each timepoint will be compared between the 1% 
OPA-15406 group and the vehicle group, and between the 0.3% OPA-15406 group and 
the vehicle group, and p-value will be calculated, using the Cochran-Mantel-Haenszel 
test stratified by baseline IGA (mild or moderate). The difference in incidence of success 
in IGA between each OPA-15406 group and the vehicle group and its two-sided 95% 
confidence interval (a Mantel-Haenszel estimator of the common risk difference and 
its two-sided 95% confidence interval) will be computed. Additionally, two-sided 95% 
confidence interval for the incidence of success in IGA in each treatment group will also 
be calculated using Clopper-Pearson method. 
The analyses will be applied to the 3 assessments defined in “Section 6.3.1 Response in 
Investigator’s Global Assessment, 2) Sensitivity Analyses.” 
The SAS code to compare the incidence of success in IGA by the 
Cochran-Mantel-Haenszel test and to calculate the difference in incidence of success in 
IGA and its two-sided 95% confidence interval is shown below. 
 
proc freq ; 
 tables BaselineIGA*Treatment*Response/riskdiff(common) cmh; 
run; 
 
 Change from baseline in IGA 
Based on the OC data set, the change from baseline in IGA (at Week 1, Week 2, and 
Week 4; if the timing of discontinuation falls within the allowable window of a 
timepoint, the data at discontinuation will be included as the data for the timepoint) will 
be analyzed using the mixed model repeated measures (MMRM) analysis with treatment 
(0.3% or 1% OPA-15406 group, and vehicle group), timepoint, and interaction between 
treatment and timepoint as factors and baseline IGA as a covariate. An unstructured 
covariance matrix will be used to model the within-subject errors and Kenward-Roger 


Protocol 271-102-00002 
 
 
18 
 
method will be used to calculate the standard error of fixed-effects and the degree of 
freedom. If the MMRM procedure fails to converge under unstructured covariance 
structure, the following structure will be used in the order of 1) heterogeneous toeplitz, 2) 
heterogeneous autoregressive of order 1, 3) heterogeneous compound symmetry and the 
first (co)variance structure converging to the best fit will be used. The least square mean 
of each treatment group will be calculated by timepoint. The difference in the least square 
mean between the vehicle group and each OPA-15406 group, and the two-sided 95% 
confidence interval and p-value will also be calculated at Week 1, Week 2, and Week 4. 
The least square mean and the standard error will be plotted by timepoint for each 
treatment group. 
The SAS code to conduct the MMRM analysis is shown below. 
 
proc mixed method = reml; 
 
class Treatment Visit Subject; 
 
model Change = Treatment Visit Treatment*Visit Baseline/s ddfm = kr; 
 
repeated Visit/type = un sub = Subject; 
 
lsmeans Treatment*Visit/pdiff cl alpha = 0.05; 
run; 
“Baseline” represents the IGA at baseline. 
 
The SAS code to use when the MMRM procedure fails to converge under the 
unstructured covariance structure is shown below. (Designate type = TOEPH for 
heterogeneous toeplitz, type = ARH(1) for heterogeneous autoregressive of order 1, and 
type = CSH for heterogeneous compound symmetry). 
proc mixed method = reml empirical; 
 
class Treatment Visit Subject; 
 
model Change = Treatment Visit Treatment*Visit Baseline/s ; 
 
repeated Visit/type= TOEPH sub = Subject; 
 
lsmeans Treatment*Visit/pdiff cl alpha = 0.05; 
run; 
 


Protocol 271-102-00002 
 
 
19 
 
Based on the OC and LOCF data sets, analysis of covariance (ANCOVA) model with 
treatment (0.3% or 1% OPA-15406 group, and vehicle group) as a factor and baseline 
IGA as a covariate will be applied to the change from baseline up to each timepoint. The 
least square mean of each treatment group will be calculated by timepoint. The difference 
in the least square mean between the vehicle group and each OPA-15406 group, and the 
two-sided 95% confidence interval and p-value will also be calculated at Week 1, Week 
2, and Week 4. Based on the OC and LOCF data sets, measured values and changes from 
baseline in IGA at Week 1, Week 2, and Week 4 will be summarized by treatment group 
using descriptive statistics. 
Shift tables will be created for the change from baseline in IGA (−3, −2, −1, ±0, +1, +2) 
at Week 1, Week 2, and Week 4. 
 
10.1.2 
Changes From Baseline in Overall EASI Score and EASI 
Symptom Scores 
Based on the OC data set, the change from baseline in EASI score (at Week 1, Week 2, 
and Week 4; if the timing of discontinuation falls within the allowable window of a 
timepoint, the data at discontinuation will be included as the data for the timepoint) will 
be analyzed using the MMRM analysis with treatment (0.3% or 1% OPA-15406 group, 
and vehicle group), timepoint, and interaction between treatment and timepoint as factors 
and baseline EASI score as a covariate. An unstructured covariance matrix will be used 
to model the within-subject errors and Kenward-Roger method will be used to calculate 
the standard error of fixed-effects and the degree of freedom. If the MMRM procedure 
fails to converge under unstructured covariance structure, the following structure will be 
used in the order of 1) heterogeneous toeplitz, 2) heterogeneous autoregressive of order 1, 
3) heterogeneous compound symmetry and the first (co)variance structure converging to 
the best fit will be used. 
The least square mean of each treatment group will be calculated by timepoint. For 
overall EASI score, the least square mean and the standard error will be plotted by 
timepoint for each treatment group. The difference in the least square mean between the 
vehicle group and each OPA-15406 group, and the two-sided 95% confidence interval 
and p-value will be calculated at Week 1, Week 2, and Week 4. 
Based on the OC and LOCF data sets, ANCOVA model with treatment (0.3% or 1% 
OPA-15406 group, and vehicle group) as a factor and baseline EASI score as a covariate 
will be applied to the change from baseline up to each timepoint. The least square mean 
in each treatment group will be calculated by timepoint. The difference in the least square 


Protocol 271-102-00002 
 
 
20 
 
mean between the vehicle group and each OPA-15406 group, and the two-sided 
95% confidence interval and p-value will be calculated at Week 1, Week 2, and Week 4. 
Based on the OC and LOCF data sets, measured values and changes from baseline 
in IGA at Week 1, Week 2, and Week 4 will be summarized by treatment group using 
descriptive statistics. For the overall EASI score, the mean with standard error of 
measured values (in the OC and LOCF data sets) will be plotted by timepoint for each 
treatment group. 
EASI scores for body regions (face, neck, and head; upper limbs; trunk; and lower limbs) 
will be analyzed in the same manner as the overall EASI score. 
 
10.1.3 
Change From Baseline in Visual Analogue Scale for Pruritus 
The change from baseline in visual analogue scale (VAS) for pruritus will be analyzed in 
the same manner as that in the overall EASI score or each EASI symptom score. 
 
10.1.4 
Change From Baseline in VRS for Pruritus up to Day 7 
The change from baseline in VRS score for pruritus up to Day 7 will be analyzed in the 
same manner as that in overall EASI score or each EASI symptom score. Data will be 
collected at baseline, 4, 8, and 12 hours after the start of administration, 1 day after the 
start of administration (morning and night), and thereafter in the same manner up to Day 
7 (morning). The same analysis will be performed by the time zone of assessment 
(morning or evening). Morning or evening will be determined based on the time label 
entered in the case report form (CRF), not using the timepoints defined in Table 6.4-2, 
except the baseline, which is irrespective of the time zone of assessment. Data will be 
collected at baseline, and the timepoints specified above on Day 1 to Day 7. 
 
10.1.5 
Change From Baseline in Patient-Oriented Eczema Measure 
Score 
The change from baseline in Patient-Oriented Eczema Measure (POEM) score will be 
analyzed in the same manner as that in the overall EASI score or each EASI symptom 
score. 
 


Protocol 271-102-00002 
 
 
21 
 
10.1.6 
Change From Baseline in Overall Percentage Affected BSA 
The change from baseline in overall percentage affected BSA will be analyzed in the 
same manner as that in the overall EASI score or each EASI symptom score. 
 
10.1.7 
Percent Changes From Baseline in Overall EASI Score, EASI 
Symptom Scores, VAS for Pruritus, and POEM Scores 
The percent changes from baseline in overall EASI score, EASI symptom scores, EASI 
scores for body regions, VAS for pruritus, and POEM score will be analyzed in the same 
manner as the changes from baseline in the respective scores. 
 
10.1.8 
Time to Response in IGA 
For the time to response in IGA (days to the first response in IGA in each subject), a 
cumulative response rate will be computed by treatment group using the Kaplan-Meier 
method and plotted. At each timepoint, the number of subjects (at risk), the p-value of the 
log-rank test comparing the vehicle group and each OPA-15406 group, and the time until 
one half of the subjects have achieved a response (medial survival time [MST]) will be 
provided. Subjects with an IGA of 0 (clear) or 1 (almost clear) with an improvement by 
at least 2 grades from the baseline are defined as responders. The starting point is the 
baseline. Subjects who have failed to achieve a response will be treated as censored on 
the day of the final IGA assessment. 
 
10.1.9 
Time to Response in VRS 
The time to response in VRS (time to the first response in VRS in each subject) will be 
analyzed in the same manner as the time to response in IGA. Subjects with a VRS score 
of 0 (none) or 1 (mild) with an improvement by at least 1 grade from the baseline are 
defined as responders. The starting point is baseline. Subjects who have failed to achieve 
a response will be treated as censored on the day of the final VRS assessment. 
 
10.2 
Other Efficacy Endpoints 
Not applicable. 
 


Protocol 271-102-00002 
 
 
22 
 
10.3 
Adjustments for Covariates 
In the analysis of the incidence of success in IGA, the Cochran-Mantel-Haenszel test 
stratified by baseline IGA (mild or moderate) will be conducted. 
 
10.4 
Subgroup Analysis 
Incidence of success in IGA will also be analyzed in the following subgroups in the same 
manner as described in Section 10.1.1. 
Age: <7 or ≥7 years old 
Gender: Male or female 
Baseline IGA score: 2 (mild) or 3 (moderate) 
 
11 
Pharmacokinetic Analyses 
11.1 
Pharmacokinetics Analysis Set 
The pharmacokinetic analysis set consists of all subjects who have received the IMP at 
least once and have at least one evaluable plasma drug concentration measured. 
 
11.2 
Pharmacokinetic Endpoints 
 Plasma trough concentration of OPA-15406 (predose at Week 1 and Week 4) 
 
11.3 
Method of Calculation of Pharmacokinetic Endpoints 
1) Plasma concentrations below the lower limit of quantification will be treated as 
zero (ng/mL) for the calculation of descriptive statistics. 
2) Plasma trough concentrations will be handled as follows: 
 If the time of the blood sampling was within 6 hours from the last IMP 
administration, the sampling point will be excluded from the analysis. 
 If the treatment area (%) was changed (including non-compliance of IMP) within 
3 days before the sampling point, the sampling point will be excluded from the 
analysis. 
3) The timepoint of blood sampling for the pharmacokinetic endpoint at withdrawal 
will be handled as follows: If the blood sampling at withdrawal meets neither of 
the exclusion criteria in (2) and falls within the allowable window shown below, 
the sampling point will be included in the analyses. If the blood sampling at 


Protocol 271-102-00002 
 
 
23 
 
withdrawal coincides with any pharmacokinetic timepoint, the blood sampling 
at withdrawal will not be included in the analyses. 
Timepoint 
Study Day 
Allowable Window (Day) 
Baseline 
1 
 
- 
1 
Week 1 
8 
4 
- 
22 
Week 4 
29 
23 
- 
50 
 
4) The dose used for the dose adjustment of concentration will be calculated as 
follows: 
Dose (mg) = [the subject’s BSA (m2)] × [treatment area (%)] × [10 g/m2] × 
[formulation strength (0.3% or 1%)] × 1000 
 
11.4 
Method of Display 
1) When plotting the plasma drug concentration-time profile, arithmetic means and 
standard deviations will be used. 
2) Descriptive statistics of the plasma trough concentrations and 
dose(mg)-normalized plasma trough concentrations will be calculated by 
treatment group and pharmacokinetic timepoint. 
3) Descriptive statistics of the total treatment area (%) will be calculated by 
treatment group and pharmacokinetic timepoint. 
4) In 2) or 3) above, when the number of analyzed subjects is zero (0), only the 
number of subjects will be calculated; when only one (1) subject is analyzed, only 
the number of subjects, arithmetic mean, and geometric mean will be calculated; 
and when two (2) subjects are analyzed, only the number of subjects, arithmetic 
mean, geometric mean, and maximum and minimum values will be calculated. 
 
11.5 
Handling of Values 
Among descriptive statistics, the number of subjects will be displayed in integers, and 
minimum and maximum will be displayed as it is in the same number of digits (n-digit) 
as that of an individual value of the target data. For arithmetic mean, geometric mean, 
median, and standard deviation values, a value of “n + 1” figures will be rounded off to 
obtain a value of “n” figures so that the number of digits will be the same number of 
digits (n-digit) as that of an individual value of the target data. For coefficient of variation, 
2 decimal places will be rounded to obtain 1 decimal place. 
 


Protocol 271-102-00002 
 
 
24 
 
12 
Rationale for Target Number of Subjects 
12.1 
Target Number of Subjects 
60 subjects 
 
12.2 
Rationale for the Number of Subjects 
The sample size of 20 subjects for each group, a total of 60 subjects, has been established 
in consideration of the feasibility of the trial and the number of subjects needed to 
evaluate efficacy and safety. Assuming that the probabilities of success in IGA for each 
group are the same as those in the phase 2 trial outside Japan (271-12-205), the expected 
incidence of success in the 1% OPA-15406 group, the 0.3% OPA-15406 group, and the 
vehicle group is 20.93%, 14.63%, and 2.7%, respectively. In that case, the probability of 
the 1% group > the vehicle group, the 0.3% group > the vehicle group, and the 1% group 
minus the vehicle group > 10% in the point estimate of incidence of success is 96.2%, 
88.3%, and 71.5%, respectively. Also, the probability of the 1% group > the 0.3% group 
≥ the vehicle group in point estimate of incidence of success is 60.6%. 
 
13 
Changes From Analysis Planned in the Protocol 
13.1 
Changes From the Efficacy Analyses Planned in the Protocol 
 The factors/covariates included in the MMRM or ANCOVA model were described 
consistently. A categorical variable included in the model was described as a factor, 
and a continuous variable as a covariate. 
Rationale for change: To further clarify the analytical methods  
 
13.2 
Changes From the Pharmacokinetic Analyses Planned in the 
Protocol 
 The descriptive statistics of the plasma trough concentrations of OPA-15406 will not 
be calculated by affected BSA at baseline. The plasma trough concentrations of 
OPA-15406 will be normalized by dose (mg), not by affected BSA.  
Rationale for change: Calculation of dose-normalized plasma trough concentration 
was considered adequate, the concentrations will not be computed by or normalized 
by affected BSA. 
 The descriptive statistics for age, treatment area at baseline, and amount of 
administration will not be calculated by the affected BSA. 


Protocol 271-102-00002 
 
 
25 
 
Rationale for change: These were considered not necessary for interpretation of the 
data. 
 The descriptive statistics of total treatment area (%) will be calculated by treatment 
group and pharmacokinetic timepoint. 
Rationale for change: These were considered necessary for interpretation of the data. 
 
14 
References 
Not applicable. 
 


Protocol 271-102-00002 
 
 
26 
 
15 
Revision History 
Not applicable. 
Table 15-1 
Revision History 
Version Number 
Date of Revision 
Section 
Original Description 
Revised Description 
Reason for Revision 
− 
− 
− 
− 
− 
− 
 
 


Protocol 271-102-00002 
 
 
27 
 
16 
Appendix 
16.1 
Criteria for Potentially Clinically Significant 
Table 16.1-1 
Criteria for Potentially Clinically Significant Vital Sign 
Abnormalities 
TEST 
CRITERIA 1 
CRITERIA 2 
DIASTOLIC BLOOD 
PRESSURE (MMHG) 
DIASTOLIC BLOOD PRESSURE 
(mmHg) < 50 AND DECREASE >= 
15 
DIASTOLIC BLOOD PRESSURE 
(mmHg) > 105 AND INCREASE 
>= 15 
HEART RATE 
(BEATS/MIN) 
HEART RATE (BPM) < 50 AND 
DECREASE >= 15 
HEART RATE (BPM) > 120 AND 
INCREASE >= 15 
SYSTOLIC BLOOD 
PRESSURE (MMHG) 
SYSTOLIC BLOOD PRESSURE 
(mmHg) < 90 AND DECREASE >= 
20 
SYSTOLIC BLOOD PRESSURE 
(mmHg) > 180 AND INCREASE 
>= 20 
TEMPERATURE (°C) 
- 
TEMPERATURE (°C) >= 37.8 
AND INCREASE >= 1.1°C 
WEIGHT (KG) 
WEIGHT (kg) DECREASE >= 7% 
WEIGHT (kg) INCREASE >= 7% 
 
Table 16.1-2 
Criteria for Potentially Clinically Significant ECG 
Abnormalities 
CLASSIFICATION 
CATEGORY 
CRITERIA 
VENT RATE 
OUTLIERS 
NOTABLE 
INCREASES 
25% INCREASE FROM BASELINE AND 
VENTRICULAR RATE > 100 BPM 
VENT RATE 
OUTLIERS 
NOTABLE 
DECREASES 
25% DECREASE FROM BASELINE AND 
VENTRICULAR RATE < 50 BPM 
PR OUTLIERS 
NOTABLE CHANGES 
>= 25% CHANGE FROM BASELINE WHEN PR > 
200 MSEC 
QRS OUTLIERS 
NOTABLE CHANGES 
>= 25% CHANGE FROM BASELINE WHEN QRS 
> 100 MSEC 
QT 
NEW ONSET (>= 450 
MSEC) 
NEW ONSET (>= 450 MSEC) IN QT MEANS A 
SUBJECT WHO ATTAINS A VALUE >= 450 
MSEC DURING TREATMENT PERIOD BUT 
NOT AT EACH BASELINE 
QTcB 
NEW ONSET (>= 450 
MSEC) IN MALE OR 
(>= 470 MSEC) IN 
FEMALE 
NEW ONSET (>= 450 MSEC IN MALE OR >= 470 
MSEC IN FEMALE) IN QTCB MEANS A 
SUBJECT WHO ATTAINS A VALUE >= 450 OR 
>= 470 MSEC DURING TREATMENT PERIOD 
BUT NOT AT EACH BASELINE 
QTcB 
NEW ONSET (>= 450 
MSEC) AND >= 10% 
INCREASE 
NEW ONSET (>= 450 MSEC) AND >= 10% 
INCREASE IN QTCB MEANS A SUBJECT WHO 
ATTAINS A VALUE >= 450 MSEC AND >= 10% 
INCREASE DURING TREATMENT PERIOD 
BUT NOT AT EACH BASELINE 
QTcB 
INCREASE 30 - 60 
MSEC 
INCREASE IN CHANGE FROM BASELINE 
VALUE >= 30 AND <= 60 MSEC 
QTcB 
INCREASE > 60 MSEC 
INCREASE IN CHANGE FROM BASELINE 
VALUE > 60 MSEC 


Protocol 271-102-00002 
 
 
28 
 
Table 16.1-2 
Criteria for Potentially Clinically Significant ECG 
Abnormalities 
CLASSIFICATION 
CATEGORY 
CRITERIA 
QTcF 
NEW ONSET (>= 450 
MSEC) IN MALE OR 
(>= 470 MSEC) IN 
FEMALE 
NEW ONSET (>= 450 MSEC IN MALE OR >= 470 
MSEC IN FEMALE) IN QTCB MEANS A 
SUBJECT WHO ATTAINS A VALUE >= 450 OR 
>= 470 MSEC DURING TREATMENT PERIOD 
BUT NOT AT EACH BASELINE 
QTcF 
NEW ONSET (>= 450 
MSEC) AND >= 10% 
INCREASE 
NEW ONSET (>= 450 MSEC) AND >= 10% 
INCREASE IN QTCB MEANS A SUBJECT WHO 
ATTAINS A VALUE >= 450 MSEC AND >= 10% 
INCREASE DURING TREATMENT PERIOD 
BUT NOT AT EACH BASELINE 
QTcF 
INCREASE 30 - 60 
MSEC 
INCREASE IN CHANGE FROM BASELINE 
VALUE >= 30 AND <= 60 MSEC 
QTcF 
INCREASE > 60 MSEC 
INCREASE IN CHANGE FROM BASELINE 
VALUE > 60 MSEC 
 
16.2 
Table of Contents 
CT-1 Subject Disposition 
CT-2 Reasons for Discontinuation 
CT-3 Demographic Characteristics 
CT-4.1 Concomitant Medications: Medications Taken Prior to Start of Study Therapy 
CT-4.2 Concomitant Medications: Medications Taken During Study Therapy 
CT-4.3 Concomitant Medications: Medications Taken After Study Therapy 
CT-5.1.1 Analysis of Responder Rate for Overall IGA Score 
CT-5.1.2 Sensitivity Analysis of Responder Rate for Overall IGA Score - LOCF 
CT-5.1.3 Sensitivity Analysis of Responder Rate for Overall IGA Score - OC 
CT-5.1.4 Sensitivity Analysis of Responder Rate for Overall IGA Score - Revised 
Responder Definition 
CT-5.1.5 Shift Tables of Overall IGA Score - OC 
CT-5.1.6 Shift Tables of Overall IGA Score - LOCF 
CT-5.2.1 Analysis of Baseline and Change from Baseline in Overall IGA Score - 
MMRM 
CT-5.2.2 Analysis of Baseline and Change from Baseline in Overall IGA Score - 
ANCOVA OC 


Protocol 271-102-00002 
 
 
29 
 
CT-5.2.3 Analysis of Baseline and Change from Baseline in Overall IGA Score - 
ANCOVA LOCF 
CT-5.3.1.1 Analysis of Baseline and Change from Baseline in Overall EASI Score - 
MMRM 
CT-5.3.1.2 Analysis of Baseline and Change from Baseline in Overall EASI Score - 
ANCOVA OC 
CT-5.3.1.3 Analysis of Baseline and Change from Baseline in Overall EASI Score - 
ANCOVA LOCF 
CT-5.3.1.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score - MMRM 
CT-5.3.1.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score - ANCOVA OC 
CT-5.3.1.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score - ANCOVA LOCF 
CT-5.3.2.1 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Erythema - MMRM 
CT-5.3.2.2 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Erythema - ANCOVA OC 
CT-5.3.2.3 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Erythema - ANCOVA LOCF 
CT-5.3.2.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Erythema - MMRM 
CT-5.3.2.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Erythema - ANCOVA OC 
CT-5.3.2.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Erythema - ANCOVA LOCF 
CT-5.3.3.1 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Induration/Papulation - MMRM 
CT-5.3.3.2 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Induration/Papulation - ANCOVA OC 
CT-5.3.3.3 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Induration/Papulation - ANCOVA LOCF 


Protocol 271-102-00002 
 
 
30 
 
CT-5.3.3.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Induration/Papulation - MMRM 
CT-5.3.3.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Induration/Papulation - ANCOVA OC 
CT-5.3.3.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Induration/Papulation - ANCOVA LOCF 
CT-5.3.4.1 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Excoriation - MMRM 
CT-5.3.4.2 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Excoriation - ANCOVA OC 
CT-5.3.4.3 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Excoriation - ANCOVA LOCF 
CT-5.3.4.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Excoriation - MMRM 
CT-5.3.4.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Excoriation - ANCOVA OC 
CT-5.3.4.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Excoriation - ANCOVA LOCF 
CT-5.3.5.1 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Lichenification - MMRM 
CT-5.3.5.2 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Lichenification - ANCOVA OC 
CT-5.3.5.3 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Lichenification - ANCOVA LOCF 
CT-5.3.5.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Lichenification - MMRM 
CT-5.3.5.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Lichenification - ANCOVA OC 
CT-5.3.5.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Lichenification - ANCOVA LOCF 
CT-5.3.6.1 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
HEAD/NECK - MMRM 


Protocol 271-102-00002 
 
 
31 
 
CT-5.3.6.2 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
HEAD/NECK - ANCOVA OC 
CT-5.3.6.3 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
HEAD/NECK - ANCOVA LOCF 
CT-5.3.6.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, HEAD/NECK - MMRM 
CT-5.3.6.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, HEAD/NECK - ANCOVA OC 
CT-5.3.6.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, HEAD/NECK - ANCOVA LOCF 
CT-5.3.7.1 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
UPPER LIMBS - MMRM 
CT-5.3.7.2 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
UPPER LIMBS - ANCOVA OC 
CT-5.3.7.3 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
UPPER LIMBS - ANCOVA LOCF 
CT-5.3.7.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, UPPER LIMBS - MMRM 
CT-5.3.7.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, UPPER LIMBS - ANCOVA OC 
CT-5.3.7.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, UPPER LIMBS - ANCOVA LOCF 
CT-5.3.8.1 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
TRUNK - MMRM 
CT-5.3.8.2 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
TRUNK - ANCOVA OC 
CT-5.3.8.3 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
TRUNK - ANCOVA LOCF 
CT-5.3.8.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, TRUNK - MMRM 
CT-5.3.8.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, TRUNK - ANCOVA OC 


Protocol 271-102-00002 
 
 
32 
 
CT-5.3.8.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, TRUNK - ANCOVA LOCF 
CT-5.3.9.1 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
LOWER LIMBS - MMRM 
CT-5.3.9.2 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
LOWER LIMBS - ANCOVA OC 
CT-5.3.9.3 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
LOWER LIMBS - ANCOVA LOCF 
CT-5.3.9.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, LOWER LIMBS - MMRM 
CT-5.3.9.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, LOWER LIMBS - ANCOVA OC 
CT-5.3.9.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, LOWER LIMBS - ANCOVA LOCF 
CT-5.4.1 Analysis of Baseline and Change from Baseline in VAS for Pruritus Score - 
MMRM 
CT-5.4.2 Analysis of Baseline and Change from Baseline in VAS for Pruritus Score - 
ANCOVA OC 
CT-5.4.3 Analysis of Baseline and Change from Baseline in VAS for Pruritus Score - 
ANCOVA LOCF 
CT-5.4.4 Analysis of Baseline and Percent Change from Baseline in VAS for Pruritus 
Score - MMRM 
CT-5.4.5 Analysis of Baseline and Percent Change from Baseline in VAS for Pruritus 
Score - ANCOVA OC 
CT-5.4.6 Analysis of Baseline and Percent Change from Baseline in VAS for Pruritus 
Score - ANCOVA LOCF 
CT-5.5.1 Analysis of Baseline and Change from Baseline in Overall Percentage 
Affected Body Surface Area - MMRM 
CT-5.5.2 Analysis of Baseline and Change from Baseline in Overall Percentage 
Affected Body Surface Area - ANCOVA OC 
CT-5.5.3 Analysis of Baseline and Change from Baseline in Overall Percentage 
Affected Body Surface Area - ANCOVA LOCF 


Protocol 271-102-00002 
 
 
33 
 
CT-5.6.1 Analysis of Baseline and Change from Baseline in POEM Score - MMRM 
CT-5.6.2 Analysis of Baseline and Change from Baseline in POEM Score - 
ANCOVA OC 
CT-5.6.3 Analysis of Baseline and Change from Baseline in POEM Score - 
ANCOVA LOCF 
CT-5.6.4 Analysis of Baseline and Percent Change from Baseline in POEM Score - 
MMRM 
CT-5.6.5 Analysis of Baseline and Percent Change from Baseline in POEM Score - 
ANCOVA OC 
CT-5.6.6 Analysis of Baseline and Percent Change from Baseline in POEM Score - 
ANCOVA LOCF 
CT-5.7.1 Analysis of Baseline and Change from Baseline in VRS for Pruritus Score - 
MMRM 
CT-5.7.2 Analysis of Baseline and Change from Baseline in VRS for Pruritus Score - 
ANCOVA OC 
CT-5.7.3 Analysis of Baseline and Change from Baseline in VRS for Pruritus Score - 
ANCOVA LOCF 
CT-5.7.4 Analysis of Baseline and Change from Baseline in VRS for Pruritus Score 
(Morning / Evening) - MMRM 
CT-5.7.5 Analysis of Baseline and Change from Baseline in VRS for Pruritus Score 
(Morning / Evening) - ANCOVA OC 
CT-5.8.1 Subgroup Analysis of Responder Rate for Overall IGA Score - by Age 
CT-5.8.2 Subgroup Analysis of Responder Rate for Overall IGA Score - by Gender 
CT-5.8.3 Subgroup Analysis of Responder Rate for Overall IGA Score - by IGA 
Score at Baseline 
CT-7.1.1 Summary of Treatment Compliance 
CT-7.1.2 Summary of Treatment Compliance for Number of Administrations 
CT-7.2 Extent of Exposure to Trial Medication 
CT-8.1.1 Adverse Events (All Causalities) 
CT-8.1.2 Adverse Events According to Application Site (All Causalities) 
CT-8.2.1.1 Incidence of Treatment-emergent Adverse Events by System Organ Class 


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CT-8.2.1.2 Incidence of Treatment-emergent Adverse Events by System Organ Class 
CT-8.2.1.3 Incidence of Treatment-emergent Adverse Events by System Organ Class 
CT-8.2.2.1 Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term 
CT-8.2.2.2 Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term 
CT-8.2.2.3 Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term 
CT-8.2.3.1 Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Severity 
CT-8.2.3.2 Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Severity 
CT-8.2.3.3 Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Severity 
CT-8.2.4.1 Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and CTCAE Grade 
CT-8.2.4.2 Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and CTCAE Grade 
CT-8.2.4.3 Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and CTCAE Grade 
CT-8.3.1.1 Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class 
CT-8.3.1.2 Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class 
CT-8.3.1.3 Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class 
CT-8.3.2.1 Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class and Preferred Term 
CT-8.3.2.2 Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class and Preferred Term 
CT-8.3.2.3 Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class and Preferred Term 


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CT-8.3.3.1 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class, Preferred Term and Severity 
CT-8.3.3.2 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class, Preferred Term and Severity 
CT-8.3.3.3 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class, Preferred Term and Severity 
CT-8.3.4.1 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class, Preferred Term and CTCAE Grade 
CT-8.3.4.2 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class, Preferred Term and CTCAE Grade 
CT-8.3.4.3 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class, Preferred Term and CTCAE Grade 
CT-8.4.1.1 Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class 
CT-8.4.1.2 Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class 
CT-8.4.1.3 Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class 
CT-8.4.2.1 Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class and Preferred Term 
CT-8.4.2.2 Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class and Preferred Term 
CT-8.4.2.3 Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class and Preferred Term 
CT-8.5.1.1 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class 
CT-8.5.1.2 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class 
CT-8.5.1.3 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class 
CT-8.5.2.1 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class and Preferred Term 


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CT-8.5.2.2 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class and Preferred Term 
CT-8.5.2.3 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class and Preferred Term 
CT-8.5.3.1 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and Severity 
CT-8.5.3.2 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and Severity 
CT-8.5.3.3 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and Severity 
CT-8.5.4.1 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and CTCAE Grade 
CT-8.5.4.2 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and CTCAE Grade 
CT-8.5.4.3 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and CTCAE Grade 
CT-8.6.1.1 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class 
CT-8.6.1.2 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class 
CT-8.6.1.3 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class 
CT-8.6.2.1 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.6.2.2 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.6.2.3 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.6.3.1 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.6.3.2 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 


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CT-8.6.3.3 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.6.4.1 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.6.4.2 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.6.4.3 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.7.1.1 Incidence of Treatment-emergent Adverse Events Greater Than or Equal 
to 5% in Any Group by System Organ Class and Preferred Term 
CT-8.7.1.2 Incidence of Treatment-emergent Adverse Events Greater Than or Equal 
to 5% in Any Group by System Organ Class and Preferred Term 
CT-8.7.1.3 Incidence of Treatment-emergent Adverse Events Greater Than or Equal 
to 5% in Any Group by System Organ Class and Preferred Term 
CT-8.8.1.1 Incidence of Non-Serious Treatment-emergent Adverse Events Greater 
Than or Equal to 5% in Any Group by System Organ Class and Preferred Term 
CT-8.8.1.2 Incidence of Non-Serious Treatment-emergent Adverse Events Greater 
Than or Equal to 5% in Any Group by System Organ Class and Preferred Term 
CT-8.8.1.3 Incidence of Non-Serious Treatment-emergent Adverse Events Greater 
Than or Equal to 5% in Any Group by System Organ Class and Preferred Term 
CT-8.9.1.1 Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term According to Application Site 
CT-8.9.1.2 Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term According to Application Site 
CT-8.9.1.3 Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term According to Application Site 
CT-8.10.1.1 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class and Preferred Term According to Application Site 
CT-8.10.1.2 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class and Preferred Term According to Application Site 
CT-8.10.1.3 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class and Preferred Term According to Application Site 


Protocol 271-102-00002 
 
 
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CT-9.1 Listing of Deaths 
CT-9.2 Listing of Serious Adverse Events 
CT-9.3 Listing of Study Drug Discontinuations Due to Adverse Events 
CT-9.4 Incidence of Potential Hy's Law Cases 
CT-9.5 Listing of Potential Hy's Law Cases - by Subject 
CT-10.1.1 Mean Change From Baseline in Laboratory Test Values: Serum Chemistry 
CT-10.1.2 Mean Change From Baseline in Laboratory Test Values: Hematology 
CT-10.2.1 Shift Tables of Clinical Laboratory Test Results: Serum Chemistry 
CT-10.2.2 Shift Tables of Clinical Laboratory Test Results: Hematology 
CT-10.2.3 Shift Tables of Clinical Laboratory Test Results: Urinalysis 
CT-11.1 Mean Change From Baseline in Vital Sign Parameters 
CT-11.2 Listing of Vital Signs Abnormalities 
CT-11.3 Incidence of Potential Clinical Significance in Vital Signs 
CT-11.4 Criteria for Vital Signs Potential Clinical Significance 
CT-12.1 Mean Change From Baseline in ECG Evaluations 
CT-12.2 Incidence of Categorical Changes in ECG Evaluations 
CT-12.3 Listing of Categorical Changes in ECG Evaluations 
CT-12.4 Criteria for Categorical Changes in ECG Evaluations 
 
PKT-1.1 Individual and Summary of OPA-15406 Plasma Trough Concentrations 
Following Topical Administration of 0.3 % OPA-15406 Ointment to Child Subjects 
With Atopic Dermatitis 
PKT-1.2 Individual and Summary of OPA-15406 Plasma Trough Concentrations 
Following Topical Administration of 1 % OPA-15406 Ointment to Child Subjects 
With Atopic Dermatitis 
PKT-2.1 Individual and Summary of Normalized OPA-15406 Plasma Trough 
Concentrations by Dose Derived From % BSA Treated Following Topical 
Administration of 0.3 % OPA-15406 Ointment to Child Subjects With Atopic 
Dermatitis 


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PKT-2.2 Individual and Summary of Normalized OPA-15406 Plasma Trough 
Concentrations by Dose Derived From % BSA Treated Following Topical 
Administration of 1 % OPA-15406 Ointment to Child Subjects With Atopic 
Dermatitis 
PKF-1.1 Mean OPA-15406 Plasma Trough Concentrations Following Topical 
Administration of OPA-15406 Ointment to Child Subject With Atopic Dermatitis 
PKF-1.2 Mean Normalized OPA-15406 Plasma Trough Concentrations by Dose 
Derived From % BSA Treated Following Topical Administration of OPA-15406 
Ointment to Child Subject With Atopic Dermatitis 
 
PDATA-1.1 Inclusion and Exclusion Criteria 
PDATA-1.2 Subject Disposition 
PDATA-2.1 Medical History 
PDATA-2.2 History of Atopic Dermatitis 
PDATA-3.1 Concomitant Medications: Medications Taken Prior to Start of Study 
Therapy 
PDATA-3.2 Concomitant Medications: Medications Taken During Study Therapy 
PDATA-3.3 Concomitant Medications: Medications Taken After Study Therapy 
PDATA-4.1 Exposure to Trial Medication 
PDATA-4.2 Listing of Trial Medication by Subject 
PDATA-5.1 Physical Examination 
PDATA-6 Adverse Events 
PDATA-7 Vital Signs 
PDATA-8 Electrocardiogram Results 
PDATA-9 Blood Sampling for Pharmacokinetics 
PDATA-10 Screening Failures 
PDATA-11 Protocol Deviations (Major) - CRF 
PDATA-12 Patch Application and Removal 
PDATA-13 Eczema Area and Severity Index 
PDATA-14 Visual Analog Scale for Pruritus 


Protocol 271-102-00002 
 
 
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PDATA-15 Verbal Rating Scale 
PDATA-16 Overall Investigator's Global Assessment of Disease Severity 
PDATA-17 Patient-Oriented Eczema Measure 
PDATA-18 Affected Body Surface Area 
PDATA-19 Treatment Area 
 
DREAS-1 Discontinued Subjects and Reasons for Discontinuations 
 
DEMOG-1 Demographic Characteristics 
DEMOG-2 Informed Consent 
 
AE-1 Adverse Events 
 
SMED-1 Investigational Medicinal Product Compliance 
SMED-2 Actual Exposure to Study Medication 
SMED-3 Investigational Medicinal Product Compliance for Number of 
Administrations 
 
EFF-1 Change from Baseline in IGA Score and Response with Overall IGA Score 
EFF-2 Change from Baseline in Total EASI Score 
EFF-3 Change from Baseline in EASI Score, Erythema 
EFF-4 Change from Baseline in EASI Score, Induration/Papulation 
EFF-5 Change from Baseline in EASI Score, Excoriation 
EFF-6 Change from Baseline in EASI Score, Lichenification 
EFF-7 Change from Baseline in EASI Score, HEAD/NECK 
EFF-8 Change from Baseline in EASI Score, UPPER LIMBS 
EFF-9 Change from Baseline in EASI Score, TRUNK 
EFF-10 Change from Baseline in EASI Score, LOWER LIMBS 


Protocol 271-102-00002 
 
 
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EFF-11 Change from Baseline in VAS Score 
EFF-12 Change from Baseline in Overall Percentage Affected Body Surface Area 
EFF-13 Change from Baseline in POEM Score 
EFF-14 Change from Baseline in VRS Score 
 
LAB-1 Laboratory Test Results: Serum Chemistry 
LAB-2 Laboratory Test Results: Hematology 
LAB-3 Laboratory Test Results: Urinalysis 
 
PDEV-1 Summary of Subjects with Major Protocol Deviations by Type of Deviation 
 
SUBEX-1 Subjects Excluded From Analysis Set