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: PHASE2
Conditions: Atopic Dermatitis
Sponsor: Otsuka Pharmaceutical Co., Ltd.

 
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 
 
Confidential - Proprietary Information 
 
 
2
Version 1.0, 06 Oct 2016 
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 
 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
3
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
4
Version 1.0, 06 Oct 2016 
 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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
5
Version 1.0, 06 Oct 2016 
(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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
6
Version 1.0, 06 Oct 2016 
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  
 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
7
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
8
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
9
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
10 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
11 
Version 1.0, 06 Oct 2016 
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 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
12 
Version 1.0, 06 Oct 2016 
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 
 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
13 
Version 1.0, 06 Oct 2016 
List of In-text Figures 
Figure 3.1-1 
Trial Design Schematic ..................................................................33 
 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
14 
Version 1.0, 06 Oct 2016 
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 
 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
15 
Version 1.0, 06 Oct 2016 
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 
 
 
 
 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
16 
Version 1.0, 06 Oct 2016 
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 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
17 
Version 1.0, 06 Oct 2016 
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. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
18 
Version 1.0, 06 Oct 2016 
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%). 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
19 
Version 1.0, 06 Oct 2016 
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-

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
20 
Version 1.0, 06 Oct 2016 
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. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
21 
Version 1.0, 06 Oct 2016 
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) 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
22 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
23 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
24 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
25 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
26 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
27 
Version 1.0, 06 Oct 2016 
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).   
 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
28 
Version 1.0, 06 Oct 2016 
 
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. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
29 
Version 1.0, 06 Oct 2016 
 
 
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) 
 
 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
30 
Version 1.0, 06 Oct 2016 
 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
31 
Version 1.0, 06 Oct 2016 
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. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
32 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
33 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
34 
Version 1.0, 06 Oct 2016 
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. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
35 
Version 1.0, 06 Oct 2016 
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). 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
36 
Version 1.0, 06 Oct 2016 
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. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
37 
Version 1.0, 06 Oct 2016 
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. 
 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
38 
Version 1.0, 06 Oct 2016 
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, 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
39 
Version 1.0, 06 Oct 2016 
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 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
40 
Version 1.0, 06 Oct 2016 
[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] 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
41 
Version 1.0, 06 Oct 2016 
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.” 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
42 
Version 1.0, 06 Oct 2016 
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. 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
43 
Version 1.0, 06 Oct 2016 
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 
 
 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
44 
Version 1.0, 06 Oct 2016 
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. 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
45 
Version 1.0, 06 Oct 2016 
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) 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
46 
Version 1.0, 06 Oct 2016 
 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. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
47 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
48 
Version 1.0, 06 Oct 2016 
 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.) 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
49 
Version 1.0, 06 Oct 2016 
 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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
50 
Version 1.0, 06 Oct 2016 
 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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
51 
Version 1.0, 06 Oct 2016 
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.   

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
52 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
53 
Version 1.0, 06 Oct 2016 
 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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
54 
Version 1.0, 06 Oct 2016 
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. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
55 
Version 1.0, 06 Oct 2016 
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. 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
56 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
57 
Version 1.0, 06 Oct 2016 
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.) 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
58 
Version 1.0, 06 Oct 2016 
 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, 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
59 
Version 1.0, 06 Oct 2016 
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. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
60 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
61 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
62 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
63 
Version 1.0, 06 Oct 2016 
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. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
64 
Version 1.0, 06 Oct 2016 
 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. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
65 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
66 
Version 1.0, 06 Oct 2016 
(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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
67 
Version 1.0, 06 Oct 2016 
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. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
68 
Version 1.0, 06 Oct 2016 
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. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
69 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
70 
Version 1.0, 06 Oct 2016 
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. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
71 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
72 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
73 
Version 1.0, 06 Oct 2016 
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. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
74 
Version 1.0, 06 Oct 2016 
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 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
75 
Version 1.0, 06 Oct 2016 
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. 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
76 
Version 1.0, 06 Oct 2016 
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) 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
77 
Version 1.0, 06 Oct 2016 
 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; 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
78 
Version 1.0, 06 Oct 2016 
 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. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
79 
Version 1.0, 06 Oct 2016 
 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. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
80 
Version 1.0, 06 Oct 2016 
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. 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
81 
Version 1.0, 06 Oct 2016 
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 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
82 
Version 1.0, 06 Oct 2016 
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. 
1986;49:74-80. 
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 
competent. Exp Dermatol. 2010;19:483-492. 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
83 
Version 1.0, 06 Oct 2016 
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. 
 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
84 
Version 1.0, 06 Oct 2016 
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 
 
 
 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
85 
Version 1.0, 06 Oct 2016 
Appendix 2 
Visual Analogue Scale (VAS) Sheet for Pruritus 
 
 
 
 
 
 
 
 
No Itching 
Maximum Itching 
0 
100 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
86 
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 
 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
87 
Version 1.0, 06 Oct 2016 
 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
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 
% 

 
 
Protocol 271-102-00002 
 
Confidential - Proprietary Information 
 
 
89 
Version 1.0, 06 Oct 2016 
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 
%