Conditions: Atopic Dermatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 251
Healthy volunteers: no

Brief summary:
To demonstrate the superiority of the investigational medicinal product (IMP; 0.3% OPA-15406 ointment, 1% OPA-15406 ointment, or vehicle) to the vehicle when administered twice daily for 4 weeks using success rate in Investigator's Global Assessment (IGA) at Week 4 as the primary endpoint in pediatric patients with Atopic Dermatitis (AD).

Detailed description:

Arms:
arm 1: Twice daily arm 2: Twice daily arm 3: Twice daily

Interventions: intervention 1: 0.3% OPA-15406 intervention 2: 1% OPA-15406 intervention 3: Placebos
Intervention descriptions: intervention 1: Twice daily intervention 2: Twice daily intervention 3: Twice daily

Protocol document:
Prot_001.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A Multicenter, Randomized, Double-blind, Vehicle-controlled, Parallel-group 
Comparison Trial to Demonstrate the Superiority of 0.3% and 1% OPA-15406 
Ointment to the Vehicle in Pediatric Patients with Atopic Dermatitis (Phase 3 Trial) 
 
 
 
NCT Number: NCT03911401 
PRT NO.: 271-102-00008 
Version Date: 01 February 2019 (Version 3.0) 


Protocol 271-102-00008
Confidential - Proprietary Information
Version 2.0, 14 Dec 2018
Otsuka Pharmaceutical Co., Ltd.
Investigational Medicinal Product
OPA-15406
CLINICAL PROTOCOL
<Protocol Title>
A Multicenter, Randomized, Double-blind, Vehicle-controlled, Parallel-group 
Comparison Trial to Demonstrate the Superiority of 0.3% and 1% OPA-15406 Ointment 
to the Vehicle in Pediatric Patients with Atopic Dermatitis (Phase 3 Trial)
Protocol No. 271-102-00008
(Translated Version)
CONFIDENTIAL – PROPRIETARY INFORMATION
Clinical Development Phase:
3
Sponsor:
Otsuka Pharmaceutical Co., Ltd.
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_271-102-00008@otsuka.jp
Issue Date:
1 Feb 2019
Version No.:
3.0
Date of Translation
09 Apr 2019


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Protocol Synopsis
Name of Sponsor: Otsuka Pharmaceutical Co., Ltd.
Name of Investigational Medicinal Product: 
OPA-15406
Protocol No.: 271-102-00008
Protocol Title:
A Multicenter, Randomized, Double-blind, Vehicle controlled, 
Parallel-group Comparison Trial to Demonstrate the 
Superiority of 0.3% and 1% OPA-15406 Ointment to the 
Vehicle in Pediatric Patients with Atopic Dermatitis (Phase 3 
Trial)
Clinical Phase/Trial 
Type:
Phase: 3
Type of trial: Confirmatory trial
Treatment Indication: Atopic dermatitis (AD)
Objective(s):
Primary Objective: To demonstrate the superiority of the 
investigational medicinal product (IMP; 0.3% OPA-15406
ointment, 1% OPA-15406 ointment, or vehicle) to the vehicle 
when administered twice daily for 4 weeks using success rate 
in Investigator’s Global Assessment (IGA) at Week 4 as the 
primary endpoint in pediatric patients with AD.
Secondary Objective: To evaluate the efficacy (secondary 
endpoint) and safety of the IMP (0.3% OPA-15406 ointment, 
1% OPA-15406 ointment, or vehicle) when administered twice 
daily for 4 weeks in pediatric patients with AD and to confirm 
the dose-response relationship.
Trial Design:
Multicenter, randomized, double-blind, vehicle-controlled, 
parallel-group comparison trial
Subject Population:
Pediatric patients with AD and IGA score of 2 or 3
240 subjects in total (the target inclusion ratio for “2 - 6 years” 
to “7 - 14 years” of age is 1:1)
Inclusion/Exclusion 
Criteria:
Main inclusion criteria

Age: 2 to 14 years, inclusive (at time of obtaining informed 
consent)

Able to obtain written informed consent from the subject’s 
legal guardian.

Diagnosis of AD based on the Japanese Dermatological 
Association’s criteria (refer to Appendix 1)

Atopic dermatitis affecting ≥5% to ≤40% of body surface 
area (BSA, excluding scalp) at the screening and baseline 
examinations


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
IGA score of 2 or 3 at the screening and baseline 
examinations
Main exclusion criteria

Subjects who have an AD or contact dermatitis flare-up 
defined as a rapid intensification of AD, within 28 days 
prior to the baseline examination.

Subjects who are unable to stop using ultraviolet light A 
(UVA) therapy, narrowband ultraviolet B (NB-UVB)
therapy, or ultraviolet light B (UVB) from 28 days prior to 
the baseline examination until the Week 4 examination.

Subjects who are unable to stop using systemic 
corticosteroids, systemic immunosuppressants, systemic 
antimetabolites, systemic retinoids and biologics from 28 
days prior to the baseline examination until the Week 4 
examination.

Subjects who are unable to stop using topical 
corticosteroids for skin (excluding scalp) categorized as 
very strong or higher potency in the “Guidelines for 
Management of Atopic Dermatitis” from 21 days prior to 
the baseline examination until the Week 4 examination.

Subjects who are unable to stop using topical 
corticosteroids for skin (excluding scalp) categorized as 
strong potency in the “Guidelines for Management of 
Atopic Dermatitis,” topical corticosteroids other than those 
for skin, topical immunosuppressants, topical retinoids, 
topical antihistamine, and topical non-steroidal 
anti-inflammatory drugs (excluding for scalp) from 7 days 
prior to the baseline examination until the Week 4 
examination. However, intra-ocular, intra-nasal, intra-
auricular, and inhaled corticosteroids and intra-ocular, 
intra-nasal, and inhaled corticosteroids antihistamines may 
be considered if the investigator or subinvestigator judges 
that their use will not impact assessment of the affected 
area.

Subjects who are unable to stop using topical 
corticosteroids for skin (excluding scalp) categorized as 
low or medium potency in the “Guidelines for
Management of Atopic Dermatitis” from 4 days prior to 
the baseline examination until the Week 4 examination.

Subjects who are unable to continue in the trial without 
changing the dosage and administration of systemic 
antihistamines, sodium cromoglicate, tranilast, or suplatast 


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tosilate from 7 days prior to the baseline examination until 
the Week 4 examination
Trial Sites:
Approximately 30 sites in Japan


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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 administration for 4 weeks
Trial Assessments:
Efficacy: IGA, Eczema Area and Severity Index (EASI), 
Verbal Rating Scale (VRS) for pruritus, Patient-Oriented 
Eczema Measure (POEM), affected BSA
Safety: Adverse events, physical examination, vital signs, body 
weight, and clinical laboratory values
Screening/Other: Medical history, previous medications and 
pregnancy test
Criteria for 
Evaluation:
Primary Endpoint: Success rate in IGA at Week 4: Percentage 
of subjects in whom IGA score is 0 or 1 and improved at least 
2 grades from baseline.
Secondary Endpoints: Success rate in IGA at Week 4: 
Percentage of subjects in whom IGA score improves to 0 or 1, 
success rates in EASI 75 (improvement ≥75% in EASI), EASI 
90 (improvement ≥90% in EASI), and EASI 50 (improvement 
≥50% in EASI) at Week 4, changes from baseline in each 
parameter (IGA, EASI, VRS for pruritus [7 - 14 years of age 
only], POEM, affected BSA) at Week 4, and change in VRS 
for pruritus from baseline to Day 7.
Criteria for Safety Evaluation: Adverse events, clinical 
laboratory values, vital signs, and body weight.
Statistical Methods:
The superiority of the 0.3% and 1% OPA-15406 group to the 
vehicle group will be demonstrated based on the primary 
endpoint, success rate in IGA at Week 4 in the full analysis set 
(FAS). Overall type I errors will be controlled using a closed 
testing procedure. First, the 1% OPA-15406 treatment group 
and the vehicle group will be compared. If significant at the
two-sided significance level of 5%, the 0.3% OPA-15406 
treatment group and the vehicle group will then be compared 
at the two-sided significance level of 5%. 
The Cochran-Mantel-Haenszel test will be conducted for 
comparison using the baseline IGA (2 or 3) and age (“2 - 6 
years” or “7 - 14 years”) as a stratification factor.
The difference in the success rate in IGA and its two-sided 
95% confidence interval (common risk difference adjusted by 
Mantel Haenszel method and its two-sided 95% confidence 


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interval) between the vehicle group and 0.3% or the 1% 
OPA-15406 group will be determined. Also, the two-sided 
95% confidence interval of the success rate in IGA in each 
treatment group (based on Clopper-Pearson method) will be 
calculated.
Trial Duration:
Duration of the trial: Mar 2019 to Nov 2019
Screening period: 2 to 30 days
Assessment period: 4 weeks


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Table of Contents 
Protocol Synopsis...........................................................................................2
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 ........................................................................................18
1.1
Nonclinical Study Results .................................................................................19
1.2
Clinical Study Results .......................................................................................21
1.2.1
Phase 1 Trial in Healthy Adult Subjects in the United States (Trial 
271-11-202) ....................................................................................................21
1.2.2
Phase 1 Trial in Healthy Adult Male Subjects in Japan (Trial 
271-14-001) ....................................................................................................21
1.2.3
Trial for Phototoxicity in Healthy Adult Subjects in the United States 
(Trial 271-12-212) ..........................................................................................22
1.2.4
Trial for Photoallergy in Healthy Adult Subjects in the United States 
(Trial 271-12-213) ..........................................................................................22
1.2.5
Phase 1 Trial in Atopic Dermatitis Patients in the United States (Trial 
271-12-204) ....................................................................................................22
1.2.6
Phase 2 Trial in Atopic Dermatitis Patients Outside Japan (Trial 
271-12-205) ....................................................................................................23
1.2.7
Pharmacokinetic Phase 2 Trial in Atopic Dermatitis Patients Outside 
Japan (Trial MEDI-MM 36-206)....................................................................24
1.2.8
Phase 2 Trial in Adult Atopic Dermatitis Patients in Japan (Trial 
271-15-001) ....................................................................................................24
1.2.9
Phase 2 Trial in Pediatric Atopic Dermatitis Patients in Japan (Trial 
271-102-00002) ..............................................................................................25
1.3
Known and Potential Risks and Benefits ..........................................................26
2
Trial Rationale and Objectives..........................................................27
2.1
Trial Rationale...................................................................................................27
2.2
Dosing Rationale...............................................................................................28
2.3
Rationale for Severity and Age Setting.............................................................29
2.4
Trial Objectives.................................................................................................29


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3
Trial Design.........................................................................................29
3.1
Type/Design of Trial .........................................................................................29
3.2
Methods of Administration ...............................................................................31
3.2.1
Dose, Regimen, and Treatment Period...........................................................31
3.2.2
Treatment Area ...............................................................................................32
3.3
Trial Population.................................................................................................33
3.3.1
Number of Subjects and Description of Population .......................................33
3.3.2
Issue of Subject Identification Number..........................................................33
3.4
Eligibility Criteria..............................................................................................33
3.4.1
Informed Consent ...........................................................................................33
3.4.2
Inclusion Criteria ............................................................................................34
3.4.3
Exclusion Criteria...........................................................................................35
3.5
Endpoints...........................................................................................................38
3.5.1
Primary Endpoint............................................................................................38
3.5.2
Secondary Endpoints ......................................................................................38
3.5.3
Safety Endpoints.............................................................................................39
3.6
Measures to Minimize/Avoid Bias....................................................................39
3.7
Trial Procedures ................................................................................................40
3.7.1
Schedule of Assessments................................................................................43
3.7.1.1
Acquisition of Informed Consent................................................................43
3.7.1.2
Screening Examination ...............................................................................43
3.7.1.3
Subject Demographics ................................................................................43
3.7.1.4
Subject Registration ....................................................................................44
3.7.1.5
Baseline Examination (2 - 30 Days After the Screening Examination)......44
3.7.1.6
Randomization (Allocation of Investigational Medicinal Products to 
Subjects)......................................................................................................45
3.7.1.7
Between the Day After the Baseline Examination and the Day Prior 
to the Week 1 Examination.........................................................................45
3.7.1.8
Week 1 Examination (±2 Days)..................................................................45
3.7.1.9
Week 2 Examination (±3 Days)..................................................................46
3.7.1.10
Week 4 Examination (±3 Days) or Withdrawal Examination ....................47
3.7.1.11
Unscheduled Visits .....................................................................................47
3.7.2
Status of Investigational Medicinal Product Administration..........................48


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3.7.3
Photograph of the Target Site.........................................................................48
3.7.4
Severity of Atopic Dermatitis.........................................................................48
3.7.5
Efficacy Assessments .....................................................................................49
3.7.5.1
Investigator’s Global Assessment...............................................................49
3.7.5.2
Eczema Area and Severity Index................................................................49
3.7.5.3
Verbal Rating Scale for Pruritus .................................................................50
3.7.5.4
Patient-Oriented Eczema Measure..............................................................50
3.7.5.5
Affected Body Surface Area.......................................................................50
3.7.6
Safety Assessments.........................................................................................51
3.7.6.1
Adverse Events............................................................................................51
3.7.6.2
Clinical Laboratory Tests............................................................................51
3.7.6.3
Physical Examination..................................................................................52
3.7.6.4
Vital Signs and Body Weight......................................................................52
3.7.7
Previous Medications and Concomitant Medications ....................................53
3.7.8
End of Trial.....................................................................................................53
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................53
3.8.1
Termination or Interruption of the Entire Trial ..............................................53
3.8.2
Termination or Interruption of the Trial at Individual Trial Sites ..................53
3.8.3
Individual Subject Discontinuation ................................................................54
3.8.3.1
Treatment Discontinuation..........................................................................54
3.8.3.2
Discontinuation Criteria..............................................................................54
3.8.3.3
Documenting Reasons for Treatment Discontinuation...............................55
3.8.3.4
Withdrawal of Consent ...............................................................................55
3.8.3.5
Procedures to Encourage Continued Trial Participation.............................57
3.9
Screen Failures ..................................................................................................57
3.10
Definition of Completed Subjects.....................................................................57
3.11
Definition of Subjects Lost to Follow-up..........................................................57
3.12
Subject (including Subject’s Legal Guardian) Compliance..............................58
3.13
Deviations from the Trial Protocol....................................................................58
4
Restrictions..........................................................................................59
4.1
Prohibited Concomitant Drugs and Therapies ..................................................59
5
Reporting of Adverse Events.............................................................60


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5.1
Definitions.........................................................................................................60
5.2
Eliciting and Reporting Adverse Events ...........................................................62
5.3
Immediately Reportable Events ........................................................................63
5.4
Potential Serious Hepatotoxicity.......................................................................63
5.5
Implementation of Patch Test............................................................................63
5.6
Pregnancy..........................................................................................................64
5.7
Procedure for Breaking the Blind......................................................................65
5.8
Follow-up of Adverse Events............................................................................66
5.8.1
Follow-up of Non-serious Adverse Events.....................................................66
5.8.2
Follow-up of Serious Adverse Events and Immediately Reportable 
Events .............................................................................................................66
5.8.3
Follow-up and Reporting of Serious Adverse Events and Immediately 
Reportable Events Occurring After Day of Trial Completion (Final 
Observation Day)............................................................................................66
6
Pharmacokinetic Analysis..................................................................67
7
Statistical Analysis..............................................................................67
7.1
Sample Size.......................................................................................................67
7.2
Datasets for Analysis.........................................................................................67
7.3
Handling of Missing Data .................................................................................68
7.4
Primary and Secondary Endpoint Analyses ......................................................68
7.4.1
Primary Endpoint Analysis.............................................................................68
7.4.2
Secondary Endpoint Analysis.........................................................................68
7.4.3
Subgroup Analysis..........................................................................................69
7.4.4
Exploratory Analysis of Age Factor...............................................................69
7.5
Analysis of Demographic and Other Baseline Characteristics .........................70
7.6
Safety Analysis..................................................................................................70
7.6.1
Adverse Events ...............................................................................................70
7.6.2
Clinical Laboratory Tests ...............................................................................70
7.6.3
Vital Signs and Body Weight .........................................................................71
8
Management of Investigational Medicinal Product........................71
8.1
Packaging and Labeling ....................................................................................71
8.2
Storage...............................................................................................................71
8.3
Accountability ...................................................................................................71


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8.4
Returns and Destruction....................................................................................72
8.5
Reporting of Product Quality Complaints.........................................................72
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................72
8.5.2
Information Required for Reporting Product Quality Complaints.................73
8.5.3
Return Process in the Case of Product Quality Complaints ...........................73
8.5.4
Assessment/Evaluation...................................................................................73
9
Records Management.........................................................................73
9.1
Source Documents.............................................................................................73
9.2
Data Collection..................................................................................................74
9.3
File Management at the Trial Site.....................................................................74
9.4
Records Retention at the Trial Site....................................................................75
10
Quality Control and Quality Assurance...........................................75
10.1
Monitoring.........................................................................................................75
10.2
Auditing.............................................................................................................75
11
Ethics and Responsibility...................................................................76
12
Confidentiality ....................................................................................76
13
Amendment Policy..............................................................................77
14
Publication Authorship Requirements.............................................77
15
References............................................................................................78


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List of In-text Tables
Table 1.3-1
Adverse Events in OPA-15406 Treatment Groups Reported 
at a Higher Frequency Than in the Vehicle Group and 
Observed in at Least 2 Percent of the Subjects in Trials 
Enrolling Subjects With Atopic Dermatitis.................................. 27
Table 3.4.2-1
Inclusion Criteria .......................................................................... 35
Table 3.4.3-1
Exclusion Criteria ......................................................................... 35
Table 3.7-1
Schedule of Assessments.............................................................. 41
Table 3.7.4-1
Severity of atopic dermatitis......................................................... 48
Table 3.7.5.1-1
Investigator’s Global Assessment................................................. 49
Table 3.7.5.2-1
Eczema Area and Severity Index.................................................. 49
Table 3.7.6.2-1
Clinical Laboratory Assessments.................................................. 52
Table 4.1-1
Prohibited Concomitant Drugs and Therapies.............................. 59
Table 5.5-1
Reading Criteria............................................................................ 64


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List of In-text Figures
Figure 3.1-1
Trial Design .................................................................................. 31


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List of Appendices
Appendix 1
Diagnostic Criteria for Atopic Dermatitis (Japanese 
Dermatological Association’s Criteria) ........................................ 80
Appendix 2
Patient-Oriented Eczema Measure (POEM)................................. 81
Appendix 3
Human Body Drawing for Children Aged 8 to 14 Years Old ...... 83
Appendix 4
Human Body Drawing for Children Aged 2 to 7 Years Old ........ 84
Appendix 5
Protocol Amendments and Administrative Changes.................... 85


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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
AD
Atopic dermatitis
AE
Adverse Event
ALT (GPT)
Alanine aminotransferase
AST (GOT)
Aspartate aminotransferase
BSA
Body surface area
cAMP
Cyclic adenosine 3', 5'-monophosphate
Cmax
Peak (maximal) concentration of drug in plasma
CMH
Cochran Mantel Haenszel 
CRF
Case report form
CYP
Cytochrome P450
EASI
Eczema Area and Severity Index
ECG
Electrocardiogram
FAS
Full Analysis Set
GCP
Good Clinical Practice 
ICF
Informed consent form
ICH
International Council for Harmonization of Technical Requirements 
for Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IGA
Investigator’s Global Assessment
IMP
Investigational Medicinal Product
IRB
Institutional review board 
IRE
Immediately reportable event 
IWRS
Interactive Web Response System
LOCF
Last Observation Carried Forward
MMRM
mixed model repeated measure
NB-UVB
Narrow-band ultraviolet B
NOAEL
No observed adverse effect level
OC
Observed Cases
PDE
Phosphodiesterase
POEM
Patient-Oriented Eczema Measure
PQC
Product Quality Complaint 
SAE
Serious adverse event 
SS
Safety Set 
TEAE
Treatment-emergent adverse event
US
United States
VRS
Verbal Rating Scale


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List of Pharmacokinetic Parameters
Abbreviation and 
Term
Unit
Expansion or Definition
AUC8h
ng∙h/mL
Area under the concentration-time curve from time 
zero to 8 hours 
Cmax
ng/mL
Maximum (peak) plasma concentration of the drug
R4w,ac(Cmax/Dose)
Ratio of Cmax/Dose at Week 4 of multiple 
administration to single administration
R4w,ac(AUC8h/Dose)
Ratio of AUC8h/Dose at Week 4 of multiple 
administration to single administration


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1
Introduction
Atopic dermatitis (AD) is defined as “a disease with repeated exacerbations/remissions of 
which the main lesion is eczema with pruritus, and most patients have atopic 
predisposition. Atopic predisposition means 1) having a family history/medical history 
(one or more diseases of bronchial asthma, allergic rhinitis/conjunctivitis, or atopic 
dermatitis) or 2) predisposition to producing IgE antibody.”1 In some patients, AD that 
occurred in infancy may spontaneously resolve with age. However, some AD that 
occurred or recurred in adulthood may become refractory AD.1
Diagnostic criteria for the disease were established by Hanifin and Rajka in 19802, and in 
Japan, Guidelines for Management of Atopic Dermatitis was published by the Japanese 
Dermatological Association and Japanese Society of Allergology.1 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.
The basic therapy for AD are topical agents such as steroids and calcineurin inhibitors 
(immunosuppressors) for 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 is the 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). Topical agents of calcineurin inhibitors are also 
used to control inflammation, but a burning sensation may occur after administration. In 
addition, although the situations of AD patients are different from those of transplantation 
patients with continuously elevated blood concentrations of calcineurin, the daily amount 
of topical drugs is limited considering the possibility of systemic side effects which may 
be observed in the transplanted areas. Under these circumstances, 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 neutrophi. In AD patients, elevated PDE activity in peripheral blood 
leukocytes and reduced intracellular cAMP levels have been reported. PDE4 inhibitors 
have been shown to exert their antiinflammatory activity by increasing intracellular 
cAMP levels and suppressing production of chemical mediators such as inflammatory 
cytokines. Therefore, PDE4 inhibitors have been considered effective for treatment of 
AD.3 In the United States (US), the Food and Drug Administration approved Eucrisa®


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ointment 2% (generic name: Crisaborole) as a topical agent for pediatric (aged 2 years 
and older) and adult patients with mild to moderate AD in 2016.
OPA-15406 is a PDE4 inhibitor synthesized by Otsuka Pharmaceutical Co., Ltd. In a 
mouse chronic contact hypersensitivity model4, 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.
Clinical development OPA-15406 was first initiated outside Japan, and the phase 2 trial 
in AD patients (aged 10 - 70 years old) and the pharmacokinetic trial in AD patients 
(aged 
2 - 17 years) have been completed outside Japan. In Japan, the phase 1 trial in healthy 
adult male subjects, and the subsequent phase 2 trial in adult AD patients (aged 15 - 70 
years old) and the phase 2 trial in pediatric patients with AD (aged 2 - 14 years old) have 
been completed. In healthy adult subjects (phase 1 trials in Japan and US), OPA-15406 
ointment showed no clinical relevant safety issues but good tolerability. In AD patients 
(phase 1 trials in US and phase 2 trials in Japan), 1% OPA 15406 ointments showed 
efficacy on adult AD, and 0.3% and 1% OPA-15406 ointments showed efficacy on 
pediatric AD. Based on results of the above-mentioned clinical trials, this trial is designed 
to demonstrate the superiority of 0.3% and 1% OPA-15406 ointments to the vehicle 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 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% - 3%) for chronic allergic 
dermatitis was assessed. Four weeks of topical administration of the OPA-15406 
ointment showed dose-dependent efficacy in improving dermatitis 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 


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scratching. The efficacy was superior to that 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%).
When OPA-15406 ointment was administered to rats and miniature pigs, the dermal 
absorption of OPA-15406 was low. When 14C-labeled OPA-15406 ointment 
(14C-OPA-15406) was administered percutaneously in rats, the absorbed radioactivity 
was distributed through various tissues of the body, but the level of radioactivity in the 
central nervous system (cerebrum and cerebellum) was lower than that in plasma. Several 
metabolites were identified in human plasma and urine collected in the phase 1 trial in 
Japan (Trial 271-14-001), but it was judged that there are no human-specific metabolites 
since all metabolites were detected in animal plasma. The main excretion route of 
radioactivity was biliary excretion and fecal elimination. The in vitro protein binding 
rates of 14C-OPA-15406 in human and animal serum were high (>99%). OPA-15406 
(and its metabolites) did not readily bind to melanin.
Cytochrome P450 (CYP) 1A2 and CYP3A4 were involved in the metabolism of 
OPA-15406. OPA-15406 directly inhibited CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19 and CYP2D6 (Ki: 1.284 - 8.833 mol/L) and showed metabolism-dependent 
inhibition of CYP2B6 and CYP3A4. The pharmacokinetic interaction risk of OPA-15406 
is considered to be low since Ki values were much higher than the plasma exposure in the 
clinical trial. On the other hand, OPA 15406 showed an inducing effect on CYP1A2, 
CYP2B6 and CYP3A4.
In the 4, 13 and 26-week repeated-dose percutaneous toxicity studies in rats, OPA-15406 
ointment was administered to intact skin (open cutaneous) once daily. As a result, no 
changes associated with the test substance were observed at the administration sites in 
any OPA-15406 ointment (vehicle, 0.1%, 0.3%, 1% and 3%) groups. Although 
suppressed weight increase was observed, it was not exacerbated in a prolonged 
treatment period. The no observed adverse effect level (NOAEL) for systemic toxicity in 
the 26 week repeated-dose percutaneous toxicity study was estimated to be 2.95 mg/kg 
(1% ointment) in the male rats and 1.07 mg/kg (0.3% ointment) in the female rats.
In the 4, 13 and 39-week repeated-dose percutaneous toxicity studies in miniature pigs, 
OPA-15406 ointment was administered to intact or abraded skin (open cutaneous) once 
daily. As a result, no changes associated with the test substance were observed in any 


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OPA-15406 ointment (vehicle, 0.3%, 1% and 3%) groups. The NOAEL for systemic 
toxicity in the 39 week repeated-dose percutaneous toxicity study was estimated to be 8.1 
mg/kg (3% ointment) in the male rats and 8.3 mg/kg (3% ointment) in the female rats.
In a 4-week repeated-dose percutaneous toxicity study in rabbits, OPA-15406 ointment 
was administered to intact skin. The OPA-15406 ointment (vehicle, 0.1%, 0.3%, 1% and 
3%) was classified as weak skin irritation at all concentrations according to the Draize 
scale for skin irritation. 
For further information, refer to the Investigator’s Brochure.
1.2
Clinical Study Results
Phase 2 trials in AD patients have been completed both in Japan and outside Japan.
For further information, refer to the Investigator’s Brochure.
1.2.1
Phase 1 Trial in Healthy Adult Subjects in the United States (Trial 
271-11-202)
In the phase 1 trial in healthy adult subjects (aged 18 - 64 years old) in the 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 (SAEs) were 
reported and no subjects were withdrawn from the trial due to adverse events (AEs).
1.2.2
Phase 1 Trial in Healthy Adult Male Subjects in Japan (Trial 
271-14-001)
In the phase 1 trial in healthy adult male subjects (aged 20 - 40 years old) in Japan, a 
single-dose or 2-week twice-daily multiple doses of the 0.3%, 1%, or 3% OPA-15406 
ointment (8 subjects for each group) or the vehicle of OPA-15406 ointment (placebo) as 
the control were administered to a 1000 cm2 area (about 5% of body surface area [BSA])
on the back of the subject at 5 g per dose to assess the safety and pharmacokinetics of the 
OPA-15406 ointment in Japanese subjects. In the 0.3%, 1%, and 3% OPA-15406 groups, 
the mean maximum plasma concentration (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 


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proportional increase was observed. In all multiple-dose groups, the 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 AEs were 
reported, and no subjects were withdrawn from the trial. In physical findings and 
subjective symptoms, vital signs, skin findings, standard 12-lead electrocardiogram 
(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
Trial for Phototoxicity in Healthy Adult Subjects in the United 
States (Trial 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 AEs were observed. Also, no SAEs were reported, and no subjects 
were withdrawn from the trial due to AEs.
1.2.4
Trial for Photoallergy in Healthy Adult Subjects in the United 
States (Trial 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 AE, which was moderate in severity and 
determined as investigational medicinal product (IMP)-related. No SAEs were reported. 
One subject discontinued the trial due to the onset of an AE, pneumonia; however, a 
causal relationship with the IMP was ruled out.
1.2.5
Phase 1 Trial in Atopic Dermatitis Patients in the United States
(Trial 271-12-204)
In the phase 1 trial in AD patients (aged 18 - 65 years old) in the US, 0.3%, 1%, or 3% 
formulation of OPA-15406 ointment (15 subjects for each group) or the vehicle of 
OPA-15406 ointment (placebo) as the control were administered to 5% of BSA (about 
1000 cm2) as 4-week, twice-daily, multiple administrations. OPA-15406 ointment 1% 
formulation (7 subjects) and 3% formulation (8 subjects), and 0.1% tacrolimus ointment 
(15 subjects) were then administered to 10% or more at about 1g per 5% twice daily as 4-
week multiple administrations. 


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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 SAE of cholelithiasis occurred in the 1% OPA-15406 group, but 
its causal relationship with the IMP was ruled out. Two subjects discontinued treatment 
with the IMP due to AEs; one of the subjects was in the 3% OPA-15406 group (name of 
AE: hypersensitivity) and the other was in the 0.1% tacrolimus group (name of AE: 
allergic dermatitis), and both events were judged to be IMP-related. 
For efficacy assessed in 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.
1.2.6
Phase 2 Trial in Atopic Dermatitis Patients Outside Japan (Trial
271-12-205)
In the phase 2 trial in AD patients (aged 10 - 70 years old) outside Japan, the efficacy, 
safety, and tolerability of the 8-week twice-daily multiple doses of OPA-15406 ointment 
was 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 success rate in IGA (percentage of subjects with IGA score of 0 or 1 
with improvement by at least 2 grades) at Week 4, and the success rate 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 
success rate in IGA than in the vehicle group; however, no significant difference was 
observed between the groups (p = 0.0690, Cochran-Mantel-Haenszel [CMH] test). In the 
1% OPA-15406 group, a significant difference was observed in the success rate in IGA 
compared to the vehicle group (p = 0.0165, CMH test). Discontinuations due to AEs 
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. 
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 


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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. 
1.2.7
Pharmacokinetic Phase 2 Trial in Atopic Dermatitis Patients 
Outside Japan (Trial MEDI-MM 36-206) 
In the pharmacokinetic phase 2 trial in pediatric AD patients (aged 2 - 17 years old) 
outside Japan, 1% OPA-15406 ointment was administered twice daily for 4 weeks in 
subjects aged 2 to 11 years old with affected BSA ≥35% and subjects aged 7 to 17 years 
old with affected BSA ≥25% to assess pharmacokinetics and safety. The mean Cmax was 
23.1 ng/mL on Day 1 and 16.9 ng/mL on Day 15 and accumulation was not observed. 
Although 9 AEs were reported, no SAEs were reported. Eight events were mild in 
severity and one event was moderate. Vomiting, rash, and application site burning 
sensation were reported as AEs for which a causal relationship with the IMP cannot be 
ruled out. The rash was moderate in severity, leading to the discontinuation of IMP 
administration. Efficacy was explored and a decrease in Eczema Area and Severity Index 
(EASI) score and a reduction of affected BSA were observed after administration.
1.2.8
Phase 2 Trial in Adult Atopic Dermatitis Patients in Japan (Trial
271-15-001)
In the phase 2 trial in AD patients (aged 15 - 70 years old) in Japan, the efficacy, safety, 
and pharmacokinetics of the 8-week twice-daily multiple doses of the 0.3% or 1% 
OPA-15406 ointment (60 subjects for each group) were investigated using the vehicle of 
OPA-15406 ointment (placebo) as the control. The primary efficacy endpoint was 
established as the success rate in IGA (percentage of subjects with IGA score of 0 or 1 
with improvement by at least 2 grades) at Week 4, and the success rate in IGA was 
14.93%, 22.39%, and 9.09% 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 
success rate in IGA than the vehicle group; however, no significant difference was 
observed between the treatment groups (p = 0.3004, CMH test). In the 1% OPA 15406 
group, a significant difference was observed in the success rate in IGA compared to the 
vehicle group (p = 0.0328, CMH test). No SAEs were observed in either group. 
Discontinuations due to AEs occurred with 15 subjects (22.4%), 7 subjects (10.4%), and 
15 subjects (22.7%) in the 0.3% OPA-15406 group, the 1% OPA-15406 group, and the 
vehicle group, respectively. In the 0.3% OPA-15406 group, AEs were reported as 
dermatitis atopic in 10 subjects, pruritus in 4 subjects, and pruritus and application site 
pain in 1 subject. Of these, 4 of the subjects with dermatitis atopic, 2 of the subjects with 


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pruritus and the 1 subject with application site pain were judged to be IMP-related. In the 
1% OPA-15406 group, AEs were reported as dermatitis atopic in 6 subjects and pruritus 
in 1 subject. Of these, 4 of the subjects with dermatitis atopic were judged to be 
IMP-related. In the vehicle group, AEs were reported as dermatitis atopic in 11 subjects, 
pruritus in 4 subjects, and dermatitis atopic and pruritus in 1 subject. Of these, 6 of the 
subjects with dermatitis atopic were judged to be 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 mean plasma trough concentration of OPA-15406 (median treatment 
area: 16.5% to 19.5%) was 1.74 ng/mL (Week 1), 1.71 ng/mL (Week 4) and 1.51 ng/mL 
(Week 8) in the 0.3% OPA-15406 group and 4.96 ng/mL (Week 1), 5.22 ng/mL (Week 
4) and 5.22 ng/mL (Week 8) in the 1% OPA-15406 group. The plasma trough 
concentrations of OPA-15406 adjusted for amount of administration were similar at 
Week 1, Week 4 and Week 8, suggesting no accumulation of OPA-15406 after Week 1. 
Regarding pharmacokinetics investigated in the subgroups, the median R4w,ac(Cmax/Dose) 
at Week 4 was 0.907 in the 0.3% OPA-15406 group and 1.58 in the 1% OPA-15406 
group while the median R4w,ac(AUC8h/Dose) at Week 4 was 1.13 in the 0.3% 
OPA-15406 group and 1.75 in the 1% OPA-15406 group, suggesting a slight 
accumulation of OPA-15406 after multiple doses compared to a single-dose.
1.2.9
Phase 2 Trial in Pediatric Atopic Dermatitis Patients in Japan 
(Trial 271-102-00002)
In the phase 2 trial in AD patients (aged 2 - 14 years old) in Japan, the safety, efficacy, 
and pharmacokinetics of the 4-week twice-daily multiple doses of the OPA-15406 
ointment were investigated by selecting 0.3% and 1% formulations (20 subjects for each 
group) for which the efficacy was suggested in the phase 1 in the US using the vehicle of 
OPA-15406 ointment (placebo) as the control. No SAEs were observed in either group.
The AE leading to discontinuation was dermatitis atopic and it occurred in 1 subject 
(4.2%), 1 subject (4.0%) and 4 subjects (16.7%) in the 0.3% OPA-15406 group, the 1% 
OPA-15406 group, and the vehicle group, respectively. Of these, 1 subject in the 1% 
OPA-15406 group was judged to be IMP-related. In the results of the clinical laboratory 
tests, vital signs, and 12-lead ECG, no marked difference was observed among the 3 
groups. The efficacy endpoint was established as the success rate in IGA (percentage of 
subjects with IGA score of 0 or 1 with improvement by at least 2 grades) at Week 4, and 
the success rate in IGA was 37.50%, 40.00%, and 8.33% in the 0.3% OPA-15406 group, 
the 1% OPA-15406 group, and the vehicle group, respectively. The success rates were 
much higher in the 0.3% and 1% OPA-15406 groups than in the vehicle group (p = 
0.0114 and p = 0.0113, CMH test). The mean plasma trough concentration of 


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OPA-15406 (median treatment area: 12.0% to 20.0%) was 0.842 ng/mL (Week 1) and 
0.946 ng/mL (Week 4) in the 0.3% OPA-15406 group and 2.90 ng/mL (Week 1) and 2.21 
ng/mL (Week 4) in the 1% OPA-15406 group. The plasma trough concentrations of 
OPA-15406 adjusted for amount of administration were similar at Week 1 and Week 4, 
suggesting no accumulation of OPA-15406.
1.3
Known and Potential Risks and Benefits
As of the data cutoff date (18 Feb 2018), in the phase 1 trial in healthy adults in the US 
(Trial 271-11-202), the trial for phototoxicity in the US (Trial 271-12-212), the trial for 
photoallergy in the US (Trial 271-12-213), the phase 1 trial in healthy adult male subjects 
in Japan (Trial 271-14-001), the phase 1 trial in AD patients in the US (Trial 271-12-
204), the phase 2 trial outside Japan (Trial 271-12-205), the phase 2 pharmacokinetic trial 
outside Japan (Trial MEDI-MM36-206), the phase 2 trial in adult AD patients in Japan 
(Trial 271-15-001) and the phase 2 trial in pediatric AD patients in Japan (Trial 271-102-
00002), OPA-15406 was administered to 174 healthy adult subjects and 358 AD patients. 
The longest duration of dosing was 8 weeks.
In AD patients treated with OPA-15406, 5 SAEs (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.
In trials in patients with AD, the most frequently reported AEs in the OPA-15406 
treatment group were upper respiratory tract infection, viral upper respiratory tract 
infection, headache, upper respiratory tract inflammation, dermatitis atopic, and pruritus.
Of those, the AEs in the OPA-15406 treatment groups that were reported at higher 
frequency than in the vehicle group and observed in at least 2% of the subjects are upper 
respiratory tract infection, headache, and upper respiratory tract inflammation, all of 
which were judged as not IMP-related (Table 1.3-1).
For other information, refer to the Investigator’s Brochure.


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Table 1.3-1
Adverse Events in OPA-15406 Treatment Groups Reported at 
a Higher Frequency Than in the Vehicle Group and Observed 
in at Least 2 Percent of the Subjects in Trials Enrolling 
Subjects With Atopic Dermatitis
Preferred Term
OPA-15406 (N=358)
n (%)
Vehicle 
(N=142)
n (%)
Severity
Seriousness
Total
Mild
Moderate
Severe
Un-
classified
Serious
Non-serious
Upper respiratory 
tract infection
1
(0.3)
1
(0.3)
0
(0.0)
6
(1.7)
0
(0.0)
8
(2.2)
8 
(2.2)
0
(0.0)
Headache
1
(0.3)
0
(0.0)
0
(0.0)
7
(2.0)
0
(0.0)
8
(2.2)
8 
(2.2)
0
(0.0)
Upper respiratory 
tract 
inflammation
8
(2.2)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
8
(2.2)
8 
(2.2)
2
(1.4)
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 
indicated for AD have been approved in Japan.
2
Trial Rationale and Objectives
2.1
Trial Rationale
In the phase 2 trial in pediatric AD patients in Japan (Trial 271-102-00002), which were 
conducted prior to the present trial, the safety, efficacy, and tolerability of the 4-week 
twice-daily multiple doses of the 0.3% or 1% OPA-15406 ointment or the vehicle 
(placebo) were investigated. There were no particular safety concerns since no SAEs 
related to the IMP or adverse reactions were identified in the trial. The efficacy endpoint 
success rate in IGA (percentage of subjects with IGA score of 0 or 1 with improvement 
by at least 2 grades) at Week 4 was 37.50%, 40.00% and 8.33% in the 0.3% OPA-15406 
group, the 1% OPA-15406 group, and the vehicle group, respectively. The success rates 
were much higher in the 0.3% and 1% OPA-15406 groups than in the vehicle group (p = 
0.0114 and p = 0.0113, CMH test). 
In the phase 2 pharmacokinetic trial in pediatric AD patients outside Japan who received 
the 1% OPA-15406 ointment (Trial MEDI-MM36-206), no SAEs related to the IMP or 
safety concerns were identified.


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In the phase 2 trial in adult AD patients in Japan (Trial 271-15-001), the efficacy, safety, 
and pharmacokinetics of the multiple doses of the 0.3% or 1% OPA-15406 ointment or 
the vehicle (placebo) were investigated when administered twice-daily for 8 weeks. The 
efficacy endpoint success rate in IGA (percentage of subjects with IGA score of 0 or 1 
with improvement by at least 2 grades) at Week 4 was 14.93%, 22.39% and 9.09% in the 
0.3% OPA-15406 group, the 1% OPA-15406 group, and the vehicle group, respectively. 
In the 1% OPA15406 group, a significant difference was observed in the success rate in 
IGA compared to the vehicle group (p = 0.0328, CMH test). There were no SAEs related 
to the IMP or safety concerns.
As described above, efficacy of the 0.3% and 1% OPA-15406 ointment groups surpassed 
that of the vehicle group in pediatric AD patients in the Japanese phase 2 trial results, and
significant difference was observed in the efficacy of the 1% OPA-15406 ointment group 
against the vehicle group in adult AD patients in the Japanese phase 2 trial results. The 
number of patients in the phase 2 pediatric AD trial in Japan is approximately one third of 
that in the phase 2 adult AD trial. Thus, it was considered that the recommended dose 
should be established after evaluating the efficacy of 0.3% and 1% OPA-15406 ointment 
in pediatric AD patients in a large-scale trial and considering the risk-benefit profile not 
only in the overall group but also by ages. Therefore, it was judged ethically and 
scientifically appropriate to conduct this trial to demonstrate the superiority of 0.3% and 
1% OPA-15406 ointment to the vehicle in pediatric AD patients when administered the 
0.3% or 1% OPA-15406 ointment twice-daily for 4 weeks.
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 
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 2 trial in pediatric patients in Japan (Trial 271-102-00002), the efficacy 
endpoint was established as the success rate in IGA (percentage of subjects with IGA 
score of 0 or 1 with improvement by at least 2 grades) at Week 4. The success rate was
comparable between 0.3% and 1% OPA-15406 groups and significantly higher in 
OPA-15406 groups than in the vehicle group. There was no significant difference in the 


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safety endpoints among the vehicle, 0.3% formulation and 0.1% formulation. Thus, it 
was considered that the recommended dose should be established in consideration of the 
risk-benefit profile after the efficacy of 0.3% and 1% OPA-15406 ointment was 
evaluated in a large-scale trial in pediatric AD patients.
Therefore, the 0.3% and 1% formulations are selected.
2.3
Rationale for Severity and Age Setting
Atopic dermatitis is mainly treated with topical drugs. However, for severe patients, oral 
agents and ultraviolet therapy are often combined due to inadequate response to topical 
drugs alone. Thus, the phase 2 trials in Japan (Trials 271-15-001 and 271-102-00002) 
were conducted in mild to moderate AD patients in whom topical drugs are the main 
treatment and the efficacy of OPA-15406 could be evaluated appropriately. As the results 
of these trials demonstrated the efficacy and safety, the present trial was designed to 
include patients with mild to moderate AD.
The phase 2 trial (Trial 271-102-00002) in Japan was conducted in pediatric patients 
(aged 2 - 14 years old), showing the efficacy of OPA-15406 ointment without any 
particular safety concerns. Therefore, subjects aged 2 to 14 years old were included in 
this trial.
2.4
Trial Objectives
Primary Objective: To demonstrate the superiority of the investigational medicinal 
product (IMP; 0.3% OPA-15406 ointment, 1% OPA-15406 ointment, or vehicle) to the 
vehicle when administered twice daily for 4 weeks using success rate in IGA at Week 4
as the primary endpoint in pediatric patients with AD.
Secondary Objective: To evaluate the efficacy (secondary endpoint) and safety of the 
IMP (0.3% OPA-15406 ointment, 1% OPA-15406 ointment, or vehicle) when 
administered twice daily for 4 weeks in pediatric patients with AD and to confirm the 
dose-response relationship.
3
Trial Design
3.1
Type/Design of Trial
This trial is a multicenter, randomized, double-blind, vehicle-controlled, parallel group, 
comparison trial to demonstrate the superiority of 0.3% and 1% OPA-15406 ointment to 


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the vehicle in pediatric AD patients. 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 informed consent from the subject’s legal guardian (and, if possible, 
after obtaining assent from the subject), the investigator or subinvestigator will 
perform a screening examination. The screening period is defined as the period 
between the day of screening examination and the day of baseline examination (2 - 30 
days).
2) Assessment period (treatment period)
The assessment period is defined as the period between the day of baseline 
examination and the end of Week 4 examination (or the end of withdrawal 
examination). The subjects who meet the inclusion and exclusion criteria at the 
baseline examination will be allocated to the IMP (0.3% and 1% formulation of 
OPA-15406) or the comparator (vehicle [placebo]). The allocated IMP will be 
administered to the treatment area from the day of baseline examination twice daily 
for 4 weeks. After the baseline examination, the examinations will be performed at 
Weeks 1, 2, and 4.
If a subject discontinues the IMP administration between the day of baseline 
examination and the day of Week 4 examination, a withdrawal examination will be 
performed for that subject.
3) Trial period
The trial period for individual subjects is the period from the day of obtaining the 
written informed consent from the subject’s legal guardian to the day of the Week 4 
examination or withdrawal examination. For subjects who missed the Week 4 
examination or withdrawal examination, the day of discontinuation will be the day 
when the investigator or subinvestigator determined that the subject was to be 
withdrawn from the trial. It does not include the follow-up period for AEs.


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Screening period
(2 - 30 days)
Assessment period
Twice daily administration
(4 weeks)
0.3% OPA-15406 group
1% OPA-15406 group
Vehicle group
Figure 3.1-1
Trial Design
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 10 g/m2 BSA and 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)5
2) The treatment area will be specified
Screening examination
Informed consent
IMP allocation
Baseline examination
Week 4 examination (day of trial 
completion [final observation day])
Week 2 examination
Week 1 examination


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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.”6 In consideration of this standard AD treatment policy, in the phase 2 trial in 
pediatric patients in Japan (Trial 271-102-00002), patients received the IMP for 4 weeks 
and the primary efficacy endpoint was established as the success rate in IGA (percentage 
of subjects with IGA score of 0 or 1 with improvement by at least 2 grades) at Week 4. 
As a result, the success rate was significantly higher in the 0.3% OPA-15406 group and 
1% OPA-15406 group than in the vehicle group. Also, no particular safety concerns were 
identified at Week 4.
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 Section 3.7.5.5, Affected Body Surface Area). 

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’s legal guardian (if possible, 
the subject) regarding the method of administration by specifying the treatment area (%) 
and the total amount of administration (g) for each treatment area using the human body 
drawing (see Appendix 3 or Appendix 4), and will give the human body drawing (copy) 
to the subject or subject’s legal guardian. The investigator or subinvestigator will record 
the treatment area (%) of the 4 body regions [face, neck, and head (excluding scalp); 
upper limbs; trunk; and lower limbs] in the source document and case report form (CRF).


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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 AD patient with an IGA score of 2 or 3. 
Subjects will be included in the trial to reach the target number of 240 subjects for IMP 
administration (the target inclusion ratio for “2 - 6 years old” and “7 - 14 years old” of 
age is 1:1). Any withdrawals will not be supplemented.
3.3.2
Issue of Subject Identification Number
A subject identification number ([3 digit number of site ID] + subject number [S + 5 digit 
number]) will be assigned to the subject providing written informed consent. The sponsor 
will provide the trial site number. The subject number will be a serial number assigned at 
the trial site starting from S00001 in the order of subjects providing written informed 
consent.
3.4
Eligibility Criteria
3.4.1
Informed Consent
Freely given written informed consent will be obtained from the subject’s legal guardian 
(guardians or legal representatives, as applicable by law) instead of the subject. The 
relationship between the subject and the subject’s legal guardian will be confirmed and 
recorded. If possible, assent (consent not bound by the legal restrictions obtained from
pediatric subjects) will be obtained from the subject. A signed informed consent form
(ICF) and signed assent form will be retained as documents. The explanatory document,
ICF, and assent form will be approved by the same institutional review board (IRB) 
responsible for approval of this protocol.
Each explanatory document and ICF should include the elements required by the 
International Council for Harmonization of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) Guidelines for Good Clinical Practice (GCP)7 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 the subject’s legal guardian before 
obtaining consent. However, written informed consent must be obtained prior to the 


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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 the 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 the 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 subject’s age have been provided by the investigator or 
subinvestigator, the IRB-approved ICF 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 ICF and assent form, and the originals 
will be kept by the investigator or subinvestigator.
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 #7 in Table 
3.4.2-1 at the screening examination, and #6 and #7 at the screening examination and the 
baseline examination.


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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
Able to obtain written informed consent from the subject’s legal guardian
5
Diagnosis of AD based on the Japanese Dermatological Association’s criteria1 (refer to Appendix 
1)
6
Atopic dermatitis affecting ≥5% to ≤40% of BSA (excluding scalp)
7
IGA score of 2 or 3
[Rationale for Inclusion Criteria]
1)
Atopic dermatitis occurs in both males and females.
2)
Most patients to be included in this trial are outpatients.
3)
The phase 2 trial (Trial 271-102-00002) in Japan was conducted in pediatric 
patients (aged 2 - 14 years old), showing efficacy OPA-15406 ointment without 
no particular safety concerns. Therefore, subjects aged 2 to 14 years old are 
included in the present trial.
4)
To conduct the trial without any ethical problems.
5)
Patients with AD who meet the Japanese Dermatological Association’s criteria 
are included in order to evaluate the efficacy and safety of the IMP in AD 
patients in Japan.
6)-7) To appropriately evaluate the efficacy of the IMP on the target disease.
3.4.3
Exclusion Criteria
Subjects who fall under any of the criteria in Table 3.4.3-1 at either the screening or 
baseline examination will be excluded from the trial:
Table 3.4.3-1
Exclusion Criteria
1
Female children aged 7 to 14 years old who are pregnant or possibly pregnant, or whose legal 
guardians are unable to agree to avoid sexual activity during the trial period and up until 30 days 
after the final administration of IMP.
2
Subjects who have an AD or contact dermatitis flare-up defined as a rapid intensification of AD, 
within 28 days prior to the baseline examination
3
Subjects who have a concurrent or history of skin disease other than AD (eg, acne, psoriasis, etc) 
and who are judged inappropriate for assessment of AD in the present trial
4
Subjects who have an active viral skin infection (eg, herpes simplex, herpes zoster, chicken pox) or 
clinical signs of such infection
5
Subjects with a current or history of malignancy


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Table 3.4.3-1
Exclusion Criteria
6
Subjects with a current or history of recurrent bacterial infection resulting in hospitalization or 
requiring intravenous antibiotic treatment within the past 2 years
7
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 
assessment of the IMP:

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, carriers of hepatitis B, hepatitis C, etc)

Renal disease

Hematologic disease

Immunologic or immunocompromised disease (eg, 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 efficacy assessment of the IMP
8
Subjects who are judged by the investigator or subinvestigator to be unable to safely complete the 
trial based on laboratory results at screening examination.
9
Subjects who are judged by the investigator or subinvestigator to have a clinically abnormal blood 
pressure or pulse rate at the screening and baseline examinations
10
Subjects who are judged by the investigator or subinvestigator to be unable to undergo blood 
sampling.
11
Subjects who are unable to stop allergen immunotherapy (or desensitization therapy) from 3 
months prior to providing informed consent until the Week 4 examination (or at the time of 
withdrawal examination). However, if the subjects have continued the allergen immunotherapy for 
more than 3 months prior to providing informed consent and symptoms of AD have not changed 
judged by the investigator or subinvestigator , subjects may continue such therapy until the Week 4 
examination as long as no changes are made to the therapy (types or amount of allergen or
frequency of therapy, etc).
12
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
13
Subjects who are unable to stop using systemic corticosteroids, systemic immunosuppressants, 
systemic antimetabolites, systemic retinoids, and biologics from 28 days prior to the baseline 
examination until the Week 4 examination
14
Subjects who are unable to stop using topical corticosteroids for skin (excluding scalp) categorized 
as very strong or higher potency in the “Guidelines for Management of Atopic Dermatitis1” from 
21 days prior to the baseline examination until the Week 4 examination.
15
Subjects who are unable to stop using topical corticosteroids for skin (excluding scalp) categorized 
as strong potency in the “Guidelines for Management of Atopic Dermatitis1”, topical 
corticosteroids other than those for skin, topical immunosuppressants, topical retinoids, topical 
antihistamine and topical non-steroidal anti-inflammatory drugs (excluding for scalp) from 7 days 
prior to the baseline examination until the Week 4 examination. Intra-ocular, intra-nasal, intra-
auricular, and inhaled corticosteroids and antihistamines may be considered if the investigator or 
subinvestigator judges that their use will not impact assessment of the affected area.


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Table 3.4.3-1
Exclusion Criteria
16
Subjects who are unable to stop using topical corticosteroids for skin (excluding scalp) categorized 
as low or medium potency in the “Guidelines for Management of Atopic Dermatitis1” from 4 days 
prior to the baseline examination until the Week 4 examination.
17
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
18
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)
19
Subjects with known plans to receive any of the prohibited concomitant drugs or therapies during 
the trial period
20
Subjects who have participated in previous trials for OPA-15406 and have been administered the 
IMP
21
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
22
Subjects who have never been treated with a prescription medication for AD or who are satisfied 
with their current AD treatment regimen
23
Subjects who do not respond at all to treatment with existing topical drugs for AD
24
Subjects who are judged by the investigator or subinvestigator to be inappropriate to participate in 
the trial for any other reason
[Rationale for Exclusion Criteria]
1)
In consideration of safety to eliminate any unknown impact of the IMP on 
pregnant women, fetuses, and infants.
2)
Due to a possible impact on the efficacy assessment of the IMP.
3)
Due to a possible impact on the safety and efficacy assessments of the IMP.
4)-6)
In consideration of safety.
7)
Due to a possible impact on the safety and efficacy assessments of the IMP.
8)-10)
In consideration of safety.
11)-17) Due to a possible impact on the efficacy assessment of the IMP.
18)
In consideration of safety.
19)
Due to a possible impact on the efficacy and safety assessments of the IMP.
20)-21) In reference to the “Criteria for Period to Avoid Participation in Clinical 
Studies” of the Japan Association of Contract Institutes for Clinical 
Pharmacology.


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22)
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.
23)
To exclude severe patients who do not respond to topical drugs.
24)
To allow the investigator or subinvestigator to judge in consideration of other 
factors.
3.5
Endpoints
3.5.1
Primary Endpoint
Success rate in IGA at Week 4: percentage of subjects with IGA score of 0 or 1 with
improvement by at least 2 grades. Subjects with missing IGA data will be handled as 
non-responders.
[Rationale for Primary Endpoint]
Investigator’s Global Assessment evaluates the systemic clinical characteristics 
(erythema, infiltration, papulation, oozing, and crusting) by the severity score of IGA (0 
= Clear, 1 = Almost clear, 2 = Mild disease, 3 = Moderate disease, 4 = Severe 
disease/Very severe disease) and clearly distinguishes each score. In patients with AD, as
remission or close to remission is the goal of the treatment1, clinical characteristics of 
remission or close to remission are defined as IGA score of 0 (Clear) or 1 (Almost clear), 
and clinically significant improvement as improvement in IGA by at least 2 grades.
Based on the above, the success rate in IGA (percentage of subjects with IGA score of 0 
or 1 with improvement by at least 2 grades) at Week 4 is established as the primary 
efficacy endpoint.
3.5.2
Secondary Endpoints

Success rate in IGA at Week 4: percentage of subjects with IGA score of 0 or 1 

Change from baseline in IGA at Week 4

Success rate in EASI 75 (improvement ≥75% in EASI), EASI 90 (improvement 
≥90% in EASI) and EASI 50 (improvement ≥50% in EASI) at Week 4

Change from baseline in the total score of EASI and each clinical sign score at 
Week 4

Change from baseline in Verbal Rating Scale (VRS) for pruritus at Week 4

Change from baseline in VRS for pruritus up to Day 7


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
Change from baseline in the total score of Patient-Oriented Eczema Measure
(POEM) at Week 4

Change from baseline in the total affected BSA (%) at Week 4
3.5.3
Safety Endpoints

Adverse events
1) AEs occurring after the start of IMP administration (Treatment-emergent adverse 
event [TEAE])
2) TEAEs by severity
3) TEAEs resulting in death
4) Serious TEAEs
5) TEAEs leading to discontinuation of IMP administration
6) TEAEs (skin and subcutaneous tissue disorders) by grade
7) TEAEs at treatment areas

Clinical laboratory tests

Vital signs and body weight
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 SAE.
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.
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 “5.7 Procedure for Breaking the Blind.”
When IMPs are recovered by the sponsor prior to unblinding, they are to be recovered 
sealed by the IMP manager.


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The subjects will be allocated using dynamic allocation (minimization method). Details 
will be provided in a separate specification.
3.7
Trial Procedures
Table 3.7-1 shows the schedule of assessment.


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Table 3.7-1
Schedule of Assessments
Evaluation 
Screening period 
(2–30 days)
Assessment period 
(4 weeks)
Screening 
examination
Baseline 
examination
Week 1 
examinationa
(± 2 days)b
Week 2 
examinationa
(± 3 days)c
Week 4 
examinationa
(± 3 days)c
Withdrawal 
examinationd
Unscheduled 
visit
Informed consent 
○e
Inclusion and exclusion criteria
○
○
Subject demographics
○
Physical examination
○
○
○
○
○
○f
Vital signs and body weight
○
○
○
○
○
○f
Clinical laboratory tests
○
○
○
○f
Pregnancy testg
○
○
○
○f
IGA 
○
○
○
○
○
○f
EASI
○
○
○
○
○
○f
VRS for pruritush
  ○i
○i
○
○
○f
POEM
○
○
○
○
○f
Affected BSA 
○
○
○
○
○
○
Treatment area 
○
○
○
○f
Administration diary
  ○j
○
Severity of AD
○
○
Photograph of the target site
○
○
○
○
○f
Status of IMP administration
○
○
○
Prescription and collection of IMP
○k
○l
○
  ○m
○l
IMP administration
○n
AEs
Concomitant medications and therapies 
Patch testo


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aThe reference date of the Week 1 examination, Week 2 examination and Week 4 examination will be the same day of the week as the baseline examination.
bAcceptable window of ±2 days 
cAcceptable window of ±3 days 
dWithdrawal examination should be conducted as soon as possible.
eInformed consent is to be obtained prior to screening examination (possibly on the same day).
fIs to be conducted, as necessary.
gShould be conducted only for female children aged 7 to 14 years old.
hShould be conducted only for female children aged 7 to 14 years old (at time of obtaining informed consent). The most intense pruritus in the past 24 hours will 
be evaluated. The investigator or subinvestigator will interview the subjects during scheduled visits after the baseline examination.
iThe subjects will keep a pruritus diary once daily, every day, at the same time in principle as the time of baseline examination from the day after the baseline 
examination until the day before the Week 1 examination. However, the subjects should keep the pruritus diary up to Day 8 if they are to visit on Day 9 or 
later.
jThe subjects should keep an administration diary every day from the baseline examination to the Week 4 examination (withdrawal examination). 
kOnly IMP prescription.
lIMP will be additionally prescribed, as necessary. 
mOnly IMP collection.
nThe IMP administration should be started at the trial site after all baseline examinations are finished.
oIf any AE 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 (see Section 5.5, Implementation of Patch Test)


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3.7.1
Schedule of Assessments
Regarding assessments to be performed by the investigator or subinvestigator, the tasks
that a clinical trial associate is able to perform (eg, subject demographics survey and
tasks related to clinical laboratory tests) may be performed by the clinical trial associate 
under the supervision of the investigator.
3.7.1.1
Acquisition of Informed Consent
The investigator or subinvestigator will obtain written consent from the subject’s legal 
guardian. The investigator or subinvestigator will assign a subject identification number 
([3 digit number of site ID] + subject number [S + 5 digit serial number starting from 
00001]) to the subject providing consent.
3.7.1.2
Screening Examination
After acquisition of informed consent, the investigator or subinvestigator will perform the 
following examinations, observations, and evaluations, and select subjects who meet the 
inclusion criteria and do not fall under any of the exclusion criteria.

Subject demographics

Physical examination

Vital signs and body weight

Clinical laboratory tests

Pregnancy test (only for female children aged 7 - 14 years old)

IGA

EASI

Affected BSA 

Severity of AD

AEs 

Concomitant medications and therapies
Investigator or subinvestigator will record the results of the eligibility of subjects on the 
list of screened subjects and the list of enrolled subjects.
3.7.1.3
Subject Demographics
The investigator or subinvestigator is to record the following information in the source 
document and CRF.

Date of informed consent

Sex

Date of birth


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
Height (unit in cm: measurement indicated as an integer value; if measurement to one 
decimal place is possible, then the number is to be rounded to nearest integer value.)

Complications

Date of onset of AD 

Medical history (within 6 months prior to the date of informed consent)

In- or outpatient status (outpatient)

Subject identification number

Country where the trial is conducted (Japan)

Race

Ethnicity 

Possibility of pregnancy
3.7.1.4
Subject Registration
The investigator or subinvestigator will register all subjects in the Interactive Web 
Response System (IWRS).
3.7.1.5
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.

Confirmation of inclusion/exclusion criteria

Physical examination

Vital signs and body weight

Pregnancy test (only for female children aged 7 - 14 years old)

IGA

EASI

VRS for pruritus (only for subjects aged 7 - 14 years old)

POEM

Affected BSA 

Treatment area

Severity of AD

Photograph of the target site

AEs 

Concomitant medications and therapies


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3.7.1.6
Randomization (Allocation of Investigational Medicinal 
Products to Subjects)
The investigator or subinvestigator will enter the necessary information for the 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, 1% 
OPA-15406 group, or vehicle group. The investigator or subinvestigator will confirm the 
allocation result and the amount 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 (unit in g; rounded to the one decimal place; same method for all 
subsequent IMP weight measurements hereinafter). The IMP administration will be 
started at the trial site after all baseline examinations are finished. The investigator or 
subinvestigator will instruct the subjects to record the status of IMP administration in the 
administration diary daily and bring the diary with them to their next visits.
Information on randomization (date of randomization or registration, subject number or 
treatment group) will be recorded in the source document and CRF.
3.7.1.7
Between the Day After the Baseline Examination and the Day 
Prior to the Week 1 Examination
The investigator or subinvestigator will instruct the subject to evaluate and record the 
following item in the pruritus diary in relation to the most intense pruritus in the past 24 
hours once daily, every day, at the same time as the baseline examination in principle 
from the day after the baseline examination to the day before the Week 1 examination.
However, the subject will keep the pruritus diary up to Day 8 if scheduled to visit on Day 
9 or later.

VRS for pruritus (only for subjects aged 7 - 14 years old)
3.7.1.8
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 and body weight

IGA

EASI

VRS for pruritus (only for subjects aged 7 - 14 years old)

POEM

Affected BSA 


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
Treatment area

Photograph of the target site

AEs 

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 dispensed IMP will be measured. The investigator 
or subinvestigator will instruct the subjects to record the status of IMP administration in 
the administration diary daily and bring the diary with them to their next visits.
3.7.1.9
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 and body weight

IGA

EASI

VRS for pruritus (only for subjects aged 7 - 14 years old)

POEM

Affected BSA 

Treatment area

Photograph of the target site

AEs 

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 investigator or 
subinvestigator will instruct the subjects to record the status of IMP administration in the 
administration diary daily and bring the diary with them to their next visits.


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3.7.1.10
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. 
Withdrawal examinations should be conducted if at all possible.

Physical examination

Vital signs and body weight

Clinical laboratory tests

Pregnancy test (only for female children aged 7 - 14 years old)

IGA

EASI

VRS for pruritus (only for subjects aged 7 - 14 years old)

POEM

Affected BSA 

Photograph of the target site

AEs 

Concomitant medications and therapies

Status of IMP administration
The investigator or subinvestigator will collect the IMP and measure the weight of the 
collected IMP.
3.7.1.11
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 

AEs

Concomitant medications and therapies
The following examinations will be conducted as necessary:

Physical examinations

Vital signs and body weight

Clinical laboratory values

Pregnancy test (only for female children aged 7 - 14 years old)

IGA

EASI

VRS for pruritus (only for subjects aged 7 - 14 years old)


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
POEM

Treatment area

Photograph of the target site
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 Investigational Medicinal Product Administration
Details of the administration diary will be recorded in the CRF. Administration status will 
be recorded as poor if the frequency of IMP administration is less than 80%. The 
investigator or subinvestigator will confirm the status of IMP administration based on 
details in the administration diary and instruct the subjects as needed.
3.7.3
Photograph of the Target Site
The investigator or subinvestigator will take photographs of the target site in accordance 
with the photography manual. The investigator or subinvestigator will select one affected 
BSA (excluding the face to prevent individuals from being identified) showing the 
severity of IGA in the subject as the target site and record the site on the human body 
drawing at the baseline examination. The investigator or subinvestigator will continue 
taking photographs of the target site even after the symptoms at the target site are 
resolved. The investigator or subinvestigator will retain the photographs (electronic data) 
as the source document and the sponsor will collect the photographs (electronic data).
3.7.4
Severity of Atopic Dermatitis
The investigator or subinvestigator will determine the severity8 of AD (mild, moderate, 
severe, or very severe) and record the result in the source document and CRF.
Table 3.7.4-1
Definition of Severity of Atopic Dermatitis
Definition
Severity
Only mild rashesa regardless of the area
Mild
Skin eruption with severe inflammationb on less than 10% of the BSA
Moderate
Skin eruption with severe inflammationb on ≥10% to <30% of the BSA
Severe
Skin eruption with severe inflammationb on ≥30% of the BSA 
Very severe
aMild rash: Lesions are seen chiefly with mild erythema, dry skin, or desquamation.
bRashes with severe inflammation: Lesion with erythema, papule, erosion, infiltration, or 
lichenification, etc.


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3.7.5
Efficacy Assessments
3.7.5.1
Investigator’s Global Assessment
The investigator or subinvestigator will evaluate skin symptoms according to IGA.9 The 
investigator or subinvestigator will score the severity (0 = Clear; 1 = Almost clear; 2 = 
Mild disease; 3 = Moderate disease; 4 = Severe disease/Very severe disease) of clinical 
characteristics (erythema, infiltration, papulation, oozing, and crusting). The result will 
be recorded in the source document and CRF. The same subject should be evaluated by 
the same physician.
Table 3.7.5.1-1
Investigator’s Global Assessment
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 disease
Moderate erythema and moderate papulation/infiltration
3 = Moderate disease
Severe erythema, and severe papulation/infiltration
Severe erythema, and severe crusting papulation/infiltration with oozing
4 = Severe disease/Very 
severe disease
3.7.5.2
Eczema Area and Severity Index
The investigator or subinvestigator will evaluate skin symptoms according to EASI.10
The investigator or subinvestigator will score the severity (0 - 3 points) and affected BSA 
(%) based on the 4 clinical signs (erythema, infiltration/papulation, excoriation, and 
lichenification) on the 4 body regions (face, neck, and head [excluding scalp]; 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 should be evaluated by the same 
physician.
Table 3.7.5.2-1
Eczema Area and Severity Index
Body region
Calculation of the score for each region 
Face, neck, and head 
(E ＋I ＋Ex ＋L) × score of BSA ×0.1 (×0.2 for subjects aged 2 - 7 years 
old [at time of obtaining informed consent])
Upper limbs
(E ＋I ＋Ex ＋L) × score of BSA ×0.2
Trunk
(E ＋I ＋Ex ＋L) × score of BSA ×0.3
Lower limbs
(E ＋I ＋Ex ＋L) × score of BSA ×0.4 (×0.3 for subjects aged 2 - 7 years 
old [at time of obtaining informed consent])
E = severity score of erythema; I = severity score of infiltration/papulation; Ex = severity score of 
excoriation; L = severity score of lichenification 
Severity score: no disease = 0; very mild = 0.5; mild = 1; mild-moderate = 1.5; moderate = 2; severe = 
2.5; very severe = 3
Score of affected BSA (for each region): no eruption = 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


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3.7.5.3
Verbal Rating Scale for Pruritus
The most intense pruritus in the past 24 hours will be evaluated according to the 
following VRS criteria:11
0: None
1: Mild
2: Moderate
3: Severe 
The investigator or subinvestigator will interview the subject during the scheduled visits 
after the baseline examination. The subject will evaluate the pruritus and record the 
outcome in the pruritus diary once daily, every day at the same time in principle as the 
baseline examination from the day after the baseline examination until the Week 1 
examination. However, the subject will keep the pruritus diary up to Day 8 if scheduled 
to visit on Day 9 or later.
The investigator or subinvestigator will record the results on visits in the source 
document and CRF, and details of the pruritus diary written by the subject in the CRF.
The pruritus diary will be kept as the source document.
3.7.5.4
Patient-Oriented Eczema Measure
Eczema will be evaluated according to POEM (see Appendix 2).12 The subjects will 
answer 7 questions and describe their eczema. If it is difficult to obtain answers from the 
subject, the subject’s legal guardian will evaluate the subject’s eczema and answer 
questions. The investigator or subinvestigator will confirm their responses and record the 
results in the source document and CRF. The total score of POEM is 28 points at the 
most. The POEM will be kept as source documents.
3.7.5.5
Affected Body Surface Area
The investigator or subinvestigator will draw the affected BSA (range of skin eruption 
with inflammation at the time of examination) on the human body drawing (see
Appendix 3 or Appendix 4) to determine the affected areas (%) on the respective 4 body 
regions (head, face, and neck [excluding scalp]; upper limbs; trunk; and lower limbs). 
The respective affected areas (%) will be recorded in the source document and CRF. The
affected BSA does not include dry skin sites. One palm of the subject corresponds to 1% 
BSA.


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3.7.6
Safety Assessments
3.7.6.1
Adverse Events
Refer to Section 5, Reporting of Adverse Events.
3.7.6.2
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. 


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Table 3.7.6.2-1
Clinical Laboratory Assessments
Hematology
Hemoglobin
Hematocrit
Red blood cell count
White blood cell count and differential white blood 
cell count (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils)
Platelets
Qualitative urinalysis
Glucose
Protein
Serum chemistry
Alkaline phosphatase 
ALT (GPT)
AST (GOT)
Total bilirubin
Blood urea nitrogen
Total cholesterol
Creatinine
γ-glutamyl transpeptidase 
Lactate dehydrogenase
Total protein
Albumin
Serum electrolytes (Ca, Na, K, Cl)
Additional tests
Urine and/or serum pregnancy for female children 
aged 7 to 14 years olda
aA serum pregnancy test will be conducted if the urine test results in positive or false positive outcome, 
or if the urine pregnancy test cannot be conducted.
The tests will be performed at the central laboratory. The investigator or subinvestigator 
will confirm the tests 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 
tests 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 the Week 4 examination).
For female children aged 7 to 14 years old, a pregnancy test will be performed at the 
screening examination, and the result must be obtained prior to the IMP administration.
3.7.6.3
Physical Examination
The investigator or subinvestigator will assess the subject’s physical condition by 
interview, visual examination, auscultation, or palpation. The same investigator should
conduct the individual subject’s physical examination by the same investigator 
throughout the trial period.
3.7.6.4
Vital Signs and 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 


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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.
3.7.7
Previous Medications and Concomitant Medications
The investigator or subinvestigator will record in the source document and CRF the 
name, purpose of use, dosage per administration, frequency, route of administration, and 
start/end date of administration of any medications other than the IMP (excluding 
cosmetics) used from 30 days prior to the screening examination until the Week 4 
examination (or examination at discontinuation) regardless of whether or not their 
concomitant use is allowed. The investigator or subinvestigator will also record in the 
source document and CRF the name, purpose for conduct, and start/end date of any 
concomitant therapies conducted 30 days prior to screening examination until Week 4 
examination (or examination at discontinuation) regardless of whether or not such is 
prohibited.
3.7.8
End of Trial
The “end of trial date” is defined as “the last date of visit or contact” or “the date judged 
as terminated” for the last subject completing or withdrawing from the trial. It does not 
include the period for follow-up of the last subject’s AEs.
3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Termination or Interruption of the Entire Trial
When the sponsor decides to terminate or interrupt the trial for some reason, the sponsor 
will promptly notify the head of the trial site and the regulatory authority in accordance 
with regulatory requirements.
3.8.2
Termination or Interruption of the Trial at Individual Trial Sites
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB if judged to be necessary for medical, safety, regulatory, ethical or other reasons 
consistent with applicable laws, regulations, and GCP. The head of the trial site will 
notify the sponsor promptly if the trial is terminated by the investigator or the IRB at the 
site.


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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 randomization, the investigator or subinvestigator may discontinue IMP 
administration for various reasons. These reasons for discontinuation include a request 
from the subject or subject’s legal guardian who is not satisfied with IMP administration 
or occurrence of an AE, 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 
investigator or subinvestigator must confirm details of such circumstances and provides 
the subject or subject’s legal guardian with all possible choices to continue with the IMP 
administration according to Section 3.8.3.5, Procedures to Encourage Continued Trial 
Participation.
3.8.3.2
Discontinuation Criteria 
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 AE 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 AE that makes it difficult for the subject to continue 
administration of IMP (including a suspected treatment-related AE of skin 
hypersensitivity on the treatment area)
4) Discovery that the subject is pregnant or suspected to be pregnant
5) Judgment by the investigator or subinvestigator that it is necessary to withdraw 
the subject from the trial


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3.8.3.3
Documenting Reasons for Treatment Discontinuation
All subjects and subject’s legal guardians have the right to discontinue the trial and the 
investigator or subinvestigator can also discontinue a subject’s participation in the trial at 
any time if medically necessary. If subjects discontinue their participation in the trial,
only one reason (main reason) for withdrawal should be recorded in the CRF.

Reasons related to AEs:
Request from the subject due to distress or discomfort associated with a 
non-serious AE 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 concern)

SAE

Other safety concerns or AEs possibly related to IMP

Death

Withdrawal of consent (complete documented withdrawal of consent)

Judgment by physician

Lost to follow-up 

Pregnancy (see Section 5.6, Pregnancy)

Entire or partial discontinuation of the trial by the sponsor

Lack of efficacy

Deviation from the protocol

Other
If the subject discontinued the IMP administration due to an AE, the investigator, 
subinvestigator, or other clinical trial associates will follow the AE until it resolves or 
stabilizes, or the subject is lost to follow-up or dies, as much as possible, according to the 
procedures specified in Section 3.8.3.1, Treatment Discontinuation.
3.8.3.4
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 and the subject’s legal 
guardian withdraw consent in written form, or unless the investigator or subinvestigator 
prepares a document which confirms the verbal consent for complete withdrawal from 


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the trial by the subject and the 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 and the subject’s legal guardian 
refuses all of the following follow-up procedures (These methods of follow-up will also 
be noted in the trial ICF).

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 (if some parts of the follow-
up procedures are refused by the subject and/or the subject’s legal guardian, those 
agreed between the subject, 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, 
spouse, partner, 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, 
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 (see Section 3.8.3.1, Treatment Discontinuation and Section 3.8.3.2, Discontinuation 
Criteria), 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 accordance with Section 3.8.3.3, 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 


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subjects and subjects’ legal guardians who have refused all of the above follow-up 
procedures.
3.8.3.5
Procedures to Encourage Continued Trial Participation
If discontinuation of IMP administration or withdrawal of consent is expected, the 
investigator or subinvestigator will meet with the subject and the subject’s legal guardian 
and talk about the possible options for them to continue participating (preferably, to 
continue treatment) in the trial. The investigator or subinvestigator will confirm the 
reason(s) for the subject’s and the subject’s legal guardian’s desire to withdraw 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 who has a signed ICF, but who has not been randomized or to whom an 
IMP was not allocated.
If a subject is a screen failure, the following information should be recorded in the source 
document and CRF for screen failure subjects.
Subject identification number, date of informed consent, date of screening examination, 
date of birth, sex, date of judgment as screen failure, 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 safety 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 Week 4 examination are defined as completed 
subjects.
3.11
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on and before the Week 4 examination during the 
treatment period, subjects who do not have a known reason for discontinuation (eg, 
withdrew consent or AE) and subjects whose survival is unknown on the trial completion 
day will be classified as lost to follow-up. The subject’s survival can be judged by 
various information sources by obtaining the proper documents which indicate death (ie, 


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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 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 considered as “lost to follow-up.” If the subject is lost to follow-
up, the contact date and contact method will be recorded in the source document and the 
last date on which an attempt was made to reach the subject and the contact method will 
be recorded in the CRF.
3.12
Subject (including 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.

The subject will evaluate the most intense pruritus in the past 24 hours once daily, 
every day, at the same time as the baseline examination in principle from the day after 
the baseline examination until the day before the Week 1 examination and describe it 
in a pruritus diary for subjects aged 7 to 14 years old. However, the subject will keep 
the pruritus diary up to Day 8 if scheduled to visit on Day 9 or later.

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 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.
3.13
Deviations from the Trial Protocol
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant medication criteria), the investigator, subinvestigator or designee will 
contact the sponsor at the earliest possible time by telephone. The investigator or 
subinvestigator and sponsor will come as quickly as possible to a joint decision regarding 
the subject’s continuation in the trial. This decision will be documented by the 


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investigator or subinvestigator and the sponsor, and reviewed by the site monitor. If any 
major deviations occur, the date of occurrence and details of the major deviation will be 
recorded in the CRF.
The investigator or subinvestigator will record all deviations from the protocol. Major 
protocol deviations will be recorded in the CRF such as “subjects who entered the trial 
even though they did not meet the inclusion or exclusion criteria,” “subjects who 
developed withdrawal criteria during the trial but were not withdrawn,” “protocol 
deviations that affect the primary endpoint assessment,” “subjects who received the 
wrong treatment or incorrect dose,” or “subjects who received a prohibited concomitant 
therapy.”
4
Restrictions
4.1
Prohibited Concomitant Drugs and Therapies
Prohibited concomitant drugs and therapies are shown in Table 4.1-1. The use of drugs 
on the scalp is not restricted since the IMP will not be applied to the scalp. 
Table 4.1-1
Prohibited Concomitant Drugs and Therapies
Duration
Provision
From 3 months prior to obtaining informed consent 
to the Week 4 examination (or withdrawal 
examination)
Allergen immunotherapy (desensitization therapy)
However, if subjects have continued allergen 
immunotherapy for more than 3 months prior to
informed consent or earlier, and the investigator or 
subinvestigator judges that no changes in AD 
symptoms are observed, subjects may continue such 
therapy until Week 4 examination as long as no 
changes are made to the therapy (types or amount of 
allergen, frequency, etc).
From 28 days prior to the baseline examination until 
the Week 4 examination (or withdrawal 
examination)
Ultraviolet light A, narrowband ultraviolet B 
(NB-UVB), ultraviolet light B
Systemic corticosteroids, systemic 
immunosuppressants, systemic antimetabolites, 
systemic retinoids, and biologics
From 21 days prior to the baseline examination until 
the Week 4 examination (or withdrawal 
examination)
Topical corticosteroids for skin categorized as very 
strong or higher potency in the “Guidelines for 
Management of Atopic Dermatitis1”
From 7 days prior to the baseline examination until 
the Week 4 examination (or withdrawal 
examination)
Topical corticosteroids for skin categorized as 
strong potency in the “Guidelines for Management 
of Atopic Dermatitis1”, topical corticosteroids other 
than those for skin, topical immunosuppressants, 
topical retinoids, topical antihistamine, and topical 
non-steroidal anti-inflammatory drugs. However, 
intra-ocular, intra-nasal, intra-auricular, and inhaled
corticosteroids and antihistamines may be 
considered if the investigator or subinvestigator


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Table 4.1-1
Prohibited Concomitant Drugs and Therapies
judges that their use will not impact assessment of
the affected area.
Systemic antihistamines, sodium cromoglicate, 
tranilast, suplatast tosilate 
However, if these medications were being used 
prior to obtaining consent, their use may be 
continued without changing the dosage and 
administration.
From 4 days prior to the baseline examination until 
the Week 4 examination (or withdrawal 
examination)
Topical corticosteroids for skin categorized as low 
or medium potency in the “Guidelines for
Management of Atopic Dermatitis1”
From the baseline examination until the Week 4 
examination (or withdrawal examination)
All topical drugs (including ethical drugs, 
over-the-counter products, herbal medicine, 
quasi-drugs, and cosmetic products) on the 
treatment area.
However, if cosmetic products were being used on 
the face and neck prior to obtaining consent, their 
use may be continued only if the same products are 
used at the same frequency.
AD: Atopic dermatitis; NB-UVB: Narrow-band ultraviolet B
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 
examination and the Week 4 examination.
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. Adverse Events 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.
An SAE includes any event that results in any of the following outcomes:

Death


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
Life-threatening; ie, the subject was, in the opinion of the investigator or 
subinvestigator, 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.
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.
Non-serious AEs 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 serious hepatotoxicity (see Section 5.4, Potential Serious Hepatotoxicity). 

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. Pregnancies of the subjects or their partners will be 
included in the above.
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 


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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.
1 = Mild: Discomfort noticed, but no disruption to daily activity.
2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe: Inability to work or perform normal daily activity.
Skin and subcutaneous tissue disorders will be graded according to the Common 
Terminology Criteria for Adverse Events v4.0 Japan Clinical Oncology Group edition.
IMP Causality: Assessment of causal relationship of an AE to the use of the IMP is 
judged according to the following criteria:
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?” The names, dates of occurrence, dates of outcomes, 
seriousness, severity, causal relationship with the IMP, measures related to IMP 
administration, outcomes, and occurrences at administration sites of all AEs reported by 
the subject must be recorded on the source documents and CRFs provided by the sponsor. 
Eliciting AEs and SAEs will be started after the subject has signed an ICF.
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. 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 e-mail of any IREs in principle 
according to the procedure outlined below, in Section 5.3, Immediately Reportable 
Events. Special attention should be paid to recording hospitalization and concomitant 
medications.


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5.3
Immediately Reportable Events
After either the investigator, subinvestigator, or designated person becomes aware of any 
SAE, any AE related to occupational exposure, potential serious hepatotoxicity, or 
confirmed pregnancy, the investigator or subinvestigator must immediately report the 
event to the sponsor by e-mail in principle (see cover page of this protocol for contact 
information). An IRE form, etc. must be completed and sent by e-mail in principle to the 
sponsor. Please note that the IRE form is NOT the AE section of CRF.
Subjects experiencing SAEs and IREs 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 Serious Hepatotoxicity
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, all values should be 
recorded on an IRE form, etc. and report as an AE on the CRF.
5.5
Implementation of Patch Test 
If any AE 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 again, 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-


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associated irritant reaction disappears. Then, subsequent 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 Dermatitis13
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 in this clinical trial, 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, the legal guardians of female pediatric subjects (potential) aged 7 
to 14 years old 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 ICF stating that the above-mentioned risk factors and 
consequences were discussed with her.
At the screening, baseline, Week 4, and withdrawal examinations, female children aged 7 
to 14 years old should undergo a urine pregnancy test. If a positive or false positive urine 
test result is obtained or the urine test is not possible, a serum pregnancy test (human 
chorionic gonadotropin test) will be conducted.
During the trial, female children and subject’s legal guardians should be instructed to 
contact the investigator or subinvestigator immediately if they suspect they might be 
pregnant.


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If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of pregnancy tests are available. If the pregnancy is 
confirmed, the subject must not receive the IMP and must not be enrolled in the trial. If 
pregnancy is suspected while the subject is taking IMP, the IMP must be withheld 
immediately (if reasonable, taking into consideration any potential withdrawal risks) until 
the result of the pregnancy test is known. If pregnancy is confirmed, the IMP will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety) and the subject will be withdrawn from the trial. 
The investigator or subinvestigator must immediately notify the sponsor of any 
pregnancy associated with IMP exposure during the trial and for 30 days after the last 
dose of IMP, and record the event on the IRE form, etc. and forward it to the sponsor.
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
The investigator or subinvestigator is encouraged to contact the sponsor to discuss their 
rationale for unblinding. However, to prevent delays to the investigator, subinvestigator 
or medical personnel responding to a potentially emergent situation, unblinding of IMP 
will not be dependent upon the investigator receiving approval from the sponsor (ie, the 
investigator or subinvestigator will be able to obtain the code break information 
independent of the sponsor). The investigator or subinvestigator must contact the sponsor 
by telephone or e-mail with an explanation of the need for opening the treatment 
assignment code within 24 hours of opening the code. If the blind is broken, the Clinical 
Safety and Pharmacovigilance department must be notified immediately (see the cover 
page of this protocol for contact information). Documentation of breaking the blind 
should be recorded in the subject’s medical record with the date and time the blind was 
broken and the names of the personnel involved. Once the blind is broken for a subject, 
that subject may not reinitiate treatment with the IMP. Please refer to the “Procedure for 
Emergency Code Breaking” for more detailed information.


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5.8
Follow-up of Adverse Events 
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 (ongoing or recovered/resolved). All non-serious AEs 
(excluding IREs) that are ongoing at the day of trial completion (final observation day) 
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 by the sponsor
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 day of trial completion (final observation day) will be recorded in medical 
records.
5.8.2
Follow-up of Serious Adverse Events and Immediately 
Reportable Events
In this trial, subjects will be actively observed for occurrence of any SAEs and IREs until 
the Week 4 examination or withdrawal examination (the day of trial completion [final 
observation day]).
Serious Adverse Events and IREs that are identified up to the day of trial completion or 
are ongoing on the day of trial completion must be recorded on the AE section of CRF. If 
new information on applicable SAEs or IREs (eg, “recovered”) is obtained from the day 
of a subject’s trial completion to the day of trial completion of the last subject during the 
trial period, it should be reported to the sponsor using the IRE form, etc. and must be 
recorded on the AE section of CRF. Any SAEs or IREs should be followed and any 
significant follow-up information should be reported to the sponsor using the IRE form, 
etc. until the events are resolved or clinically stabilized, or the subject is lost to follow-up 
or dies.
5.8.3
Follow-up and Reporting of Serious Adverse Events and 
Immediately Reportable Events Occurring After Day of Trial 
Completion (Final Observation Day)
Any new SAEs and IREs reported 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. These events may 
include SAEs and IREs that are captured on follow-up telephone contact or at any other 
timepoint after the defined trial period. The investigator or subinvestigator should follow 


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any SAEs and IREs identified after the defined trial period and report any significant 
follow-up information to the sponsor using the IRE form, etc. until the event has been
resolved or clinically stabilized, or the subject is lost to follow-up or dies.
6
Pharmacokinetic Analysis
No pharmacokinetic analysis is planned.
7
Statistical Analysis
7.1
Sample Size
The target sample size is set to achieve a power of 90% for the comparison of the 1% 
OPA-15406 group and vehicle group, which is firstly conducted in a closed testing 
procedure. In the phase 2 trial in pediatric patients in Japan (Trial 271-102-00002), the 
success rate in IGA was 37.5% (9/24), 40.0% (10/25) and 8.3% (2/24) in the 0.3% 
OPA-15406 group, 1% OPA-15406 group and vehicle group, respectively. However, for 
reasons such as the sample size of the phase 2 trial in pediatric patients in Japan being 
small and in order to conservatively consider the robustness of the trial results based on 
the characteristics of the primary endpoint, it is assumed that if the number of responders 
increased by one and decreased by one in the 1% OPA-15406 group and vehicle group, 
respectively, then the success rate in IGA is 36% and 12%. In the case of this condition, it 
is necessary to have 72 subjects per group to achieve a power of 90% using a two-sided 
significance level of 5%. In consideration of an exploratory assessment of age categories, 
however, the target sample size has been set as 80 subjects in each group, for a total of 
240 subjects.
7.2
Datasets for Analysis

Safety Set (SS):
The SS consists of all subjects who have received the IMP at least once.

Full Analysis Set (FAS):
The FAS consists of all subjects who have received the IMP at least once.


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7.3
Handling of Missing Data
For the success rate in IGA, the primary endpoint, subjects with missing IGA data will be 
handled as non-responders.
7.4
Primary and Secondary Endpoint Analyses
Efficacy will be analyzed in the FAS.
7.4.1
Primary Endpoint Analysis
The primary endpoint is the success rate in IGA (percentage of subjects with an IGA 
score of 0 or 1 with an improvement of at least 2 grades) at Week 4.
The efficacy of the 0.3% and 1% OPA-15406 groups will be demonstrated compared to 
the vehicle group based on the primary endpoint, the success rate in IGA at Week 4. 
Overall type I errors will be controlled using a closed testing procedure. First, the 1% 
OPA-15406 treatment group and the vehicle group will be compared. If significant at the 
two-sided significance level of 5%, the 0.3% OPA-15406 treatment group and the vehicle 
group will then be compared at the two-sided significance level of 5%. The 
Cochran-Mantel-Haenszel test will be conducted for comparison using the baseline IGA 
(2 or 3) and age (“2 - 6 years” or “7 - 14 years”) as a stratification factor. The difference 
in the success rate in IGA and its two-sided 95% confidence interval (common risk 
difference adjusted by Mantel Haenszel method and its two-sided 95% confidence 
interval) between the vehicle group and 0.3% or the 1% OPA-15406 group will be 
determined. Also, the two-sided 95% confidence interval of the success rate in IGA in 
each treatment group (based on Clopper-Pearson method) will be calculated. In addition, 
the success rate in IGA in each treatment group and its two-sided 95% confidence 
interval will be plotted and the dose-response relationship will be graphically assessed. 
Also, a supplementary analysis will be performed using data which includes missing data 
imputed by Last Observation Carried Forward (LOCF) and Observed Cases (OC) data 
which does not include the imputed missing data in the same manner.
7.4.2
Secondary Endpoint Analysis

The success rate in IGA achieving a score of 0 or 1 at Week 4 and the success rate in 
EASI 75, EASI 90, and EASI 50 at Week 4
The secondary endpoint will be analyzed in the same manner as the primary endpoint.
For IGA, subjects who achieve a score of 0 or 1 in IGA will be handled as responders and 
subjects who do not achieve a score 0 or 1 in IGA will be handled as non-responders.
Subjects with missing IGA data will be handled as non-responders.


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EASI 75 will be set as the important secondary endpoint, and subjects whose percentage 
change in their total EASI score from baseline decreases by ≥75% will be handled as 
responders and subjects whose percentage change from baseline does not decrease by 
≥75% will be handled as non-responders. Subjects with missing EASI 75 data will be 
handled as non-responders. EASI 90 and EASI 50 will be analyzed in the same manner. 
Similarities with the primary endpoint results will be assessed using the response rates in 
EASI (EASI 75, EASI 90, and EASI 50). 

Change from baseline at Week 4 in the IGA score; the total EASI score; each EASI 
clinical sign score; VRS for pruritus (including Day 7); the total POEM score; and the 
total affected BSA (%).
Based on the OC data set, change from baseline (Week 1, Week 2, and Week 4) will be 
analyzed using a mixed model repeated measure (MMRM) with treatment (0.3% 
OPA-15406 or 1% OPA-15406, and vehicle), timepoint, interaction between the 
treatment and timepoint as factors and baseline values as covariates. An unstructured 
error covariance matrix will be used and Kenward-Roger method will be used to 
calculate the degree of freedom. If the MMRM procedure fails to converge under 
unstructured covariance structure, the following structure will be used in the order of 1) 
heterogeneous toeplitz, 2) heterogeneous autoregressive of order 1, and 3) heterogeneous 
compound symmetry, and the first error covariance structure converging will be used. 
The MMRM analysis with the structured error covariance matrix will use a sandwich 
estimator. The least square mean will be calculated by treatment group and timepoint.
7.4.3
Subgroup Analysis
Success rate in IGA by subgroup will be analyzed in the same manner as the analysis of 
the primary endpoint as follows:

Age: 2 to 6 years old, 7 to 14 years old

Sex: male, female

IGA score at baseline: 2 or 3
7.4.4
Exploratory Analysis of Age Factor
Logistic regression analysis will be performed using treatment group as the main effect, 
baseline IGA (2 or 3) and age as covariates, and success rate in IGA at Week 4 as a 
response variable. An adjusted odds ratio and its 95% confidence interval will be 
determined.
For the age factor, in addition to age categories of “2 to 6 years old” and “7 to 14 years 
old,” no categorized age and other categorized age factor will be used.


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7.5
Analysis of Demographic and Other Baseline Characteristics
For demographic and other baseline characteristics, the descriptive statistics or frequency 
distribution will be created by treatment group and for all subjects treated with 
OPA-15406 depending on the characteristics of the respective parameters in the FAS and 
SS.
7.6
Safety Analysis
Safety analysis will be performed in the SS.
7.6.1
Adverse Events
All AEs will be coded using the Medical Dictionary for Regulatory Activities/Japanese 
version (MedDRA/J) system organ class and preferred term. The percentage of subjects 
experiencing the following AEs will be calculated for all subjects treated with 
OPA-15406 by treatment group.

TEAEs

TEAEs by severity

TEAEs resulting in death

Serious TEAEs

TEAEs leading to discontinuation of IMP administration

TEAEs (skin and subcutaneous tissue disorders) by grade

TEAEs at treatment areas
Treatment-emergent adverse events related to IMP will also be calculated in the same 
manner.
7.6.2
Clinical Laboratory Tests
For each parameter (except qualitative urinalysis), the descriptive statistics will be 
calculated for measured values and changes from the baseline at each timepoint for all 
subjects treated with OPA-15406 and by treatment group. For qualitative urinalysis 
values of clinical laboratory tests, a shift table at each timepoint against the baseline will 
be created for all subjects treated with OPA-15406 and each treatment group. For clinical 
laboratory tests except qualitative urinalysis, the number and percentage of subjects who 
are in the potentially clinically significant range will be calculated. The number and 
percentage of potential Hy’s Law Cases will be calculated for all subjects treated with 
OPA-15406 and by treatment group.


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7.6.3
Vital Signs and Body Weight
For each parameter and body weight, the descriptive statistics will be calculated for 
measured values and changes from baseline at each timepoint for all subjects treated with 
OPA-15406 and by treatment group. The number and percentage of subjects with 
clinically abnormal changes will be calculated for all subjects treated with OPA-15406 
and by treatment group.
8
Management of Investigational Medicinal Product
For further information about the management of the IMP, refer to the Investigator’s 
Brochure.
8.1
Packaging and Labeling
The IMP will be provided to 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 identification 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. The IMP manager may not 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.


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8.4
Returns and Destruction
Upon completion or termination of the trial, all unused, used 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 and be identified by protocol number with trial site number on the outermost 
shipping container. 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.
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 product, empty blister)

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_271-102-00008@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.


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8.5.2
Information Required for Reporting Product Quality Complaints

Description of compliant

Reporter identification (eg, subject, investigator or subinvestigator, trial site, etc.)

Reporter contact information (eg, address, phone number, e-mail address)

ID of material (compound name, kit number)

Clinical protocol reference (number and/or trial name)

Dosage form/strength (if known)

Pictures (if available)

Availability for return of the sample of complaints
8.5.3
Return Process in the Case of Product Quality Complaints
Indicate during the PQC report if the complaint sample is available for return. The 
sponsor may provide instructions for the return process of the sample, as necessary.
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 medical 
records, electronic data, screening logs, and recorded data from automated instruments.
All source documents pertaining to this trial will be maintained by the institutions 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.


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9.2
Data Collection
During each subject’s visit to the clinic, a clinician participating in the trial will record 
medical records 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;

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 medical records.
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the medical records as 
described above. Any changes to information in the medical records 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 
investigator or subinvestigator. If electronic data systems are being utilized, a full audit 
trail of changes must be maintained.
Information from the medical records and other source documents will be entered by 
investigative site personnel directly onto electronic CRFs in the sponsor’s electronic data 
capture. 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 E6 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.


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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.

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 GCP Guidelines (E6), 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, 


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the informed consent process, and comparison of CRFs with source documents. The 
investigator agrees to participate with audits.
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 number 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 country 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 identification numbers in CRFs. If 
further subject identification is required, subjects’ full names may be made known to a 
regulatory agency or other authorized officials if necessary, subject to local regulations.


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13
Amendment Policy
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB. Any permanent 
change to the protocol, whether an overall change or a change for specific trial site(s), 
must be handled as a protocol amendment. Any amendment will be written by the 
sponsor. Each amendment will be submitted to the IRB, as required by local regulations.
Except for “administrative” or “non-substantial” amendments, investigators will wait for 
IRB approval/favorable opinion of the amended protocol before implementing the 
change(s). Administrative amendments are defined as having no effect on the safety of 
subjects, conduct or management of the trial, trial design, or the quality or safety of IMP 
used in the trial. A protocol change intended to eliminate an apparent immediate hazard 
to subjects should be implemented immediately after agreement by the sponsor and 
investigator, followed by IRB notification within local applicable timelines. The sponsor 
will submit protocol amendments to the applicable regulatory agencies within local 
applicable timelines.
When the IRB, investigators, and/or the sponsor conclude that the protocol amendment 
substantially alters the trial design and/or increases the potential risk to the subject, the 
currently approved written ICF will require similar modification. In such cases, after 
approval/favorable opinion of the new ICF by the IRB, repeat written informed consent 
will be obtained from subjects and 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
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.


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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
Kato N, Ohya Y, Ikeda M, Ebihara T, Katayama I, Saeki H, et al. Guidelines for 
Management of Atopic Dermatitis 2018. The Japanese Journal of 
Dermatology. 2018;128(12):2431-502. 
2
Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta 
Dermatol Suppl.1980;92:44-7.
3
Hanifin JM, Butler JM, Chan SC. Immunopharmacology of the atopic diseases. 
J Invest Dermatol. 1985;85:161s-4s.
4
Kitagaki H, Hiyama H, Kitazawa T, Shiohara T. Psychological stress with long-
standing allergic dermatitis causes psychodermatological conditions in mice. J Invest 
Dermatol. 2014;134:1561-69.
5
Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 
1987;317:1098.
6
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.
7
International Council for Harmonisation (ICH) [Internet homepage]. E6(R2): Good 
Clinical Practice: Integrated Addendum to ICH E6(R1) [finalized 2016 November; 
cited 2018 Nov 9]. Available from: 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/
E6/E6_R2__Step_4_2016_1109.pdf.
8
Kohno Y, supervised by Yamamoto S. Guidelines for Treatment of Atopic Dermatitis 
2008. Available from: http://www.jaanet.org/pdf/guideline_skin02.pdf
9
Leung DYM, 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.
10 Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M., EASI Evaluator 
Group. The eczema area and severity index (EASI): assessment of reliability in atopic 
dermatitis. Exp Dermatol. 2001;10:11-8.


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11 Phan NQ, Blome C, Fritz F, Gerss 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. 2012;92:449-581.
12 Charman CR, Venn AJ, Ravenscroft JC, Williams HC. 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.
13 Takayama K, Yokozeki H, Matsunaga K, Katayama I, Aiba S, Itoh M, et 
al. Guidelines for Management of Contact Dermatitis. The Japanese Journal 
of Dermatology. 2009;119(9):1757-93.


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Appendix 1
Diagnostic Criteria for Atopic Dermatitis (Japanese 
Dermatological Association’s Criteria)
1. Pruritus
2. Typical morphology and distribution:
(1) Eczematous dermatitis

Acute lesions: erythema, exudation, papules, vesiculopapules, scales, crusts

Chronic lesions: infiltrated erythema, lichenification, prurigo, scales, crusts
(2) Distribution

Symmetrical
Predilection sites: forehead, periorbital area, perioral area, lips, periauricular area, neck, joint 
areas of limbs, trunk

Age-related characteristics 
Infantile phase: starts on the scalp and face, often spreads to the trunk and extremities
Childhood phase: neck, the flexural surfaces of the arms and legs
Adolescence and adult phase: tendency to be severe on the upper half of body (face, neck, 
anterior chest and back)
3. Chronic or chronically relapsing course (usually coexistence of old and new lesions):
More than 2 months in infancy, and more than 6 months in childhood, adolescence, and 
adulthood
Definitive diagnosis of atopic dermatitis requires the presence of all three features without any 
consideration of severity. Other cases should be evaluated on the basis of the age and clinical course with 
the tentative diagnosis of acute or chronic, non-specific eczema.
Differential diagnosis (association may occur)

Contact dermatitis

Seborrhoeic dermatitis

Prurigo simplex

Scabies

Miliaria

Ichthyosis

Xerotic eczema

Hand eczema (non-atopic)

Cutaneous lymphoma

Psoriasis

Immune deficiency diseases

Collagen diseases (systemic lupus 
erythematosus, dermatomyositis)

Netherton’s syndrome
Diagnostic aids

Family history (bronchial asthma, allergic rhinitis and/or conjunctivitis, atopic dermatitis)

Complications (bronchial asthma, allergic rhinitis and/or conjunctivitis)

Follicular papules (goose-skin)

Elevated serum IgE level
Clinical type (not applicable to the infantile phase)

Flexural surface type

Extensor surface type

Dry form in childhood

Head, neck, upper chest, back type

Prurigo type

Erythroderma type

Combinations of various types are common
Significant complications

Ocular complication (cataract and/or retinal 
detachment): especially in patients with severe 
facial lesions

Kaposi’s varicelliform eruption

Molluscum contagiosum,

Impetigo contagiosa


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Appendix 2
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 legal representatives will answer them instead.
© The University of Nottingham


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Appendix 3
Human Body Drawing for Children Aged 8 to 14 Years Old
              Day/  ____Month/20___(             examination) Subject identification number: S000
      
Affected site
Affected 
area (%)
Administration site
Treatment 
area (%)
Total amount of 
administration
_____   g
Appropriate amount 
of administration per 
1%
g
Face, neck, and head
%
Face, neck, and head
%
Upper limbs
%
Upper limbs
%
Trunk
%
Trunk
%
Lower limbs
%
Lower limbs
%
Total
%
Total
%
Signature of the investigator/subinvestigator
_______________________________________________________Day/_____Month/20_____


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Appendix 4
Human Body Drawing for Children Aged 2 to 7 Years Old
              Day/  ____Month/20___(             examination) Subject identification number: S000
Affected site
Affected 
area (%)
Administration site
Treatment 
area (%)
Total amount of 
administration
_____   g
Appropriate amount 
of administration per 
1%
g
Face, neck, and head
(excluding scalp)
%
Face, neck, and head
(excluding scalp)
%
Upper limbs
%
Upper limbs
%
Trunk
%
Trunk
%
Lower limbs
%
Lower limbs
%
Total
%
Total
%
Signature of the investigator/subinvestigator
_______________________________________________________Day/_____Month/20_____


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Appendix 5
Protocol Amendments and Administrative Changes
Amendment No.: 2 (First amendment after submission of protocol)
Date created:  1 Feb 2019
Purpose: To clarify the prohibited concomitant drugs and therapies and exclusion criteria 
related to prohibited concomitant drugs and therapies and to provide more appropriate 
wording.
Background: Amendments were made upon judgment that clarifications on prohibited 
concomitant medication and more appropriate terminology were necessary.
Amendments to protocol:

The sentence below was added to Section 4.1 Prohibited Concomitant Drugs and 
Therapies. Also, more details were added to clarify the language regarding steroids in 
Table 4.1-1 Prohibited Concomitant Drugs and Therapies.  
The use of drugs on the scalp is not restricted since the IMP will not be applied to the 
scalp.

In accordance with the above changes, a sentence related to corticosteroids was added 
to Exclusion Criteria 14 to 16 to allow for the use of corticosteroids on the scalp, and 
changes to the wording related to corticosteroids were made. 

Exclusion Criteria 14
Prior to change:
Subjects who are unable to stop using topical corticosteroids categorized as very 
strong or higher potency in the “Guidelines for Management of Atopic Dermatitis1” 
from 21 days prior to the baseline examination until the Week 4 examination.
After change:
Subjects who are unable to stop using topical corticosteroids for skin (excluding 
scalp) categorized as very strong or higher potency in the “Guidelines for 
Management of Atopic Dermatitis1” from 21 days prior to the baseline examination 
until the Week 4 examination.

Exclusion Criteria 15
Prior to change:
Subjects who are unable to stop using topical corticosteroids categorized as strong 
potency in the “Guidelines for Management of Atopic Dermatitis1”, topical 
immunomodulators, topical retinoids, topical antihistamine and topical non-steroidal 
anti-inflammatory drugs from 7 days prior to the baseline examination until the Week 
4 examination. Intra-ocular, intra-nasal, and intra-auricular corticosteroids, inhaled 
corticosteroids, intra-ocular and intra-nasal antihistamines or inhaled antihistamines 
may be considered if, in the opinion of the investigator or subinvestigator, their use 
will not impact assessment of the affected area.
After change:
Subjects who are unable to stop using topical corticosteroids for skin (excluding 
scalp) categorized as strong potency in the “Guidelines for Management of Atopic 


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Dermatitis1”, topical corticosteroids other than those for skin, topical 
immunosuppressants, topical retinoids, topical antihistamine and topical non-
steroidal anti-inflammatory drugs (excluding for scalp) from 7 days prior to the 
baseline examination until the Week 4 examination. Intra-ocular, intra-nasal, intra-
auricular, and inhaled corticosteroids and antihistamines may be considered if the 
investigator or subinvestigator judges that their use will not impact assessment of the 
affected area.

Exclusion Criteria 16
Prior to change:
Subjects who are unable to stop using topical corticosteroids categorized as low or 
medium potency in the “Guidelines for Management of Atopic Dermatitis1” from 4 
days prior to the baseline examination until the Week 4 examination.
After change:
Subjects who are unable to stop using topical corticosteroids for skin (excluding 
scalp) categorized as low or medium potency in the “Guidelines for Management of 
Atopic Dermatitis1” from 4 days prior to the baseline examination until the Week 4 
examination.

The following sentence was added to Section 3.7.1 Schedule of Assessments:
Regarding assessments to be performed by the investigator or subinvestigator, the 
assessments that a clinical trial associate is able to perform (eg, subject 
demographics and clinical laboratory tests) may be performed by the clinical trial 
associate under the supervision of the investigator.

Other changes were made to correct minor typos and to reflect changes to the 
template.
In this English translation version, the term “immunomodulators” was changed to 
“immunosuppressants” to standardize terminology across protocols.
Additional risks to subjects: No additional risks will be imposed on the subjects.
Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, OPA-15406 ointment, the concurrent 
medications, the efficacy and safety parameters and the conduct of the trial in general. I am 
aware that this protocol must be approved by the Institutional Review Board (IRB) responsible for 
such matters in the clinical trial facility where OPA-15406 ointment will be tested prior to 
commencement of this trial. I agree to adhere strictly to the attached protocol (unless amended in 
the manner set forth in the sponsor's Clinical Trial Agreement, at which time I agree to adhere 
strictly to the protocol as amended).


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I understand that this IRB-approved protocol will be submitted to the appropriate regulatory 
authority by the sponsor. I agree that clinical data entered on case report forms by me and my 
staff will be utilized by the sponsor in various ways, such as for submission to governmental 
regulatory authorities and/or in combination with clinical data gathered from other research sites, 
whenever applicable. I agree to allow sponsor and designee monitors and auditors full access to 
all medical records at the research facility for subjects screened or enrolled in the trial.
I agree to await IRB approval before implementation of any substantial amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IRB within the required local applicable timelines. 
Administrative changes to the protocol will be transmitted to the IRB for informational purposes 
only, if required by local regulations.
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse experiences in 
accordance with the terms of the sponsor's Clinical Trial Agreement and the relevant regional 
regulation(s) and guideline(s). I further agree to provide all required information regarding 
financial certification or disclosure to the sponsor for all investigators and sub-investigators in 
accordance with the terms of the relevant regional regulation(s). I understand that participation in 
the protocol involves a commitment to publish the data from this trial in a cooperative publication 
before publication of efficacy and safety results on an individual basis may occur, and I consent to 
be acknowledged in any such cooperative publications that result.
_________________________________
____________________________
Principal Investigator Name
Trial Site
_____________________________
DD Mon 20XX
Signature
Date
The signature of the sponsor is electronically captured. The electronic signature page is attached 
to this agreement.

SAP_000.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
A Multicenter, Randomized, Double-blind, Vehicle-controlled, Parallel-group 
Comparison Trial to Demonstrate the Superiority of 0.3% and 1% OPA-15406 
Ointment to the Vehicle in Pediatric Patients with Atopic Dermatitis (Phase 3 Trial) 
 
 
 
 
 
NCT Number: NCT03911401 
PRT NO.: 271-102-00008 
Version Date: 30 January 2020 (Version 1.0) 


 
 
 
 
Otsuka Pharmaceutical Co., Ltd. 
 
 
Investigational Medicinal Product 
OPA-15406 
 
 
 
Protocol No. 271-102-00008 
 
 
 
A Multicenter, Randomized, Double-blind, Vehicle-controlled, Parallel-group 
Comparison Trial to Demonstrate the Superiority of 0.3% and 1% OPA-15406 Ointment 
to the Vehicle in Pediatric Patients with Atopic Dermatitis (Phase 3 Trial) 
 
Statistical Analysis Plan 
 
Version: 1.0 
Issue Date: 30 Jan 2020 
Clinical Protocol Version 3.0 Date: 1 Feb 2019 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
May not be used, divulged, published, or otherwise disclosed without the prior written 
consent of Otsuka Pharmaceutical Co., Ltd. 
 


Protocol 271-102-00008 
 
 
Statistical Analysis Plan  
2 of 37 
Version: 1.0 Date: 01/30/2020 
 
Table of Contents 
Table of Contents ........................................................................................... 2 
List of Appendices.......................................................................................... 4 
List of Abbreviations and Definition of Terms ........................................... 5 
1 
Introduction .......................................................................................... 6 
2 
Trial Objectives ..................................................................................... 6 
3 
Trial Design ........................................................................................... 6 
3.1 
Type/Design of Trial ...........................................................................................6 
3.2 
Methods of Administration .................................................................................8 
3.2.1 
Dose, Regimen, and Treatment Period .............................................................8 
3.2.2 
Treatment Area .................................................................................................8 
3.3 
Trial Population ...................................................................................................9 
3.4 
Trial Visit Window ..............................................................................................9 
4 
Sample Size .......................................................................................... 10 
5 
Statistical Analysis Datasets .............................................................. 11 
5.1 
Full Analysis Set (FAS) ....................................................................................11 
5.2 
Safety Set (SS)...................................................................................................11 
5.3 
Handling of Missing Data .................................................................................11 
6 
Primary and Secondary Outcome Variables ................................... 11 
6.1 
Primary Outcome Variable ................................................................................11 
6.2 
Secondary Outcome Variables ..........................................................................11 
7 
Disposition and Demographic Analysis ............................................ 12 
7.1 
Subject Disposition............................................................................................12 
7.2 
Demographic and Baseline Characteristics .......................................................12 
7.3 
Baseline Disease Evaluation .............................................................................12 
7.4 
Treatment Compliance ......................................................................................13 
7.5 
Prior and Concomitant Medications ..................................................................13 
7.6 
Protocol Deviations ...........................................................................................13 
8 
Efficacy Analysis ................................................................................. 13 
8.1 
Primary Efficacy Endpoint ................................................................................13 
8.1.1 
Primary Efficacy Analysis ..............................................................................14 


Protocol 271-102-00008 
 
 
Statistical Analysis Plan  
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Version: 1.0 Date: 01/30/2020 
 
8.2 
Secondary Efficacy Endpoints ..........................................................................14 
8.2.1 
Success Rates in IGA (Revised Definition) and EASI ...................................14 
8.2.2 
Change From Baseline Through Week 4 in the IGA Score ...........................15 
8.2.3 
Shift Table for Investigator’s Global Assessment Scores up to Week 4 ........16 
8.2.4 
Change From Baseline Through Week 4 in the Total EASI Score and 
Each EASI Clinical Sign Score ......................................................................16 
8.2.5 
Change From Baseline Through Day 8 in VRS for Pruritus ..........................17 
8.2.6 
Change From Baseline Through Week 4 in VRS for Pruritus .......................17 
8.2.7 
Change From Baseline Through Week 4 in the Total POEM Score ..............17 
8.2.8 
Change From Baseline Through Week 4 in the Total Affected BSA (%) .....17 
8.3 
Subgroup Analyses ............................................................................................17 
8.4 
Exploratory Analysis of Age Factor ..................................................................17 
9 
Safety Analyses ................................................................................... 18 
9.1 
Extent of Exposure ............................................................................................18 
9.2 
Adverse Events ..................................................................................................18 
9.3 
Clinical Laboratory Tests ..................................................................................19 
9.4 
Vital Signs and Body Weight ............................................................................19 
9.5 
Physical Examination ........................................................................................19 
9.6 
Electrocardiogram .............................................................................................19 
9.7 
Liver Function Tests ..........................................................................................20 
10 
Pharmacokinetic Analysis .................................................................. 20 
11 
Pharmacodynamic Analysis .............................................................. 20 
12 
Pharmacogenomic Analysis ............................................................... 20 
13 
Interim Analysis .................................................................................. 20 
14 
Changes in the Planned Analyses ...................................................... 20 
15 
References ............................................................................................ 20 
 


Protocol 271-102-00008 
 
 
Statistical Analysis Plan  
4 of 37 
Version: 1.0 Date: 01/30/2020 
 
List of Appendices 
Appendix 1 
Criteria for Vital Signs Potential Clinical Significance ................ 21 
Appendix 2 
Criteria for Potential Hy’s Law..................................................... 22 
Appendix 3 
List of Summary Tables ................................................................ 23 
Appendix 4 
List of Subject Data Listings......................................................... 35 


Protocol 271-102-00008 
 
 
Statistical Analysis Plan  
5 of 37 
Version: 1.0 Date: 01/30/2020 
 
List of Abbreviations and Definition of Terms 
List of Abbreviations 
Abbreviation 
Expansion or Definition 
AE 
Adverse event 
BMI 
Body mass index 
BSA 
Body surface area  
CRF 
Case report form 
EASI 
Eczema Area and Severity Index 
FAS 
Full Analysis Set 
IGA 
Investigator’s Global Assessment 
IMP 
Investigational medicinal product 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
OC 
Observed Cases 
POEM 
Patient-Oriented Eczema Measure 
SS 
Safety Set 
TEAE 
Treatment-emergent adverse event 
VRS 
Verbal Rating Scale 
 
List of Definitions of Terms 
Term 
Definition 
Descriptive statistics 
Number of subjects, mean, standard deviation, maximum, 
median, and minimum 
Frequency distribution 
Number and percentage of subjects 
 
 
 


Protocol 271-102-00008 
 
 
Statistical Analysis Plan  
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Version: 1.0 Date: 01/30/2020 
 
1 
Introduction 
This statistical analysis plan describes in detail the methodology for statistical analysis 
planned in the protocol for Trial 271-102-00008. 
2 
Trial Objectives 
Primary objective: To demonstrate the superiority of 0.3% and 1% OPA-15406 ointment 
to the vehicle when administered the investigational medicinal product (IMP; 0.3% and 
1% OPA-15406 ointment or vehicle) twice daily for 4 weeks in pediatric patients with 
atopic dermatitis (AD), using success rate in Investigator’s Global Assessment (IGA) at 
Week 4 as the primary endpoint. 
Secondary objective: To evaluate the efficacy (secondary endpoint) and safety of 0.3% 
and 1% OPA-15406 ointment when administered the IMP twice daily for 4 weeks in 
pediatric patients with AD and to confirm the dose-response relationship. 
3 
Trial Design 
3.1 
Type/Design of Trial 
This trial is a multicenter, randomized, double-blind, vehicle-controlled, parallel-group, 
comparison trial to demonstrate the superiority of 0.3% and 1% OPA-15406 ointment to 
the vehicle in pediatric AD patients. This trial consists of the 0.3% OPA-15406 group, 
1% OPA-15406 group, and the vehicle group. The trial design is shown in Figure 3.1-1. 
1) Screening period 
After obtaining informed consent from the subject’s legal guardian (and, if possible, 
after obtaining assent from the subject), the investigator or subinvestigator will 
perform a screening examination. The screening period is defined as the period 
between the day of screening examination and the day of baseline examination (2 to 
30 days). 
2) Assessment period (treatment period) 
The assessment period is defined as the period between the day of baseline 
examination and the end of Week 4 examination (or the end of withdrawal 
examination). The subjects who meet the inclusion and exclusion criteria at the 
baseline examination will be allocated to 0.3% or 1% OPA-15406 ointment or the 
comparator (vehicle [placebo]). The allocated IMP will be administered to the 
treatment area from the day of baseline examination twice daily for 4 weeks. After 
the baseline examination, the examinations will be performed at Weeks 1, 2, and 4. 


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If a subject discontinues the IMP administration between the day of the baseline 
examination and the day of the Week 4 examination, a withdrawal examination will 
be performed for that subject. 
3) Trial period 
The trial period for individual subjects is the period from the day of obtaining the 
written informed consent from the subject’s legal guardian to the day of the Week 4 
examination or withdrawal examination. For subjects who missed the Week 4 
examination or withdrawal examination, the day of discontinuation will be the day 
when the investigator or subinvestigator determined that the subject was to be 
withdrawn from the trial. It does not include the follow-up period for adverse events 
(AEs). 
 
 
Screening period 
(2 to 30 days) 
Assessment period 
Twice daily administration 
(4 weeks) 
 
 
 
0.3% OPA-15406 group 
 
 
1% OPA-15406 group 
 
Vehicle group 
 
 
 
 
Informed consent 
Screening examination 
Baseline examination 
IMP allocation 
Week 1 examination 
Week 2 examination 
Week 4 examination (day of trial completion 
[final observation day]) 
Figure 3.1-1 
Trial Design 
 


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3.2 
Methods of Administration 
3.2.1 
Dose, Regimen, and Treatment Period 
The 0.3% or 1% formulation or the vehicle of OPA-15406 ointment will be administered 
twice daily (approximately 12 hours apart between morning and night administration) for 
4 weeks. The amount of IMP (g) per dose is 10 g/m2 BSA and 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) 
 
2) The treatment area will be specified. 
3) The amount of IMP (g) per dose will be calculated as  
“subject’s BSA (m2)” × “treatment area (%)” × “10 g/m2.” 
4) Example: In case of a BSA of 0.7m2 and an affected BSA of 32%:  
0.7 m2 × 0.32 × 10 g/m2 = 2.24g 
 
3.2.2 
Treatment Area 
The treatment area with the IMP is defined as follows. 
 The treatment area selected at the baseline examination will be the affected area 
determined at the baseline examination. 
 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’s legal guardian (if possible, 
the subject) regarding the method of administration by specifying the treatment area (%) 
and the total amount of administration (g) for each treatment area using the human body 
drawing, and will give the human body drawing (copy) to the subject or subject’s legal 
guardian. The investigator or subinvestigator will record the treatment area (%) of the 
4 body regions (face, neck, and head [excluding scalp]; upper limbs; trunk; and lower 
limbs) in the source document and case report form (CRF). 


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3.3 
Trial Population 
The target population of this trial is pediatric AD patients with an IGA score of 2 or 3. 
Subjects will be included in the trial to reach the target number of 240 subjects for IMP 
administration (the target inclusion ratio of “2 to 6 years old” to “7 to 14 years old” of 
age is 1:1). Any withdrawal will not be supplemented. 
3.4 
Trial Visit Window 
The start date of IMP administration is defined as baseline (Day 1) to count the number 
of days after starting IMP administration. Unscheduled visit data and withdrawal visit 
data as well as scheduled visit data will be included to determine timepoints for analysis. 
For efficacy endpoints, data up to 3 days after the end of IMP administration (final day of 
IMP administration + 3 days) will be included in the analysis. For safety endpoints, all 
data from the first IMP administration will be included in the analysis. Timepoints for 
analysis and acceptable windows are shown in Table 3.4-1. If there are multiple data 
points within an acceptable window, the last one in the window will be used. The Last 
Visit data for efficacy endpoints will be from the last visit during the period from the day 
after the first day of IMP administration (Day 2) through the third day after the last IMP 
administration (including unscheduled and withdrawal visit data), and those for safety 
endpoints will be from the last visit available from all data after the first day of IMP 
administration. 
The baseline data for analysis will be from the visit closest and prior to the first day of 
IMP administration. 
For the Verbal Rating Scale (VRS), the patient diary will be used as the source of data for 
the period from the start date of IMP administration (Day 1) through Day 8. After Week 
1, CRF Visit data (including unscheduled and withdrawal visit data) excluding patient 
diary data will be used to specify the timepoints for analysis according to Table 3.4-1. If 
there are multiple data points within an acceptable window, the last one in the window 
will be used. 
 
 


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Table 3.4-1 
Trial Day and Visit Windows 
Timepoint 
Target Day 
Interval (days after starting administration) 
Baseline 
1 
 
to 
1 
1 day after start of IMP 
administration (VRS alone) 
2 
 
to 
 
2 days after start of IMP 
administration (VRS alone) 
3 
 
to 
 
3 days after start of IMP 
administration (VRS alone) 
4 
 
to 
 
4 days after start of IMP 
administration (VRS alone) 
5 
 
to 
 
5 days after start of IMP 
administration (VRS alone) 
6 
 
to 
 
6 days after start of IMP 
administration (VRS alone) 
7 
 
to 
 
7 days after start of IMP 
administration (VRS alone) 
8 
 
to 
 
8 days after start of IMP 
administration (VRS alone) 
9 
 
to 
 
Week 1 
8 
2 
to 
10 
Week 2 
15 
11 
to 
21 
Week 4 
29 
22 
to 
32 
 
4 
Sample Size 
The target sample size is set to achieve a power of 90% for the comparison of the 1% 
OPA-15406 group and the vehicle group, which is firstly conducted in a closed testing 
procedure. In the phase 2 trial in pediatric patients in Japan (Trial 271-102-00002), the 
success rate in IGA was 37.5% (9/24), 40.0% (10/25), and 8.3% (2/24) in the 0.3% 
OPA-15406 group, the 1% OPA-15406 group, and the vehicle group, respectively. 
However, for reasons such as the sample size of the phase 2 trial in pediatric patients in 
Japan being small and in order to conservatively consider the robustness of the trial 
results based on the characteristics of the primary endpoint, it is assumed that if the 
number of responders decreased by one and increased by one in the 1% OPA-15406 
group and vehicle group, respectively, then the success rate in IGA is 36% and 12%. In 
the case of this condition, it is necessary to have 72 subjects per group to achieve a power 
of 90% at a two-sided significance level of 5%. In consideration of an exploratory 
assessment of age categories, however, the target sample size has been set as 80 subjects 
in each group, for a total of 240 subjects. 
 


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5 
Statistical Analysis Datasets 
5.1 
Full Analysis Set (FAS) 
The FAS consists of all subjects who have received the IMP at least once. 
5.2 
Safety Set (SS) 
The SS consists of all subjects who have received the IMP at least once. 
5.3 
Handling of Missing Data 
For the success rate in IGA, the primary endpoint, subjects with missing IGA data will be 
handled as non-responders. Subjects with only baseline values or with data missing at any 
timepoint will also be handled as non-responders. 
 
6 
Primary and Secondary Outcome Variables 
6.1 
Primary Outcome Variable 
Success rate in IGA at Week 4: percentage of subjects with IGA score of 0 or 1 with 
improvement by at least 2 grades. 
6.2 
Secondary Outcome Variables 
 Success rate in IGA at Week 4: percentage of subjects with improved IGA score of 0 
or 1 (revised definition from primary outcome variable) 
 Change from baseline at Week 4 in the IGA score 
 Success rate in EASI 75 (improvement of ≥75% in EASI), EASI 90 (improvement of 
≥90% in EASI), and EASI 50 (improvement of ≥50% in EASI) at Week 4 
 Change from baseline at Week 4 in the total EASI score and each EASI clinical sign 
score 
 Change from baseline at Week 4 in VRS for pruritus 
 Change from baseline through Day 8 in VRS for pruritus 
 Change from baseline at Week 4 in the total Patient-Oriented Eczema Measure 
(POEM) score 
 Change from baseline at Week 4 in the total affected BSA (%) 
 


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7 
Disposition and Demographic Analysis 
7.1 
Subject Disposition 
The number of subjects screened and the number of subjects allocated will be calculated. 
Unless specified otherwise, the following tabulations will be presented by treatment 
group (0.3% OPA-15406, 1% OPA-15406, or vehicle). Frequency distribution (number 
and percentage, the same hereinafter) will be provided for subjects who received, who 
completed, and who discontinued IMP administration. Also, the number and percentage 
of subjects included in the statistical analysis datasets will be presented. The number of 
allocated subjects will be used as the denominator to calculate the percentage. For 
subjects who discontinued treatment, the frequency distribution by reason for 
discontinuation will be presented. Tabulations will also be presented by age categories (2 
to 6 years old and 7 years and older). 
7.2 
Demographic and Baseline Characteristics 
Based on the FAS and SS, age, sex, disease duration, body weight, height, body mass 
index (BMI), race, and severity of AD will be presented by treatment group and in total. 
The descriptive statistics will be presented for age, disease duration, body weight, height, 
and BMI; and frequency distribution for sex, race, and severity of AD. Medical histories 
and complications will be coded by System Organ Class (SOC) and Preferred Term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA). Medical histories and 
complications will be listed but not summarized. Tabulations will also be presented by 
age categories (2 to 6 years old and 7 years and older). 
For the computation of disease duration, date data that are partially missing will not be 
imputed. Where the month and day are missing, only the year will be used, and where the 
day is missing, the year and month will be used for calculation. 
Where the “year, month, and day” are available:  
(Year-Month-Day − Year-Month-Day + 1) / 365.25 
Where only the “year and month” are available:  
[(Year × 12 + Month) − (Year × 12 + Month) + 1] / 12 
Where only the “year” is available: Year − Year + 1 
7.3 
Baseline Disease Evaluation 
Based on the FAS and SS, the frequency distribution of baseline IGA scores (2 or 3) and 
the descriptive statistics for the total EASI (Eczema Area and Severity Index) score at 
baseline will be presented by treatment group and in total. The affected area will be 


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classified in the following categories, and the frequency distribution calculated by 
treatment group and in total. Tabulations will also be presented by age categories (2 to 6 
years old and 7 years and older). 
Affected area categories: ≥5% to <10%, ≥10% to <30%, and ≥30% 
7.4 
Treatment Compliance 
Based on the SS, the compliance with the amount and number of doses from the baseline 
through Week 4 will be classified in the following categories, and the number and 
percentage of subjects will be calculated by treatment group and for all subjects. Also, the 
number and percentage of subjects administered will be calculated by week (Weeks 1, 2, 
3, 4, 5, and Any Exposure). The method for calculating compliance will be defined in a 
separate analysis data set specification, etc. 
Categories for compliance with the amount and number of doses:  
<50%, ≥50% to <60%, ≥60% to <70%, ≥70% to <80%, ≥80% to <90%, ≥90% to <100%, 
≥100% to <110%, ≥110% to <120%, and ≥120% 
Where the weight of IMP at retrieval is unknown, the amount of administration will be 
calculated by assuming that the retrieved weight is 0. 
7.5 
Prior and Concomitant Medications 
Based on the SS, the number and percentage of subjects taking medications before the 
start of, during, and after the end of IMP administration will be calculated for each 
medication by treatment group and in total. Medications will be coded using WHO Drug 
Dictionary and summarized by ATC classifications level 2 and preferred name. 
Concomitant therapies will be listed but not summarized. 
7.6 
Protocol Deviations 
Based on the allocated subjects, the number and percentage of subjects with major 
protocol deviations will be presented by treatment group and in total. Also for each site, 
the number and percentage of subjects with major protocol deviations will be presented 
by treatment group and in total. 
8 
Efficacy Analysis 
Based on the FAS, the following analysis will be performed. 
8.1 
Primary Efficacy Endpoint 
The primary endpoint is the success rate in IGA at Week 4 (percentage of subjects with 
IGA score of 0 or 1 with improvement by at least 2 grades). 


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8.1.1 
Primary Efficacy Analysis 
The efficacy of the 0.3% and 1% OPA-15406 groups will be demonstrated compared to 
the vehicle group based on the primary endpoint, the success rate in IGA at Week 4. 
Overall type I errors will be controlled using a closed testing procedure. First, the 1% 
OPA-15406 treatment group and the vehicle group will be compared. If significant at the 
two-sided significance level of 5%, the 0.3% OPA-15406 treatment group and the vehicle 
group will then be compared at the two-sided significance level of 5%. The Cochran-
Mantel-Haenszel test will be conducted for comparison using the baseline IGA (2 or 3) 
and age (“2 to 6 years” or “7 to 14 years”) as a stratification factor. The difference in the 
success rate in IGA and its two-sided 95% confidence interval (common risk difference 
adjusted by Mantel Haenszel method and its two-sided 95% confidence interval) between 
the vehicle group and 0.3% or the 1% OPA-15406 group will be determined. Also, the 
two-sided 95% confidence interval of the success rate in IGA in each treatment group 
(based on Clopper-Pearson method) will be calculated. In addition, the success rate in 
IGA in each treatment group at Week 4 and its two-sided 95% confidence interval will be 
plotted and the dose-response relationship will be graphically assessed. 
The SAS code for the Cochran-Mantel-Haenszel test and to determine the difference in 
the success rate and two-sided 95% confidence interval is as follows: 
proc freq ; 
tables Agegroup*BaselineIGA*Treatment*Response / riskdiff(common) cmh ; 
run; 
 
A supplementary analysis will be performed using data which includes missing data 
imputed by Last Observation Carried Forward (LOCF) and Observed Cases (OC) data 
which does not include the imputed missing data in the same manner. 
Data at Weeks 1 and 2 will also be analyzed in the same manner as the primary endpoint 
at Week 4. 
8.2 
Secondary Efficacy Endpoints 
8.2.1 
Success Rates in IGA (Revised Definition) and EASI 
The success rate in achieving an IGA score of 0 or 1 (revised definition from primary 
efficacy endpoint) by Week 4 and the success rate in EASI 75, EASI 90, and EASI 50 by 
Week 4 will be analyzed in the same manner as the primary endpoint in Section 8.1.1 


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For IGA, subjects who achieve a score of 0 or 1 in IGA will be handled as responders and 
subjects who do not achieve a score 0 or 1 in IGA will be handled as non-responders. 
Subjects with missing IGA data will be handled as non-responders. 
EASI 75 will be set as the important secondary endpoint, and subjects whose percentage 
change in their total EASI score from baseline decreases by ≥75% will be handled as 
responders and subjects whose percentage change from baseline does not decrease by 
≥75% will be handled as non-responders. Subjects with missing EASI 75 data will be 
handled as non-responders. EASI 90 and EASI 50 will be analyzed in the same manner. 
Similarities with the primary endpoint results will be assessed using response rates in 
EASI (EASI 75, EASI 90, and EASI 50). 
8.2.2 
Change From Baseline Through Week 4 in the IGA Score 
Based on the OC data set, change from baseline (Week 1, Week 2, and Week 4) will be 
analyzed using a mixed-model repeated measure (MMRM) with treatment (0.3% 
OPA-15406 or 1% OPA-15406 and vehicle), timepoint, interaction between the treatment 
and timepoint as factors and baseline values as covariates. An unstructured error 
covariance matrix will be used and Kenward-Roger method will be used to calculate the 
degree of freedom. If the MMRM procedure fails to converge under unstructured 
covariance structure, the following structure will be used in the order of 1) heterogeneous 
toeplitz, 2) heterogeneous autoregressive of order 1, and 3) heterogeneous compound 
symmetry, and the first error covariance structure converging will be used. The MMRM 
analysis with the structured error covariance matrix will use a sandwich estimator. The 
least square mean will be calculated by treatment group and timepoint. 
The SAS code for MMRM analysis is as follows: 
proc mixed method = reml ; 
class Treatment Visit Subject ; 
model Change = Treatment Visit Treatment*Visit Baseline / s ddfm = kr ; 
repeated Visit / type = un sub = Subject ; 
lsmeans Treatment*Visit / pdiff cl alpha = 0.05 ; 
run; 
 “Baseline” is baseline IGA data. “Visit” includes data at Weeks 1, 2, and 4. 
 


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The SAS code used in the case of convergence failure is as follows: (Specify type = 
TOEPH for heterogeneous toeplitz, type = ARH(1) for heterogeneous autoregressive of 
order 1, and type = CSH for heterogeneous compound symmetry.) 
proc mixed method = reml empirical ; 
class Treatment Visit Subject ; 
model Change = Treatment Visit Treatment*Visit Baseline / s ; 
repeated Visit / type = TOEPH sub = Subject ; 
lsmeans Treatment*Visit / pdiff cl alpha = 0.05 ; 
run; 
 
Based on the OC and LOCF data sets, change from baseline at each timepoint will be 
analyzed using an ANCOVA model with treatment (0.3% OPA-15406 or 1% OPA-15406 
and vehicle) as factors and baseline IGA scores as covariates. The least square mean will 
be calculated at each timepoint (Weeks 1, 2, and 4) for each treatment group. Also, the 
difference in the least square mean between the vehicle group and each OPA-15406 
group will be calculated along with its two-sided 95% confidence interval and p value. 
Based on the OC and LOCF data sets, the descriptive statistics will be calculated for 
measured values and changes from the baseline at each timepoint by treatment group. 
A graph will be created for the least square mean and standard deviation for the change 
from baseline in IGA calculated by MMRM for each treatment group. 
8.2.3 
Shift Table for Investigator’s Global Assessment Scores up to 
Week 4 
Based on the OC and LOCF data sets, a shift table will be created for IGA scores (0, 1, 2, 
3, and 4) at Weeks 1, 2, and 4. 
8.2.4 
Change From Baseline Through Week 4 in the Total EASI Score 
and Each EASI Clinical Sign Score 
Based on the OC and LOCF data sets, the analysis will be performed in the same manner 
as for the change from baseline in IGA scores. In addition to clinical signs (erythema, 
infiltration/papule, excoriation, and lichenification), scores on body regions (face, neck, 
and head; upper limbs; trunk; and lower limbs) will also be analyzed in the same manner. 
For EASI, the percentage change will also be analyzed. A graph will be created for the 
least square mean and standard deviation for the change from baseline in the total EASI 
score calculated by MMRM for each treatment group. 


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8.2.5 
Change From Baseline Through Day 8 in VRS for Pruritus 
Based on the OC data set, the analysis will be performed in the same manner as for the 
change from baseline in IGA scores. Timepoints will include baseline through Day 8. 
8.2.6 
Change From Baseline Through Week 4 in VRS for Pruritus 
Based on the OC and LOCF data sets, the analysis will be performed in the same manner 
as for the change from baseline in IGA scores. Timepoints will include baseline, Weeks 
1, 2, and 4. 
8.2.7 
Change From Baseline Through Week 4 in the Total POEM Score 
Based on the OC and LOCF data sets, the analysis will be performed in the same manner 
as for the change from baseline in IGA scores. The percentage change in the total POEM 
score will also be analyzed in the same manner. 
8.2.8 
Change From Baseline Through Week 4 in the Total Affected BSA 
(%) 
Based on the OC and LOCF data sets, the analysis will be performed in the same manner 
as for the change from baseline in IGA scores. 
8.3 
Subgroup Analyses 
The success rate in IGA (IGA of 0 or 1 with improvement of at least 2 grades) and EASI 
75 will be analyzed for each of the following subgroups in the same manner as the 
primary endpoint in Section 8.1.1. 
Age: 2 to 6 years old, 7 years and older 
Sex: male, female 
IGA score at baseline: 2 (mild), 3 (moderate) 
Severity of AD: mild, moderate, severe, very severe 
Total EASI score at baseline: less than 15, 15 and above 
Affected BSA at baseline: less than 20%, 20% and above 
8.4 
Exploratory Analysis of Age Factor 
Logistic regression analysis will be performed using treatment group as the main effect, 
baseline IGA (2 or 3) and age as covariates, and success rate in IGA (IGA of 0 or 1 with 
improvement of at least 2 grades) at Week 4 as a response variable. An adjusted odds 
ratio along with its 95% confidence interval and p value will be determined. For the age 


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factor, in addition to age categories of “2 to 6 years old” and “7 to 14 years old,” data will 
be exploratorily analyzed as a continuous value or, if necessary, in other age categories. 
The SAS code is given below. 
proc logistic ; 
class Treatment(param=ref ref=“Placebo”) Agegroup BaselineIGA; 
model Response(event=“有効”) = Treatment Agegroup BaselineIGA /clodds=wald 
orpvalue; 
run; 
9 
Safety Analyses 
The following analyses will be performed in the SS. 
9.1 
Extent of Exposure 
Based on the SS, the descriptive statistics will be presented for the total amount and the 
amount per dose of the IMP by treatment group and in total. Also, descriptive statistics 
will be presented in the same manner by taking into consideration the concentration of 
the IMP (0.3% OPA-15406, 1% OPA-15406, and vehicle [0%]). Where the weight of 
IMP at retrieval is unknown, the amount of administration will be calculated by assuming 
that the retrieved weight is 0. 
9.2 
Adverse Events 
All AEs will be coded by System Organ Class (SOC) and Preferred Term (PT) using the 
MedDRA. 
For the following treatment-emergent adverse events (TEAEs) occurring after the start of 
IMP administration, the number and percentage of subjects will be calculated by 
treatment group and for all subjects. Skin and subcutaneous tissue disorders will be 
summarized in the same manner by grade as specified in the Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 translated into Japanese by JCOG. 
 TEAEs 
 TEAEs resulting in death 
 Serious TEAEs 
 TEAEs leading to discontinuation of IMP administration 
 TEAEs by severity 
 TEAEs (skin and subcutaneous tissue disorders alone) by CTCAE grade 
 TEAEs in treatment areas 


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Also, for the TEAEs and non-serious TEAEs occurring in at least 5% of subjects in each 
treatment group, the number and percentage of subjects will be calculated for each 
treatment group. 
Adverse reactions (TEAEs for which a causal relationship with the IMP cannot be ruled 
out) will be analyzed in the same manner as TEAEs. 
If the same event occurs more than once in the same subject, the most severe will be 
used. 
The above data will also be presented by age category (2 to 6 years old and 7 years and 
older). 
9.3 
Clinical Laboratory Tests 
For each parameter (except qualitative urinalysis), the descriptive statistics will be 
calculated for measured values and changes from the baseline at each timepoint by 
treatment group. For qualitative urinalysis values of clinical laboratory tests, a shift table 
at each timepoint against the baseline will be created for each treatment group. For 
clinical laboratory tests except qualitative urinalysis, a shift table for values before and 
after administration categorized as normal, high, or low relative to the reference value 
will be created for each treatment group. 
9.4 
Vital Signs and Body Weight 
For body weight, body temperature, blood pressure (systolic and diastolic), and pulse 
rate, the descriptive statistics will be calculated for measured values and changes from 
baseline at each timepoint by treatment group. The number and percentage of subjects 
with clinically abnormal changes (Appendix 1) in body temperature, blood pressure 
(systolic and diastolic), and pulse rate will be calculated by treatment group and for all 
subjects. For clinically abnormal changes, all data after starting administration, except for 
baseline or missing timepoints, will be included in the evaluation. Also, a list of subjects 
with clinically abnormal changes will be created. 
9.5 
Physical Examination 
Not applicable. 
9.6 
Electrocardiogram 
Not applicable. 


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9.7 
Liver Function Tests 
The number and percentage of subjects with abnormal changes in liver function 
(Appendix 2) will be calculated by treatment group. Also, a list of abnormal changes in 
liver function will be created. For clinically abnormal changes, all data after starting 
administration, except for baseline or missing timepoints, will be included in the 
evaluation. 
 
10 
Pharmacokinetic Analysis 
Not applicable. 
 
11 
Pharmacodynamic Analysis 
Not applicable. 
 
12 
Pharmacogenomic Analysis 
Not applicable. 
 
13 
Interim Analysis 
Not applicable. 
 
14 Changes in the Planned Analyses 
The following calculations specified in Section 7.6.2 in the protocol were not performed. 
 The number and percentage of subjects who are in the potentially clinically 
significant range will be calculated. 
 
15 
References 
None. 
 


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Appendix 1 
Criteria for Vital Signs Potential Clinical Significance 
 
Variable 
CRITERIA 1 
CRITERIA 2 
DIASTOLIC BLOOD 
PRESSURE (mmHg) 
DIASTOLIC BLOOD PRESSURE 
(mmHg) <50 AND DECREASE 
≥15 
DIASTOLIC BLOOD PRESSURE 
(mmHg) >105 AND INCREASE 
≥15 
PULSE RATE (beats/min) 
PULSE RATE (BPM) <50 AND 
DECREASE ≥15 
PULSE RATE (BPM) >120 AND 
INCREASE ≥15 
SYSTOLIC BLOOD 
PRESSURE (mmHg) 
SYSTOLIC BLOOD PRESSURE 
(mmHg) <90 AND DECREASE 
≥20 
SYSTOLIC BLOOD PRESSURE 
(mmHg) >180 AND INCREASE 
≥20 
TEMPERATURE (°C) 
 
TEMPERATURE (°C) ≥37.8 AND 
INCREASE ≥1.1°C 
WEIGHT (kg) 
WEIGHT (kg) DECREASE ≥7% 
WEIGHT (kg) INCREASE ≥7% 
 


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Appendix 2 
Criteria for Potential Hy’s Law 
The potential Hy’s Law Cases are defined as subjects with the following criteria: 
ALT>=3xULN (OR SCREENING VALUE) OR AST>=3xULN (OR SCREENING 
VALUE) AND BILIRUBIN>=2xULN (OR SCREENING VALUE) 


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Appendix 3 
List of Summary Tables 
CT-1 
Subject Disposition 
CT-2 
Reasons for Discontinuation  
CT-3.1 
Demographic Characteristics Safety Set 
CT-3.2 
Demographic Characteristics Efficacy Set 
CT-4.1 
Concomitant Medications: Medications Taken Prior to Start of Study 
Therapy 
CT-4.2 
Concomitant Medications: Medications Taken During Study Therapy 
CT-4.3 
Concomitant Medications: Medications Taken After Study Therapy 
CT-5.1.1 
Analysis of Responder Rate for Overall IGA Score 
CT-5.1.2 
Supplementary Analysis of Responder Rate for Overall IGA Score - 
LOCF 
CT-5.1.3 
Supplementary Analysis of Responder Rate for Overall IGA Score - OC 
CT-5.1.4 
Analysis of Responder Rate for Overall IGA Score - Revised Responder 
Definition 
CT-5.1.5 
Shift Tables of Overall IGA Score - OC 
CT-5.1.6 
Shift Tables of Overall IGA Score - LOCF 
CT-5.2.1 
Analysis of 75% Over Responder Rate for Overall EASI Score 
CT-5.2.2 
Analysis of 90% Over Responder Rate for Overall EASI Score 
CT-5.2.3 
Analysis of 50% Over Responder Rate for Overall EASI Score 
CT-5.3.1 
Analysis of Baseline and Change from Baseline in Overall IGA Score - 
MMRM 
CT-5.3.2 
Analysis of Baseline and Change from Baseline in Overall IGA Score - 
ANCOVA OC 
CT-5.3.3 
Analysis of Baseline and Change from Baseline in Overall IGA Score - 
ANCOVA LOCF 
CT-5.4.1.1 
Analysis of Baseline and Change from Baseline in Overall EASI Score - 
MMRM 
CT-5.4.1.2 
Analysis of Baseline and Change from Baseline in Overall EASI Score - 
ANCOVA OC 


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CT-5.4.1.3 
Analysis of Baseline and Change from Baseline in Overall EASI Score - 
ANCOVA LOCF 
CT-5.4.1.4 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score - MMRM 
CT-5.4.1.5 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score - ANCOVA OC 
CT-5.4.1.6 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score - ANCOVA LOCF 
CT-5.4.2.1 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Erythema - MMRM 
CT-5.4.2.2 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Erythema - ANCOVA OC 
CT-5.4.2.3 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Erythema - ANCOVA LOCF 
CT-5.4.2.4 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Erythema - MMRM 
CT-5.4.2.5 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Erythema - ANCOVA OC 
CT-5.4.2.6 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Erythema - ANCOVA LOCF 
CT-5.4.3.1 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Induration/Papulation - MMRM 
CT-5.4.3.2 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Induration/Papulation - ANCOVA OC 
CT-5.4.3.3 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Induration/Papulation - ANCOVA LOCF 
CT-5.4.3.4 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Induration/Papulation - MMRM 
CT-5.4.3.5 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Induration/Papulation - ANCOVA OC 
CT-5.4.3.6 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Induration/Papulation - ANCOVA LOCF 


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CT-5.4.4.1 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Excoriation - MMRM 
CT-5.4.4.2 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Excoriation - ANCOVA OC 
CT-5.4.4.3 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Excoriation - ANCOVA LOCF 
CT-5.4.4.4 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Excoriation - MMRM 
CT-5.4.4.5 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Excoriation - ANCOVA OC 
CT-5.4.4.6 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Excoriation - ANCOVA LOCF 
CT-5.4.5.1 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Lichenification - MMRM 
CT-5.4.5.2 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Lichenification - ANCOVA OC 
CT-5.4.5.3 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Lichenification - ANCOVA LOCF 
CT-5.4.5.4 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Lichenification - MMRM 
CT-5.4.5.5 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Lichenification - ANCOVA OC 
CT-5.4.5.6 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Lichenification - ANCOVA LOCF 
CT-5.4.6.1 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
HEAD/NECK - MMRM 
CT-5.4.6.2 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
HEAD/NECK - ANCOVA OC 
CT-5.4.6.3 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
HEAD/NECK - ANCOVA LOCF 
CT-5.4.6.4 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, HEAD/NECK - MMRM 


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CT-5.4.6.5 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, HEAD/NECK - ANCOVA OC 
CT-5.4.6.6 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, HEAD/NECK - ANCOVA LOCF 
CT-5.4.7.1 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
UPPER LIMBS - MMRM 
CT-5.4.7.2 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
UPPER LIMBS - ANCOVA OC 
CT-5.4.7.3 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
UPPER LIMBS - ANCOVA LOCF 
CT-5.4.7.4 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, UPPER LIMBS - MMRM 
CT-5.4.7.5 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, UPPER LIMBS - ANCOVA OC 
CT-5.4.7.6 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, UPPER LIMBS - ANCOVA LOCF 
CT-5.4.8.1 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
TRUNK - MMRM 
CT-5.4.8.2 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
TRUNK - ANCOVA OC 
CT-5.4.8.3 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
TRUNK - ANCOVA LOCF 
CT-5.4.8.4 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, TRUNK - MMRM 
CT-5.4.8.5 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, TRUNK - ANCOVA OC 
CT-5.4.8.6 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, TRUNK - ANCOVA LOCF 
CT-5.4.9.1 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
LOWER LIMBS - MMRM 
CT-5.4.9.2 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
LOWER LIMBS - ANCOVA OC 


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CT-5.4.9.3 
Analysis of Baseline and Change from Baseline in Overall EASI Score, 
LOWER LIMBS - ANCOVA LOCF 
CT-5.4.9.4 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, LOWER LIMBS - MMRM 
CT-5.4.9.5 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, LOWER LIMBS - ANCOVA OC 
CT-5.4.9.6 
Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, LOWER LIMBS - ANCOVA LOCF 
CT-5.5.1 
Analysis of Baseline and Change from Baseline in VRS for Pruritus Score 
- MMRM 
CT-5.5.2 
Analysis of Baseline and Change from Baseline in VRS for Pruritus Score 
- ANCOVA OC 
CT-5.5.3 
Analysis of Baseline and Change from Baseline in VRS for Pruritus Score 
- ANCOVA LOCF 
CT-5.5.4 
Analysis of Baseline and Change from Baseline in VRS for Pruritus Score 
(Week 1) - MMRM 
CT-5.5.5 
Analysis of Baseline and Change from Baseline in VRS for Pruritus Score 
(Week 1) - ANCOVA OC 
CT-5.6.1 
Analysis of Baseline and Change from Baseline in POEM Score - MMRM 
CT-5.6.2 
Analysis of Baseline and Change from Baseline in POEM Score - 
ANCOVA OC 
CT-5.6.3 
Analysis of Baseline and Change from Baseline in POEM Score - 
ANCOVA LOCF 
CT-5.6.4 
Analysis of Baseline and Percent Change from Baseline in POEM Score - 
MMRM 
CT-5.6.5 
Analysis of Baseline and Percent Change from Baseline in POEM Score - 
ANCOVA OC 
CT-5.6.6 
Analysis of Baseline and Percent Change from Baseline in POEM Score - 
ANCOVA LOCF 
CT-5.7.1 
Analysis of Baseline and Change from Baseline in Overall Percentage 
Affected Body Surface Area - MMRM 


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CT-5.7.2 
Analysis of Baseline and Change from Baseline in Overall Percentage 
Affected Body Surface Area - ANCOVA OC 
CT-5.7.3 
Analysis of Baseline and Change from Baseline in Overall Percentage 
Affected Body Surface Area - ANCOVA LOCF 
CT-6.1.1 
Subgroup Analysis of Responder Rate for Overall IGA Score - by Age 
CT-6.1.2 
Subgroup Analysis of Responder Rate for Overall IGA Score - by Sex 
CT-6.1.3 
Subgroup Analysis of Responder Rate for Overall IGA Score - by IGA 
Score at Baseline 
CT-6.1.4 
Subgroup Analysis of Responder Rate for Overall IGA Score - by Severity 
of Atopic Dermatitis 
CT-6.1.5 
Subgroup Analysis of Responder Rate for Overall IGA Score - by Total 
EASI Score at Baseline (<15, 15=<) 
CT-6.1.6 
Subgroup Analysis of Responder Rate for Overall IGA Score - by 
Affected Body Surface Area (<20%, 20%=<) 
CT-6.2.1 
Subgroup Analysis of 75% Over Responder Rate for Overall EASI Score - 
by Age 
CT-6.2.2 
Subgroup Analysis of 75% Over Responder Rate for Overall EASI Score - 
by Sex 
CT-6.2.3 
Subgroup Analysis of 75% Over Responder Rate for Overall EASI Score - 
by IGA Score at Baseline 
CT-6.2.4 
Subgroup Analysis of 75% Over Responder Rate for Overall EASI Score - 
by Severity of Atopic Dermatitis 
CT-6.2.5 
Subgroup Analysis of 75% Over Responder Rate for Overall EASI Score - 
by Total EASI Score at Baseline (<15, 15=<) 
CT-6.2.6 
Subgroup Analysis of 75% Over Responder Rate for Overall EASI Score - 
by Affected Body Surface Area (<20%, 20%=<) 
CT-6.3.1 
Exploratory Analysis of Impact of Age Factor to efficacy by Logistic 
Analysis -by Age (Continual) 
CT-6.3.2 
Exploratory Analysis of Impact of Age Factor to efficacy by Logistic 
Analysis -by Age (2-6 Years, 7-14 Years)  
CT-7.1.1 
Summary of Treatment Compliance 


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CT-7.1.2 
Summary of Treatment Compliance for Number of Administrations 
CT-7.2.1 
Extent of Exposure to Trial Medication 
CT-7.2.2 
Summary of Exposure 
CT-8.1.1 
Adverse Events (All Causalities) 
CT-8.1.2 
Adverse Events According to Application Site (All Causalities) 
CT-8.2.1.1 
Incidence of Treatment-emergent Adverse Events by System Organ Class 
CT-8.2.1.2 
Incidence of Treatment-emergent Adverse Events by System Organ Class 
CT-8.2.1.3 
Incidence of Treatment-emergent Adverse Events by System Organ Class 
CT-8.2.2.1 
Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term 
CT-8.2.2.2 
Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term 
CT-8.2.2.3 
Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term 
CT-8.2.3.1 
Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Severity 
CT-8.2.3.2 
Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Severity 
CT-8.2.3.3 
Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Severity 
CT-8.2.4.1 
Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and CTCAE Grade 
CT-8.2.4.2 
Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and CTCAE Grade 
CT-8.2.4.3 
Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and CTCAE Grade 
CT-8.3.1.1 
Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class 
CT-8.3.1.2 
Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class 


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CT-8.3.1.3 
Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class 
CT-8.3.2.1 
Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class and Preferred Term 
CT-8.3.2.2 
Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class and Preferred Term 
CT-8.3.2.3 
Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class and Preferred Term 
CT-8.3.3.1 
Incidence of Potentially Drug-related Treatment-emergent Adverse Events 
by System Organ Class, Preferred Term and Severity 
CT-8.3.3.2 
Incidence of Potentially Drug-related Treatment-emergent Adverse Events 
by System Organ Class, Preferred Term and Severity 
CT-8.3.3.3 
Incidence of Potentially Drug-related Treatment-emergent Adverse Events 
by System Organ Class, Preferred Term and Severity 
CT-8.3.4.1 
Incidence of Potentially Drug-related Treatment-emergent Adverse Events 
by System Organ Class, Preferred Term and CTCAE Grade 
CT-8.3.4.2 
Incidence of Potentially Drug-related Treatment-emergent Adverse Events 
by System Organ Class, Preferred Term and CTCAE Grade 
CT-8.3.4.3 
Incidence of Potentially Drug-related Treatment-emergent Adverse Events 
by System Organ Class, Preferred Term and CTCAE Grade 
CT-8.4.1.1 
Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class 
CT-8.4.1.2 
Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class 
CT-8.4.1.3 
Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class 
CT-8.4.2.1 
Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class and Preferred Term 
CT-8.4.2.2 
Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class and Preferred Term 
CT-8.4.2.3 
Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class and Preferred Term 


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CT-8.5.1.1 
Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class 
CT-8.5.1.2 
Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class 
CT-8.5.1.3 
Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class 
CT-8.5.2.1 
Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class and Preferred Term 
CT-8.5.2.2 
Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class and Preferred Term 
CT-8.5.2.3 
Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class and Preferred Term 
CT-8.5.3.1 
Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and Severity 
CT-8.5.3.2 
Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and Severity 
CT-8.5.3.3 
Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and Severity 
CT-8.5.4.1 
Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and CTCAE Grade 
CT-8.5.4.2 
Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and CTCAE Grade 
CT-8.5.4.3 
Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and CTCAE Grade 
CT-8.6.1.1 
Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class 
CT-8.6.1.2 
Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class 
CT-8.6.1.3 
Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class 
CT-8.6.2.1 
Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 


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CT-8.6.2.2 
Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.6.2.3 
Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.6.3.1 
Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class, Preferred Term and 
Severity 
CT-8.6.3.2 
Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class, Preferred Term and 
Severity 
CT-8.6.3.3 
Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class, Preferred Term and 
Severity 
CT-8.6.4.1 
Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class, Preferred Term and 
CTCAE Grade 
CT-8.6.4.2 
Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class, Preferred Term and 
CTCAE Grade 
CT-8.6.4.3 
Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class, Preferred Term and 
CTCAE Grade 
CT-8.7.1.1 
Incidence of Treatment-emergent Adverse Events Greater Than or Equal 
to 5% in Any Group by System Organ Class and Preferred Term 
CT-8.7.1.2 
Incidence of Treatment-emergent Adverse Events Greater Than or Equal 
to 5% in Any Group by System Organ Class and Preferred Term 
CT-8.7.1.3 
Incidence of Treatment-emergent Adverse Events Greater Than or Equal 
to 5% in Any Group by System Organ Class and Preferred Term 
CT-8.8.1.1 
Incidence of Non-Serious Treatment-emergent Adverse Events Greater 
Than or Equal to 5% in Any Group by System Organ Class and Preferred 
Term 


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CT-8.8.1.2 
Incidence of Non-Serious Treatment-emergent Adverse Events Greater 
Than or Equal to 5% in Any Group by System Organ Class and Preferred 
Term 
CT-8.8.1.3 
Incidence of Non-Serious Treatment-emergent Adverse Events Greater 
Than or Equal to 5% in Any Group by System Organ Class and Preferred 
Term 
CT-8.9.1.1 
Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term According to Application Site 
CT-8.9.1.2 
Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term According to Application Site 
CT-8.9.1.3 
Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term According to Application Site 
CT-8.10.1.1 
Incidence of Potentially Drug-related Treatment-emergent Adverse Events 
by System Organ Class and Preferred Term According to Application Site 
CT-8.10.1.2 
Incidence of Potentially Drug-related Treatment-emergent Adverse Events 
by System Organ Class and Preferred Term According to Application Site 
CT-8.10.1.3 
Incidence of Potentially Drug-related Treatment-emergent Adverse Events 
by System Organ Class and Preferred Term According to Application Site 
CT-9.1 
Listing of Deaths 
CT-9.2 
Listing of Serious Adverse Events 
CT-9.3 
Listing of Study Drug Discontinuations Due to Adverse Events 
CT-9.4 
Incidence of Potential Hy’s Law Cases 
CT-9.5 
Listing of Potential Hy’s Law Cases - by Subject 
CT-10.1.1 
Mean Change From Baseline in Laboratory Test Values: Serum Chemistry 
CT-10.1.2 
Mean Change From Baseline in Laboratory Test Values: Hematology 
CT-10.2.1 
Shift Tables of Clinical Laboratory Test Results: Serum Chemistry 
CT-10.2.2 
Shift Tables of Clinical Laboratory Test Results: Hematology 
CT-10.2.3 
Shift Tables of Clinical Laboratory Test Results: Urinalysis 
CT-11.1 
Mean Change From Baseline in Vital Sign Parameters 
CT-11.2 
Listing of Vital Signs Abnormalities 


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CT-11.3 
Incidence of Potential Clinical Significance in Vital Signs 
CT-11.4 
Criteria for Vital Signs Potential Clinical Significance 
 
CF-1.0 
Responder Rate for Overall IGA Score by Visit 
CF-1.1 
Incidence of Responder Rate for Overall IGA Score by Visit 
CF-1.2 
Incidence of 75% Over Responder Rate for Overall EASI Score by Visit 
CF-1.3 
Incidence of 90% Over Responder Rate for Overall EASI Score by Visit 
CF-1.4 
Incidence of 50% Over Responder Rate for Overall EASI Score by Visit 
CF-1.5 
Incidence of Responder Rate for Overall IGA Score by Visit - Less Than 7 
Years 
CF-1.6 
Incidence of Responder Rate for Overall IGA Score by Visit - Greater 
Than or Equal to 7 Years 
CF-2.1 
Least Square Means of Change from Baseline in Overall IGA Score by 
Visit - MMRM 
CF-2.2 
Least Square Means of Change from Baseline in Overall EASI Score by 
Visit - MMRM 
 


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Appendix 4 
List of Subject Data Listings 
PDATA-1.1 
Inclusion and Exclusion Criteria Not Met 
PDATA-1.2 
Subject Disposition 
PDATA-2.1 
Medical History 
PDATA-2.2 
History of Atopic Dermatitis 
PDATA-3.1 
Concomitant Medications and Therapy Taken Prior to Start of Study 
Therapy 
PDATA-3.2 
Concomitant Medications and Therapy Taken During Study Therapy 
PDATA-3.3 
Concomitant Medications and Therapy Taken After Study Therapy 
PDATA-4.1 
Exposure to Trial Medication 
PDATA-4.2 
Listing of Trial Medication by Subject 
PDATA-5.1 
Physical Examination 
PDATA-6 
Adverse Events 
PDATA-7 
Vital Signs 
PDATA-8 
Screening Failures 
PDATA-9 
Protocol Deviations (Major) - CRF 
PDATA-10 
Patch Application and Removal 
PDATA-11 
Overall Investigator’s Global Assessment of Disease Severity 
PDATA-12 
Eczema Area and Severity Index 
PDATA-13 
Verbal Rating Scale 
PDATA-14 
Patient-Oriented Eczema Measure 
PDATA-15 
Affected Body Surface Area 
PDATA-16 
Treatment Area 
 
DREAS-1 
Discontinued Subjects and Reasons for Discontinuations 
 
DEMOG-1 
Demographic Characteristics 
DEMOG-2 
Informed Consent 


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AE-1 
Adverse Events 
 
SMED-1 
Investigational Medicinal Product Compliance 
SMED-2 
Actual Exposure to Study Medication 
SMED-3 
Investigational Medicinal Product Compliance for Number of 
Administrations 
 
EFF-1 
Change from Baseline in IGA Score and Response with Overall IGA 
Score 
EFF-2 
Change from Baseline in Total EASI Score 
EFF-3 
Change from Baseline in EASI Score, Erythema 
EFF-4 
Change from Baseline in EASI Score, Induration/Papulation 
EFF-5 
Change from Baseline in EASI Score, Excoriation 
EFF-6 
Change from Baseline in EASI Score, Lichenification 
EFF-7 
Change from Baseline in EASI Score, HEAD/NECK 
EFF-8 
Change from Baseline in EASI Score, UPPER LIMBS 
EFF-9 
Change from Baseline in EASI Score, TRUNK 
EFF-10 
Change from Baseline in EASI Score, LOWER LIMBS 
EFF-11 
Change from Baseline in VRS Score 
EFF-12 
 Change from Baseline in POEM Score 
EFF-13 
Change from Baseline in Overall Percentage Affected Body Surface Area 
 
LAB-1 
Laboratory Test Results: Serum Chemistry 
LAB-2 
Laboratory Test Results: Hematology 
LAB-3 
Laboratory Test Results: Urinalysis 
 


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PDEV-1 
Summary of Subjects with Major Protocol Deviations by Type of 
Deviation 
 
SUBEX-1 
Subjects Excluded From Analysis Set