A Multicenter, Randomized, Double-blind, Vehicle Controlled, Parallel-group Comparison Trial to Demonstrate the Superiority of 1% OPA-15406 Ointment to the Vehicle in Adult Patients With Atopic Dermatitis (Phase 3 Trial)
Phase: PHASE3
Conditions: Atopic Dermatitis
Sponsor: Otsuka Pharmaceutical Co., Ltd.

 
 
CLINICAL STUDY PROTOCOL 
 
 
A Multicenter, Randomized, Double-blind, Vehicle-controlled, 
Parallel-group Comparison Trial to Demonstrate the Superiority of 
1% OPA-15406 Ointment to the Vehicle in Adult Patients with 
 Atopic Dermatitis (Phase 3 Trial) 
 
 
 
 
NCT Number: 03908970 
PRT NO.: 271-102-00007 
Version Date: 01 February 2019 (Version 3.0) 

Protocol 271-102-00007
Confidential - Proprietary Information
Version 2.0, 14 Dec 2018
Otsuka Pharmaceutical Co., Ltd.
Investigational Medicinal Product
OPA-15406
CLINICAL PROTOCOL
A Multicenter, Randomized, Double-blind, Vehicle-controlled, Parallel-group 
Comparison Trial to Demonstrate the Superiority of 1% OPA-15406 Ointment to the 
Vehicle in Adult Patients with Atopic Dermatitis (Phase 3 Trial)
Protocol No. 271-102-00007
(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_271-102-00007@otsuka.jp
Issue Date:
01 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.: 271-102-00007
Protocol Title:
A Multicenter, Randomized, Double-blind, 
Vehicle-controlled, Parallel-group Comparison Trial to 
Demonstrate the Superiority of 1% OPA-15406 Ointment to 
the Vehicle in Adult Patients with Atopic Dermatitis (Phase 3 
Trial)
Clinical Phase/Trial 
Type:
Phase 3
Confirmatory trial
Treatment Indication: Atopic dermatitis (AD)
Objective(s):
Primary Objective: To demonstrate the superiority of IMP (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 adult patients with AD.
Secondary Objective: To evaluate the efficacy (secondary 
endpoint) and safety of IMP (1% OPA-15406 ointment or 
vehicle) when administered twice daily for 4 weeks in 
adult patients with AD.
Trial Design:
Multicenter, randomized, double-blind, 
vehicle-controlled, parallel-group comparison trial
Subject Population:
Adult patients with AD and IGA score of 2 or 3
340 subjects in total
Inclusion/Exclusion 
Criteria:
Main inclusion criteria

Age: 15 to 70 years, inclusive (at time of 
obtaining informed consent)

Able to provide written informed consent. For 
subjects under 20 years of age, written informed consent 
must be obtained from both the subject and the subject’s 
legal guardian.

Diagnosis of AD based on the Japanese Dermatological 
Association’s criteria (see Appendix 1)

History of AD for at least 3 years

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 treatment with ultraviolet 
light A (UVA), narrowband ultraviolet B (NB-UVB), 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 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 tosilate from 7 days prior to the baseline 
examination until the Week 4 examination 

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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: 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), Skindex-16, and 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 of ≥75% in EASI), 
EASI 90 (improvement of ≥90% in EASI), EASI 50 
(improvement of ≥50% in EASI) at Week 4, change from 
baseline in each parameter (IGA, EASI, VRS for pruritus, 
POEM, Skindex-16, and 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 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).
The Cochran-Mantel-Haenszel (CMH) test will be conducted 
using the baseline IGA (2 or 3) as a stratification factor with a 
two-sided significance level of 5%. 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 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 Jan 2020
Screening period: 2 to 30 days

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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.............................................................28
2.4
Trial Objectives.................................................................................................28

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Trial Design.........................................................................................29
3.1
Type/Design of Trial .........................................................................................29
3.2
Methods of Administration ...............................................................................30
3.2.1
Dose, Regimen, and Treatment Period...........................................................30
3.2.2
Treatment Area ...............................................................................................31
3.3
Trial Population.................................................................................................32
3.3.1
Number of Subjects and Description of Population .......................................32
3.3.2
Issue of Subject Identification Number..........................................................32
3.4
Eligibility Criteria..............................................................................................32
3.4.1
Informed Consent ...........................................................................................32
3.4.2
Inclusion Criteria ............................................................................................33
3.4.3
Exclusion Criteria...........................................................................................34
3.5
Endpoints...........................................................................................................37
3.5.1
Primary Endpoint............................................................................................37
3.5.2
Secondary Endpoints ......................................................................................37
3.5.3
Safety Endpoints.............................................................................................38
3.6
Measures to Minimize/Avoid Bias....................................................................38
3.7
Trial Procedures ................................................................................................38
3.7.1
Schedule of Assessments................................................................................42
3.7.1.1
Acquisition of Informed Consent................................................................42
3.7.1.2
Screening Examination ...............................................................................42
3.7.1.3
Subject Demographics ................................................................................42
3.7.1.4
Subject Registration ....................................................................................43
3.7.1.5
Baseline Examination (2-30 Days After the Screening Examination)........43
3.7.1.6
Randomization (Allocation of Investigational Medicinal Products to 
Subjects)......................................................................................................44
3.7.1.7
Between the Day After the Baseline Examination and the Day Prior 
to the Week 1 Examination.........................................................................44
3.7.1.8
Week 1 Examination (±2 Days)..................................................................44
3.7.1.9
Week 2 Examination (±3 Days)..................................................................45
3.7.1.10
Week 4 Examination (±3 Days) or Withdrawal Examination ....................46
3.7.1.11
Unscheduled Visits .....................................................................................46
3.7.2
Status of Investigational Medicinal Product Administration..........................47

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3.7.3
Photograph of the Target Site.........................................................................47
3.7.4
Severity of Atopic Dermatitis.........................................................................47
3.7.5
Efficacy Assessments .....................................................................................48
3.7.5.1
Investigator’s Global Assessment...............................................................48
3.7.5.2
Eczema Area and Severity Index................................................................48
3.7.5.3
Verbal Rating Scale for Pruritus .................................................................49
3.7.5.4
Patient-Oriented Eczema Measure..............................................................49
3.7.5.5
Skindex-16 ..................................................................................................49
3.7.5.6
Affected Body Surface Area.......................................................................49
3.7.6
Safety Assessments.........................................................................................50
3.7.6.1
Adverse Events............................................................................................50
3.7.6.2
Clinical Laboratory Tests............................................................................50
3.7.6.3
Physical Examination..................................................................................51
3.7.6.4
Vital Signs and Body Weight......................................................................51
3.7.7
Previous Medications and Concomitant Medications ....................................51
3.7.8
End of Trial.....................................................................................................51
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................51
3.8.1
Termination or Interruption of the Entire Trial ..............................................51
3.8.2
Termination or Interruption of the Trial at Individual Trial Sites ..................52
3.8.3
Individual Subject Discontinuation ................................................................52
3.8.3.1
Treatment Discontinuation..........................................................................52
3.8.3.2
Discontinuation Criteria..............................................................................52
3.8.3.3
Documenting Reasons for Treatment Discontinuation...............................53
3.8.3.4
Withdrawal of Consent ...............................................................................53
3.8.3.5
Procedures to Encourage Continued Trial Participation.............................55
3.9
Screen Failures ..................................................................................................55
3.10
Definition of Completed Subjects.....................................................................55
3.11
Definition of Subjects Lost to Follow-up..........................................................55
3.12
Subject Compliance...........................................................................................56
3.13
Deviations from the Trial Protocol....................................................................56
4
Restrictions..........................................................................................57
4.1
Prohibited Concomitant Drugs and Therapies ..................................................57

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5
Reporting of Adverse Events.............................................................58
5.1
Definitions.........................................................................................................58
5.2
Eliciting and Reporting Adverse Events ...........................................................60
5.3
Immediately Reportable Events ........................................................................60
5.4
Potential Serious Hepatotoxicity.......................................................................61
5.5
Implementation of Patch Test............................................................................61
5.6
Pregnancy..........................................................................................................62
5.7
Procedure for Breaking the Blind......................................................................63
5.8
Follow-up of Adverse Events............................................................................64
5.8.1
Follow-up of Nonserious Adverse Events......................................................64
5.8.2
Follow-up of Serious Adverse Events and Immediately Reportable 
Events .............................................................................................................64
5.8.3
Follow-up and Reporting of Serious Adverse Events and Immediately 
Reportable Events Occurring After Day of Trial Completion (Final 
Observation Day)............................................................................................65
6
Pharmacokinetic Analysis..................................................................65
7
Statistical Analysis..............................................................................65
7.1
Sample Size.......................................................................................................65
7.2
Datasets for Analysis.........................................................................................65
7.3
Handling of Missing Data .................................................................................65
7.4
Primary and Secondary Endpoint Analyses ......................................................65
7.4.1
Primary Endpoint Analysis.............................................................................66
7.4.2
Secondary Endpoint Analysis.........................................................................66
7.5
Analysis of Demographic and Other Baseline Characteristics .........................67
7.6
Safety Analysis..................................................................................................67
7.6.1
Adverse Events ...............................................................................................67
7.6.2
Clinical Laboratory Tests ...............................................................................68
7.6.3
Vital Signs and Body Weight .........................................................................68
8
Management of Investigational Medicinal Product........................68
8.1
Packaging and Labeling ....................................................................................68
8.2
Storage...............................................................................................................68
8.3
Accountability ...................................................................................................68
8.4
Returns and Destruction....................................................................................69

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8.5
Reporting of Product Quality Complaints.........................................................69
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................69
8.5.2
Information Required for Reporting Product Quality Complaints.................70
8.5.3
Return Process in the Case of Product Quality Complaints ...........................70
8.5.4
Assessment/Evaluation...................................................................................70
9
Records Management.........................................................................70
9.1
Source Documents.............................................................................................70
9.2
Data Collection..................................................................................................70
9.3
File Management at the Trial Site.....................................................................71
9.4
Records Retention at the Trial Site....................................................................71
10
Quality Control and Quality Assurance...........................................72
10.1
Monitoring.........................................................................................................72
10.2
Auditing.............................................................................................................72
11
Ethics and Responsibility...................................................................73
12
Confidentiality ....................................................................................73
13
Amendment Policy..............................................................................73
14
Publication Authorship Requirements.............................................74
15
References............................................................................................75

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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.................................. 26
Table 3.4.2-1
Inclusion Criteria .......................................................................... 33
Table 3.4.3-1
Exclusion Criteria ......................................................................... 34
Table 3.7-1
Schedule of Assessments.............................................................. 39
Table 3.7.4-1
Definition of Severity in Atopic Dermatitis.................................. 47
Table 3.7.5.1-1
Investigator's Global Assessment ................................................. 48
Table 3.7.5.2-1
Eczema Area and Severity Index.................................................. 48
Table 3.7.6.2-1
Clinical Laboratory Assessments.................................................. 50
Table 4.1-1
Prohibited Concomitant Drugs and Therapies.............................. 57
Table 5.5-1
Reading Criteria............................................................................ 62

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List of In-text Figures
Figure 3.1-1
Trial Design .................................................................................. 30

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List of Appendices
Appendix 1
Diagnostic Criteria for Atopic Dermatitis (Japanese 
Dermatological Association’s Criteria) ........................................ 77
Appendix 2
Patient-Oriented Eczema Measure (POEM)................................. 79
Appendix 3
Skindex-16.................................................................................... 81
Appendix 4
Human Body Drawing.................................................................. 82
Appendix 5
Protocol Amendments and Administrative Changes.................... 83
Appendix 1
Diagnostic Criteria for Atopic Dermatitis (Japanese 
Dermatological Association’s Criteria) ........................................ 77
Appendix 2
Patient-Oriented Eczema Measure (POEM)................................. 79
Appendix 3
Skindex-16.................................................................................... 81
Appendix 4
Human Body Drawing.................................................................. 82
Appendix 5
Protocol Amendments and Administrative Changes.................... 83

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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
AD
Atopic dermatitis
AE
Adverse event
ALT
Alanine transaminase
ALT (GPT)
Alanine aminotransferase
AST
Aspartate transaminase
AST (GOT)
Aspartate aminotransferase
BSA
Body surface area
cAMP
Cyclic adenosine 3', 5'-monophosphate
CRF
Case report form
CYP
Cytochrome P450
CMH
Cochran Mantel Haenszel 
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
IgE
Immunoglobulin E
IMP
Investigational Medicinal Product
IRB
Institutional review board
IRE
Immediately reportable event
IUD
intrauterine device

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IWRS
Interactive Web Response System
MedDRA/J
Medical Dictionary for Regulatory Activities/ Japanese Version
MMRM
Mixed-model repeated measure
NB-UVB
Narrow-band UVB 
NOAEL
No observed adverse effect level
NSAIDs
Non-steroidal anti-inflammatory drugs 
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
WOCBP
Women of child-bearing potential

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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 immunoglobulin E (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 therapies 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, and the elimination of as many 
aggravating factors as possible. 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 

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Administration approved Eucrisa® 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 of 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 old) 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 and outside Japan), 1% 
OPA-15406 ointment 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 1% OPA-15406 
ointment to the vehicle in adult AD patients (aged 15 - 70 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 

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the frequency of 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 μmol/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 

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daily. As a result, no changes associated with the test substance were observed in any 
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 

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than the dose ratio, and no dose 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) at about 1 g 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 1 g 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 trial 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 

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trough concentration of 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 the trials in patients with AD, the most frequently reported AEs in the OPA-15406 
treatment groups 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, upper respiratory tract inflammation, all of which 
were judged as not IMP-related (Table 1.3-1). For additional information, refer to the IB.
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)

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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 
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 trials in adult AD patients both in Japan and outside Japan (Trials 271-12-
205 and 271-15-001), which were conducted prior to the present trial, the efficacy, safety, 
and tolerability of the 8-week twice-daily multiple doses of the 0.3% or 1% OPA-15406 
ointment or the vehicle (placebo) were investigated. In both trials, 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. In the phase 2 trial 
outside Japan (Trial 271-12-205), the success rate 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. 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). In the phase 2 
trial in Japan (Trial 271-15-001), the success rate 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% OPA-15406 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 in either trial.
As described above, the efficacy of the 1% OPA-15406 ointment was demonstrated in 
adult AD patients both in Japan and outside Japan, and no particular safety concerns of 
OPA-15406 ointment were identified. Therefore, it was judged ethically and scientifically 

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appropriate to conduct this trial to demonstrate the superiority of 1% OPA-15406 
ointment to the vehicle in adult AD patients when administered the 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 adult patients in Japan (Trial 271-15-001), 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 was 
significantly higher in the 1% OPA-15406 group than in the vehicle group and the 
success rate was much higher in the 1% OPA-15406 group than in the 0.3% OPA-15406 
group. No particular safety concerns were identified with both formulations.
Therefore, the 1% formulation is 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 treatments 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 271-15-001) in Japan was conducted in adult patients (aged 15 -
70 years old), showing the efficacy of OPA-15406 ointment without any particular safety 
concerns. Therefore, subjects aged 15 to 70 years old were included in this trial.
2.4
Trial Objectives
Primary Objective: To demonstrate the superiority of the IMP (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 adult AD patients.

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Secondary Objective: To evaluate the efficacy (secondary endpoint) and safety of 1%
OPA-15406 ointment when administered twice daily for 4 weeks in adult AD patients.
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 1% OPA-15406 
ointment to the vehicle in adult AD patients. This trial consists of 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, 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 test product (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 subject’s written informed consent 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)
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 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
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
Screening examination
Informed consent
IMP allocation
Baseline examination
Last day of Trial (Last 
day of observation)
Week 2 examination
Week 1 examination

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[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 
adult patients in Japan (Trial 271-15-001), 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 the 1% OPA-15406 
group was significantly higher than in the vehicle group and was higher than in the 0.3% 
OPA-15406 group. Also, no particular safety concerns were identified at Week 8. Based 
on the above, the treatment period of this trial was established as 4 weeks.
3.2.2
Treatment Area
The treatment area with the IMP is defined as follows.

The treatment area selected at baseline examination will be the affected area 
determined at the baseline examination (see 3.7.5.6 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 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 
4), and will give the human body drawing (copy) to the subject. 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).
The method of IMP administration is specified in the separate procedure for IMP 
administration.

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3.3
Trial Population
3.3.1
Number of Subjects and Description of Population
The target population of this trial is adult AD patient with an IGA score of 2 or 3.
Subjects will be included in the trial to reach the target number of 340 subjects for IMP 
administration. 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 all subjects (or the subject’s 
legal guardian [guardian or legal representative, as applicable by local law] if the subject 
is under 20 years old). If the subject is under 20 years old, the relationship between the 
subject and the subject’s legal guardian will be confirmed and recorded. A signed 
informed consent form (ICF) will be retained as a document. The explanatory document 
and ICF 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 if the 
subject is under 20 years old) before obtaining consent. However, written informed 
consent must be obtained prior to the initiation of any procedures that are performed 
solely for the purpose of determining eligibility for this trial, including withdrawal from 
current medications.
The potential subject (and the subject’s legal guardian if the subject is under 20 years old) 
can refuse to participate in or withdraw from the trial at any time without any justifiable 

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reason. The refusal or withdrawal by the potential subject (and the subject’s legal 
guardian if the subject is under 20 years old) will not affect any future treatments.
Once the appropriate essential information and a full explanation in layman’s language 
appropriate have been provided by the investigator or subinvestigator and an opportunity 
for subjects (and the subject’s legal guardian if the subject is under 20 years old) to ask 
questions has been documented, the IRB-approved ICF will be personally signed and 
dated by the subject (and the subject’s legal guardian if the subject is under 20 years old), 
the person obtaining informed consent (investigator or subinvestigator) and the person 
designated by the IRB. When a supplemental explanation is given by a clinical trial 
associate, the clinical trial associate will also sign and date the form. The subject (and the
subject’s legal guardian if the subject is under 20 years old) will be given the explanatory 
document and copies of the signed ICF, and the originals will be kept in the file by the 
investigator or subinvestigator.
If an amendment to the protocol substantially increases or alters the trial procedures, the 
subject (and the subject’s legal guardian if the subject is under 20 years old) 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 #8 in Table 
3.4.2-1 at the screening examination, and #7 and #8 at the baseline examination.
Table 3.4.2-1
Inclusion Criteria
1
Sex: Either male or female
2
Hospitalization status: Outpatient
3
Age: 15 to 70 years, inclusive (at time of obtaining informed consent)
4
Able to provide written informed consent. For subjects under 20 years of age, written informed 
consent must be obtained from both the subject and the subject’s legal guardian.
5
Diagnosis of AD based on the Japanese Dermatological Association’s criteria  (see Appendix 1)
6
History of AD for at least 3 years
7
Atopic dermatitis affecting ≥5% to ≤40% of BSA (excluding scalp)
8
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 271-15-001) in Japan was conducted in adult patients
(aged 15 - 70 years old), showing efficacy OPA-15406 ointment without no 

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particular safety concerns. Therefore, subjects aged 15 to 70 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)-8) 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
Subjects who are pregnant, possibly pregnant, or breastfeeding, who desire to become pregnant or 
to have their partner become pregnant during the trial period and up until 30 days after the final 
administration of IMP, or who are unable to either remain abstinent or employ at least two of the 
specified birth control methods (vasectomy, tubal ligation, vaginal diaphragm, intrauterine device 
[IUD], birth control pill, condom with spermicide, etc) 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 within the previous 5 years.
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, etc)

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Table 3.4.3-1
Exclusion Criteria

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 with any of the following hematology or serum chemistry results at screening 
examination:

White blood cell count: ≤3, 000/μL or >14, 000/μL

Platelets: ≤100, 000/μL

Hemoglobin: <11 g/dL

Serum creatinine: ≥2 mg/dL

Aspartate aminotransferase (AST) (glutamic oxaloacetic transaminase [GOT]): >1.5 × ULN

Alanine aminotransferase (ALT) (glutamic pyruvic transaminase [GPT]): >1.5 × ULN

Total bilirubin: ≥2.0 mg/dL

Any other abnormal laboratory test result that the investigator or subinvestigator judges to be a 
clinically significant abnormality
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 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 the symptoms of AD have not 
changed judged by the investigators or subinvestigators, 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).
11
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
12
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
13
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.
14
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. However, intra-ocular, intra-nasal, 
intra-auricular, and inhaled corticosteroids and intra-ocular, intra-nasal, and inhaled antihistamines 
may be considered if the investigator or subinvestigator judges that their use will not impact 
assessment of the affected area.
15
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.
16
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
17
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 
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Table 3.4.3-1
Exclusion Criteria
18
Subjects with known plans to receive any of the prohibited concomitant drugs or therapies 
during the trial period
19
Subjects who have participated in previous trials for OPA-15406 and have been administered the 
IMP
20
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
21
Subjects who have never been treated with a prescription medication for AD or who are satisfied 
with their current AD treatment regimen
22
Subjects who do not respond at all to treatment with existing topical drugs for AD
23
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)-9)
In consideration of safety.
10)-16) Due to a possible impact on the efficacy assessment of the IMP.
17)
In consideration of safety.
18)
Due to a possible impact on the safety and efficacy assessments of the IMP.
19)-20) In reference to the “Criteria for Period to Avoid Participation in 
Clinical Studies” of the Japan Association of Contract Institutes for Clinical 
Pharmacology.
21)
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.
22)
To exclude severe patients who do not respond to topical drugs.
23)
To allow the investigator or subinvestigator to judge in consideration of 
other factors.

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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 improved IGA score 
of 0 or 1 

Change from baseline in IGA at Week 4

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 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

Change from baseline in the total score of Patient-Oriented Eczema Measure 
(POEM) at Week 4

Change from baseline in the item score, scale score (mean score of item scores of 
each scale [characteristics, emotions, functions]) and mean score of the 16 items 
of Skindex-16 at Week 4

Change from baseline in the total affected BSA (%) at Week 4

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3.5.3
Safety Endpoints

Adverse events
1. AEs occurring after the start of IMP administration (TEAEs)
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.
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 assessments.

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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
Skindex-16
○
○
○
○
○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

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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
IMP administration
○n
AEs
Concomitant medications 
and therapies 
Patch testo
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 (possible on the same day)
fIs to be conducted, as necessary.
gShould be conducted only for women with childbearing potential. 
hThe 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 is to be additionally prescribed, as necessary. 
mOnly IMP collection.

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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 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 directly from subjects 
prior to the screening examination. If the subject is under 20 years old, written 
informed consent should be obtained from the subject and 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 women of childbearing potential)

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

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
Date of birth

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 women of childbearing potential)

IGA

EASI

VRS for pruritus

POEM

Skindex-16

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 1% OPA-15406 group or 
the 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 day of 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
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

POEM

Skindex-16

Affected BSA

Treatment area

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
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 every day and bring the diary with them to the 
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

POEM

Skindex-16

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 every day and bring the diary with them to the 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 women of childbearing potential)

IGA

EASI

VRS for pruritus

POEM

Skindex-16

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 are to be conducted as necessary:

Physical examinations

Vital signs and body weight

Clinical laboratory values

Pregnancy test (only for women of childbearing potential)

IGA

EASI

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
VRS for pruritus

POEM

Skindex-16

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. 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 in Atopic Dermatitis
Definition
Severity
Only mild rashesa are observed irrespective of area
Mild
Rashes with severe inflammationb are observed in less than 10% of the BSA
Moderate
Rashes with severe inflammationb are observed in ≥10% to <30% of the BSA
Severe
Rashes with severe inflammationb are observed in ≥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
Symptoms
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
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
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 VRS11 criteria:
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. 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
Skindex-16
The effects of symptoms on daily life will be evaluated according to Skindex-16 (see 
Appendix 3).13,14 The subjects will answer a total of 16 questions and describe the effects 
of the symptoms on their daily life (scale: symptoms, emotions, and functioning). The 
investigator or subinvestigator will confirm their responses and record the results in the 
source document and CRF. Skindex-16 will be kept as source documents.
3.7.5.6
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 

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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.
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. 
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 women of 
childbearing potentiala
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).

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For women of childbearing potential, 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 
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 
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 the CRF the 
name, purpose for 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, 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.

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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.
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 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 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)

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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
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 
nonserious 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 becomes 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 

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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 
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 or the subject’s legal guardian has felt that
continued participation in the trial is causing some burden regarding their work or social 

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activities. Therefore, in accordance with Section 3.8.3.3 Documenting Reasons for 
Treatment Discontinuation, the investigator or subinvestigator will determine whether 
continued participation in the trial is possible by adjusting the schedule of administration 
or evaluations. Complete withdrawal of consent for trial participation is established only 
for those subjects and subjects’ legal guardians who have refused all of the above follow-
up procedures.
3.8.3.5
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 signed the 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, and 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 

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various information sources by obtaining the proper documents which indicate death (ie, 
death certificate, medical record, public record, or statement by a family member or their 
doctor in charge) or those which indicate survival (ie, meeting record with the subject, 
medical record, contact record with the subject by phone, statement by a family member 
or their doctor in charge, or public record).
If the subject cannot be contacted even after calling 3 times, the 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 classified 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 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. 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. The investigator or subinvestigator and the sponsor

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will document and the site monitor will review this decision. 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 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, biologics
From 21 days prior to the baseline 
examination until the Week 4 examination 
(or withdrawal examination)
Topical corticosteroids 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 categorized for skin 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 NSAIDs. However, intra-ocular, intra-
nasal, intra-auricular, and inhaled corticosteroids and intra-
ocular, intra-nasal, and inhaled antihistamines may be 
considered if the investigator or subinvestigator judges that
their use will not impact assessment of the affected area.
Systemic antihistamines, sodium cromoglicate, tranilast, 
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Table 4.1-1
Prohibited Concomitant Drugs and Therapies
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 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 UVB; NSAIDs: Non-steroidal anti-inflammatory drugs
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 drug 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

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.

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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.
Nonserious 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 
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.

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2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe: Inability to work or perform normal daily activity.
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.
If an AE has occurred on the application site, it will also be recorded. 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.
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 

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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 or die. 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 aspartate transaminase (AST) or Alanine 
transaminase (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 (and the subject’s legal guardian if the subject is under 20 years old) 
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-
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 Dermatitis15
issued by the Japanese Dermatological Association for procedures of the patch test).

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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
Women of child-bearing potential (WOCBP) are defined as female subjects for whom 
menstruation has started and who are not documented as sterile (ie, have had a bilateral 
oophorectomy and/or hysterectomy or who have been postmenopausal for at least 12 
months).
For WOCBP and for men who are sexually active, there must be a documented 
agreement that the subject and/or their partner will take effective measures (ie, double 
barrier method) or remain abstinent to prevent pregnancy during the course of the trial 
and for 30 days after the last dose of IMP. Unless the subject is sterile (ie, women who 
have had a bilateral oophorectomy and/or hysterectomy or who have been 
postmenopausal for at least 12 consecutive months; or men who have had a bilateral 
orchidectomy) or remains abstinent, 2 of the following precautions must be used:
vasectomy, tubal ligation, vaginal diaphragm, intrauterine device (IUD), birth control 
pill, condom with spermicide. Any single method of birth control, including vasectomy 
and tubal ligation, may fail, leading to pregnancy.
Before enrolling WOCBP in this clinical trial, the investigator or subinvestigator must 
review the trial participation guidelines for all WOCBP. The topics should generally 
include:

General information

Informed consent form

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Guidelines for the follow-up of a reported pregnancy
Before trial enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during their trial participation and the potential risk factors of an unintentional 

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pregnancy. The subjects 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, all WOCBP 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, all WOCBP should be instructed to contact the investigator or 
subinvestigator immediately if they suspect they might be pregnant (eg, missed or late 
menstrual cycle).
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. The same shall apply if pregnancy in the subject’s partner becomes 
known.
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 

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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.
5.8
Follow-up of Adverse Events 
5.8.1
Follow-up of Nonserious Adverse Events
Nonserious 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 nonserious 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.

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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 
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
In the phase 2 trial in adult patients in Japan (Trial 271-15-001), the success rate in IGA 
was 22.4% and 9.1% in the 1% OPA-15406 and the vehicle group, respectively. With the 
assumption that a similar success rate is obtained in each group, 167 subjects are
necessary to achieve a power of 90% using a two-sided significance level of 5%.
Therefore, the target sample size is 170 subjects in each group, a total of 340 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.
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.

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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 1% OPA-15406 group will be demonstrated compared to the vehicle 
group based on the primary endpoint, the success rate in IGA at Week 4. The CMH test 
will be conducted at a two-sided significance level of 5% using the baseline IGA (2 or 3) 
as a stratification factor. The difference in the success rate in IGA and its two-sided 95% 
confidence interval (common risk difference adjusted by the Mantel-Haenszel method 
and its two-sided 95% confidence interval) between the vehicle group and the 1% OPA-
15406 group will be determined. Also, the two-sided 95% confidence interval of the 
success rate in IGA in the treatment group (based on Clopper-Pearson method) will be 
calculated.
Also, a supplemental 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.
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).

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; each 
item score, the scale score (mean score of item scores on each scale [symptoms, 
emotions, and functions]), and the mean score of 16 items of Skindex-16; and the 
total affected BSA (%).

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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 (1% 
OPA-15406 or vehicle), timepoint, interaction between the treatment and timepoint as 
factors and baseline values as covariates. An unstructured 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 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.
7.5
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 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 terms. The percentage of subjects 
experiencing the following AEs will be calculated by treatment group.

Treatment-emergent adverse events (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.

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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 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, 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 by treatment 
group.
7.6.3
Vital Signs and Body Weight
For each vital sign and body weight parameter, 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 will be calculated by 
treatment group.
8
Management of Investigational Medicinal Product
Refer to IB for OPA-15406 for details in the management of the IMP.
8.1
Packaging and Labeling
The IMP will be provided to the IMP manager by the sponsor or its 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_271-102-00007@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)

Product information (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.
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:

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
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.
9.4
Records Retention at the Trial Site
The trial site will retain all the trial-related documents and records for the longer of the 
following 2 periods. If the sponsor requires a longer period of archiving, the trial site will 
consult with the sponsor on the period and procedures of record retention.

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
A period of at least 2 years following the date on which approval to market the drug 
is obtained. If IMP development is discontinued, or if it is notified that the trial results 
will not be attached to the application for approval, a period of at least 3 years 
following the date on which the development discontinuation is determined or the 
date on which the notification indicating that the results will not be attached to the 
application for approval is received.

A period of at least 3 years following the date on which the trial is discontinued or 
completed
The trial site must not dispose of any records relevant to this trial without either (1) 
written permission from the sponsor or (2) provision of an opportunity for the sponsor to 
collect such records. The trial site will be responsible to maintain adequate and accurate 
electronic or hard copy source documents of all observations and data generated during 
this trial including any data clarification forms received from the sponsor. Such 
documentation is subject to inspection by the sponsor and the relevant regulatory 
authorities.
10
Quality Control and Quality Assurance 
10.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH 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, 
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.

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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.
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 

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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.
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.

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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.
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 Chren MM, Lasek RJ, Sahay AP, Sands LP. Measurement properties of Skindex-16: 
a brief quality-of-life measure for patients with skin disease. J Cutan Med Surg. 
2001;5:105-110.

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14 Higaki Y, Kawamoto K, Kamo T, Horikawa N, Kawashima M, Chren MM: The 
Japanese version of Skindex-16: a brief quality-of-life measure for patients with skin 
diseases. J Dermatol. 2002;29:693-698.
15 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
Adolescent 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

Seborrheic 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, AD)

Complications (bronchial asthma, allergic rhinitis and/or conjunctivitis)

Follicular papules (goose-skin) 

Elevated serum IgE level
Clinical types (not applicable to the infantile phase)

Flexural surface type

Extensor surface type

Dry form in childhood

Head/neck/upper chest/back type

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
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.
© The University of Nottingham

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Appendix 3
Skindex-16
The Skindex-16 questionnaire is as follows:
Source: “Measurement Properties of Skindex-16: A Brief Quality-of-Life Measure for 
Patients with Skin Diseases”

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Appendix 4
Human Body Drawing
              Day/  ____Month/20___(             examination) Subject identification number: 3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 corticosteroids 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.

In accordance with the above changes, a sentence related to corticosteroids was added 
to Exclusion Criteria 13 to 15 to allow for the use of corticosteroids on the scalp, and 
changes to the wording related to corticosteroids were made. 

Exclusion Criteria 13
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 14
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 (NSAIDs) 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 

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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. However, intra-ocular, intra-
nasal, intra-auricular, and inhaled corticosteroids and intra-ocular, intra-nasal, and 
inhaled antihistamines may be considered if the investigator or subinvestigator 
judges that their use will not impact assessment of the affected area.

Exclusion Criteria 15
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 3.7.1Schedule 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 survey and tasks related to 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.

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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).
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.