A Multicenter, Open-label, Uncontrolled, Long-term Trialto Demonstrate the Safety and Efficacy of 1% OPA-15406 Ointment in Adult Patients With Atopic Dermatitis and of 0.3% and 1% OPA-15406 Ointments in Pediatric Patients With Atopic Dermatitis (Phase 3 Trial)
Phase: PHASE3
Conditions: Atopic Dermatitis
Sponsor: Otsuka Pharmaceutical Co., Ltd.

 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A Multicenter, Open-label, Uncontrolled, Long-term Trial to Demonstrate the Safety and 
Efficacy of 1% OPA-15406 Ointment in Adult Patients with Atopic Dermatitis and of 
0.3% and 1% OPA-15406 Ointments in Pediatric Patients with Atopic Dermatitis 
(Phase 3 Trial) 
 
 
 
 
NCT Number: NCT03961529 
PRT NO.: 271-102-00006 
Version Date: 01 February 2019 (Version 3.0) 

Otsuka Pharmaceutical Co., Ltd.
Investigational Medicinal Product
OPA-15406 
CLINICAL PROTOCOL
<Protocol Title>
A Multicenter, Open-label, Uncontrolled, Long-term Trial to Demonstrate the Safety and 
Efficacy of 1% OPA-15406 Ointment in Adult Patients with Atopic Dermatitis and of 
0.3% and 1% OPA-15406 Ointments in Pediatric Patients with Atopic Dermatitis 
(Phase 3 Trial)
Protocol No. 271-102-00006
(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_271-102-00006@otsuka.jp
Issue Date:
1 Feb 2019
Version No.:
3.0
Date of Translation
28 Mar 2019

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Protocol Synopsis
Name of Sponsor: Otsuka Pharmaceutical Co., Ltd.
Name of Investigational Medicinal Product: 
OPA-15406
Protocol No.: 271-102-00006
Protocol Title:
A Multicenter, Open-label, Uncontrolled, Long-term Trial to 
Demonstrate the Safety and Efficacy of 1% OPA-15406
Ointment in Adult Patients with Atopic Dermatitis and of 0.3% 
and 1% OPA-15406 Ointments in Pediatric Patients with 
Atopic Dermatitis (Phase 3 Trial)
Clinical Phase/Trial 
Type:
Phase: 3
Long-term trial
Treatment Indication: Atopic dermatitis (AD)
Objective(s): 
Primary Objective: To demonstrate the safety of 1% 
OPA-15406 ointment in adult patients with AD and of 0.3% 
and 1% OPA-15406 ointments in pediatric patients with AD
administered twice daily for 52 weeks.
Secondary Objective: To evaluate the efficacy of 1% 
OPA-15406 ointment in adult patients with AD and of 0.3% 
and 1% OPA-15406 ointments in pediatric patients with AD
administered twice daily for 52 weeks.
Trial Design:
Multicenter, open-label, uncontrolled, long-term trial
Subject Population:
Patients with AD and Investigator’s Global Assessment (IGA) 
score of at least 2
330 subjects in total (150 adult subjects, 180 pediatric subjects 
[2 - 6 years, 7 - 14 years, each with at least 80 subjects])
Inclusion/Exclusion 
Criteria: 
Main inclusion criteria

Age: At least 2 years (at time of obtaining informed 
consent)

Able to provide written informed consent for subjects at
least 20 years of age. For subjects 15 years or older 
and under 20 years of age, written informed consent must 
be obtained from both the subject and the subject’s 
legal guardian. For subjects under 15 years of age, written 
informed consent must be obtained from the subject’s 
legal guardian.

Diagnosis of AD based on the Japanese Dermatological 
Association’s criteria (refer to Appendix 1)

Atopic dermatitis affecting ≥5% of body surface area 
(BSA, excluding scalp) at the screening and baseline 
examinations

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
IGA score of at least 2 at the screening and baseline 
examinations
Main exclusion criteria

Subjects who have an AD or contact dermatitis flare-up 
defined as a rapid intensification of AD, within 28 days 
prior to the baseline examination.

Subjects who are unable to stop using UVA therapy, 
narrowband UVB therapy, UVB therapy, and biologics 
from 28 days prior to the baseline examination until the 
baseline examination.

Subjects who are unable to stop using 
systemic corticosteroids, systemic immunosuppressants, or 
systemic antimetabolites from 28 days prior to the baseline 
examination until the Week 52 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 52 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” or topical corticosteroids other than 
those for skin or topical immunosuppressants (excluding 
for scalp) from 7 days prior to the baseline examination 
until the Week 52 examination. However, intra-ocular, 
intra-nasal, intra-auricular, and inhaled corticosteroids and
immunosuppressants 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 52 examination.
Trial Sites:
Approximately 35 sites in Japan

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Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration:
Adult Subjects
Twice daily administration (morning and night, approximately 
every 12 hours) of 1% OPA-15406 ointment for 52 weeks 
If all skin symptoms resolve, IMP administration may be 
suspended based on the judgment of the investigator or 
subinvestigator. If skin symptoms relapse, IMP administration 
will be restarted.
Pediatric Subjects
Twice daily administration (morning and night, approximately 
every 12 hours) of 0.3% formulation as a starting dose for 52 
weeks
However, the starting dose will be 1% if necessary based on 
the judgment of the investigator or subinvestigator in 
consideration of each subject’s condition (eg, severity of rash, 
affected area, etc). 
In addition, the 1% formulation may be used if no 
improvement in skin symptoms can be observed following 
administration of the 0.3% formulation for 1 month or more 
(allowable window from 21 days or after).
If improvement in skin symptoms can be observed and the 1% 
formulation is judged as unnecessary, it may be reduced to the 
0.3% formulation.
If all skin symptoms resolve, IMP administration may be 
suspended based on the judgment of the investigator or 
subinvestigator. If IMP administration is continued, the 0.3% 
formulation will be used. If skin symptoms relapse, IMP 
administration will be restarted.
Trial Assessments:
Safety: Adverse events, physical examination, vital signs, body 
weight, and clinical laboratory values
Screening/Other: Medical history, previous medications, 
pregnancy test, and height
Efficacy: IGA, Eczema Area and Severity Index (EASI), 
Patient-Oriented Eczema Measure (POEM), affected BSA, 
total serum IgE level, serum Thymus and activation-regulated 
chemokine (TARC)/Chemokine (C-C motif) ligand 17
(CCL17) level
Criteria for 
Evaluation:
Criteria for Safety Evaluation: Adverse events, clinical 
laboratory values, vital signs, and body weight.
Criteria for Efficacy Evaluation: Success rates in IGA 

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(Percentage of subjects with an IGA score of 0 or 1 with 
improvement by at least 2 grades), response time to IGA, 
success rates in EASI, changes from baseline (IGA, EASI, 
POEM, affected area, total serum IgE level, serum 
TARC/CCL17 level)
Statistical Methods:
Safety Analysis
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 (number) 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

TEAEs by timing of onset
Treatment-emergent adverse events related to IMP will also be 
calculated in the same manner. Besides, TEAEs excluding 
those occur during a washout period will be calculated in the 
same manner.
2) Clinical Laboratory Tests
For each parameter (except qualitative urinalysis), the 
descriptive statistics will be calculated for measured values 
and changes from the baseline at each timepoint. For 
qualitative urinalysis values of clinical laboratory tests, a shift 
table at each timepoint against the baseline will be created. 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.
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. The number and percentage of 
subjects with clinically abnormal changes will be calculated.

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Trial Duration:
Duration of the trial: May 2019 to Nov 2020
Screening period: 2 to 30 days
Assessment period: 52 weeks

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Table of Contents
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) ....................................................................................................22
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) ....................................................................................................23
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...............................................................................................29
2.3
Rationale for Severity and Age Setting.............................................................30
2.4
Trial Objectives.................................................................................................30
3
Trial Design.........................................................................................30

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3.1
Type/Design of Trial .........................................................................................30
3.2
Methods of Administration ...............................................................................32
3.2.1
Dose, Regimen, and Treatment Period...........................................................32
3.2.2
Treatment Area ...............................................................................................33
3.3
Trial Population.................................................................................................34
3.3.1
Number of Subjects and Description of Population .......................................34
3.3.2
Issue of Subject Identification Number..........................................................34
3.4
Eligibility Criteria..............................................................................................34
3.4.1
Informed Consent ...........................................................................................34
3.4.2
Inclusion Criteria ............................................................................................36
3.4.3
Exclusion Criteria...........................................................................................37
3.5
Endpoints...........................................................................................................39
3.5.1
Safety Endpoints.............................................................................................39
3.5.2
Efficacy Endpoints..........................................................................................40
3.6
Measures to Minimize/Avoid Bias....................................................................40
3.7
Trial Procedures ................................................................................................40
3.7.1
Schedule of Assessments................................................................................43
3.7.1.1
Acquisition of Informed Consent................................................................43
3.7.1.2
Screening Examination ...............................................................................43
3.7.1.3
Subject Demographics ................................................................................44
3.7.1.4
Subject Registration ....................................................................................44
3.7.1.5
Baseline Examination (2-30 Days After the Screening Examination)........44
3.7.1.6
Prescription of Investigational Medicinal Products to Subjects .................45
3.7.1.7
Week 2 Examination (±3 Days)..................................................................45
3.7.1.8
Week 4, 8, 12, 16, 20, 28, 32, 36, 40, 44, and 48 Examination (±7 
Days) ...........................................................................................................46
3.7.1.9
Week 24 Examination (±7 Days)................................................................47
3.7.1.10
Week 52 Examination (±7 Days) or Withdrawal Examination ..................47
3.7.1.11
Unscheduled Visits .....................................................................................48
3.7.2
Status of Investigational Medicinal Product Administration..........................49
3.7.3
Reasons for the Decision Regarding the Concentration of Prescribed 
IMP (for Pediatric Patients only)....................................................................49
3.7.4
Interruption .....................................................................................................49

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3.7.4.1
Decision for Interruption.............................................................................49
3.7.4.2
Provision During Interruption.....................................................................49
3.7.4.3
Restarting IMP Administration After Interruption .....................................50
3.7.5
Severity of Atopic Dermatitis.........................................................................50
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, Height, and Body Weight........................................................52
3.7.6.5
Other Safety Assessments...........................................................................52
3.7.7
Efficacy Assessments .....................................................................................52
3.7.7.1
Investigator’s Global Assessment...............................................................52
3.7.7.2
Eczema Area and Severity Index................................................................52
3.7.7.3
Patient-Oriented Eczema Measure..............................................................53
3.7.7.4
Affected Body Surface Area.......................................................................53
3.7.7.5
Total Serum IgE Level................................................................................53
3.7.7.6
Serum TARC/CCL17 Level (Thymus and Activation-Regulated 
Chemokine [TARC]/Chemokine [C-C motif] Ligand 17 [CCL17]) ..........54
3.7.8
Previous Medications and Concomitant Medications ....................................54
3.7.9
End of Trial.....................................................................................................54
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................54
3.8.1
Termination or Interruption of the Entire Trial ..............................................54
3.8.2
Termination or Interruption of the Trial at Individual Trial Sites ..................54
3.8.3
Individual Subject Discontinuation ................................................................55
3.8.3.1
Treatment Discontinuation (Except Interruption).......................................55
3.8.3.2
Discontinuation Criteria..............................................................................55
3.8.3.3
Documenting Reasons for Treatment Discontinuation (Except 
Interruption) ................................................................................................56
3.8.3.4
Withdrawal of Consent ...............................................................................56
3.8.3.5
Procedures to Encourage Continued Trial Participation.............................58
3.9
Screen Failures ..................................................................................................58
3.10
Definition of Completed Subjects.....................................................................58
3.11
Definition of Subjects Lost to Follow-up..........................................................58

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3.12
Subject (including Subject’s Legal Guardian) Compliance..............................59
3.13
Deviations from the Trial Protocol....................................................................59
4
Restrictions..........................................................................................60
4.1
Prohibited Concomitant Drugs and Therapies ..................................................60
4.2
Allowed Concomitant Drugs and Therapies .....................................................61
5
Reporting of Adverse Events.............................................................61
5.1
Definitions.........................................................................................................61
5.2
Eliciting and Reporting Adverse Events ...........................................................63
5.3
Immediately Reportable Events ........................................................................63
5.4
Potential Serious Hepatotoxicity.......................................................................64
5.5
Implementation of Patch Test............................................................................64
5.6
Pregnancy..........................................................................................................65
5.6.1
Female Subjects Aged 7 to 14 Years Old.......................................................65
5.6.2
Female Subjects Aged ≥15 Years Old............................................................65
5.6.3
Pregnancy is Suspected or Discovered...........................................................66
5.7
Procedure for Breaking the Blind......................................................................67
5.8
Follow-up of Adverse Events............................................................................67
5.8.1
Follow-up of Non-serious Adverse Events.....................................................67
5.8.2
Follow-up of Serious Adverse Events and Immediately Reportable 
Events .............................................................................................................68
5.8.3
Follow-up and Reporting of Serious Adverse Events and Immediately 
Reportable Events Occurring After Day of Trial Completion (Final 
Observation Day)............................................................................................68
6
Pharmacokinetic Analysis..................................................................68
7
Statistical Analysis..............................................................................68
7.1
Sample Size.......................................................................................................68
7.2
Datasets for Analysis.........................................................................................69
7.3
Handling of Missing Data .................................................................................69
7.4
Analysis of Demographic and Other Baseline Characteristics .........................69
7.5
Safety Analysis..................................................................................................69
7.5.1
Adverse Events ...............................................................................................69
7.5.2
Clinical Laboratory Tests ...............................................................................70
7.5.3
Vital Signs and Body Weight .........................................................................70

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7.6
Efficacy Analysis ..............................................................................................70
8
Management of Investigational Medicinal Product........................71
8.1
Packaging and Labeling ....................................................................................71
8.2
Storage...............................................................................................................71
8.3
Accountability ...................................................................................................72
8.4
Returns and Destruction....................................................................................72
8.5
Reporting of Product Quality Complaints.........................................................72
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................72
8.5.2
Information Required for Reporting Product Quality Complaints.................73
8.5.3
Return Process in the Case of Product Quality Complaints ...........................73
8.5.4
Assessment/Evaluation...................................................................................73
9
Records Management.........................................................................73
9.1
Source Documents.............................................................................................73
9.2
Data Collection..................................................................................................74
9.3
File Management at the Trial Site.....................................................................75
9.4
Records Retention at the Trial Site....................................................................75
10
Quality Control and Quality Assurance...........................................75
10.1
Monitoring.........................................................................................................75
10.2
Auditing.............................................................................................................76
11
Ethics and Responsibility...................................................................76
12
Confidentiality ....................................................................................76
13
Amendment Policy..............................................................................77
14
Publication Authorship Requirements.............................................77
15
References............................................................................................79

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List of In-text Tables
Table 1.3-1
Adverse Events in OPA-15406 Treatment Groups Reported 
at a Higher Frequency Than in the Vehicle Group and 
Observed in at Least 2 Percent of the Subjects in Trials 
Enrolling Subjects With Atopic Dermatitis.................................. 27
Table 3.4.2-1
Inclusion Criteria .......................................................................... 36
Table 3.4.3-1
Exclusion Criteria ......................................................................... 37
Table 3.7-1
Schedule of Assessments.............................................................. 41
Table 3.7.5-1
Definition of Severity of Atopic Dermatitis ................................. 50
Table 3.7.6.2-1
Clinical Laboratory Assessments.................................................. 51
Table 3.7.7.1-1
Investigator’s Global Assessment................................................. 52
Table 3.7.7.2-1
Eczema Area and Severity Index.................................................. 53
Table 4.1-1
Prohibited Concomitant Drugs and Therapies.............................. 60
Table 5.5-1
Reading Criteria............................................................................ 65

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List of In-text Figures
Figure 3.1-1
Trial Design .................................................................................. 32

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List of Appendices
Appendix 1
Diagnostic Criteria for Atopic Dermatitis (Japanese 
Dermatological Association’s Criteria) ........................................ 80
Appendix 2
Patient-Oriented Eczema Measure (POEM)................................. 81
Appendix 3
Human Body Drawing  (at the time of obtaining consent: ≥8
years old)....................................................................................... 83
Appendix 4
Human Body Drawing  (at the time of obtaining consent: 2 -
7 years old).................................................................................... 84

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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
AD
Atopic dermatitis
AE
Adverse event
ALP
Alkaline phosphatase
ALT (GPT)
Alanine aminotransferase
AST (GOT)
Aspartate aminotransferase
BSA
Body surface area
BUN
Blood urea nitrogen
cAMP
Cyclic adenosine 3', 5'-monophosphate
CCL17
Chemokine (C-C motif) ligand 17
CMH
Cochran Mantel Haenszel 
CRF
Case report form
CYP
Cytochrome P450
EASI
Eczema Area and Severity Index
ECG
Electrocardiogram
FAS
Full Analysis Set
GCP
Good Clinical Practice 
γ-GTP
Gamma glutamyl transpeptidase
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 
IWRS
Interactive Web Response System
LDH
Lactic dehydrogenase
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Regulatory Activities
NB-UVB
Narrow-band UVB
NOAEL
No observed adverse effect level
OC
Observed Cases
PDE
Phosphodiesterase

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POEM
Patient-Oriented Eczema Measure
PQC
Product Quality Complaint
SAE
Serious adverse event
SS
Safety Set
TARC
Thymus and activation-regulated chemokine
TEAE
Treatment-emergent adverse event

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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 1980,2 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 model,4 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 the results of the above-mentioned 
clinical trials, a phase 3 trial to compare the efficacy of 1% OPA-15406 ointment and the 
vehicle in adult AD patients (aged 15 - 70 years old) (Trial 271-102-00007) and a phase 3 
trial to compare the efficacy of 0.3% and 1% OPA-15406 ointment and the vehicle in 
pediatric AD patients (aged 2 - 14 years old) (Trial 271-102-00008) will be performed as 
a confirmatory trial. Since OPA-15406 ointment is expected to be administered to AD 
patients on a long term-basis in clinical settings, the present trial is designed as a trial to 
demonstrate the safety and efficacy of OPA-15406 ointment when 1% OPA-15406 
ointment is administered to adult AD patients (aged 15 - 70 years old) and 0.3% and 1% 
OPA-15406 ointment is administered to pediatric AD patients twice daily for 52 weeks.
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 

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of tacrolimus ointment, a calcineurin inhibitor. Four weeks of multiple administrations of 
3% OPA-15406 ointment significantly suppressed infiltration of inflammatory cells such 
as CD3 positive cells, eosinophils, and neutrophils in skin lesions.
Using a mouse scratching-induced chronic dermatitis model, the efficacy of 
OPA-15406 (1% and 3%) dissolved in a solvent (1:1 mixture of acetone and methanol) 
was assessed. Six weeks of topical administration of OPA-15406 (1% or 3%) 
significantly improved the skin symptoms, though no particular effect was observed on 
the frequency of scratching. The efficacy was superior to 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 

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any OPA-15406 ointment (vehicle, 0.1%, 0.3%, 1%, and 3%) groups. Although 
suppressed weight increase was observed, it was not exacerbated in a prolonged 
treatment period. The no observed adverse effect level (NOAEL) for systemic toxicity in 
the 26-week repeated-dose percutaneous toxicity study was estimated to be 2.95 mg/kg 
(1% ointment) in the male rats and 1.07 mg/kg (0.3% ointment) in the female rats.
In the 4, 13, and 39-week repeated-dose percutaneous toxicity studies in miniature pigs, 
OPA-15406 ointment was administered to intact or abraded skin (open cutaneous) once 
daily. As a result, no changes associated with the test substance were observed in any 
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).

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1.2.2
Phase 1 Trial in Healthy Adult Male Subjects in Japan (Trial 
271-14-001)
In the phase 1 trial in healthy adult male subjects (aged 20 - 40 years old) in Japan, 
a single-dose or 2-week twice-daily multiple doses of the 0.3%, 1%, or 3% 
OPA-15406 ointment (8 subjects for each group) or the vehicle of OPA-15406 ointment 
(placebo) as the control were administered to a 1000 cm2 area (about 5% of body surface 
area [BSA]) on the back of the subject at 5 g per dose to assess the safety and 
pharmacokinetics of the OPA-15406 ointment in Japanese subjects. In the 0.3%, 1%, and 
3% OPA-15406 groups, the mean maximum plasma concentration (Cmax) was 0.508, 
0.838, and 1.61 ng/mL, respectively, after the single-dose, and it was 0.506, 0.795, and 
1.65 ng/mL, respectively, after the multiple doses. The Cmax increased with dose after 
both the single and multiple administrations; however, the level of increase was lower 
than the dose ratio, and no dose 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 

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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.
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%, 

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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 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 

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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 
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 

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either group. The AE leading to discontinuation was dermatitis atopic and it occurred in 1 
subject (4.2%), 1 subject (4.0%) and 4 subjects (16.7%) in the 0.3% OPA-15406 group, 
the 1% OPA-15406 group, and the vehicle group, respectively. Of these, 1 subject in the 
1% OPA-15406 group was judged to be IMP-related. In the results of the 
clinical laboratory tests, vital signs, and 12-lead ECG, no marked difference was 
observed among the 3 groups. The efficacy endpoint was established as the success rate 
in IGA (percentage of subjects with IGA score of 0 or 1 with improvement by at least 2
grades) at Week 4, and the success rate in IGA was 37.50%, 40.00%, and 8.33% in 
the 0.3% OPA-15406 group, the 1% OPA-15406 group, and the vehicle group, 
respectively. The success rates were much higher in the 0.3% and 1% OPA-15406 groups
than in the vehicle group (p = 0.0114 and p = 0.0113, CMH test). The mean plasma 
trough concentration of 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 after multiple doses 
compared to a single-dose.
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 

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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)
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 

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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.
In addition, in the phase 2 trial in pediatric AD patients in Japan (Trial 271-102-00002), 
which was conducted prior to the present trial, the safety, efficacy, and tolerability of the 
4-week twice-daily multiple doses of the 0.3% or 1% OPA-15406 ointment or the vehicle 
(placebo) were investigated. There were no particular safety concerns since no SAEs 
related to the IMP or adverse reactions were identified in the trial. The efficacy endpoint 
success rate in IGA (percentage of subjects with IGA score of 0 or 1 with improvement 
by at least 2 grades) at Week 4 was 37.50%, 40.00% and 8.33% in the 0.3% OPA-15406 
group, the 1% OPA-15406 group, and the vehicle group, respectively. The success rates 
were much higher in the 0.3% and 1% OPA-15406 groups than in the vehicle group (p = 
0.0114 and p = 0.0113, CMH test). 
In the phase 2 pharmacokinetic trial in pediatric AD patients outside Japan who received 
the 1% OPA-15406 ointment (Trial MEDI-MM36-206), no SAEs related to the IMP or 
safety concerns were identified.
As described above, the efficacy of 1% OPA-15406 ointment was demonstrated in adult 
AD patients both in and outside of Japan, and the efficacy of 0.3% and 1% OPA-15406
ointment was demonstrated in pediatric AD patients in Japan. No particular 
safety concerns for OPA-15406 ointment were identified either in or outside of Japan. 
Since AD is a disease with repeated exacerbations/remissions and long-term 
administration of OPA-15406 ointment is expected, “Extent of Population Exposure to 
Assess Clinical Safety for Drugs Intended for Long-term Treatment of Non-Life-
Threatning Conditions (PAB/ELD Notification No. 592, dated May 24, 1995)” is 
considered to be applicable. In addition, the detailed safety profile and long-term efficacy 
when OPA-15406 ointment is administered on a long-term basis in the Japanese medical 
environment should be confirmed. Therefore, it was judged ethically and scientifically 
appropriate to conduct this trial to evaluate the safety and efficacy of OPA-15406 
ointment by 1% OPA-15406 ointment administration to adult AD patients and 0.3% and 
1% OPA-15406 ointment administration to pediatric AD patients twice daily for 52 
weeks.

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2.2
Dosing Rationale
[Adult and pediatric subjects] 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.
[Adult subjects] 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 for adults. In addition, 
considering use in actual clinical practice, treatment interruption is allowed when skin 
symptoms are resolved.
[Pediatric subjects] In the phase 2 trial in pediatric patients in Japan (Trial 271-102-
00002), the efficacy endpoint was established as the success rate in IGA (percentage of 
subjects with IGA score of 0 or 1 with improvement by at least 2 grades) at Week 4. The 
success rate was comparable between 0.3% and 1% OPA-15406 groups and significantly 
higher in OPA-15406 groups than in the vehicle group. No particular safety concerns 
were identified with either formulation. Therefore, in the phase 3 trial in pediatric 
patients in Japan (Trial 271-102-00008), which is conducted simultaneously with the 
present trial, two doses (0.3% and 1%) were selected, and the recommended dose should 
be established in consideration of the benefit-risk of OPA-15406 ointment. If the 
superiority of 0.3% OPA-15406 ointment to the vehicle is established in the phase 3 trial 
in pediatric patients in Japan, 0.3% OPA-15406 ointment will be the recommended dose. 
However, if the benefit-risk of 1% OPA-15406 ointment is superior to that of 0.3% OPA-
15406 ointment, 1% OPA-15406 ointment may be included in the recommended dose. 
Based on the above, the starting dose of this trial is 0.3% OPA-15406 ointment; however, 
1% OPA-15406 ointment can be used as the starting dose, based on the judgment of the 
investigator or subinvestigator in consideration of each subject’s condition (eg, severity 
of rash, affected area). In addition, the dose can be adjusted appropriately according to 
symptoms, and treatment can be suspended when skin symptoms have resolved.

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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.
The results of these trials demonstrated efficacy and safety. Since OPA-15406 ointment 
is expected to be used also in severe patients, information regarding the use of OPA-
15406 ointment in severe patients should be collected. Therefore, the present trial was 
designed to include patients with mild to severe AD.
The phase 2 trials (Trial 271-15-001, Trial 271-102-00002) in Japan were conducted in 
patients aged 2 - 70 years old, and demonstrated the efficacy of OPA-15406 ointment 
with no particular safety concerns. In addition, OPA-15406 ointment is expected to be 
used in patients aged 70 years or older in clinical settings. Therefore, subjects aged 2 
years or older were included in this trial.
2.4
Trial Objectives
Primary Objective: To evaluate the safety of OPA-15406 ointment when 1% OPA-15406
ointment is administered to adult AD patients and 0.3% or 1% OPA-15406 ointment is 
administered to pediatric AD patients twice daily for 52 weeks.
Secondary Objective: To evaluate the efficacy of OPA-15406 ointment by 1% 
OPA-15406 ointment administration to adult AD patients and 0.3% or 1% OPA-15406 
ointment administration to pediatric AD patients twice daily for 52 weeks.
3
Trial Design
3.1
Type/Design of Trial
This trial is being conducted to evaluate the safety and efficacy of OPA-15406 ointment 
by 1% OPA-15406 ointment administration to adult AD patients and 0.3% or 1% OPA-
15406 ointment administration to pediatric AD patients twice daily for 52 weeks. The 
trial design is shown in Figure 3.1-1.
1) Screening period

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After obtaining informed consent from the subject for subjects aged ≥20 years old, 
from both the subject and the subject’s legal guardian for subjects aged ≥15 to <20
years old, and from the subject’s legal guardian for subjects aged <15 years old, the 
investigator or subinvestigator will perform the 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 52 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 (Adult patients will be 
prescribed with 1% OPA-15406 ointment. Pediatric patients will be prescribed with 
0.3% OPA-15406 ointment; however, the starting dose will be 1% if necessary based 
on the judgment of the investigator or subinvestigator in consideration of each 
subject’s condition [eg, severity of rash, affected area, etc]). The allocated IMP will 
be administered to the treatment area from the day of baseline examination twice 
daily for 52 weeks. After the baseline examination, the examinations will be 
performed at Weeks 2, 4, 8,12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52.
If a subject discontinues the IMP administration between the day of baseline 
examination and the day of Week 52 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 52 examination or 
withdrawal examination. For subjects who missed the Week 52 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 (52 weeks)
Visit every 4 weeks after the Week 4 
examination
Adult
subjects
1% OPA-15406 ointment
Pediatric
subjects
0.3% or 1% OPA-15406 ointment
(dose should be adjusted based on each 
subject’s condition)
Figure 3.1-1
Trial Design
3.2
Methods of Administration
3.2.1
Dose, Regimen, and Treatment Period
[Adult subjects] 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 52 weeks. If all skin symptoms have resolved, IMP administration 
may be suspended based on the judgment of the investigator or subinvestigator. If skin 
symptoms relapse, IMP administration will be restarted.
[Pediatric subjects] The 0.3% formulation of OPA-15406 ointment will be administered 
as the starting dose, twice daily (approximately 12 hours apart between morning and 
night administration) for 52 weeks. However, the 1% formulation of OPA-15406 
ointment will be administered as the starting dose, if judged necessary by the investigator 
or subinvestigator in consideration of each subject’s condition (eg, severity of rash,
affected area, etc).
Week 52 examination
Week 4 examination
Week 2 examination
IMP prescription
Baseline examination
Screening examination
Informed consent
Week 8 examination
......

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In addition, 1% OPA-15406 ointment can be used if subjects show no improvement in 
skin symptoms after administration of 0.3% OPA-15406 ointment for ≥1 month (with an 
acceptable window of ≥21 days).
When subjects show an improvement in skin symptoms and the use of 1% OPA-15406 
ointment is considered unnecessary, the dosage can be reduced to 0.3% OPA-15406 
ointment.
If all skin symptoms have resolved, IMP administration may be suspended based on the 
judgment of the investigator or subinvestigator. If IMP administration is continued, 0.3% 
OPA-15406 ointment will be used. If skin symptoms relapse, IMP administration will be 
restarted.
The amount of IMP (g) per dose is 10 g/m2 BSA, which is calculated as follows.  
1) The subject’s BSA (m2) will be calculated based on height and body weight at 
each 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
[Rationale for treatment period]
“Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-
term Treatment of Non-Life-Threatning Conditions (PAB/ELD Notification No. 592 
dated May 24, 1995)” is considered to be applicable to this trial. Therefore, a 52-week 
assessment period was employed to confirm the detailed safety profile and long-term 
efficacy when OPA-15406 ointment is administered on a long-term basis in the Japanese 
medical environment.
3.2.2
Treatment Area
The treatment area with the IMP is defined as follows. 

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
The treatment area will be the affected area determined at each examination until the 
time of the next examination (see 3.7.7.4 Affected Body Surface Area).

Even when the affected area is relieved after the baseline examination, the IMP 
administration should be continued there as the treatment area based on the judgment 
of the investigator or subinvestigator.
The investigator or subinvestigator will instruct the subject or the subject’s legal guardian 
regarding the method of administration by specifying the treatment area (%) and the total 
amount of administration (g) for each treatment area using the human body drawing (see
Appendix 3 or Appendix 4), and will give the human body drawing (copy) to the subject 
or the subject’s legal guardian. The investigator or subinvestigator will record the 
treatment area (%) of the 4 body regions [face, neck, and head (excluding scalp); upper 
limbs; trunk; and lower limbs] in the source document and case report form (CRF).
The method of IMP administration is specified in the separate procedure for IMP 
administration.
3.3
Trial Population
3.3.1
Number of Subjects and Description of Population
The target population of this trial is pediatric AD patients with an IGA score ≥2. Subjects 
will be included in the trial to reach the target number of 330 subjects (150 adult subjects, 
180 pediatric subjects [2 - 6 years, 7 - 14 years, each with at least 80 subjects]) for IMP 
administration.
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 (from the 
subject and the subject’s legal guardian [guardian or legal representative, as applicable by 
local laws] if the subject is aged ≥15 to <20 years old, or from the subject’s legal 
guardian if the subject is aged <15 years old). If the subject is under 20 years old, the 

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relationship between the subject and the subject’s legal guardian will be confirmed and 
recorded. For subjects aged <15 years old, if possible, assent (consent not bound by the 
legal restrictions obtained from pediatric subjects) will be obtained from the subject. A 
signed Informed consent form (ICF) and signed assent form will be retained as 
documents. The explanatory document, ICF, and assent form will be approved by the 
same institutional review board (IRB) responsible for approval of this protocol.
Each explanatory document and ICF should include the elements required by the 
International Council for Harmonization of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) Guidelines for Good Clinical Practice (GCP)6 and local regulatory 
requirements.
The investigator or subinvestigator may discuss the availability of the trial and the 
possibility for entry with a potential subject and the subject’s legal guardian before 
obtaining consent. However, written informed consent must be obtained prior to the 
initiation of any procedures that are performed solely for the purpose of determining 
eligibility for this trial, including withdrawal from current medications.
The potential subject and the subject’s legal guardian can refuse to participate in or 
withdraw from the trial at any time without any justifiable reason. The refusal or 
withdrawal by the potential subject and the subject’s legal guardian will not affect any 
future treatments.
Once the appropriate essential information and a full explanation in layman’s language 
appropriate for the potential subject’s age have been provided by the investigator or 
subinvestigator and an opportunity for subjects and the subject’s legal guardian to ask 
questions has been documented, the IRB-approved ICF will be personally signed and 
dated by the subject and/or subject’s legal guardian, or the person obtaining informed 
consent (investigator or subinvestigator) and the person designated by the IRB. When 
assent is also obtained from the subject, the assent form will be personally signed and 
dated by the subject (if possible) and the person obtaining informed consent (investigator 
or subinvestigator), in the same manner. When a supplemental explanation is given by a
clinical trial associate, the clinical trial associate will also sign and date the form. The 
subject or the subject’s legal guardian will be given the explanatory document and copies 
of the signed ICF and assent form, and the originals will be kept by the investigator or 
subinvestigator.
If an amendment to the protocol substantially increases or alters the trial procedures, the 
subject and/or the subject’s legal guardian may be asked for an additional consent and to 
again sign the form.

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3.4.2
Inclusion Criteria
Subjects are required to meet the following inclusion criteria #1 through #7 in Table 
3.4.2-1 at the screening examination, and #6 and #7 at the screening examination and the 
baseline examination.
Table 3.4.2-1
Inclusion Criteria
1
Sex: Either male or female
2
Hospitalization status: Outpatient
3
Age: At least 2 years (at time of obtaining informed consent)
4
Able to provide written informed consent, for subjects aged ≥20 years old. For subjects aged ≥15 
to <20 years old, written informed consent must be obtained from both the subject and the 
subject’s legal guardian. For subjects aged <15 years old, written informed consent must be 
obtained from the subject’s legal guardian.
5
Diagnosis of AD based on the Japanese Dermatological Association’s criteria1 (refer to Appendix 
1)
6
Atopic dermatitis affecting ≥5% of BSA (excluding scalp)
7
IGA score ≥2
[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)
Since there were no particular safety concerns in either the phase 2 trial (Trial 271-
102-00002) in pediatric patients aged 2 - 14 years old in Japan or the phase 2 trial 
(Trial 271-15-001) in adult patients aged 15 - 70 years old in Japan, and OPA-
15406 ointment is expected to be used in patients aged >70 years old, subjects aged 
≥2 years old were 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 safety and efficacy of the IMP in AD patients in 
Japan.
6)-7) To appropriately evaluate the safety and efficacy of the IMP on the target disease, 
in patients expected to receive the IMP.

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3.4.3
Exclusion Criteria
Subjects who fall under any of the criteria in Table 3.4.3-1 at either the screening or 
baseline examination will be excluded from the trial:
Table 3.4.3-1
Exclusion Criteria
1
(Female children aged 7 to 14 years old)
Female children aged 7 to 14 years old who are pregnant or possibly pregnant, or whose legal 
guardians are unable to agree to avoid sexual activity during the trial period and up until 30 days 
after the final administration of IMP.
(Subjects aged ≥15 years old)
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, hepatitis B, hepatitis C)

Renal disease

Hematologic disease

Immunologic or immunocompromised disease (eg, acquired immunodeficiency syndrome, 
Wiskott-Aldrich syndrome, carriers of human immunodeficiency virus [HIV] antibodies)

Other major disease (eg, systemic fungal infection) or other severe uncontrolled condition (eg, 
drug or alcohol abuse) judged by the investigator or subinvestigator to pose a health risk to the 
subject or to have the potential to impact efficacy assessment of the IMP
8
Subjects who are judged by the investigator or subinvestigator to be unable to safely complete the 
trial based on laboratory results at screening examination.
9
Subjects who are judged by the investigator or subinvestigator to have a clinically abnormal blood 
pressure or pulse rate at the screening and baseline examinations

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Table 3.4.3-1
Exclusion Criteria
10
Subjects who are judged by the investigator or subinvestigator to be unable to undergo blood 
sampling.
11
Adult subjects who are unable to stop treatment with ultraviolet A, narrowband ultraviolet B, 
ultraviolet B, and biologics from 28 days prior to the baseline examination until the baseline 
examination
12
Pediatric subjects who are unable to stop treatment with ultraviolet A, narrowband ultraviolet B, 
and ultraviolet B from the baseline examination until the Week 52 examination
13
Subjects who are unable to stop using systemic corticosteroids, systemic immunomodulators, and 
systemic antimetabolites from 28 days prior to the baseline examination until the Week 52
examination
14
Subjects who are unable to stop using topical corticosteroids for skin (excluding scalp) categorized 
as very strong or higher potency in the “Guidelines for Management of Atopic Dermatitis1” from 
21 days prior to the baseline examination until the Week 52 examination.
15
Subjects who are unable to stop using corticosteroids for skin (excluding scalp) categorized as 
strong potency in the “Guidelines for Management of Atopic Dermatitis1” or topical 
corticosteroids other than those for skin or topical immunosuppressants (excluding scalp) from 7
days prior to the baseline examination until the Week 52 examination. However, intra-ocular, intra-
nasal, intra-auricular, and inhaled corticosteroids and immunomodulators may be considered if the 
investigator or subinvestigator judges that their use will not impact assessment of the affected area.
16
Subjects who are unable to stop using topical corticosteroids for skin (excluding scalp) categorized 
as low or medium potency in the “Guidelines for Management of Atopic Dermatitis1” from 4 days 
prior to the baseline examination until the Week 52 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 
propylene carbonate)
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.

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7)
Due to a possible impact on the safety and efficacy assessments of the IMP. 
8)-10)
In consideration of safety.
11)-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 efficacy and safety 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.
3.5
Endpoints
3.5.1
Safety Endpoints

Adverse events
1) AEs occurring after the start of IMP administration (Treatment-emergent adverse 
event [TEAE])
2) TEAEs by severity
3) TEAEs resulting in death
4) Serious TEAEs
5) TEAEs leading to discontinuation of IMP administration
6) TEAEs (skin and subcutaneous tissue disorders) by grade
7) TEAEs at treatment areas
8) TEAEs by time of onset

Clinical laboratory tests

Vital signs and body weight

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[Rationale for Safety Endpoints]
To appropriately evaluate the safety of the IMP.
3.5.2
Efficacy Endpoints

Success rate in IGA at Week 4: percentage of subjects with improved IGA score of 0 
or 1 with an improvement of at least 2 grades

Time to IGA response (IGA score of 0 or 1, with improvement by at least 2 grades)

Success rate in EASI 90 (improvement of ≥90% in EASI), EASI 75 (improvement of
≥75% in EASI), and EASI 50 (improvement of ≥50% in EASI)

Change from baseline in IGA score

Change from baseline in the total score of EASI and each clinical sign score

Change from baseline in the total score of Patient-Oriented Eczema Measure (POEM)

Change from baseline in the total affected BSA (%)

Change from baseline in total serum IgE levels

Change from baseline in serum TARC/CCL17 levels
[Rationale for Efficacy Endpoints]
IGA, EASI, POEM, affected BSA, total serum IgE levels, serum TARC/CCL17 levels 
were selected as efficacy endpoints, in order to appropriately evaluate the efficacy of 
long-term treatment in a multifaceted manner.
3.6
Measures to Minimize/Avoid Bias
This is an uncontrolled trial.
3.7
Trial Procedures
Table 3.7-1 shows the schedule of assessment.

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Table 3.7-1
Schedule of Assessments
Evaluation 
Screening period 
(2–30 days)
Assessment period 
(52 weeks)
Screening 
examination
Baseline 
examination
Week 2 
examination
Week 4, 8, 12, 
16, 20, 28, 32, 
36, 40, 44, and 
48 examination
Week 24 
examination
Week 52 
examination
Withdrawal 
examinationa
Unscheduled 
visit
Acceptable window
−
−
±3 days
±7 days
−
Informed consent 
  ○b
Inclusion and exclusion criteria
○
○
Subject demographics
○
Physical examination
○
○
○
○
○
○
○c
Vital signs, height, and body weight
○
○
○
○
○
○
○c
Clinical laboratory tests
  ○d
○e
○
○c
Pregnancy testf
○
○
○
○c
IGA 
○
○
○
○
○
○
○c
EASI
○
○
○
○
○
○
○c
POEM
○
○
○
○
○
○c
Affected BSA 
○
○
○
○
○
○
○
Treatment area 
○
○
○
○
○c
Administration diary
  ○g
Severity of AD
○
○
Status of IMP administration
○
○
○
○
Prescription and collection of IMP
○h
○i
○
○
  ○j
○i
IMP administration
○k
AEs
Concomitant medications and 
therapies 
Patch testl

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a The withdrawal examination should be conducted, if possible.
b Informed consent is to be obtained prior to screening examination (possibly on the same day) 
c Is to be conducted, as necessary.
d Clinical laboratory tests except total IgE levels and serum TARC/CCL17 levels should be conducted.
e Only clinical laboratory tests for total IgE levels and serum TARC/CCL17 levels should be conducted.
f Should be conducted only for women of childbearing potential; female children aged 7 - 14 years old, women aged 15 - 19 years old, and women aged ≥20 
years old.
g The subjects should keep a diary every day from the baseline examination to the Week 52 examination (withdrawal examination).
h Only IMP prescription.
i IMP will be additionally prescribed, as necessary.
j Only IMP collection.
k The IMP administration should be started at the trial site after all baseline examinations are finished.
l If any AE of suspected hypersensitivity occurred at the treatment area, verbal consent should be obtained again from the subject to conduct a patch test, and the 
patch test should be conducted according to the procedure (see Section 5.5, Implementation of Patch Test)

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3.7.1
Schedule of Assessments
Regarding assessments to be performed by the investigator or subinvestigator, the tasks
that a clinical trial associate is able to perform (eg, subject demographics survey and 
tasks related to clinical laboratory tests) may be performed by the clinical trial associate 
under the supervision of the investigator.
Regarding the tasks to be performed by the subject’s legal guardian, in cases when it is 
difficult for the legal guardian to perform these assessments, a subject guardian who 
understands the subject’s daily status can perform the assessments on behalf of the legal 
guardian, with the exception of consent in written form or verbal consent (consent for 
trial participation, additional procedures, or trial discontinuation).
3.7.1.1
Acquisition of Informed Consent
The investigator or subinvestigator will obtain written consent prior to the screening 
examination directly from subjects for subjects aged 20 years or older, from both the 
subject and the subject’s legal guardian for subjects aged ≥15 to <20 years, and from the 
subject’s legal guardian for subjects aged <15 years. 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, height, and body weight

Clinical laboratory tests (except total IgE levels and serum TARC/CCL17 levels)

Pregnancy test (only for women of childbearing potential; female children aged 7 - 14 
years old, women aged 15 - 19 years old, and women aged ≥20 years old)

IGA

EASI

Affected BSA 

Severity of AD

AEs 

Concomitant medications and therapies
Investigator or subinvestigator will record the results of the eligibility of subjects on the 
list of screened subjects and the list of enrolled subjects.

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3.7.1.3
Subject Demographics
The investigator or subinvestigator will record the following information in the source 
document and CRF.

Date of informed consent

Sex

Date of birth

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, height, and body weight

Clinical laboratory tests (total IgE levels and serum TARC/CCL17 levels only)

Pregnancy test (only for women of childbearing potential; female children aged 7 - 14 
years old, women aged 15 - 19 years old, and women aged ≥20 years old) 

IGA

EASI

POEM

Affected BSA 

Treatment area

Severity of AD

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
Photograph of the target site

AEs

Concomitant medications and therapies

The concentration of the prescribed IMP (for pediatric patients only: 0.3% or 1% 
OPA-15406 ointment; for 1% OPA-15406 ointment, a reason for use should be 
reported in the source document and CRF.)
3.7.1.6
Prescription 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, adult subjects who are 
confirmed to be registered in the IWRS will be prescribed with 1% OPA-15406, and 
pediatric subjects (aged 2 - 14 years old at the time of informed consent) will be 
prescribed with 0.3% or 1% OPA-15406 ointment. The investigator or subinvestigator 
will confirm the allocation result and the amount of IMP to be prescribed for 4 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 and/or the subject’s legal
guardian to record the status of IMP administration in the administration diary daily and 
bring the diary with them to their next visits.
3.7.1.7
Week 2 Examination (±3 Days)
The investigator or subinvestigator will perform the following examinations, observations, 
and evaluations, and record the results in the source document and CRF. 

Physical examination

Vital signs, height, and body weight

IGA

EASI

POEM

Affected BSA 

Treatment area

AEs 

Concomitant medications and therapies

Status of IMP administration

Decision for IMP continuation or interruption (if IMP administration is interrupted, 
reason for the interruption), or a decision to restart IMP administration

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
The concentration of the prescribed IMP (for pediatric patients only: 0.3% or 1% 
OPA-15406 ointment; for 1% OPA-15406 ointment, a reason for use should be 
recorded in the source document and CRF)
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 and/or the subject’s legal 
guardian to record the status of IMP administration in the administration diary every day 
and bring the diary with them to the next visits.
3.7.1.8
Week 4, 8, 12, 16, 20, 28, 32, 36, 40, 44, and 48 Examination (±7 
Days)
The investigator or subinvestigator will perform the following examinations, observations, 
and evaluations, and record the results in the source document and CRF.

Physical examination

Vital signs, height, and body weight

Pregnancy test (only for women of childbearing potential; female children aged 7 - 14 
years old, women aged 15 - 19 years old, and women aged ≥20 years old)

IGA

EASI

POEM

Affected BSA

Treatment area

AEs 

Concomitant medications and therapies

Status of IMP administration

Decision for IMP continuation or interruption (if IMP administration is interrupted, 
reason for the interruption), or a decision to restart IMP administration

The concentration of the prescribed IMP (for pediatric patients only: 0.3% or 1% 
OPA-15406 ointment; for 1% OPA-15406 ointment, a reason for use should be 
reported in the source document and CRF)
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 4 weeks on the IWRS screen, and prescribe the IMP. The 
weight of the dispensed IMP will be measured. The investigator or subinvestigator will 
instruct the subjects and/or the subject’s legal guardian to record the status of IMP 

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administration in the administration diary every day and bring the diary with them to the 
next visits.
3.7.1.9
Week 24 Examination (±7 Days)
The investigator or subinvestigator will perform the following examinations, observations, 
and evaluations, and record the results in the source document and CRF. 

Physical examination

Vital signs, height, and body weight

Clinical laboratory tests

Pregnancy test (only for women of childbearing potential; female children aged 7 - 14 
years old, women aged 15 - 19 years old, and women aged ≥20 years old)

IGA

EASI

POEM

Affected BSA 

Treatment area

AEs

Concomitant medications and therapies

Status of IMP administration

Decision for IMP continuation or interruption (if IMP administration is interrupted, 
the reason for the interruption), or a decision to restart IMP administration

The concentration of the prescribed IMP (for pediatric patients only: 0.3% or 1% 
OPA-15406 ointment; for 1% OPA-15406 ointment, a reason for use should be 
reported in the source document and CRF)
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 4 weeks on the IWRS screen, and prescribe the IMP. The 
weight of the dispensed IMP will be measured. The investigator or subinvestigator will 
instruct the subjects and/or the subject’s legal guardian to record the status of IMP 
administration in the administration diary every day and bring the diary with them to the 
next visits.
3.7.1.10
Week 52 Examination (±7 Days) or Withdrawal Examination
The investigator or subinvestigator will perform the following examinations, observations, 
and evaluations, and record the results in the source document and CRF.

Physical examination

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
Vital signs, height, and body weight

Clinical laboratory tests

Pregnancy test (only for women of childbearing potential; female children aged 7 - 14 
years old, women aged 15 - 19 years old, and women aged ≥20 years old)

IGA

EASI

POEM

Affected BSA

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

Decision for IMP continuation or interruption (if IMP administration is interrupted, 
the reason for the interruption), or a decision to restart IMP administration
The following examinations will be conducted as necessary:

Physical examinations

Vital signs, height, and body weight

Clinical laboratory values

Pregnancy test (only for women of childbearing potential; female children aged 7 - 14 
years old, women aged 15 - 19 years old, and women aged ≥20 years old)

IGA

EASI

POEM

Treatment area

The concentration of prescribed IMP (for pediatric patients only: 0.3% or 1% OPA-
15406 ointment; for 1% OPA-15406 ointment, a reason for use should be recorded in 
the source document and CRF)

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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
Reasons for the Decision Regarding the Concentration of 
Prescribed IMP (for Pediatric Patients only)
If 1% OPA-15406 ointment is prescribed, the reason(s) should be selected, and recorded 
in the source document and CRF.

The severity of eczema is high and the efficacy of 0.3% OPA-15406 ointment will 
not be sufficient.

Area of eczema is large

Continuation of 0.3% OPA-15406 ointment shows insufficient efficacy or 
worsening of symptoms.

Other (specify reason)
3.7.4
Interruption
3.7.4.1
Decision for Interruption
In the following situations, the investigator or subinvestigator will suspend IMP 
administration during the treatment period, and record the date of interruption and the 
reason in the CRF.
1) All skin symptoms have resolved and the investigator or subinvestigator decides 
that IMP administration is unnecessary.
2) The investigator or subinvestigator decides that IMP administration should be 
temporally switched to other topical drugs for all affected areas, due to a 
worsening of symptoms, etc.
3.7.4.2
Provision During Interruption
The investigator or subinvestigator should perform the specified assessments during 
interruption, and decide on the necessity of restarting IMP administration.

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3.7.4.3
Restarting IMP Administration After Interruption
In the following situations after interruption, IMP administration should be restarted and 
the end date of interruption should be recorded in the CRF.
1) Skin symptom(s) relapse.
2) In cases where IMP administration was suspended due to a worsening of 
symptoms and the symptoms have subsequently improved, the investigator or 
subinvestigator decides that IMP administration can be restarted.
3.7.5
Severity of Atopic Dermatitis
The investigator or subinvestigator will determine the severity7 (mild, moderate, severe, 
or very severe) and record the result in the source document and CRF.
Table 3.7.5-1
Definition of Severity of Atopic Dermatitis
Definition
Severity
Only mild rashesa are observed irrespective of the 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 
Most 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.
3.7.6
Safety Assessments
3.7.6.1
Adverse Events
Refer to Section 5, Reporting of Adverse Events.
3.7.6.2
Clinical Laboratory Tests
The investigator or subinvestigator will perform clinical laboratory tests for the following 
items. Date of blood and urine sampling will be recorded on the source document and 
CRF. 

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Table 3.7.6.2-1
Clinical Laboratory Assessments
Hematology
Hemoglobin
Hematocrit
Red blood cell count
White blood cell count and differential white blood 
cell count (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils)
Platelets
Qualitative urinalysis
Glucose
Protein
Immunohematology test
Total serum IgE
Serum TARC/CCL17
Serum chemistry
Alkaline phosphatase (ALP)
ALT (GPT)
AST (GOT)
Total bilirubin
Blood urea nitrogen (BUN)
Total cholesterol
Creatinine
γ-glutamyl transpeptidase (ϒ-GTP)
Lactate dehydrogenase (LDH)
Total protein
Albumin
Serum electrolytes (Ca, Na, K, Cl)
Additional test
Urine and/or serum pregnancy for women of 
childbearing potential; female children aged 7 - 14 
years old, women aged 15 - 19 years old, and 
women aged ≥20 years olda
a A 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 24 mL (5 mL at the screening examination, 
3 mL at the baseline examination, and 8 mL each at the Week 24 and Week 52 
examinations) during the trial period.
For women of childbearing potential (female children aged 7 - 14 years old, women aged 
15 - 19 years old, and women aged ≥20 years old), a pregnancy test will be performed at 
the screening examination, and the result must be obtained prior to the IMP 
administration. 
3.7.6.3
Physical Examination
The investigator or subinvestigator will assess the subject’s physical condition by 
interview, visual examination, auscultation, or palpation. It is desirable to conduct 
individual subject’s physical examination by the same investigator throughout the trial 
period as much as possible.

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3.7.6.4
Vital Signs, Height, 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, height 
(measured in cm, integer value; if measured to one decimal place, round off to the nearest 
integer value), 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.
3.7.6.5
Other Safety Assessments
Safety assessments other than those above have not been established.
3.7.7
Efficacy Assessments
3.7.7.1
Investigator’s Global Assessment
The investigator or subinvestigator will evaluate skin symptoms according to IGA.8 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 will be evaluated by the 
same physician, as much as possible.
Table 3.7.7.1-1
Investigator’s Global Assessment
Symptom
Severity score
No inflammatory signs of AD
0 = Clear
Just perceptible erythema and just perceptible papulation/infiltration
1 = Almost clear
Mild erythema and mild papulation/infiltration
2 = Mild disease
Moderate erythema and moderate papulation/infiltration
3 = Moderate disease
Severe erythema, and severe papulation/infiltration
Severe erythema, and severe crusting papulation/infiltration with oozing
4 = Severe disease/Very 
severe disease
3.7.7.2
Eczema Area and Severity Index
The investigator or subinvestigator will evaluate skin symptoms according to EASI.9 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 

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maximum EASI score is 72 points. The same subject will be evaluated by the same 
physician, as much as possible.
Table 3.7.7.2-1
Eczema Area and Severity Index
Body region
Calculation of the score for each region 
Face, neck, and head 
(E ＋I ＋Ex ＋L) × score of BSA ×0.1 (×0.2 for subjects aged 2 - 7 years 
old [at time of obtaining informed consent])
Upper limbs
(E ＋I ＋Ex ＋L) × score of BSA ×0.2
Trunk
(E ＋I ＋Ex ＋L) × score of BSA ×0.3
Lower limbs
(E ＋I ＋Ex ＋L) × score of BSA ×0.4 (×0.3 for subjects aged 2 - 7 years 
old [at time of obtaining informed consent])
E = severity score of erythema; I = severity score of infiltration/papulation; Ex = severity score of 
excoriation; L = severity score of lichenification 
Severity score: no disease = 0; very mild = 0.5; mild = 1; mild-moderate = 1.5; moderate = 2; severe = 
2.5; very severe = 3
Score of affected BSA (for each region): no eruption = 0; 1% to 9% = 1; 10% to 29% = 2; 30% to 49% 
= 3; 50% to 69% = 4; 70% to 89% = 5; 90% to 100% = 6
3.7.7.3
Patient-Oriented Eczema Measure
The investigator or subinvestigator will evaluate eczema according to the POEM (see 
Appendix 2).10 The subjects will answer 7 questions about their eczema. If it is difficult 
to obtain answers from the subject, the subject’s legal guardian will evaluate the subject’s 
eczema and answer questions. The investigator or subinvestigator will record the results 
in the source document and CRF. The total score of POEM is 28 points at the most.
3.7.7.4
Affected Body Surface Area
The investigator or subinvestigator will draw the affected BSA (range of skin eruption 
with inflammation at the time of examination) on the human body drawing (see
Appendix 3 or Appendix 4) to determine the affected areas (%) on the respective 4 body 
regions (head, face, and neck [excluding scalp]; upper limbs; trunk; and lower limbs). 
The respective affected areas (%) will be recorded in the source document and CRF. The 
affected BSA does not include dry skin sites. One palm of the subject corresponds to 1% 
BSA.
3.7.7.5
Total Serum IgE Level
Total serum IgE levels have been reported to be associated with the severity of AD.11

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3.7.7.6
Serum TARC/CCL17 Level (Thymus and Activation-Regulated 
Chemokine [TARC]/Chemokine [C-C motif] Ligand 17 [CCL17])
Serum TARC/CCL17 is a biomarker that reflects the condition of AD.12 Serum 
TARC/CCL17 levels have been reported to decrease with the improvement of AD 
symptoms. Refer to 3.7.6.2 Clinical Laboratory Tests for test procedures.
3.7.8
Previous Medications and Concomitant Medications
The investigator or subinvestigator will record in the source document and CRF the name, 
purpose of use, dosage per administration, frequency, route of administration, and 
start/end date of administration of any medications other than the IMP (excluding 
cosmetics) used from 30 days prior to the screening examination until the Week 52
examination (or examination at discontinuation) regardless of whether or not their 
concomitant use is allowed. The investigator or subinvestigator will also record in the 
source document and CRF the name, purpose for conduct, and start/end date of any 
concomitant therapies conducted 30 days prior to screening examination until Week 52
examination (or examination at discontinuation) regardless of whether or not such is 
prohibited.
3.7.9
End of Trial
The “end of trial date” is defined as “the last date of visit or contact” or “the date of 
making decision of discontinuation” for the last subject completing or withdrawing from 
the trial. It does not include the last subject’s follow-up period for AEs.
3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Termination or Interruption of the Entire Trial
When the sponsor decides to terminate or interrupt the trial for some reason, the sponsor 
will promptly notify the head of the trial site and the regulatory authority in accordance 
with regulatory requirements.
3.8.2
Termination or Interruption of the Trial at Individual Trial Sites
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB if judged to be necessary for medical, safety, regulatory, ethical or other reasons 
consistent with applicable laws, regulations, and GCP. The head of the trial site will 
notify the sponsor promptly if the trial is terminated by the investigator or the IRB at the 
site.

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3.8.3
Individual Subject Discontinuation
Any subject may discontinue participation in the trial at any time without any medical 
disadvantage. The investigator or subinvestigator may withdraw a subject from the trial at 
any time if it is considered necessary for medical treatment of that subject.
3.8.3.1
Treatment Discontinuation (Except Interruption)
After prescription of the IMP, the investigator or subinvestigator may discontinue IMP 
administration for various reasons. These reasons for discontinuation include a request 
from the subject or subject’s legal guardian who is not satisfied with IMP administration 
or occurrence of an AE, a condition requiring medication(s) or treatment(s) that has not 
been permitted, or some other condition that requires treatment to be discontinued at the 
discretion of the investigator or subinvestigator. Under all circumstances, each 
investigator or subinvestigator must confirm details of such circumstances and provides 
the subject or subject’s legal guardian with all possible choices to continue with the IMP 
administration according to Section 3.8.3.5, Procedures to Encourage Continued Trial 
Participation.
3.8.3.2
Discontinuation Criteria 
In any of the events listed below, the investigator or subinvestigator will discontinue IMP 
administration, perform the tests to be performed at withdrawal stipulated and promptly 
inform the sponsor of the withdrawal. The investigator or subinvestigator will record the 
date and reason for withdrawal in the CRF. If withdrawal is necessitated by problems 
with safety, such as the occurrence of an AE or aggravation of an underlying disease, the 
investigator or subinvestigator will promptly take appropriate measures and perform 
follow-up if necessary.
1) Request from the subject or subject’s legal guardian to discontinue participation 
in the trial
2) Discovery that the subject was included in the trial despite violation of the 
inclusion or exclusion criteria
3) Occurrence of any AE that makes it difficult for the subject to continue 
administration of IMP (including a suspected treatment-related AE of skin 
hypersensitivity on the treatment area)
4) Discovery that the subject is pregnant or suspected to be pregnant
5) Judgment by the investigator or subinvestigator that it is necessary to withdraw 
the subject from the trial

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3.8.3.3
Documenting Reasons for Treatment Discontinuation (Except 
Interruption)
All subjects and subject’s legal guardians have the right to discontinue the trial and the 
investigator or subinvestigator can also discontinue a subject’s participation in the trial at 
any time if medically necessary. If subjects discontinue their participation in the trial, 
only one reason (main reason) for withdrawal should be recorded in the CRF.

Reasons related to AEs: 
Request from the subject due to distress or discomfort associated with a 
non-serious AE that does not place the subject at excessive risk in normal cases 
Decision by the investigator or subinvestigator that continuing with IMP 
administration places the subject at excessive risk (eg, cases with IMP-related 
safety concern)

Serious adverse events (SAE)

Other safety concerns or AEs possibly related to IMP

Death

Withdrawal of consent (complete documented withdrawal of consent)

Judgment by physician

Lost to follow-up 

Pregnancy (see Section 5.6 Pregnancy)

Entire or partial discontinuation of the trial by the sponsor

Lack of efficacy

Deviation from the protocol

Other
If the subject discontinued the IMP administration due to an AE, the investigator, 
subinvestigator, or other clinical trial associates will follow the AE until it resolves or 
stabilizes, or the subject is lost to follow-up or dies, as much as possible, according to the 
procedures specified in Section 3.8.3.1, Treatment Discontinuation (Except Interruption).
3.8.3.4
Withdrawal of Consent
All subjects and subjects’ legal guardians have the right to withdraw their consent of trial 
participation at any time without any disadvantages. The subjects and the subjects’ legal 
guardians can only withdraw their consent for future trial participation, but they cannot 
withdraw consent for the use of data that has already been collected as part of the trial. 
The investigator or subinvestigator can also discontinue a subject’s participation in the 
trial at any time if medically necessary. Unless the subject and the subject’s legal 
guardian withdraw consent in written form, or unless the investigator or subinvestigator 
prepares a document which confirms the verbal consent for complete withdrawal from 

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the trial by the subject and the subject’s legal guardian, the subject will undergo as many 
of the evaluations specified in the protocol as possible.
Complete withdrawal of consent means that the subject and the subject’s legal guardian 
refuses all of the following follow-up procedures (These methods of follow-up will also 
be noted in the trial ICF).

All follow-up procedures specified in the protocol (in any form such as the subject 
visiting the trial site, by telephone, or visiting the subject’s home)

Part of the follow-up procedures specified in the protocol (If some parts of the 
follow-up procedures are refused by the subject and/or the subject’s legal guardian, 
those agreed between the subject, the subject’s legal guardian and the clinical trial 
associate will be performed)

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 (Except Interruption), 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 activities. Therefore, in accordance with 
Section 3.8.3.3 Documenting Reasons for Treatment Discontinuation (Except 
Interruption), 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 

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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 an ICF, but who has not been prescribed with the IMP.
If a subject is a screen failure, the following information should be recorded in the source 
document and CRF for screen failure subjects.
Subject identification number, date of informed consent, date of screening examination, 
date of birth, sex, date of judgment as screen failure, reason for screen failure, country 
where the trial was conducted (Japan), race, ethnicity, possibility of pregnancy
3.10
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary, secondary, and/or safety endpoints, irrespective of whether the subject actually 
administered all doses of IMP. Subjects who are evaluated at the last scheduled visit 
during the treatment period will be defined as completed subjects. Based on the trial 
objectives, subjects who complete the Week 52 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 52 examination during the 
treatment period, subjects who do not have a known reason for discontinuation (eg, 
withdrew consent or AE) and subjects whose survival is unknown on the trial completion 
day will be classified as lost to follow-up. The subject’s survival can be judged by 
various information sources by obtaining the proper documents which indicate death (ie, 
death certificate, medical record, public record, or statement by a family member or their 

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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 and subject’s legal guardian cannot be contacted even after calling 3 times, 
the investigator, subinvestigator, or designated person will try to get in contact with the 
subject and subject’s legal guardian by sending a letter via registered mail or by other 
substitute methods. If these efforts are not successful, the subject is considered as “lost to 
follow-up.” If the subject is lost to follow-up, the contact date and contact method will be 
recorded in the source document and the last date on which an attempt was made to reach 
the subject and the contact method will be recorded in the CRF.
3.12
Subject (including Subject’s Legal Guardian) Compliance

To avoid using drugs that are not permitted by the investigator or subinvestigator.

To thoroughly understand the details of the administration guidance and follow it.

To keep an administration diary every day. 

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, IMP prescription 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 
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 

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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. After the baseline 
examination, use of a minimal type of topical drugs is allowed if medically required due 
to the worsening of symptoms, etc. In this case, overlapping the application of such drugs 
with the IMP is not allowed.
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 28 days prior to the baseline 
examination until the baseline 
examination
Ultraviolet light A, narrowband ultraviolet B (NB-UVB), 
ultraviolet light B (for adult subjects only)
Biologics
From 28 days prior to the baseline 
examination until the Week 52
examination (or withdrawal examination)
Ultraviolet light A, narrowband ultraviolet B (NB-UVB), 
ultraviolet light B (for pediatric subjects only)
Systemic corticosteroids, systemic immunomodulators, 
systemic antimetabolites
From 21 days prior to the baseline 
examination until the Week 52
examination (or withdrawal examination)
Topical corticosteroids categorized as very strong or 
higher potency in the “Guidelines for Management of 
Atopic Dermatitis with Topical Therapies1”
From 7 days prior to the baseline 
examination until the Week 52
examination (or withdrawal examination)
Topical corticosteroids categorized as strong potency in the 
“Guidelines for Management of Atopic Dermatitis1” Topical 
corticosteroids other than those for skin or topical 
immunomosuppretants.
However, intra-ocular, intra-nasal, intra-auricular, and inhaled
corticosteroids and immunomodulators may be considered if 
the investigator or subinvestigator judges that their use will 
not impact assessment of the affected area.
From 4 days prior to the baseline 
examination until the Week 
52examination (or withdrawal 
examination)
Corticosteroids categorized as low or medium potency in 
the “Guidelines for Management of Atopic Dermatitis with 
Topical Therapies1”
NB-UVB: Narrow-band UVB

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4.2
Allowed Concomitant Drugs and Therapies
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 52 examination. If other topical drugs are concomitantly used, 
OPA-15406 ointment will be applied first, followed by application of other topical drugs.
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.
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 

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that do not result in hospitalization, or the development of drug dependency or drug 
abuse.
Non-serious AEs are all AEs that do not meet the criteria for a “serious” AE.
Immediately Reportable Event (IRE): 

Any SAE.

Any AE related to occupational exposure.

Potential serious hepatotoxicity (see Section 5.4, Potential Serious Hepatotoxicity). 

Pregnancies are also defined as IREs. Although normal pregnancy is not an AE, it 
will mandate IMP discontinuation and must be reported on an IRE form to the 
sponsor. Pregnancy will only be documented on the AE section of CRF if there is an 
abnormality or complication. Pregnancies of the subjects or their partners will be 
included in the above.
Clinical Laboratory Test Value Changes: It is the investigator’s or subinvestigator’s
responsibility to review the results of all laboratory tests as they become available. This 
review will be documented by the investigator’s or subinvestigator’s dated signature on 
the laboratory report. For each abnormal laboratory test result, the investigator or 
subinvestigator 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 or subinvestigator 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 or subinvestigator (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.
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.

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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 or subinvestigator 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, occurrences at administration sites of all AEs, and 
interruption reported by the subject must be recorded on the source documents and CRFs 
provided by the sponsor. Eliciting AEs and SAEs will be started after the subject and/or 
the subject’s legal guardian 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 
event to the sponsor by e-mail in principle (see cover page of this protocol for contact 
information). An IRE form, etc. must be completed and sent by e-mail in principle to the 
sponsor. Please note that the IRE form is NOT the AE section of CRF.
Subjects experiencing SAEs and IREs should be followed until the events are resolved or 
clinically stabilized, or until the subjects are lost to follow-up. Recovery is defined as the 

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subject’s health returning to baseline status, and stabilization is a condition determined by 
the investigator or subinvestigator that no further improvement or worsening is likely. 
The investigator or subinvestigator should provide the subjects with appropriate 
treatments and the sponsor with prompt updates on the subjects’ status.
5.4
Potential Serious Hepatotoxicity
For a subject who experiences an elevation in AST or ALT that is ≥3 times the upper 
limit of the normal range, a total bilirubin level should also be evaluated. If the total 
bilirubin level is ≥2 times the upper limit of the normal range, all values should be 
recorded on an IRE form, etc. and report as an AE on the CRF.
5.5
Implementation of Patch Test 
If any AE suspected of hypersensitivity occurs in the treatment area, the subject will be 
withdrawn from the trial and given appropriate treatments. According to the following 
procedures, a patch test will be performed. After obtaining verbal consent to patch test 
from the subject (from both the subject and the subject’s legal guardian for subjects aged 
≥15 to <20 years old, and from the subject’s legal guardian for subjects aged <15 years) 
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 
Dermatitis13 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
5.6.1
Female Subjects Aged 7 to 14 Years Old
Before enrolling female children aged 7 to 14 years old in this clinical trial, the 
investigator or subinvestigator must review the trial participation guidelines for female 
children aged 7 to 14 years old. The topics should generally include:

Informed consent form

Guidelines for the follow-up of a reported pregnancy
Before trial enrollment, the legal guardians of female pediatric subjects (potential) aged 7 
to 14 years old must be advised of the importance of avoiding pregnancy during their trial 
participation and the potential risk factors of an unintentional pregnancy. The subject’s 
legal guardian must sign an ICF stating that the above-mentioned risk factors and 
consequences were discussed with her.
At the screening examination, baseline examination, and Weeks 4, 8, 12, 16, 20, 24, 28, 
32, 36, 40, 44, 48, and 52 examinations, female children aged 7 to 14 years old will 
undergo a urine pregnancy test, in principle. If a positive or false positive urine test result 
is obtained, or a urine test cannot be performed, a serum pregnancy test (human chorionic 
gonadotropin test) will be performed.
5.6.2
Female Subjects Aged ≥15 Years Old
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 

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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, 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 
pregnancy. The subjects must sign an ICF stating that the above-mentioned risk factors 
and consequences were discussed with her. At the screening examination, baseline 
examination, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 examinations, and 
withdrawal examinations, WOCBP aged 15 to 19 years old and aged ≥20 years old 
should undergo a urine pregnancy test, in principle. If a positive or false positive urine 
test result is obtained, or a urine test cannot be performed, a serum pregnancy test (human 
chorionic gonadotropin test) will be performed.
5.6.3
Pregnancy is Suspected or Discovered
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 

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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
Not applicable.
5.8
Follow-up of Adverse Events 
5.8.1
Follow-up of Non-serious 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 non-serious AEs 
(excluding IREs) that are ongoing at the day of trial completion (final observation day) 
will be recorded as “ongoing” on the CRF. For evaluation of AEs that occurred during 
the trial, additional relevant medical history information may be requested by the sponsor 
to further ascertain causality (including but not limited to, information such as 
risk-related behavior, family history, and occupation). Follow-up information obtained 
after the day of trial completion (final observation day) will be recorded in medical 
records.

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5.8.2
Follow-up of Serious Adverse Events and Immediately 
Reportable Events
In this trial, subjects will be actively observed for occurrence of any SAEs and IREs until 
the Week 4 examination or withdrawal examination (the day of trial completion [final 
observation day]).
Serious Adverse Events and IREs that are identified up to the day of trial completion or 
are ongoing on the day of trial completion must be recorded on the AE section of CRF. If 
new information on applicable SAEs or IREs (eg, “recovered”) is obtained from the day 
of a subject’s trial completion to the day of trial completion of the last subject during the 
trial period, it should be reported to the sponsor using the IRE form, etc. and must be 
recorded on the AE section of CRF. Any SAEs or IREs should be followed and any 
significant follow-up information should be reported to the sponsor using the IRE form, 
etc. until the events are resolved or clinically stabilized, or the subject is lost to follow-up 
or dies.
5.8.3
Follow-up and Reporting of Serious Adverse Events and 
Immediately Reportable Events Occurring After Day of Trial 
Completion (Final Observation Day)
Any new SAEs and IREs reported to the investigator or subinvestigator after the day of 
trial completion (final observation day), and are determined by the investigator or 
subinvestigator to be IMP-related should be reported to the sponsor. These events may 
include SAEs and IREs that are captured on follow-up telephone contact or at any other 
timepoint after the defined trial period. The investigator or subinvestigator should follow 
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
330 subjects (150 adult subjects, 180 pediatric subjects [2 - 6 years, 7 - 14 years, each 
with at least 80 subjects])

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[Rationale for sample size]
Enrollment of 150 adult and 150 pediatric subjects will enable a 1-year (52-week) 
observation of 100 adult and 100 pediatric subjects. However, 180 pediatric subjects (2 -
6 years, 7 - 14 years, each with at least 80 subjects) will be enrolled to evaluate safety in 
younger (2 – 6 years old) and older (7 – 14 years old) pediatric 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.
The following analyses will each be performed for pediatric subjects, adult subjects, and 
all subjects. For pediatric subjects, perform the analysis using subject grouping that takes 
into account the overall situation of treatment with 0.3% and 1% OPA-15406 ointment if 
required. Further details are provided in the statistical analysis plan.
7.3
Handling of Missing Data
Missing data will not be imputed at each timepoint and Observed Cases (OC) data will be 
used.
7.4
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 SS.
7.5
Safety Analysis
Baseline data refers to data obtained prior to the start of IMP administration.
7.5.1
Adverse Events
All AEs will be coded using the Medical Dictionary for Regulatory Activities/Japanese 
version (MedDRA/J) system organ class and preferred term. The percentage of subjects 
experiencing the following AEs will be calculated by treatment group.

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
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

TEAEs by time of onset
Treatment-emergent adverse events related to IMP will also be calculated in the same 
manner. Besides, TATEs excluding those occur during a washout period will be 
calculated in the same manner.
7.5.2
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.
7.5.3
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.
7.6
Efficacy Analysis

Subjects with IGA response: subjects with an IGA score of 0 or 1 with improvement 
by at least 2 grades
The number and percentage of subjects who showed IGA response at least one time 
after IMP administration will be calculated. In addition, the number and percentage of 
subjects with IGA response at each timepoint will be calculated using OC data. 

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Subjects with IGA response at the final visit (LOCF at Week 52) will be calculated in 
the same manner.

Time to IGA response (IGA score of 0 or 1 with improvement by at least 2 grades)
The time to the first IGA response will be summarized.

Response rate in EASI 90, EASI 75, and EASI 50
The number and percentage of subjects who showed response at each timepoint will 
be calculated.

Change from baseline in the IGA score, the total EASI score, each EASI clinical sign 
score, the total POEM score, the total affected BSA (%), total serum IgE levels, and 
serum TARC/CCL17 levels.
Descriptive statistics will be calculated using OC data for the measured values and 
changes from baseline of each item, at each timepoint.
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 designated agent. The 
IMP will be supplied in a packing box. Each packing box used in the treatment period 
will be labeled with the IMP identification number, 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.

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8.3
Accountability
The IMP manager must maintain an inventory record of IMP received, dispensed, 
administered, and returned.
8.4
Returns and Destruction
Upon completion or termination of the trial, all unused, all or 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 

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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_271-102-00006@otsuka.jp)
Identification of a PQC by the subject should be reported to the investigator or 
subinvestigator, who should then follow the above reporting procedure.
8.5.2
Information Required for Reporting Product Quality Complaints

Description of compliant

Reporter identification (eg, subject, investigator or subinvestigator, trial site, etc.)

Reporter contact information (eg, address, phone number, e-mail address)

ID of material (compound name, kit number)

Clinical protocol reference (number and/or trial name)

Dosage form/strength (if known)

Pictures (if available)

Availability for return of the sample of complaints
8.5.3
Return Process in the Case of Product Quality Complaints
Indicate during the PQC report if the complaint sample is available for return. The 
sponsor may provide instructions for the return process of the sample, as necessary.
It must be documented in the site accountability record that a complaint sample has been 
forwarded to the sponsor for complaint investigation.
8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include but are not limited to medical 
records, electronic data, screening logs, and recorded data from automated instruments. 
All source documents pertaining to this trial will be maintained by the institutions and 
made available for direct inspection by authorized persons. Investigators/institutions will 
permit trial-related monitoring, audits, IRB review, and regulatory inspection(s) by 

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providing direct access to source data/documents by authorized persons as defined in the 
ICF. In all cases, subject confidentiality must be maintained in accordance with local 
regulatory requirements.
9.2
Data Collection
During each subject’s visit to the clinic, a clinician participating in the trial will record 
progress notes to document all significant observations. At a minimum, these notes will 
contain:

Documentation of the informed consent process, including any revised consents;

Documentation of the investigator’s decision to enroll the subject into the trial, the 
review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial;

The date of the visit and the corresponding Visit or Day in the trial schedule;

General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator’s assessment of relationship to IMP must also be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed; 

The signature (or initials) and date of each clinician (or designee) who made an entry 
in the progress notes.
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above. Any changes to information in the trial progress notes and other source 
documents will be initialed and dated on the day the change is made by a site staff 
member authorized to make the change. Changes will be made by striking a single line 
through erroneous data (so as not to obliterate the original data), and clearly entering the 
correct data (eg, wrong data right data). If the reason for the change is not apparent, a 
brief explanation for the change will be written in the source documentation by the 
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. 

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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.

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.

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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.
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.

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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 
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

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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, Masanori I, 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 (1 Suppl):161s-4s.
4
Kitagaki H, Hiyama H, Kitazawa T, Shiohara T. Psychological stress with long-
standing allergic dermatitis causes psychodermatologiical 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
International Council for Harmonisation (ICH) [homepage on the Internet]. 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.
7
Kohno Y, supervised by Yamamoto S. Guidelines for Treatment of Atopic Dermatitis 
2008. Available from: http://www.jaanet.org/pdf/guideline_skin02.pdf.
8
Leung DY, Hanifin JM, Pariser DM, Barber KA, Langley RG, Schlievert PM, et al. 
Effect of pimecrolimus cream 1% in the treatment of patients with atopic dermatitis 
who demonstrate a clinical insensitivity to topical corticosteroids: a randomized, 
multicentre vehicle-controlled trial. Br J Dermatol. 2009;161:435-43.
9
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. and the EASI 
Evaluator Group. The eczema area and severity index (EASI): assessment of 
reliability in atopic dermatitis. Exp Dermatol. 2001;10:11-8.
10 Charman CR, Venn AJ, Ravenscroft JC, Williams HS. Translating Patient-Oriented 
Eczema Measure (POEM) scores into clinical practice by suggesting severity strata 
derived using anchor-based methods. Br J Dermatol. 2013;169:1326-32.
11 Laske N，N iggemann B. Does the severity of atopic dermatitis correlate with serum 
IgE levels? Pediatr Allergy lmmunol. 2004;15:86-8.
12 Fujisawa T, Nagao M, Hiraguchi Y, Katsumata H, Nishimori H, Iguchi K, et al. 
Serum measurement of thymus and activation-regulated chemokine/CCL17 in 
children with atopic dermatitis: elevated normal levels in infancy and age-specific 
analysis in atopic dermatitis. Pediatr Allergy Immunol. 2009 Nov;20(7):633-41.
13 Takayama K, Yokozeki H, Matsunaga K, Katayama I, Aiba S, Itoh M, et al. 
Guidelines for management of contact dermatitis. The Japanese Journal of 
Dermatology. 2009;119(9):1757-93.

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

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Appendix 2
Patient-Oriented Eczema Measure (POEM)
The POEM questionnaire is shown on the next page. If it is difficult for subjects to 
answer the questions, their parents will answer them instead.
© The University of Nottingham

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Appendix 3
Human Body Drawing
(at the time of obtaining consent: ≥8 years old)
              Day/  ____Month/20___(             examination) Subject identification number: S000
      
Affected site
Affected 
area (%)
Administration site
Treatment 
area (%)
Total amount of 
administration
_____   g
Appropriate amount of 
administration per 1%
g
Face, neck, and head
(excluding scalp)
%
Face, neck, and head
(excluding scalp)
%
Upper limbs
%
Upper limbs
%
Trunk
%
Trunk
%
Lower limbs
%
Lower limbs
%
Total
%
Total
%
Signature of the investigator/subinvestigator
_______________________________________________________Day/_____Month/20_____

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

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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) or receive a favorable opinion 
by the Independent Ethics Committee (IEC) 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/ies by the sponsor. I agree that clinical data entered on eCRF 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 subinvestigators 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
Trial Site
___________________________________
DD Mon 20XX
Signature
Date
The signature of the sponsor is electronically captured. The electronic signature page is attached to 
this agreement.