Clinical trial NCT02914548
Conditions: Atopic Dermatitis
Sponsor: Otsuka Pharmaceutical Co., Ltd.
Start date: 2016-09-01; Completion date: 2017-06-01
Enrollment: 200 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the efficacy and safety of OPA-15406 ointment in patients with atopic dermatitis.

Detailed description:

Arms: arm 1: Subjects were treated with assigned 0.3% OPA-15406 ointment twice daily. arm 2: Subjects were treated with assigned 1% OPA-15406 ointment twice daily. arm 3: Subjects were treated with assigned 0% OPA-15406 ointment twice daily.
Interventions: intervention 1: OPA-15406 intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects were treated with assigned 0.3% or 1% OPA-15406 ointment twice daily. intervention 2: Subjects were treated with assigned 0% OPA-15406 ointment twice daily.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
CLINICAL  STUDY  PROTOCOL 
 
 
 
 
A Multicenter, Randomized, Double-blind, Vehicle-
controlled, Parallel-group Comparison Trial to Assess 
the Efficacy and Safety of 0.3% and 1% OPA-15406 
Ointments in Patients With Atopic Dermatitis 
 
 
 
 
NCT Number:  02914548 
 
PRT NO. 271-15-001 
 
PRT Version Date: 29 December 2016（Version 4） 


Protocol No. 271-15-001 
 
 
 
 
 
 
 
 
A Multicenter, Randomized, Double-blind, Vehicle- 
controlled, Parallel-group Comparison Trial to Assess the Efficacy 
and Safety of 0.3% and 1% OPA-15406 Ointments in Patients 
With Atopic Dermatitis 
(Phase 2 Trial) 
 
 
 
Clinical Protocol 
Protocol No.: 271-15-001 
(Translated Version) 
 
 
Confidential 
 
 
 
 
 
 
 
Otsuka Pharmaceutical Co., Ltd. 
2-9 Kanda-Tsukasamachi, Chiyoda-ku, Tokyo 101-8535, Japan 
 
 
Version 4:  29 Dec 2016 
Date of Translation: 23 Feb 2017 


Protocol No. 271-15-001 
 
 
 
Statement of Confidentiality 
The trial protocol is to be treated as confidential information and is to be made 
available only to persons involved in the trial. The content of the protocol is not to be 
disclosed to any third party without the prior written consent of Otsuka Pharmaceutical 
Co., Ltd., except in the case of its being explained to a candidate trial subject. Disclosure 
of the results of the trial to academic societies or journals, etc, in part or in whole, will 
require the prior written approval of Otsuka Pharmaceutical Co., Ltd. 


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Trial Protocol Synopsis 
 
Name of 
Investigational Medicinal 
Product 
OPA-15406 Ointment 
Trial Title 
A Multicenter, Randomized, Double-blind, Vehicle- 
controlled, Parallel-group Comparison Trial to Assess the 
Efficacy and Safety of 0.3% and 1% OPA-15406 Ointments 
in Patients With Atopic Dermatitis (Phase 2 Trial) 
Trial Objectives 
Primary Objective: To evaluate Week 4 efficacy of OPA- 
15406 (0.3% and 1%) compared to the vehicle when 
administered twice daily for 8 weeks using incidence of 
success in Investigator’s Global Assessment (IGA) as the 
primary endpoint in patients with atopic dermatitis. 
Secondary Objective: To evaluate the safety of OPA- 
15406 (0.3% and 1%) when administered twice daily for 8 
weeks in patients with atopic dermatitis. 
Phase of Development 
Phase: 2 
Type of trial:  Dose-finding trial 
Trial Design 
Multicenter, randomized, double-blind, vehicle- 
controlled, parallel-group comparison trial 
Target Population 
Atopic dermatitis (AD) 
Target Number 
of Subjects 
180 subjects in total 
0.3% OPA-15406 group:  60 subjects 
1% OPA-15406 group: 60 subjects 
Vehicle group:  60 subjects 
Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible 
for inclusion in this trial. 
At the screening examination: 
1) Sex:  Either male or female 
2) Hospitalization status: Outpatient 
3) Age: 15 to 70 years, inclusive (at time of 
obtaining informed consent) 


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4) Able to provide written informed consent. For 
subjects under 20 years of age, written informed 
consent must be obtained from both the subject and 
the subject’s legal guardian. 
5) Diagnosis of AD based on the criteria of Hanifin and 
Rajka1 (Appendix 1) 
6) History of AD for at least 3 years 
At screening and baseline examinations: 
7) Atopic dermatitis affecting ≥5% to ≤40% of body 
surface area (BSA) 
8) IGA score of 2 (mild) or 3 (moderate) 
Exclusion Criteria 
Subjects who fall under any of the following criteria at either 
the screening or baseline examination will be excluded from 
the trial: 
1) Subjects who are pregnant, possibly pregnant, 
or breastfeeding, who desire to become pregnant or to 
have their partner become pregnant during the trial 
period and up until 30 days after the final 
administration of IMP, or who are unable to either 
remain abstinent or employ at least two of the 
specified birth control methods (vasectomy, tubal 
ligation, vaginal diaphragm, intrauterine device 
[IUD], birth control pill, condom with spermicide, 
etc) during the trial period and up until 30 days after 
the final administration of IMP. 
2) Subjects who have an AD or contact dermatitis flare- 
up defined as a sudden intensification of atopic 
dermatitis, 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 
atopic dermatitis in the present trial 
4) Subjects who have an active viral skin infection 
(eg, herpes simplex, herpes zoster, chicken pox) or 
clinically infected AD 
5) Subjects with a current or history of malignancy 
within the previous 5 years. However, subjects in 
whom basal-cell skin carcinoma or squamous-cell 
skin carcinoma is judged to have been cured at the 


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time of the screening examination can be included in 
the trial. 
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 
assessments: 
 Cardiac disease (eg, rheumatic fever or heart 
valve replacement) 
 Endocrinologic disease (eg, severe or 
uncontrolled diabetes) 
 Pulmonary disease 
 Neurologic disease 
 Psychiatric disease 
 Hepatic disease (eg, hepatitis B, hepatitis C) 
 Renal disease 
 Hematologic disease 
 Immunologic or immunocompromised disease 
(eg, lymphoma, acquired immunodeficiency 
syndrome, Wiskott-Aldrich syndrome, carriers of 
human immunodeficiency virus [HIV] antibodies) 
 Other major disease (eg, systemic fungal infection) 
or other severe uncontrolled condition (eg, drug 
or alcohol abuse) judged by the investigator 
or subinvestigator to pose a health risk to the subject 
or to have the potential to impact trial assessment 
8) Subjects with any of the following hematology or 
serum chemistry results at screening examination: 
 White blood cell count:  ≤3, 000/μL or >14, 000/μL 
 Platelets:  ≤100, 000/μL 
 Hemoglobin:  <11 g/dL 
 Serum creatinine:  ≥2 mg/dL 
 Aspartate aminotransferase (AST) (GOT): >1.5 
× ULN 
 Alanine aminotransferase (ALT) (GPT):  >1.5 × ULN 
 Total bilirubin:  ≥2.0 mg/dL 


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 Any other abnormal laboratory test result that 
the investigator or subinvestigator judges to be a 
clinically significant abnormality 
9) Subjects who are judged by the investigator 
or subinvestigator to have clinically 
significant electrocardiogram (ECG) findings (eg, AV 
block, prolongation of QRS complex to ≥120 msec, or 
QTcF interval of ≥450 msec) at screening 
examination 
10) Clinically significant blood pressure or pulse rate 
findings at screening examination of: 
 Age 18 to 70, inclusive: seated resting ( ≥3 
minutes) systolic blood pressure of <100 mmHg or 
≥150 mmHg or diastolic blood pressure of <50 mmHg 
or ≥90 mmHg, or pulse rate of <50 bpm or >100 bpm 
 Age 15 to 17, inclusive: seated resting ≥3 
minutes) systolic blood pressure of <95 mmHg or 
≥140 mmHg or diastolic blood pressure of <50 mmHg 
or ≥90 mmHg, or pulse rate of <50 bpm or >100 bpm 
11) Subjects who are unable to stop using 
topical corticosteroids, topical immunomodulators, 
topical retinoids and topical antihistamine from 7 days 
prior to the baseline examination until the Week 8 
assessment. However, corticosteroids categorized as 
low or medium potency in the “Guidelines of care for 
the management of atopic dermatitis, Section 2”2 
12) may be used up until the baseline examination if, in 
the opinion of the investigator or subinvestigator, their 
use is necessary, such as when the subjects have been 
using the corticosteroids prior to providing informed 
consent to participate in the trial and use of the 
corticosteroids will be tapered off and stopped during 
the screening period. 
13) Subjects who are unable to stop using 
systemic corticosteroids, systemic 
immunomodulators, systemic antimetabolites, 
systemic retinoids and biologics from 28 days prior to 
the baseline examination until the Week 
8 examination. Intra-ocular, intra-nasal, and intra- 
auricular corticosteroids or inhaled corticosteroids 
may be considered if, in the opinion of the 
investigator or subinvestigator, their use will not 
impact assessment of the affected area. 
14) Subjects who are unable to stop treatment with 


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ultraviolet light A, narrowband ultraviolet B, or 
ultraviolet light B from 28 days prior to the baseline 
examination until the Week 8 examination 
15) Subjects who are unable to stop using 
systemic antihistamines, sodium cromoglicate, 
tranilast, or suplatast tosilate from 7 days prior to the 
baseline examination until the Week 8 examination 
16) Subjects with known hypersensitivity (including 
history) to any drugs (prescription, OTC, etc) or any 
ingredient of OPA-15406 ointment 
17) Subjects with known plans to receive any of 
the prohibited concomitant drugs or therapies during 
the trial period 
18) 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 
19) Subjects who have never been treated with a 
prescription medication for AD or who are satisfied 
with their current AD treatment regimen 
20) Subjects who are judged by the investigator 
or subinvestigator to be inappropriate to participate in 
the trial for any other reason 
Discontinuation Criteria 
If any of the following events occur during the trial period, 
the investigator or subinvestigator will withdraw the subject 
from the trial: 
1) Request from the subject or subject’s legal guardian 
to discontinue participation in the trial 
2) Discovery that the subject was included in the trial 
despite violation of the inclusion or exclusion criteria 
3) Occurrence of any adverse event that makes it 
difficult for the subject to continue administration of 
IMP (including a suspected treatment-related adverse 
event of skin hypersensitivity on the treatment area) 
4) Increase in the total treatment area to more than 40% 
of BSA 
5) Discovery that the subject is pregnant or suspected to 
be pregnant 
6) Judgment by the investigator or subinvestigator that it 
is necessary to withdraw the subject from the trial 
Investigational 
Test Product:  0.3% and 1% OPA-15406 ointments 


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Medicinal Products, Dose 
and Regimen, and 
Treatment Period 
Comparator:  Vehicle of OPA-15406 ointment 
Twice daily administration (approximately 12 hours 
apart between morning and night administration) for 8 weeks 
Prohibited 
Concomitant Drugs, 
Prohibited Concomitant 
Therapies 
1) From 28 days prior to the baseline examination until 
the Week 8 examination, use of the following drugs 
and therapies is prohibited. 
 Systemic corticosteroids, systemic 
immunomodulators, systemic antimetabolites, 
systemic retinoids, and biologics 
Intra-ocular and intra-nasal corticosteroids or 
inhaled corticosteroids may be considered if, in the 
opinion of the investigator or subinvestigator, their 
use will not impact assessment of the affected area. 
 Ultraviolet light A, narrowband ultraviolet B, 
and ultraviolet light B 
2) From 7 days prior to the baseline examination until 
the Week 8 examination, use of the following drugs 
and therapies is prohibited. 
 Topical corticosteroids, topical 
immunomodulators, topical retinoids, and topical anti- 
histamine. 
 Corticosteroids categorized as low or medium potency 
in the “Guidelines of care for management of atopic 
dermatitis, Section 2” 
 may be used up until the baseline examination (up 
until the Week 8 examination on the face, neck, and 
head) if, in the opinion of the investigator or 
subinvestigator, their use is necessary, such as when 
the subjects have been using the corticosteroids prior 
to providing informed consent to participate in the 
trial and use of the corticosteroids will be tapered off 
and stopped during the screening period. 
 Systemic antihistamines, sodium 
cromoglicate, tranilast, suplatast tosilate 
3) From the baseline examination until the Week 8 
examination, use of the following drugs and products 
on the treatment area is prohibited. 
 All topical drugs (including ethical drugs, over-the- 
counter products, herbal medicine, quasi-drugs, 
and cosmetic products)  However, if cosmetic 
products were being used on the face, neck, and head 
prior to obtaining consent, their use may be continued 


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only if the same products are used at the same 
frequency. 
Variables 
Efficacy Endpoints: 
Primary Outcome Variable: 
Incidence of success in IGA at Week 4: Percentage 
of subjects in whom IGA score is 0 (clear) or 1 (almost clear) 
and improved at least 2 grades from baseline 
Secondary Outcome Variables: 
1) Incidence of success in IGA at Week 1 and Week 8 
2) Change from baseline in IGA at Week 1, Week 4, 
and Week 8 
3) Change from baseline in the total score of Eczema 
Area and Severity Index (EASI) and each symptom 
score at Week 1, Week 4, and Week 8 
4) Change from baseline in Visual Analogue Scale 
(VAS) for pruritus at Week 1, Week 4, and Week 8 
5) Change from baseline in Verbal Rating Scale (VRS) 
for pruritus up to Day 7 
6) Change from baseline in the total score of 
Dermatology Life Quality Index (DLQI) at Week 1, 
Week 4, and Week 8 
7) Change from baseline in the total score of Patient- 
Oriented Eczema Measure (POEM) at Week 1, Week 
4, and Week 8 
8) Change from baseline in the total affected BSA (%) 
at Week 1, Week 4, and Week 8 
9) Time to response in IGA and VRS 
Safety Endpoints: 
Adverse events, physical examination, vital signs 
(including body weight), clinical laboratory values, and 12- 
lead ECG 
Pharmacokinetics: 
1) Plasma trough concentrations of OPA-15406 (prior to 
IMP administration at Week 1, Week 4, and Week 8 
of IMP administration; all subjects) 
2) Plasma concentrations of OPA-15406 (prior to IMP 


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administration and 2 hours, 4 hours, and 8 hours 
postdose on Day 1 and at Week 4; specific trial sites; 
target of 6 subjects from each group) 
 Pharmacokinetic parameters of OPA-15406: Cmax, 
tmax, and AUC0-8h on Day 1 and at Week 4 of IMP 
administration 
 Accumulation of OPA-15406: Ratio of Cmax and 
AUC0-8h at Week 4 and on Day 1 of IMP 
administration 
Scheduled Duration of the 
Trial 
21 Jul 2016 to 31 Jul 2017 


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<Schedule of Observations/Examinations/Evaluations> 
 
Evaluation 
Screening 
period 
(2–30 days) 
Assessment period 
(8 weeks) 
Post-treatment 
observation 
period 
(2 weeks) 
Screening 
examination 
Baseline 
examination 
Week 1 
a 
examination 
Week 2 
examinationb 
Week 4 
examinationb 
Week 6 
examinationb 
Week 8 
examinationb 
Withdrawal 
examinationd 
Unscheduled 
visit 
Examination 
2 weeks after 
last IMP 
administrati 
c 
on 
Informed consent 
○ 
Inclusion and 
exclusion criteria 
○ 
○ 
Subject 
demographics 
○ 
Physical 
examination 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
e 
○ 
○ 
Vital signs 
(including body 
weight) 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
e 
○ 
12-lead EC  f 
G 
○ 
g 
○ 
○ 
○ 
e 
○ 
Clinical laboratory 
tests 
○ 
g 
○ 
○ 
○ 
e 
○ 
Pregnancy test h 
○ 
g 
○ 
○ 
○ 
e 
○ 
IGA 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
EASI 
○ 
○ 
○ 
○ 
○ 
○ 
VAS for pruritus 
○ 
○ 
○ 
○ 
○ 
○ 
VRS for pruritus 
i 
○ 
○ 
DLQI 
○ 
○ 
○ 
○ 
○ 
○ 
POEM 
○ 
○ 
○ 
○ 
○ 
○ 


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<Schedule of Observations/Examinations/Evaluations, Continued> 
 
Evaluation 
Screening 
period 
(2–30 days) 
Assessment period 
(8 weeks) 
Post-treatment 
observation 
period 
(2 weeks) 
Screening 
examination 
Baseline 
examination 
Week 1 
a 
examination 
Week 2 
examinationb 
Week 4 
examinationb 
Week 6 
examinationb 
Week 8 
examinationb 
Withdrawal 
examination 
Unscheduled 
visit 
Examination 
2 weeks after 
last IMP 
administrati 
c 
on 
Affected BSA 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Treatment area 
○ 
○ 
○ 
○ 
○ 
○ 
Blood sampling 
for plasma 
drug concentration 
measurement 
j 
○ 
j 
○ 
k 
○ 
Administration 
diary 
l 
○ 
○ 
Severity of AD 
○ 
Status of IMP 
administration 
○ 
○ 
○ 
○ 
○ 
Prescription and 
collection of IMP 
m 
○ 
n 
○ 
○ 
○ 
○ 
o 
○ 
n 
○ 
Adverse events 
 
Concomitant 
medications 
and therapies 
 
Patch testp 
 
AD = atopic dermatitis; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; IGA = Investigator’s Global Assessment; POEM 
= Patient-Oriented Eczema Measure; VAS = Visual Analogue Scale; VRS = Verbal Rating Scale. 
a 
Acceptable window of ±2 days 
bAcceptable window of ±3 days 


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c 
Acceptable window of ±7 days 
dWithdrawal examination should be conducted as much as possible. 
e 
May be conducted, as necessary. 
f 
Should be conducted prior to blood sampling, as much as possible. 
g 
Results of the screening examination should be used when the baseline examination is planned within 7 days of the screening examination. 
hShould be conducted only for women with childbearing potential. 
iShould be evaluated during the baseline examination, 4±2 hours, 8±2 hours, and 12±2 hours (if possible) after the first IMP administration, and then 
twice daily from the next day (before IMP administration in the morning and at night) until the morning of the Week 1 examination (without IMP 
application) (up to the morning of Day 7 at the latest). 
jOn the day of blood sampling, the first IMP application should not be done until after blood sampling when visiting the trial site. 
k 
On the day of examination, the subjects should not administer the IMP. 
lThe subjects should keep a diary every day from the baseline examination to the Week 8 examination (withdrawal examination). 
m 
Only IMP prescription. 
nIMP will be additionally prescribed, as necessary. 
oOnly IMP collection. 
pIf any adverse event of suspected hypersensitivity occurred at the treatment area, verbal consent should be obtained again from the subject to conduct a patch 
test, and the patch test should be conducted according to the procedure. 


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<Schedule of Blood Sampling for Plasma Drug Concentration> (For specific sites) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 
Acceptable window of ±2 days 
bAcceptable window of ±3 days 
c 
Acceptable window of ±7 days 
dWithdrawal examination should be conducted as much as possible. 
e 
Same as trough concentration of OPA-15406 
fAcceptable window of ± 10 minutes 
Evaluation 
Screening 
period 
(2–30 days) 
Assessment period 
(8 weeks) 
Post-treatment 
observation 
period 
(2 weeks) 
Screening 
examination 
Baseline 
examination 
Week 1 
a 
examination 
Week 2 
examinationb 
Week 4 
examinationb 
Week 6 
examinationb 
Week 8 
examinationb 
Withdrawal 
examinationd 
Unscheduled 
visit 
Examination 
2 weeks after 
last IMP 
administration 
c 
Prior to 
administration 
○ 
e 
○ 
2 hours postdosef 
○ 
○ 
4 hours postdosef 
○ 
○ 
8 hours postdosef 
○ 
○ 


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Table of Contents 
Trial Protocol Synopsis ................................................................................. 3 
Table of Contents ......................................................................................... 15 
List of Abbreviations and Definition of Terms ......................................... 18 
1 
Introduction (Background Information of the Present Trial) ....... 20 
1.1 
Background of Trial Plan .................................................................................. 20 
1.2 
Study Results and Trial Rationale ..................................................................... 21 
2 
Trial Objectives .................................................................................. 27 
3 
Trial Plan ............................................................................................. 28 
3.1 
Trial Design ...................................................................................................... 28 
3.2 
Rationale for Trial Design ................................................................................ 29 
3.3 
Variables ........................................................................................................... 29 
3.4 
Target Number of Subjects ............................................................................... 31 
4 
Investigational Medicinal Products .................................................. 31 
4.1 
Test Product and Comparator ........................................................................... 31 
4.2 
Packaging and Labeling .................................................................................... 32 
5 
Trial Population .................................................................................. 32 
5.1 
Target Disease ................................................................................................... 32 
5.2 
Inclusion Criteria .............................................................................................. 32 
5.3 
Exclusion Criteria ............................................................................................. 33 
6 
Trial Design ......................................................................................... 36 
6.1 
Dose, Regimen, and Treatment Period ............................................................. 36 
6.2 
Treatment Area ................................................................................................. 38 
6.3 
Prior and Concomitant Treatment ..................................................................... 39 
6.4 
Method of Minimizing or Avoiding Bias ......................................................... 40 
7 
Observations/Examinations/Variables, Methods and 
Implementation Timings .................................................................... 41 
7.1 
Schedule and Procedures .................................................................................. 41 
7.2 
Method of Evaluation ....................................................................................... 48 


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7.3 
Measures to Be Taken for Subjects Visiting or Planning to Visit 
Other Hospitals or Departments. ....................................................................... 53 
7.4 
Subject Management ......................................................................................... 54 
8 
Adverse Events.................................................................................... 54 
8.1 
Definitions......................................................................................................... 54 
8.2 
Response to Occurrence of Adverse Events ..................................................... 56 
8.3 
Assessment of Adverse Events ......................................................................... 58 
8.4 
Follow-up Investigation of Adverse Events ...................................................... 61 
8.5 
Pregnancy .......................................................................................................... 62 
9 
Withdrawal of Individual Subjects From the Trial ........................ 64 
9.1 
Screen Failure ................................................................................................... 64 
9.2 
Criteria and Procedures for Withdrawal of Individual Subjects ....................... 64 
9.3 
Follow-up Investigation of Subjects Who Do not Visit the Trial Site .............. 65 
10 
Collection of Case Report Form Data and Specification 
of Source Data ..................................................................................... 65 
10.1 
Collection of Case Report Form Data ............................................................... 65 
10.2 
Source Documents ............................................................................................ 66 
10.3 
Case Report Form Items Treated as Source Data ............................................. 67 
10.4 
Data to Be Collected by the Sponsor ................................................................ 67 
11 
Statistical Analysis .............................................................................. 67 
11.1 
Statistical Analysis Sets .................................................................................... 67 
11.2 
Handling of Data ............................................................................................... 67 
11.3 
Analysis Items and Method .............................................................................. 68 
11.4 
Procedures for Reporting Deviations From the Original Statistical 
Analysis Plan .................................................................................................... 73 
11.5 
Rationale for Target Number of Patients .......................................................... 74 
12 
Quality Control and Quality Assurance for the Trial..................... 74 
13 
General Items of Caution Pertaining to the Trial ........................... 74 
13.1 
Ethics and GCP Compliance ............................................................................. 74 
13.2 
Institutional Review Board ............................................................................... 75 
13.3 
Subject Consent ................................................................................................ 75 
13.4 
Management of Investigational Medicinal Products ......................................... 77 


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13.5 
Direct Access to Source Documents and Monitoring ....................................... 78 
13.6 
Deviations From and Changes or Amendments to the Trial Protocol .............. 78 
13.7 
Archiving of Records ........................................................................................ 79 
13.8 
Termination or Interruption of Part or All of the Trial ..................................... 79 
13.9 
Protection of Subjects’ Personal Information ................................................... 80 
13.10 
Compensation for Injury to Health ................................................................... 80 
13.11 
Agreement on Publication. ................................................................................ 80 
14 
Trial Administrative Structure ......................................................... 81 
15 
Scheduled Duration of the Trial........................................................ 81 
16 
References ........................................................................................... 81 
 
 
 
Annex 1: 
Emergency Contact 
Annex 2: 
Lists of Trial Sites and Investigators Participating in the Trial 
Annex 3: 
Administrative Structure 
Annex 4: 
Common Terminology Criteria for Adverse Events v4.0 Japanese 
JCOG edition 
 
Appendix 1: Diagnostic Criteria for Atopic Dermatitis (Hanifin & Rajka) 
Appendix 2:  Visual Analogue Scale (VAS) Sheet for Pruritus 
Appendix 3: Dermatology Life Quality Index (DLQI) 
Appendix 4: Patient-Oriented Eczema Measures (POEM) 
Appendix 5:  Human Body Drawing 


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List of Abbreviations and Definition of Terms 
List of Abbreviations 
 
Abbreviation 
Expansion 
AD 
Atopic dermatitis 
AST 
Aspartate aminotransferase 
ALT 
Alanine aminotransferase 
BSA 
Body Surface Area 
cAMP 
Cyclic adenosine 3', 5'-monophosphate 
COM 
Clinical Operation Manual 
DLQI 
Dermatology Life Quality Index 
EDC 
Electronic Data Capture 
EASI 
Eczema Area and Severity Index 
FAS 
Full Analysis Set 
GOT 
Glutamic oxaloacetic transaminase 
GPT 
Glutamic pyruvic transaminase 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IGA 
Investigator’s Global Assessment 
IUD 
Intrauterine Device 
IWRS 
Interactive Web Response System 
LC-MS/MS 
Liquid chromatography with tandem mass spectrometry 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measure 
OC 
Observed Case 
PDE 
Phosphodiesterase 
POEM 
Patient-Oriented Eczema Measure 
QTcF 
QT interval as correlated by Fridericia’s formula 
SS 
Safety Set 
TEAE 
Treatment-emergent Adverse Event 
NB-UVB 
Narrow-band UVB 
VAS 
Visual Analogue Scale 
VRS 
Verbal Rating Scale 


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


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1 
Introduction (Background Information of the Present Trial) 
1.1 
Background of Trial Plan 
 
Atopic dermatitis (AD) is defined as “a disease with repeated exacerbations/remissions 
of which the main lesion is eczema with pruritus, and most patients have 
atopic predisposition. Atopic predisposition means 1) having a family history/medical 
history (one or more diseases of bronchial asthma, allergic rhinitis/conjunctivitis, or 
atopic dermatitis) or 2) predisposition to producing IgE antibody.”2  In some patients, 
atopic dermatitis that occurred in infancy may spontaneously resolve with age. Some 
patients experience the onset or recurrence of the disease in adulthood, namely, refractory 
atopic dermatitis in adults. 
Diagnostic criteria for the disease were established by Hanifin and Rajka in 19801, and 
in Japan, Guidelines for Management of Atopic Dermatitis was published by the 
Japanese Dermatological Association2. 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 therapeutic strategies of AD are also common in the world. Topical agents such as 
steroids and calcineurin inhibitors (immunosuppressors) are used for the treatment of 
inflammation, topical moisturizers and protective agents for skin care to treat abnormal 
physiological functions, and oral antihistamines and antiallergic agents for pruritus as 
adjuvant treatment. Elimination of as many aggravating factors as possible has been 
established by current consensus as a basic therapy for AD. Inflammation can generally 
be suppressed by topical steroids. However, long-term use of steroids may induce 
adverse drug reactions (eg, skin atrophy, hairiness); therefore, drugs with long-term 
safety have been anticipated. 
Phosphodiesterase (PDE) 4 is an enzyme that hydrolyzes cyclic adenosine 3', 5'- 
monophosphate (cAMP) and exists in inflammatory cells, such as 
macrophages, lymphocytes, and neutrophi3. In AD patients, elevated PDE activity in 
peripheral blood leukocytes and reduced intracellular cAMP levels are observed. PDE4 
inhibitors exert their antiinflammatory activity by increasing intracellular cAMP levels 
and suppressing production of inflammatory cytokines and chemical 
mediators. Therefore, PDE4 inhibitors have been considered effective for treatment of 
atopic dermatitis. 
OPA-15406 is a PDE4 inhibitor synthesized by Otsuka Pharmaceutical Co., Ltd.  In 
a mouse chronic contact hypersensitivity model, OPA-15406 ointment demonstrated 


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its efficacy on dermatitis by improving the symptoms. Therefore, development of OPA- 
15406 ointment was started with the expectation of efficacy for AD. 
Clinical development OPA-15406 has preceded outside Japan, and the phase 2 trial 
in AD patients (271-12-205) has been completed. In Japan, the phase 1 trial in 
healthy adult male subjects has been completed. In healthy adult subjects and AD 
patients, OPA-15406 ointment showed no clinical relevant safety issues but good 
tolerability.  Also, in the phase 2 trial outside Japan, 1% OPA-15406 
ointment demonstrated the efficacy on AD.  Based on these results, the present trial 
is designed to assess the efficacy and safety of OPA-15406 ointment in Japanese AD 
patients. While this trial will be conducted in adult patients (aged 15 years and older), the 
trial design will be the same as that of the phase 2 trial outside Japan to the extent 
possible to allow comparability with the foreign trial results. 
 
 
1.2 
Study Results and Trial Rationale 
 
1.2.1 
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 
atopic dermatitis, the dose-dependent efficacy of the OPA-15406 ointment (0.03% to 3%) 
for chronic allergic dermatitis was assessed.  Four weeks of topical administration of 
the OPA-15406 ointment showed dose-dependent efficacy in improving skin thickening 
at 0.03% to 3%. The effect was inferior to that of betamethasone valerate, a strong 
steroid, and superior to that of tacrolimus ointment, a calcineurin inhibitor.  Four weeks 
of multiple administrations of 3% OPA-15406 ointment significantly suppressed 
infiltration of inflammatory cells such as CD3 positive cells, eosinophils, and neutrophils 
in skin lesions. 
Using a mouse scratching-induced chronic dermatitis model, the efficacy of OPA- 
15406 (1% and 3%) dissolved in a solvent (1:1 mixture of acetone and methanol) was 
assessed. Six weeks of topical administration of OPA-15406 (1% or 3%) significantly 
improved the skin symptoms, though no particular effect was observed on the frequency 
of scratching. The efficacy was superior to 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 


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(3%) significantly suppressed edema. The efficacy was equivalent to betamethasone 
valerate (Rinderon®-V ointment 0.12%) and tacrolimus ointment (Protopic® ointment 
0.1%). 
OPA-15406 ointment (0.1%, 0.3%, 1%, and 3%) was administered percutaneously to 
rats at 0.3, 0.9, 3, or 9 mg/kg as a single-dose. Cmax and AUC of OPA-15406 increased 
dose-dependently at 0.3 to 3 mg/kg, and reached a plateau at 3 to 9 mg/kg. 
Single percutaneous administration of the OPA-15406 1% ointment at 3 mg/kg was 
performed for abraded skin of male rats. The Cmax and AUC∞ of OPA-15406 in the 
male rats with abraded skin were 2.0 and 1.6 times that in male rats with intact skin. 
With percutaneous administration of 14C-OPA-15406 1% ointment in rats, the amount 
of detected OPA-15406 on the skin of the administration site was largest, and 
the metabolites of MAP-15484, MAP-15485, and MAP-15497 were also detected. OPA- 
15406, MAP-15484, and MAP-15485 were detected in the plasma of the rats 
treated percutaneously and subcutaneously with 14C-OPA-15406 1% ointment. 
In a 4-week repeated-dose percutaneous toxicity study in rats, white petrolatum, OPA- 
15406 ointment 0% (vehicle), 0.1% (1.06 mg/kg for male, 1.25 mg/kg for female), 
0.3% (3.27 mg/kg for male, 3.78 mg/kg for female), 1% (11.02 mg/kg for male, 12.74 
mg/kg for female), or 3% (33.56 mg/kg for male, 38.56 mg/kg for female) was 
administered to intact skin (open cutaneous) approximately equivalent to 10% of total 
body surface area (BSA) once daily. No changes associated with the test substance were 
observed at the administration sites in any treatment groups. Body weight and/or food 
consumption were reduced in the male rats treated with 1% and 3% ointments and in 
female rats treated with 0.1%, 0.3%, and 1% ointments.  These changes were reversible 
or likely to be reversible during the 4-week recovery period. In a 13-week repeated-dose 
percutaneous toxicity study in rats, white petrolatum, OPA-15406 ointment 0% (vehicle), 
0.1% (0.31 mg/kg for males, 0.38 mg/kg for females), 0.3% (0.92 mg/kg for males, 1.13 
mg/kg for females), 1% (3.08 mg/kg for males, 3.75 mg/kg for females), or 3% (9.39 
mg/kg for males, 11.47 mg/kg for females) was administered to intact skin (open 
cutaneous) approximately equivalent to 3% of total BSA once daily. No changes 
associated with the test substance were observed at the administration sites in any 
treatment groups. Increase in body weight was suppressed in the male and female rats 
with 3% ointment. The no observed adverse effect dose level of systemic toxicity was 
estimated to be 1% ointment (3.08 mg/kg) for males and 1% ointment (3.75 mg/kg) for 
females. 


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In a 4-week repeated-dose percutaneous toxicity study in rabbits, white petrolatum, OPA- 
15406 ointment 0% (vehicle), 0.1%, 0.3%, 1%, or 3% was administered to intact skin 
(open cutaneous) approximately equivalent to 10% of total BSA once daily. The OPA- 
15406 ointment was classified as weak skin irritation at all concentrations according to 
the Draize scale for skin irritation. 
In a 8-week repeated-dose percutaneous toxicity study in juvenile rats (25 days old at the 
start of administration), white petrolatum 0% (vehicle), OPA-15406 ointment 0.3% 
(male: 3.76 mg/kg; female: 4.23 mg/kg), 1% (male: 12.56 mg/kg; female: 14.32 mg/kg), 
or 3% (male: 38.52 mg/kg; female: 43.83 mg/kg) was administered once daily to 
intact skin (open cutaneous) approximately equivalent to 10% of total BSA. As a result, 
no changes associated with the test substance were observed on the administration sites in 
any of the treatment groups. Although suppressed weight increase and reductions in food 
intake and grip strength were observed in the female rats with 1% or 3% ointment, these 
changes were not developmental toxicity and they resolved with washout.  Also, there 
was no difference in the toxicity threshold between adult and juvenile rats. As the profile 
of OPA-15406 is such that it reaches the CNS and the brain is known to develop after 
birth, a 10-week repeated-dose percutaneous toxicity study was conducted in neonatal 
rats (4 days old at the start of administration) with a focus on CNS development, but no 
influence of OPA-15406 on the function or structure of the CNS was found. 
1.2.2 
Clinical Study Results 
 
Clinical development of OPA-15406 has preceded outside Japan, and the phase 2 trial 
in AD patients has been completed. In Japan, the phase 1 trial in healthy adult male 
subjects has been completed. 
1.2.2.1 
Phase 1 Trial in Healthy Adult Subjects in the US (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 were reported 
and no subjects were withdrawn from the trial due to adverse events. 


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1.2.2.2 
Phase 1 Trial in Healthy Adult Male Subjects in Japan (271-14- 
001) 
In the phase 1 trial in healthy adult male subjects (aged 20-40 years old) in Japan, 
a single-dose or 2-week twice-daily multiple doses of the 0.3%, 1%, or 3% OPA- 
15406 ointment (8 subjects for each group) was administered to a 1,000 cm2 area (about 
5% of 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 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 adverse 
events were reported, and no subjects were withdrawn from the trial. In physical findings 
and subjective symptoms, vital signs, skin findings, standard 12-lead ECG, and clinical 
laboratory tests, no clinically relevant variations or changes were observed. Also, no 
particular concerns were reported regarding the safety of OPA-15406 ointment up to 
concentrations of 3%. 
1.2.2.3 
Phase 1 Trial in AD Patients in the US (271-12-204) 
In the phase 1 trial in AD patients (aged 18-64 years old) in the US, 1 g of the 0.3%, 1%, 
or 3% formulation of OPA-15406 (15 subjects for each group) was administered to 5% of 
BSA (about 1,000 cm2) as 4-week, twice-daily, multiple administrations. OPA-15406 
ointment 1% formulation (7 subjects) and 3% formulation (8 subjects), and 0.1% 
tacrolimus ointment (15 subjects) were then administered to 10% or more of total BSA at 
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 serious adverse event of cholelithiasis occurred in the 1% OPA- 
15406 group, but its causal relationship with the investigational medicinal product 
(IMP) was ruled out. Two subjects discontinued treatment with the IMP due to adverse 
events; one of the subjects was in the 3% OPA-15406 group (name of adverse 


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event: hypersensitivity) and the other was in the 0.1% tacrolimus group (name of adverse 
event: allergic dermatitis), and both events were judged to be IMP-related. 
For efficacy, 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. 
1.2.2.4 
Phase 2 Trial in AD Patients Outside Japan (271-12-205) 
In the phase 2 trial in AD patients (aged 10-70 years old) outside Japan, the efficacy, 
safety, and pharmacokinetics of 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. The primary 
efficacy endpoint was established as the incidence of success in IGA (percentage of 
subjects with IGA score of 0 or 1 with improvement by at least 2 grades) at Week 4, and 
the incidence of success in IGA was 14.63%, 20.93%, and 2.70% in the 0.3% OPA- 
15406 group, the 1% OPA-15406 group, and the vehicle group, respectively. The 0.3% 
OPA-15406 group showed a higher incidence of success in IGA than in the vehicle 
group; however, no significant difference was observed between the groups (p = 0.0690, 
CMH test). In the 1% OPA-15406 group, a significant difference was observed in the 
incidence of success in IGA compared to the vehicle group (p = 0.0165, CMH 
test). Discontinuations due to adverse events occurred with 4 subjects (9.8%), 3 subjects 
(7.0%), and 7 subjects (18.9%) in the 0.3% OPA-15406 group, the 1% OPA-15406 group, 
and the vehicle group, respectively.  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. 
1.2.2.5 
Trial for Phototoxicity in Healthy Adult Subjects in the US (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- 


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15406 ointment or the corresponding vehicle (placebo) on the back of the subject. At 
the treatment area, no adverse events were observed. Also, no serious adverse events 
were reported, and no subjects were withdrawn from the trial due to adverse events. 
1.2.2.6 
Trial for Photoallergy in Healthy Adult Subjects in the US (271- 
12-213) 
In the trial for photoallergy in 62 healthy adult subjects in the US, photoallergy 
was evaluated by multiple administrations of 0.3%, 1%, or 3% formulation of OPA- 
15406 ointment or the corresponding vehicle (placebo) on the back of the subject by 
establishing a 19-day sensitization period and a 5-day induction period. At the treatment 
area, erythema was observed in 1 subject as an adverse event, which was moderate in 
severity and determined as IMP-related. No serious adverse events were reported. One 
subject discontinued the trial due to the onset of an adverse event, pneumonia; however, a 
causal relationship with the IMP was ruled out. 
1.2.3 
Trial Rationale 
 
In this phase 2 trial, the 0.3% or 1% formulation of OPA-15406 will be administered 
to Japanese AD patients twice daily for 8 weeks to assess the efficacy and safety of OPA- 
15406 ointment. 
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 1 trial (271-12-204) and the phase 2 trial (271-12- 
205) were conducted outside Japan in mild to moderate AD patients for whom the 
symptoms were controllable only by topical drugs. As the results of these trials 
demonstrated the efficacy and safety, the present trial was designed to include patients 
with mild to moderate AD. 
Skin preparations are always exposed to opportunities of being removed 
after administration to the skin, such opportunities as washing the face, bathing, adhesion 
to clothing, or sweating resulting in dilution. To be sure that effective concentration on 
the skin is maintained, it is desirable that the IMP be administered multiple times a day. 
In consideration of the fact that people generally wash their face and hands after getting 
up and when bathing at night, twice-daily administration is considered highly convenient 
for patients, and it may contribute to achieving the best adherence.  Therefore, twice- 
daily administration is employed. 
In the phase 1 trial in AD patients  in the US (271-12-204), the efficacy of OPA-15406 
was suggested in the 0.3% and 1% formulations from among the 0.3%, 1%, and 3% 
formulations tested.  In the phase 2 trial outside Japan (271-12-205), the efficacy of OPA- 


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15406 was investigated by selecting the 0.3% and 1% formulations. The results showed 
that the 1% formulation had a significantly higher efficacy in the primary efficacy 
endpoint compared to the vehicle, and the 0.3% formulation also had a higher efficacy 
compared to the vehicle. For this trial, the concentrations of 0.3% and 1% are selected in 
the same manner as those in the phase 2 trial outside Japan (271-12-205). 
In the phase 1 trial in healthy Japanese adult subjects (271-14-001) and the phase 2 trial 
in patients aged 10 years and older outside Japan (271-12-205), no particular 
safety concerns were identified. In the present trial, adult patients (aged 15 years and 
older) will be included. 
Usually, topical drugs for AD are evaluated for their efficacy once in 1 to 2 weeks, and if 
no improvements are observed within a month, the patient is generally considered for 
referral to a more specialized institution.  Thus, Week 4 is established as an 
assessment point of the primary efficacy endpoint, and the treatment is also to be 
continued after Week 4 to assess the efficacy and safety thereafter. In the phase 2 trial in 
AD patients outside Japan (271-12-205), the incidence of success in IGA at Week 8 was 
17.07%, 16.28%, and 10.81% in the 0.3% OPA-15406 group, the 1% OPA-15406 group, 
and the vehicle group, respectively. The incidence of success in IGA was higher in the 
0.3% and 1% OPA-15406 groups than in the vehicle group, while no 
significant difference was observed. Also, no particular safety concerns were identified 
with the 0.3% and 1% formulations of OPA-15406. In this trial, the duration of treatment 
is established as 8 weeks to assess the efficacy and safety of the IMP in Japanese patients 
up to Week 8 and to compare the results with those of the phase 2 trial outside Japan 
(271-12-205). 
Accordingly, it was judged scientifically and ethically appropriate to conduct this trial. 
 
 
2 
Trial Objectives 
Primary objective: To evaluate Week 4 efficacy of OPA-15406 (0.3% and 1%) 
compared to the vehicle when administered twice daily for 8 weeks using incidence of 
success in Investigator’s Global Assessment (IGA) as the primary endpoint in AD 
patients. 
Secondary objective: To evaluate the safety of OPA-15406 (0.3% and 1%) 
when administered twice daily for 8 weeks in AD patients. 
See the investigator’s brochure for further details of data mentioned in this 
protocol and other trial results. 


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3 
Trial Plan 
3.1 
Trial Design 
 
This trial is a multicenter, randomized, double-blind, vehicle-controlled, parallel- 
group, comparison trial to evaluate the efficacy and safety of OPA-15406 ointment in 
patients with atopic dermatitis. This trial consists of the 0.3% OPA-15406 group (60 
subjects), the 1% OPA-15406 group (60 subjects), and the vehicle group (60 subjects) 
and will be conducted according to Figure 3.1-1. 
1) Screening period 
After obtaining informed consent, the investigator or subinvestigator will perform 
a screening examination. The screening period is defined as the period between 
the day of screening examination and the day of baseline examination (2-30 
days). The subjects who meet the inclusion and exclusion criteria at the baseline 
examination will be dynamically allocated to the test product (0.3% or 1% 
formulation of OPA-15406) or the comparator (vehicle of OPA-15406), using the 
trial site and IGA at the baseline examination as the allocation factors. 
2) Assessment period (treatment period) 
Regarding the subjects who meet the inclusion criteria and do not meet the 
exclusion criteria at the baseline examination, the assessment period is defined as 
the period between the day of baseline examination and the day of Week 8 
examination (or the day of discontinuation). The allocated IMP will be 
administered to the treatment area from the day of baseline examination twice 
daily for 8 weeks. After the baseline examination, the examinations will be 
performed at Weeks 1, 2, 4, 6, and 8. 
If a subject discontinues the IMP administration between the day of baseline 
examination and the day of Week 8 examination, a withdrawal examination will 
be performed for that subject. 
3) Post-treatment observation period 
Post-treatment observation period is defined as the period between the end of 
Week 8 examination and the day of examination 2 weeks after the last IMP 
administration. The examination will be performed at 2 weeks after the last IMP 
administration.  If any adverse event remains not recovered at the examination 
2 weeks after the last IMP administration (or the day of last examination if 
the examination 2 weeks after the last IMP administration was not performed), it 
should be followed up according to the specification. 
4) 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 trial discontinuation or 
completion and does not include the follow-up period. 


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Screening 
Assessment period 
Post-treatment 
period 
Twice daily administration 
observation 
(2–30 days) 
(8 weeks) 
period 
(2 weeks) 
 
0.3% OPA-15406 group 
 
1% OPA-15406 group 
 
Vehicle group 
 
 
 
 
 
 
 
 
 
 
 
:  Treatment period 
Figure 3.1-1 
Trial Design 
 
 
3.2 
Rationale for Trial Design 
 
This trial will be conducted to evaluate the efficacy and safety of OPA-15406 ointment in 
Japanese AD patients. For objective evaluation of the efficacy and safety, a vehicle 
control is established. Also, to minimize bias in the subject selection and evaluation, a 
randomization and double-blind design is employed. 
 
 
3.3 
Variables 
 
3.3.1 
Efficacy 
 
3.3.1.1 
Primary Variable(s) 
Incidence of success in IGA at Week 4: Percentage of subjects in whom IGA score is 
0 (clear) or 1 (almost clear) and improved at least 2 grades from baseline 
3.3.1.2 
Secondary Variable(s) 
1) Incidence of success in IGA at Week 1 and Week 8 
2) Change from baseline in IGA at Week 1, Week 4, and Week 8 
3) Change from baseline in the total score of Eczema Area and Severity 
Index (EASI) and each symptom score at Week 1, Week 4, and Week 8 
Examination 2 week after 
last IMP administration 
Week 8 examination 
Week 6 examination 
Week 4 examination 
Week 2 examination 
Week 1 examination 
IMP allocation Bas
examination 
Screening examination 
Informed consent 


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4) Change from baseline in Visual Analogue Scale (VAS) for pruritus at Week 
1, Week 4, and Week 8 
5) Change from baseline in Verbal Rating Scale (VRS) for pruritus up to Day 7 
6) Change from baseline in the total score of Dermatology Life Quality 
Index (DLQI) at Week 1, Week 4, and Week 8 
7) Change from baseline in the total score of Patient-Oriented Eczema 
Measure (POEM) at Week 1, Week 4, and Week 8 
8) Change from baseline in the total affected BSA (%) at Week 1, Week 4, 
and Week 8 
9) Time to response in IGA and VRS 
3.3.2 
Safety 
 
Adverse events, physical examination, vital signs (including body weight), 
clinical laboratory values, and 12-lead ECG 
3.3.3 
Pharmacokinetics 
 
Plasma trough concentration of OPA-15406 (trough concentration at Week 1, Week 4, 
and Week 8) 
1) Plasma trough concentrations of OPA-15406 (prior to IMP administration 
at Week 1, Week 4, and Week 8 of IMP administration; all subjects) 
2) Plasma concentration of OPA-15406 (prior to IMP administration and 2 hours, 4 
hours, and 8 hours postdose on Day 1 and at Week 4; specific sites [target of 6 
subjects from each group]) 
 Pharmacokinetic parameters of OPA-15406: Cmax, tmax, AUC0-8h on Day 1 
and at Week 4 of IMP administration 
 Accumulation of OPA-15406: Ratio of Cmax and AUC0-8h at Week 4 and on 
Day 1 of IMP administration 
 
 
[Rationale for variable selection] 
[Efficacy] 
The primary variable of IGA is an indicator to assess the severity of AD and also a 
reliable indicator to determine the efficacy of the IMP; therefore, IGA has been 
established as the primary efficacy endpoint. IGA is evaluated based on the severity 
of overall symptoms (erythema, infiltration, papules, effusion, and scab formation) at 
treatment area and does not include other factors (eg, excoriation, symptoms of 
lichenification, severity of each part, subjective symptoms, affected BSA). 
Therefore, EASI, VAS and VRS for pruritus, DLQI, POEM, and affected BSA have 
been established as the secondary variables to evaluate the efficacy from multiple 


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3.4 
Target Number of Subjects 
 
180 subjects in total [group composition] 
 
Group 
Target number 
of subjects 
0.3% OPA-15406 group 
60 subjects 
1% OPA-15406 group 
60 subjects 
Vehicle group 
60 subjects 
 
4 
Investigational Medicinal Products 
4.1 
Test Product and Comparator 
 
4.1.1 
Test Product 
 
Code Name 
OPA-15406 
Generic Name 
TBD 
Content and Formulation Ointment containing 0.3% or 1% of OPA-15406 
Excipients 
White petrolatum 
Mineral oil 
Excipients 
Paraffin 
White wax 
Propylene carbonate 
Storage Conditions 
Stored at room temperature 
points of view. 
[Safety] 
To appropriately assess the safety of this product. 
[Pharmacokinetics] 
To determine pharmacokinetics of OPA-15406 and the internal exposure to OPA- 
15406 in Japanese AD patients. 


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4.1.2 
Comparator 
 
Placebo formulation apparently indistinguishable from the test product (vehicle) 
 
 
4.2 
Packaging and Labeling 
 
4.2.1 
Packaging 
 
Six aluminum tubes, each containing 27 g of the 0.3% or 1% formulation of OPA- 
15406 ointment or the vehicle, are packed in a packing box. 
4.2.2 
Contents of Label 
 
The following information is written on the labels of the aluminum tube: statement that 
the drug is for use in a clinical trial, the code name of the IMP, Protocol No., lot number, 
drug number, and name of the sponsor. 
The following information is written on the labels of the packing box: statement that the 
drug is for use in a clinical trial, the code name of the IMP, Protocol No., lot number, 
expiration date, storage conditions, drug number, name and address of the sponsor, and 
other precautions. 
 
 
5 
Trial Population 
5.1 
Target Disease 
 
Atopic dermatitis 
5.2 
Inclusion Criteria 
 
Subjects who meet all of the following criteria will be eligible for inclusion in this trial. 
At the screening examination: 
1) Sex:  Either male or female 
2) Hospitalization status: Outpatient 
3) Age: 15 to 70 years, inclusive (at time of obtaining informed consent) 
4) Able to provide written informed consent. For subjects under 20 years of 
age, written informed consent must be obtained from both the subject and 
the subject’s legal guardian. 
5) Diagnosis of AD based on the criteria of Hanifin and Rajka1 
(Appendix 1) 
6) History of AD for at least 3 years 


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At screening and baseline examinations: 
7) AD affecting ≥5% to ≤40% of BSA 
8) IGA score of 2 (mild) or 3 (moderate) 
 
 
 
5.3 
Exclusion Criteria 
 
Subjects who fall under any of the following criteria at either the screening or 
baseline examination will be excluded from the trial: 
1) Subjects who are pregnant, possibly pregnant, or breastfeeding, who desire 
to become pregnant or to have their partner become pregnant during the trial 
period and up until 30 days after the final administration of IMP, or who are 
unable to either remain abstinent or employ at least two of the specified birth 
control methods (vasectomy, tubal ligation, vaginal diaphragm, intrauterine 
device [IUD], birth control pill, condom with spermicide, etc) during the trial 
period and up until 30 days after the final administration of IMP. 
2) Subjects who have an AD or contact dermatitis flare-up defined as a sudden 
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. However, subjects in whom basal-cell skin carcinoma or squamous-cell 
[Rationale for Inclusion Criteria] 
1) AD occurs in both males and females. 
2) Most patients to be included in this trial are outpatients. 
3) In the phase 1 trial in healthy Japanese adult subjects (271-14-001) and  
the phase 2 trial in patients aged 10 years and older outside Japan (271-12- 
205), no particular safety concerns were identified. Therefore, in the present 
trial, adult patients (aged 15 years and older) will be included. 
4) To conduct the trial without any ethical problems. 
5) The criteria of Hanifin and Rajka have been most commonly used 
worldwide and have the same major diagnostic criteria as those of the 
Japanese Dermatological Association; therefore, the criteria can be used also 
in Japan without problems. 
6) -8) To appropriately evaluate the efficacy of the IMP on the target disease. 


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skin carcinoma is judged to have been cured at the time of the screening 
examination can be included in the trial. 
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 assessments: 
 Cardiac disease (eg, rheumatic fever or heart valve replacement) 
 Endocrinologic disease (eg, severe or uncontrolled diabetes) 
 Pulmonary disease 
 Neurologic disease 
 Psychiatric disease 
 Hepatic disease (eg, hepatitis B, hepatitis C) 
 Renal disease 
 Hematologic disease 
 Immunologic or immunocompromised disease (eg, lymphoma, 
acquired immunodeficiency syndrome, Wiskott-Aldrich syndrome, carriers of 
human immunodeficiency virus [HIV] antibodies) 
 Other major disease (eg, systemic fungal infection) or other severe uncontrolled 
condition (eg, drug or alcohol abuse) judged by the investigator or subinvestigator 
to pose a health risk to the subject or to have the potential to impact trial 
assessment 
8) Subjects with any of the following hematology or serum chemistry results 
at screening examination: 
 White blood cell count:  ≤3, 000/μL or >14, 000/μL 
 Platelets:  ≤100, 000/μL 
 Hemoglobin:  <11 g/dL 
 Serum creatinine:  ≥2 mg/dL 
 Aspartate aminotransferase (AST) (glutamic oxaloacetic transaminase 
[GOT]):  >1.5 × ULN 
 Alanine aminotransferase (ALT) (glutamic pyruvic transaminase [GPT]): >1.5 × 
ULN 
 Total bilirubin:  ≥2.0 mg/dL 
 Any other abnormal laboratory test result that the investigator or subinvestigator 
judges to be a clinically significant abnormality 
9) Subjects who are judged by the investigator or subinvestigator to have 
clinically significant electrocardiogram (ECG) findings (eg, AV block, 
prolongation of QRS complex to ≥120 msec, or QT interval as correlated by 
Fridericia’s formula [QTcF] interval of ≥450 msec) at screening examination 


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10) Clinically significant blood pressure or pulse rate findings at screening 
examination of: 
 Age 18 to 70, inclusive: seated resting (≥3 minutes) systolic blood pressure 
of <100 mmHg or ≥150 mmHg or diastolic blood pressure of <50 mmHg or 
≥90 mmHg, or pulse rate of <50 bpm or >100 bpm 
 Age 15 to 17, inclusive:  seated resting (≥3 minutes) systolic blood pressure 
of <95 mmHg or ≥140 mmHg or diastolic blood pressure of <50 mmHg or ≥90 
mmHg, or pulse rate of <50 bpm or >100 bpm 
11) Subjects who are unable to stop using topical corticosteroids, 
topical immunomodulators, topical retinoids and topical antihistamine from 7 
days prior to the baseline examination until the Week 8 assessment. However, 
corticosteroids categorized as low or medium potency in the “Guidelines of care 
for management of atopic dermatitis, Section 2”2 may be used up until the 
baseline examination if, in the opinion of the investigator or subinvestigator, their 
use is necessary, such as when the subjects have been using the corticosteroids 
prior to providing informed consent to participate in the trial and use of the 
corticosteroids will be tapered off and stopped during the screening period. 
12) Subjects who are unable to stop using systemic corticosteroids, 
systemic immunomodulators, systemic antimetabolites, systemic retinoids and 
biologics from 28 days prior to the baseline examination until the Week 8 
examination. Intra-ocular, intra-nasal, and intra-auricular corticosteroids or 
inhaled corticosteroids may be considered if, in the opinion of the investigator or 
subinvestigator, their use will not impact assessment of the affected area. 
13) Subjects who are unable to stop treatment with ultraviolet light A, 
narrowband ultraviolet B, or ultraviolet light B from 28 days prior to the baseline 
examination until the Week 8 examination 
14) Subjects who are unable to stop using systemic antihistamines, 
sodium cromoglicate, tranilast, or suplatast tosilate from 7 days prior to the 
baseline examination until the Week 8 examination 
15) Subjects with known hypersensitivity (including history) to any 
drugs (prescription, OTC, etc) or any ingredient of OPA-15406 ointment 
16) Subjects with known plans to receive any of the prohibited concomitant drugs 
or therapies during the trial period 
17) Subjects who have used any other investigational drug within 4 months prior 
to the baseline examination or who are scheduled to participate in any other 
clinical trial during the trial period 
18) Subjects who have never been treated with a prescription medication for AD or 
who are satisfied with their current AD treatment regimen 
19) Subjects who are judged by the investigator or subinvestigator to be 
inappropriate to participate in the trial for any other reason 


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[Rationale for Exclusion Criteria] 
1) 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) In consideration of safety. 
5) In consideration of safety. However, patients cured of basal-cell skin 
carcinoma or squamous-cell skin carcinoma are allowed to be registered 
because of the low possibility of recurrence. 
6) In consideration of safety. 
7) Due to a possible impact on the safety and efficacy assessments of the IMP. 
8) -10) In consideration of safety. 
11) -14) Due to a possible impact on the efficacy assessment of the IMP. 
15) In consideration of safety. 
16) Due to a possible impact on the safety and efficacy assessments of the IMP. 
17) In reference to the “Criteria for Period to Avoid Participation in 
Clinical Studies” of the Japan Association of Contract Institutes for Clinical 
Pharmacology. 
18) To exclude patients who are not in need of treatment and to 
prevent registering patients who are satisfied with their current treatment, 
because trials have aspects of research. 
19) To allow the investigator or subinvestigator to judge in consideration of 
other factors. 
 
 
6 
Trial Design 
6.1 
Dose, Regimen, and Treatment Period 
 
The 0.3% or 1% formulation or the vehicle of OPA-15406 ointment will be 
administered twice daily (approximately 12 hours apart between morning and night 
administration) for 8 weeks. 
The amount of IMP (g) per dose is calculated as follows. 
1) The subject’s BSA (m2) will be calculated based on height and body weight at 
the screening examination, using the following equation. 


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BSA = body surface area; 
Ht = height; Wt = body weight 
(Mosteller 1987)4 
 
 
 
2) Based on the subject’s BSA (m2), the amount of administration (g) for 1% of 
BSA will be selected from Table 6.1-1. 
3) The treatment area will be specified (see 6.2 “Treatment Area”). 
4) The amount of IMP (g) per dose will be calculated as “the amount 
of administration for 1% of BSA (g)” × “treatment area (%).” 
 
Table 6.1-1 
Amount of Administration (g) for 1% of BSA Based on 
the Subjects’ BSA (m2) 
BSA (   2) 
m 
<1.0 
≥1.0 and <1.3 
≥1.3 and <1.6 
≥1.6 and <1.9 
≥1.9 
Amount of 
administration (g) 
for 1% of BSA 
0.1 
0.15 
0.2 
0.25 
0.3 
 
 
[Rationale for dose, regimen, and treatment period] 
[Regimen] 
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. 
[Dose] 
In the phase 1 trial in AD patients in the US (271-12-204), the efficacy of OPA- 
15406 was suggested in the 0.3% and 1% formulations out of the 0.3%, 1%, and 3% 
formulations tested. In the phase 2 trial outside Japan (271-12-205), the efficacy of 
OPA-15406 was investigated by selecting the 0.3% and 1% formulations. The results 
showed that the 1% formulation had a significantly higher efficacy in the primary 
efficacy endpoint compared to the vehicle, and the 0.3% formulation also had a 
higher efficacy compared to the vehicle.  For this trial, the concentrations of 0.3% 


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6.2 
Treatment Area 
 
The treatment area with the IMP is defined as follows. 
 The treatment area selected at baseline examination will be affected 
area determined at baseline examination (see 7.2.1.7 “Affected BSA ”). 
 After the baseline examination, when the affected area has expanded or a 
new affected area is detected, the expanded or newly affected area will also 
be included in the treatment area. 
 Even when the affected area is relieved, the IMP administration should be 
continued there as the treatment area. 
The investigator or subinvestigator will instruct the subject regarding the method 
of administration by specifying the treatment area (%) and the amount of administration 
(g) for each treatment area using the human body drawing (Appendix 5), and will give 
the human body drawing (copy) to the subject or the subject’s legal guardian. The 
investigator or subinvestigator will record the treatment area (%) of the 4 body 
regions (face, neck, and head; upper limbs; trunk; and lower limbs) in the source 
document and case report form (CRF). 
and 1% are selected in the same manner as those in the phase 2 trial outside Japan 
(271-12-205). 
[Treatment period] 
Usually, topical drugs for AD are evaluated for their efficacy once in 1 to 2 weeks, 
and if no improvements are observed within a month, the patient is generally 
considered for referral to a more specialized institution.2  Thus, Week 4 is established 
as an assessment point of the primary efficacy endpoint, and the treatment is also to 
be continued after Week 4 to assess the efficacy and safety thereafter.  In the phase 
2 trial in AD patients outside Japan (271-12-205), the incidence of success in IGA 
at Week 8 was 17.07%, 16.28%, and 10.81% in the 0.3% OPA-15406 group, the 
1% OPA-15406 group, and the vehicle group, respectively. The incidence of 
success in IGA was higher in the 0.3% and 1% OPA-15406 groups than in the 
vehicle group, while no significant difference was observed. Also, no particular 
safety concerns were identified in the 0.3% and 1% formulations of OPA-15406.  In 
this trial, the 
duration of treatment is established as 8 weeks to assess the efficacy and safety of the 
IMP in Japanese patients up to Week 8 and to compare the results with those of the 
phase 2 trial outside Japan (271 12 205)


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The method of IMP administration is specified in the separate procedure for 
IMP administration. 
 
 
6.3 
Prior and Concomitant Treatment 
 
6.3.1 
Prohibited Concomitant Drugs and Therapies 
 
1) From 28 days prior to the baseline examination until the Week 8 examination, use 
of the following drugs and therapies is prohibited 
 Systemic corticosteroids, systemic immunomodulators, systemic antimetabolites, 
systemic retinoids, biologics 
Intra-ocular, intra-nasal, and intra-auricular corticosteroids or inhaled 
corticosteroids may be considered if, in the opinion of the investigator or 
subinvestigator, their use will not impact assessment of the affected area. 
 Ultraviolet light A, narrowband ultraviolet B, ultraviolet light B 
2) From 7 days prior to the baseline examination until the Week 8 examination, use 
of the following drugs and therapies is prohibited. 
 Topical corticosteroids, topical immunomodulators, topical retinoids, and topical 
antihistamine. 
However, corticosteroids categorized as low or medium potency in the 
“Guidelines of care for management of atopic dermatitis, Section 2”2 may be used 
up until the baseline examination if, in the opinion of the investigator or 
subinvestigator, their use is necessary, such as when the subjects have been using 
the corticosteroids prior to providing informed consent to participate in the trial 
and use of the corticosteroids will be tapered off and stopped during the screening 
period. 
 Systemic antihistamines, sodium cromoglicate, tranilast, suplatast tosilate 
3) From the baseline examination until the Week 8 examination, use of the 
following drugs and products on the treatment area is prohibited. 
 All topical drugs (including ethical drugs, over-the-counter products, 
herbal medicine, quasi-drugs, and cosmetic products) 
However, if cosmetic products were being used on the face, neck, and head prior 
to obtaining consent, their use may be continued only if the same products are 
used at the same frequency. 
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 8 examination.  If any drug other than the IMP is used 
between 30 days before the screening examination and the Week 8 examination, the 
name of the drug, purpose of use, amount per dose, dose frequency, route of 
administration, and dates of start and end of administration will be recorded in the source 


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document and CRF, regardless of it being prohibited or allowed for concomitant use. If 
any concomitant therapy is given between 30 days before the screening examination and 
the Week 8 examination, regardless of it being prohibited or allowed for concomitant use, 
the name of the therapy, purpose of use, and the dates of the start and end of the therapy 
will be recorded in the source document and CRF. 
 
6.4 
Method of Minimizing or Avoiding Bias 
 
This trial is a randomized, double-blind trial. 
The IMP allocation manager will prepare a master “random allocation table” 
(hereinafter, “randomization table”) and conduct IMP coding according to the operating 
procedures for randomization. Also, the IMP allocation manager will prepare an 
emergency code list for use in emergencies such as the occurrence of a serious adverse 
event. 
The investigator, subinvestigator, and subjects are blind to the IMP randomization 
code. Except for some designated personnel, the sponsor’s trial staff, including the 
personnel of contract research organizations, are also unable to access the IMP 
randomization code during the trial period. 
Prior to the trial start and unblinding, the IMP allocation manager will confirm that 
the IMPs are indistinguishable.  The randomization table is sealed by the IMP 
allocation manager just after completion of IMP randomization and it is kept under strict 
control until unblinding after fixation of all CRFs and the database. 
The emergency code list will be kept under strict control by the registration system 
until the end of the trial.  If a medical emergency occurs in a subject and knowledge of 
his or her IMP randomization code is considered important for treatment, the emergency 
code will be broken according to the “8.2.4 Emergency Code Breaking (Procedure for 
Unblinding During the Trial Period).” 
When IMPs are recovered by the sponsor prior to unblinding, they are to be 
recovered sealed by the IMP allocation manager. 
The subjects will be allocated to the 0.3% OPA-15406 group, the 1% OPA-15406 
group, and the vehicle group in a ratio of 1:1:1 using dynamic allocation to ensure 
[Rationale for prohibited concomitant drugs and therapies] 
Due to a possible impact on the efficacy and safety assessments of the IMP. 


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balance within the trial sites and that of the baseline IGA (mild or moderate at the 
baseline examination). 
The results of drug concentration measurements will not be revealed until unblinding 
at the end of the trial. 
 
 
7 
Observations/Examinations/Variables, Methods and 
Implementation Timings 
7.1 
Schedule and Procedures 
 
The schedule of observations/examinations/evaluations is presented on pages 
11 (Schedule of Observations/Examinations/Evaluations) to 14 (Schedule of Blood 
Sampling for Plasma Drug Concentration). Items that trial associates are capable of 
performing may be performed by trial associates under the supervision of 
the investigator. 
7.1.1 
Acquisition of Informed Consent 
 
The investigator or subinvestigator will obtain written consent directly from subjects 
prior to the screening examination. If the subject is under 20 years old, written 
informed consent should be obtained from the subject and the subject’s legal 
guardian. The investigator or subinvestigator will assign a subject identification code and 
subject number (3 digit number of site ID + S +5 digit serial number starting from 00001) 
to the subject providing consent. 
7.1.2 
Screening Examination (From the Day of Informed Consent to 
2 Days Prior to the Baseline 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 (including body weight) 
 Clinical laboratory tests 
 Pregnancy test (only for women of childbearing potential) 
 12-lead ECG 
 IGA 
 Affected BSA 


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 Adverse events 
 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. 
7.1.2.1 
Subject Demographics 
The investigator or subinvestigator will assess or measure the following items and 
record them in the source document and CRF. 
 Date of informed consent 
 Sex 
 Date of birth 
 Height (unit in cm: measurement indicated as an integer value; if 
measurement to one decimal place is possible, then the number is to be 
rounded to nearest integer value.) 
 Complications 
 Date of onset of AD 
 Medical history (within 6 months prior to the date of informed consent) 
 In- or outpatient status (outpatient) 
 Subject number 
 Country where the trial is conducted (Japan) 
 Race (Asian) 
 Ethnicity 
 Possibility of pregnancy 
 
7.1.3 
Subject Registration 
 
The investigator or subinvestigator will register all subjects in the Interactive 
Web Response System (IWRS). 
7.1.4 
Baseline Examination (2-30 Days After the Screening 
Examination) 
 
The investigator or subinvestigator will perform the following examinations, 
observations, and evaluations, and record the results in the source document and CRF. 
 Physical examination 
 Vital signs (including body weight) 
 Clinical laboratory tests (The screening examination results can be used 
within 7 days of the screening examination.) 


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 Pregnancy test (only for women of childbearing potential. The screening 
examination results can be used within 7 days of the screening examination.) 
 12-lead ECG (The screening examination results can be used within 7 days 
of the screening examination.) 
 IGA 
 EASI 
 VAS for pruritus 
 VRS for pruritus 
 DLQI 
 POEM 
 Affected BSA 
 Blood sampling for plasma drug concentration (to be conducted at specific 
trial sites) 
 Severity of AD 
 Adverse events 
 Concomitant medications and therapies 
The investigator or subinvestigator will select subjects who meet the inclusion criteria 
and do not meet any of the exclusion criteria based on results of the screening 
and baseline examinations. Also, the investigator or subinvestigator will record the 
results of the subject’s eligibility on the list of screened subjects and the list of enrolled 
subjects. 
7.1.5 
Allocation of Investigational Medicinal Products to Subjects 
 
The investigator or subinvestigator will enter the necessary information for the 
subject’s eligibility in the IWRS.  On the day of the baseline examination, the subjects 
confirmed to be registered in the IWRS will be allocated to the 0.3% OPA-15406 group, 
the 1% OPA-15406 group, or the vehicle group. The investigator or subinvestigator will 
confirm the allocation result and the amount of IMP to be prescribed for 2 weeks on the 
IWRS screen displaying the registration result, and prescribe the IMP.  The weight of 
the dispensed IMP will be measured (unit in g; rounded to the one decimal place; same 
method for all subsequent IMP weight measurements hereinafter) The IMP 
administration will be started at the trial site after all baseline examinations are finished, 
and the time and date of administration will be recorded. The subjects will be instructed 
to visit the trial site without morning IMP administration on the day of their next visit. 


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7.1.6 
Baseline Examination (2 Hours, 4 Hours, and 8 Hours Postdose): 
To be Conducted at Specific Trial Sites 
 
Application will be started within the trial site after all the baseline examinations are 
finished, and the source document and CRF will be recorded accordingly. 
 Blood sampling for plasma drug concentration 
 
7.1.7 
Between the Day of Baseline Examination and the Day of Week 
1 Examination 
 
The investigator or subinvestigator will instruct the subject to evaluate the following 
item at 4±2 hours, 8±2 hours, and 12±2 hours (if possible) after the first 
IMP administration on the day of the baseline examination, and then twice daily from the 
next day (before IMP administration in the morning and at night) up to the morning of 
the Week 1 examination (before administration) (up to the morning of Day 7 at the 
latest). 
 VRS for pruritus 
 
7.1.8 
Week 1 Examination (±2 Days) 
 
The investigator or subinvestigator will perform the following examinations, 
observations, and evaluations, and record the results in the source document and CRF. 
 Physical examination 
 Vital signs (including body weight) 
 IGA 
 EASI 
 VAS for pruritus 
 DLQI 
 POEM 
 Affected BSA 
 Blood sampling for plasma drug concentration measurement 
 Adverse events 
 Concomitant medications and therapies 
 Status of IMP administration 
The investigator or subinvestigator will determine the treatment area (%) and enter it 
in the IWRS.  Also, the investigator or subinvestigator will confirm the subject’s 


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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. 
7.1.9 
Week 2 Examination (±3 Days) 
 
The investigator or subinvestigator will perform the following examinations, 
observations, and evaluations, and record the results in the source document and CRF. 
 Physical examination 
 Vital signs (including body weight) 
 IGA 
 EASI 
 VAS for pruritus 
 DLQI 
 POEM 
 Affected BSA 
 Adverse events 
 Concomitant medications and therapies 
 Status of IMP administration 
The investigator or subinvestigator will collect the IMP and measure the weight of 
the collected IMP. The investigator or subinvestigator will determine the treatment area 
(%) and enter it in the IWRS. The investigator or subinvestigator will confirm the 
amount of IMP to be prescribed for the next 2 weeks and prescribe it. The weight of the 
dispensed IMP will be measured. The subjects will be instructed to visit the trial site 
without morning IMP administration on the day of the next visit. 
7.1.10 
Week 4 Examination (±3 Days) 
 
The investigator or subinvestigator will perform the following examinations, 
observations, and evaluations, and record the results in the source document and CRF. 
 Physical examination 
 Vital signs (including body weight) 
 Clinical laboratory tests 
 Pregnancy test (only for women of childbearing potential) 
 12-lead ECG 
 IGA 
 EASI 
 VAS for pruritus 
 DLQI 


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 POEM 
 Affected BSA 
 Blood sampling for plasma drug concentration measurement 
 Adverse events 
 Concomitant medications and therapies 
 Status of IMP administration 
The investigator or subinvestigator will collect the IMP and measure the weight of 
the collected IMP. The investigator or subinvestigator will determine the treatment area 
(%) and enter it in the IWRS. The investigator or subinvestigator will confirm the 
amount of IMP to be prescribed for the next 2 weeks and prescribe it. The weight of the 
dispensed IMP will be measured. 
7.1.11 
Week 4 Examination (2 Hours, 4 Hours, and 8 Hours Postdose): 
To Be Conducted at Specific Trial Sites) 
 
Application will be started within the trial site after all Week 4 examinations are finished, 
and the source document and CRF will be recorded accordingly. 
 Blood sampling for plasma drug concentration 
 
7.1.12 
Week 6 Examination (±3 Days) 
 
The investigator or subinvestigator will perform the following examinations, 
observations, and evaluations, and record the results in the source document and CRF. 
 Physical examination 
 Vital signs (including body weight) 
 IGA 
 EASI 
 VAS for pruritus 
 DLQI 
 POEM 
 Affected BSA 
 Adverse events 
 Concomitant medications and therapies 
 Status of IMP administration 
The investigator or subinvestigator will collect the IMP and measure the weight of 
the collected IMP. The investigator or subinvestigator will determine the treatment area 
(%) and enter it in the IWRS.  The investigator or subinvestigator will confirm the 


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amount of IMP to be prescribed for the next 2 weeks and prescribe it. The weight of the 
dispensed IMP will be measured. The subjects will be instructed to visit the trial site 
without morning IMP administration on the day of the next visit. 
7.1.13 
Week 8 Examination (±3 Days) or Withdrawal Examination 
 
The investigator or subinvestigator will perform the following examinations, 
observations, and evaluations, and record the results in the source document and CRF. 
Withdrawal examinations should be conducted if at all possible. 
 Physical examination 
 Vital signs (including body weight) 
 Clinical laboratory tests 
 Pregnancy test (only for women of childbearing potential) 
 12-lead ECG 
 IGA 
 EASI 
 VAS for pruritus 
 DLQI 
 POEM 
 Affected BSA 
 Blood sampling for plasma drug concentration measurement 
 Adverse events 
 Concomitant medications and therapies 
 Status of IMP administration 
The investigator or subinvestigator will collect the IMP and measure the weight of 
the collected IMP. 
7.1.14 
Examination 2 Weeks After Last IMP Administration (±7 Days) 
 
The investigator or subinvestigator will perform the following examinations, 
observations, and evaluations, and record the results in the source document and CRF. 
 Physical examination 
 Adverse events 
 
7.1.15 
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 


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perform the following examinations, observations and evaluations, and record the results 
in the source document and CRF. 
 Affected BSA 
 Adverse events 
 Concomitant medications and therapies 
The following examinations may be conducted as necessary: 
 Physical examinations 
 Vital signs (including body weight) 
 12-lead ECG 
 Clinical laboratory values 
 Pregnancy test 
The investigator or subinvestigator will determine the treatment area (%) and enter it 
in the IWRS.  Also, the investigator or subinvestigator will confirm the subject’s 
allocation status on the IWRS screen and, if necessary, prescribe additional IMP. When 
the IMP is additionally prescribed, the weight of dispensed IMP will be measured. 
 
 
7.2 
Method of Evaluation 
 
7.2.1 
Efficacy Evaluation 
 
7.2.1.1 
Investigator’s Global Assessment (IGA) 
The investigator or subinvestigator will score the severity (0 = clear, 1 = almost clear, 2 
= mild, 3 = moderate, 4 = severe/very severe) of systemic symptoms (erythema, 
infiltration, papules, effusion [liquid], and scab formation).5 The result will be 
recorded in the source document and CRF. The same subject will be evaluated by the 
same dermatologist, as much as possible. 
 
 
 
Symptom 
Severity score 
No inflammatory signs of AD 
0 = Clear 
Just perceptible erythema and just perceptible 
papulation/infiltration 
1 = Almost clear 
Mild erythema and mild papulation/infiltration 
2 = Mild 
Moderate erythema and moderate papulation/infiltration 
3 = Moderate 
Severe erythema and severe papulation/infiltration with 
oozing/crusting 
4 = Severe/very severe 


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7.2.1.2 
Eczema Area and Severity Index (EASI) 
The investigator or subinvestigator will score the severity (0-3 points) and BSA (0-6 
points) based on the 4 symptoms (erythema, infiltration/papules, excoriation, 
and lichenification) on the 4 body regions (face, neck, and head; upper limbs; trunk; and 
lower limbs) and record the results in the source document and CRF.6 As shown in the 
table below, the score of each region will be calculated and totalized. The 
maximum EASI score is 72 points.  The same subject will be evaluated by the same 
dermatologist, as much as possible. 
 
Body region 
Calculation of the score for each region 
Face, neck, and head 
(E ＋ I ＋ Ex ＋ L) × score of BSA ×0.1 
Upper limbs 
(E ＋ I ＋ Ex ＋ L) × score of BSA ×0.2 
Trunk 
(E ＋ I ＋ Ex ＋ L) × score of BSA ×0.3 
Lower limbs 
(E ＋ I ＋ Ex ＋ L) × score of BSA ×0.4 
E = severity score of erythema; I = severity score of infiltration/papules; Ex = severity score 
of excoriation; L = severity score of lichenification 
Severity score: clear = 0; slight = 0.5; mild = 1; mild-moderate = 1.5; moderate = 2; severe = 2.5; 
very severe = 3 
Score of BSA: clear = 0; 1% to 9% = 1; 10% to 29% = 2; 30% to 49% = 3; 50% to 69% = 4; 70% 
to 89% = 5; 90% to 100% = 6 
 
 
7.2.1.3 
Visual Analogue Scale (VAS) for Pruritus 
The investigator or subinvestigator will evaluate the level of pruritus based on VAS7.  
The subjects will mark the point of pruritus intensity during the last 24 hours on the line 
of a 100-mm VAS sheet (Appendix 2) between the left end (no pruritus) and the right end 
(very severe pruritus). The investigator or subinvestigator will record the length from the 
left end to the mark (integer value with mm as unit) in the medical record and CRF. The 
VAS sheet will be kept as the source document. 
7.2.1.4 
Verbal Rating Scale (VRS) for Pruritus 
The investigator or subinvestigator will evaluate the pruritus intensity based on VRS7. 
The subjects will evaluate the pruritus intensity according to the following criteria. 
The subjects will record the level of pruritus, and the time and date of evaluation in a 
pruritus diary. 
0: None 
1: Mild 
2: Moderate 
3: Severe 


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The investigator or subinvestigator will record details of the pruritus diary in the 
CRF.  The pruritus diary will be kept as the source document. 
7.2.1.5 
Dermatology Life Quality Index (DLQI) 
The investigator or subinvestigator will evaluate the effect of OPA-15406 on daily life 
according to the DLQI8 (Appendix 3). The subjects will answer 10 questions about the 
effects of the symptoms on their daily life. The investigator or subinvestigator will 
record the results in the source document and CRF. The total DLQI score is 30 points at 
the most. 
7.2.1.6 
Patient-Oriented Eczema Measure (POEM) 
The investigator or subinvestigator will evaluate eczema according to the 
POEM9 (Appendix 4). The subjects will answer 7 questions about their eczema. 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. 
7.2.1.7 
Affected BSA 
The investigator or subinvestigator will draw the affected BSA (range of skin eruption 
at the time of examination) on the human body drawing (Appendix 5) to determine 
the affected areas (%) on the respective 4 body regions (head, face, and neck; upper 
limbs; trunk; and lower limbs). The respective affected areas (%) will be recorded in the 
source document and CRF.  One palm of the subject corresponds to 1% BSA. 
7.2.2 
Safety Evaluation 
 
7.2.2.1 
Physical Examination 
The investigator or subinvestigator will assess the subject’s physical condition 
by interview, visual examination, or palpation. 
7.2.2.2 
Vital Signs (Including Body Weight) 
After the subject has rested for 3 minutes or more in a sitting position, body  
temperature (measured by 0.1°C in the armpit), blood pressure (systolic/diastolic), pulse 
rate, and body weight (unit in kg; rounded to one decimal place) will be measured, and 
the results of measurement will be recorded in the source document and CRF. 
7.2.2.3 
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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 Hematology:  differential white blood cell count (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils), white blood cell count, red 
blood cell count, hemoglobin, hematocrit, platelets 
 Serum chemistry: total cholesterol, total protein, albumin, BUN, creatinine, 
total bilirubin, AST (GOT), ALT (GPT), γ-GTP, LDH, ALP, serum 
electrolytes (Ca, Na, K, Cl) 
 Qualitative urinalysis:  glucose, protein 
The tests will be performed at the central laboratory. The investigator or subinvestigator 
will confirm the 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). 
7.2.2.4 
12-Lead ECG 
After the subject has rested for at least 10 minutes in a supine position, an ECG will 
be obtained. The ECG recording should be completed before blood sampling, as much 
as possible. For the ECG measurement, heart rate, RR interval, PR interval, QRS 
interval, QT interval, and QTc interval will be measured, using a 12-lead 
electrocardiograph obtained from the central ECG reading facility. The measurement 
results will be analyzed at the central ECG reading facility. The investigator or 
subinvestigator will confirm the “12-lead ECG analysis report” from the central ECG 
reading facility, assess whether the ECG result is normal or abnormal, and record the 
time and date of the measurement, assessment result, and findings in the source document 
and CRF. Then, the investigator or subinvestigator will put the confirmation date and his 
or her printed name and personal seal or signature on the “12-lead ECG analysis report” 
from the central ECG reading facility and retain it for each subject as the source 
document. 
If it is necessary to allocate IMP before receiving the results from the central 
ECG reading facility, the automated analysis result from the 12-lead electrocardiograph 
at the screening examination (the same ECG data as that to be sent to the central ECG 
reading facility) can be used to determine the subject’s eligibility. In such cases, the 
investigator or subinvestigator will put the date of confirmation and his or her printed 
name and personal seal or signature on the automated analysis result and retain it as the 
source document. 
The central ECG reading facility will send the 12-lead ECG analysis results (in electronic 
data format) to the sponsor. 


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7.2.3 
Pharmacokinetics 
 
Plasma OPA-15406 concentrations will be measured except for subjects in the 
vehicle group. On the day of blood sampling, the subjects will visit the trial site without 
morning IMP administration. 
1) Blood sampling timepoints 
Plasma trough concentration of OPA-15406 (prior to IMP administration at Week 
1, Week 4, and Week 8 of IMP administration; all subjects) 
Plasma concentration of OPA-15406 (prior to IMP administration and 2 hours, 4 
hours, and 8 hours postdose on Day 1 and at Week 4. [however, prior to IMP 
administration at Week 4 is the same as trough concentration at Week 4]): specific 
trial sites (target of 6 subjects from each group) 
2) Rationale for blood sampling timepoints 
Timepoints are selected to confirm the drug concentration of OPA-15406 and the 
internal exposure to OPA-15406 in Japanese AD patients and to obtain 
comparable internal exposure data to those of the phase 2 trial outside Japan (271- 
12-205). 
3) Method of blood sampling and processing 
Sufficient caution should be taken for the parts of sterilization and site of 
blood sampling to avoid the blood samples from contamination with any IMP 
remnant on the skin surface. Approximately 5 mL of blood will be collected per 
dose from arm vein using vacuum blood collection tube (with heparin Na 
contained) and sufficiently mixed. The sample will be mixed by inversion and 
cooled in ice water, and it will be centrifuged at approximately 3000 rpm for 10 
minutes within 30 minutes after blood sampling, and from which approximately 
the same amount of plasma will be promptly taken into two polypropylene tubes 
and stored frozen at −15°C or less. When a refrigerated centrifuge is available, 
the blood will be centrifuged at 4°C. For each subject, the time and date of latest 
IMP administration and blood sampling will be record on the source document 
and CRF. 
4) Sending plasma samples 
The contract research organization for clinical laboratory tests will send the 
samples divided into two tubes frozen on dry ice to the bioanalytical laboratory. 
The plasma concentration of OPA-15406 will be determined at the bioanalytical 
laboratory by using the liquid chromatography with tandem mass spectrometry 
(LC-MS/MS). The bioanalytical laboratory will measure samples of the OPA- 
15406 group according to the randomization table. Residual plasma samples after 
measurement will be stored at −15°C or less by the bioanalytical laboratory until 
the sponsor allows their disposal. The sponsor will report the completion of 
measurement to the bioanalytical laboratory. The bioanalytical laboratory will 
submit the report on results of drug concentration measurement (copy) and 
the measurement results (electronic data) to the sponsor. 


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7.2.4 
Status of IMP 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%. 
7.2.5 
Severity of AD 
The investigator or subinvestigator will determine the severity10 (mild, moderate, severe, 
or very severe) and record the result in the source document and CRF. 
 
Definition 
Severity 
Just mild skin eruption regardless of the area 
Mild 
Skin eruption with severe inflammation on <10% of the BSA 
Moderate 
Skin eruption with severe inflammation on ≥10% to <30% of the BSA 
Severe 
Skin eruption with severe inflammation on ≥30% of the BSA 
Very severe 
Mild skin eruption:  lesions mainly consisting of mild erythema, dryness, or desquamation 
Skin eruption with severe inflammation: lesions consisting of erythema, papules, erosion, infiltration, or 
lichenification 
 
 
7.3 
Measures to Be Taken for Subjects Visiting or Planning to Visit 
Other Hospitals or Departments 
 
At the time of obtaining informed consent, the investigator or subinvestigator 
will confirm whether or not the subject is receiving treatment at another hospital 
or department. If the subject is receiving treatment at another hospital or department, 
the investigator or subinvestigator will inform the attending physician of that hospital 
or department about the subject’s participation in the clinical trial and the IMP being 
used, with the subject’s consent. The investigator or subinvestigator will also obtain and 
record in the CRF information on the treatment that the subject is receiving at the other 
hospital or department (name of disease being treated and information on the type of 
treatment or measures being implemented) and judge whether or not the subject should 
participate in the trial. 
If a subject visits another hospital or department during the trial period, the 
investigator or subinvestigator will inform the attending physician of that hospital or 
department about the subject’s participation in the clinical trial and the IMP being used. 
The investigator or subinvestigator will also obtain and record in the CRF information on 
the treatment that the subject receives at the other hospital or department (name of 
disease treated and information on the type of treatment or measures implemented) and 
judge whether or not the subject should continue to participate in the trial. 


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7.4 
Subject Management 
 
Subjects will be under control of the investigator or subinvestigator during the trial 
period. The investigator or subinvestigator will instruct the subjects to adhere to the 
following matters. 
 To thoroughly understand the details of the administration guidance and 
follow it. 
 To keep an administration diary every day. 
 To keep a pruritus diary until the morning of the Week 1 examination (Day 7 
at the latest). 
 When bathing or taking a shower, to administer the IMP afterwards. 
 To visit the trial site on the specified visit days during the trial period. 
 To visit the trial site without morning IMP administration on the day of 
drug concentration measurement. 
 To bring the IMP, administration diary, and pruritus diary as instructed. 
 To avoid excessive exercises, getting a suntan, and excessive drinking and 
eating and to keep regular hours to prevent possible effects on safety. 
 Information obtained during participation in this trial must not be disclosed 
to any third party. 
 
8 
Adverse Events 
8.1 
Definitions 
 
8.1.1 
Adverse Event 
 
[ICH E2A guideline: Definition] 
Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to 
have a causal relationship with this treatment. 
An adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal 
product. a 
 
 
 
a“Clinical Safety Data Management”, Notification No. 227 of the Examination Division, 
Pharmaceutical Affairs Bureau dated 20 Mar 1995 (ICH E2A). 


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For this trial, the term “medical product” is regarded as “IMP,” and to secure the safety of 
subjects, adverse events occurring from consent to the start of IMP administration 
are included in the definition of adverse events in addition to the definition given by ICH. 
If an event, symptom, or sign existing at the time of acquisition of informed 
consent worsens after acquisition of informed consent, or if an adverse event occurring 
between the acquisition of informed consent and start of IMP administration worsens 
after administration of the IMP, the exacerbation will be treated as a new adverse event. 
“Annex 4:  Common Terminology Criteria for Adverse Events v4.0 Japanese 
JCOG edition” will be cited as reference to judge the assessment of adverse events. 
Adverse events for which a causal relationship with the IMP cannot be ruled out are 
termed as “potentially IMP-related adverse events.” 
8.1.2 
Serious Adverse Event 
 
A serious adverse event is defined as an adverse event corresponding to one of the 
events listed in 1) to 6) below.a 
The seriousness of adverse events occurring during the period from consent to the start 
of IMP administration will also be judged. 
1) An event resulting in death 
2) A life-threatening event 
The term “life-threatening” refers to an event in which the patient was at a risk 
of death at the time of the event. It does not refer to an event which 
hypothetically might have caused death, had it been more severe. 
3) An event requiring in-patient hospitalization or prolongation of 
existing hospitalization for treatment 
4) An event resulting in persistent or significant disability/incapacity 
5) An event causing a congenital anomaly/birth defect 
6) A major event resulting in other situations, such as important medical events 
that may not be immediately life-threatening or result in death or hospitalization, 
but which may jeopardize the patient or may require intervention to prevent one 
of the other outcomes listed in 1) to 5) above. Examples of such events are 
intensive treatment in an emergency room for bronchospasm, blood dyscrasias 
or convulsions that do not result in hospitalization; or development of 
drug dependency or drug abuse. 
 
Explanation of hospitalization for treatment of a serious adverse event: 
Hospitalization for treatment means that the subject must be hospitalized at a 
medical institution for treatment of an adverse event, typically for at least one night. 


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This includes hospitalization for treatment of the adverse event in which no particular 
medical procedures are carried out (rest therapy). However, it does not include 
hospitalization for undergoing tests or treatment for an underlying disease or 
complication that has not worsened since the subject’s entry into the trial, hospitalization 
for social reasons or convenience not intended for treatment of the adverse event, or 
hospitalization for treatment or tests scheduled prior to participation in the trial. 
 
 
8.2 
Response to Occurrence of Adverse Events 
 
8.2.1 
Actions to Be Taken for Subjects 
 
The investigator or subinvestigator will provide adequate medical care for all 
clinically significant, trial-related adverse events throughout the period of subject 
participation in the trial as well as thereafter. If treatment for an adverse event is 
necessary, the subject will be informed of this. 
8.2.2 
Expedited Reporting of Serious Adverse Events 
 
(1) Serious Adverse Events and Sponsor-specified Events Requiring Expedited Reporting 
1) Any serious adverse events occurring during the trial period regardless of 
causal relationship with the IMP 
2) Serious adverse events occurring during the follow-up period (see 8.4, Follow-up 
Investigation of Adverse Events), if a follow-up investigation is performed, 
for which a causal relationship with the IMP cannot be ruled out, or adverse 
events that become serious during the follow-up period for which a causal 
relationship with the IMP cannot be ruled out 
3) Among serious adverse events occurring after completion of the trial and 
reported by subjects to the investigator or subinvestigator, those for which the 
investigator or subinvestigator cannot rule out a causal relationship with the IMP 
 
(2) Procedures for Expedited Reporting 
1) When an adverse event falling under any of the above items 1) to 3) occurs, 
the investigator or subinvestigator will notify the sponsor promptly after 
becoming aware of the event (within 24 hours, in principle) orally or by 
telephone, facsimile, or e-mail (refer to Annex 1, Emergency Contact). 
2) The investigator will then promptly submit a detailed report on any 
serious adverse events occurring after the start of IMP administration to the head 
of the trial site and the sponsor within 10 days after becoming aware of them 
using the report form of the trial site or sponsor. Any additional information will 
also be promptly relayed to the sponsor (within 24 hours, in principle) orally or 
by telephone, facsimile, or e-mail, and additional reporting will be performed 
if necessary. 


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3) When the investigator or subinvestigator is requested by the sponsor, the head 
of the trial site, or the institutional review board (IRB) to prepare 
additional information (autopsy report, terminal care report, or other required 
information) on a reported serious adverse event, the investigator or 
subinvestigator will respond to the request. 
 
8.2.3 
Subjects with Possibility of Drug-induced Liver Injury 
 
After start of the IMP administration, if an AST (GOT) or ALT (GPT) level increases 
at least 3 times the upper limit of the normal range, and also if a total bilirubin 
level increases to at least 2 times the upper limit of the normal range, the investigator 
will promptly submit a detailed report (refer to Annex 1, Emergency Contact). 
8.2.4 
Emergency Code Breaking (Procedure for Unblinding During 
the Trial Period) 
 
If a serious adverse event occurs and the investigator or subinvestigator judges 
emergency code breaking necessary for the safety of a subject, the investigator or 
subinvestigator may perform emergency code breaking for the subject according to the 
stipulated procedure (“Procedure for Emergency Code Breaking”).  The investigator 
or subinvestigator will notice any case of emergency code breaking promptly to the 
sponsor, create records for the reasons and course of emergency code breaking and 
submit them to the sponsor. 
8.2.5 
Implementation of Patch Test 
 
If any adverse event suspected of hypersensitivity occurs in the treatment area, the 
subject will be withdrawn from the trial and given the appropriate treatment. 
Verbal consent will be obtained from the subject (and also from the subject’s 
legal guardian if the subject is under 20 years old) to conduct a patch test, and the record 
will be kept in the source document and CRF. The patch test should be conducted 
following a washout period after confirming recovery of symptoms in order to prevent 
the influence of medications used for treatment on the reading result of the patch test. In 
principal, the patch test will be performed after a 2-week washout period for those 
receiving systemic steroids or after a 1-week washout period for those receiving topical 
steroids or topical/systemic antihistamines. Test substances for the patch test are to 
consist of the IMP that has been allocated to the subject, vehicle, and white petrolatum. 
As a guide, 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 (acceptable window of 5 to 7 days) 


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after the application. The time and date of the reading and the reading result will be 
recorded in the source document and CRF (refer to the Guidelines for Management of 
Contact Dermatitis11 issued by the Japanese Dermatological Association for procedures 
of the patch test). 
 
Table 8.2.5-1 
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 
 
8.3 
Assessment of Adverse Events 
 
The investigator or subinvestigator will assess adverse events for the following items 
and record them in the source document and CRF. Information on adverse events 
occurring on application sites will be recorded. 
8.3.1 
Terms for Adverse Events 
 
If the disease responsible for an adverse event can be specified, the name of 
the diagnosed disease will be recorded in the source document and CRF and not 
the individual symptoms. 
8.3.2 
Date of Onset and Recovery 
 
 Date of onset: 
The date of onset of an adverse event or date confirmation of an adverse event will 
be recorded in the source document and CRF. If an event, symptom, or sign existing at 
the time of acquisition of informed consent worsens, the date of exacerbation will 
be recorded in the CRF as the date of onset of adverse event. Also, if an adverse 
event occurring between the acquisition of informed consent and start of IMP 
administration worsens after administration of the IMP, the exacerbation will be recorded 
in the CRF as a new adverse event with the date of exacerbation recorded as “date of 
onset of exacerbated adverse event.” 
 Date of recovery: 
The date of recovery of an adverse event or date of confirmation of recovery of 
an adverse event will be recorded in the CRF.  Dates of blood sampling and urine 


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collection will be recorded for abnormal laboratory parameters reported as adverse 
events.  If a subject dies, the date of death will be recorded. 
8.3.3 
Severity 
 
Severity of adverse events will be classified using the following three categories. 
Skin and subcutaneous tissue disorders will be graded according to the Common 
Terminology Criteria for Adverse Events v4.0 Japanese JCOG edition (Annex 4). 
1) Mild 
Discomfort noticed, but no disruption to daily activity 
2) Moderate 
Discomfort sufficient to limit or affect normal daily activity 
3) Severe 
Inability to work or perform normal daily activity 
 
8.3.4 
Causal Relationship With Investigational Medicinal Product 
 
The causal relationship between the IMP and adverse events occurring after the start 
of IMP administration will be judged according to the following two categories. 
1) Relationship is ruled out 
For reasons such as the following, the possibility of a relationship 
between occurrence of an adverse event and the IMP is not reasonably 
conceivable. 
a) The event can be assumed to be caused by an underlying disease, 
complication, or medical history. 
b) The event can be assumed to be associated with age, sex, or some 
other demographic factor. 
c) A temporal relationship between IMP administration and occurrence of 
the adverse event is unlikely. 
Example: An adverse event that occurs after a considerable lapse of time 
from the discontinuation of IMP administration. 
d) Considering the time course of the adverse event and IMP administration, 
a relationship with the IMP is unlikely. 
Example: Despite continuous administration of the IMP, the adverse event 
disappears spontaneously without any treatment (except cases in which it 
is judged that the subject became habituated to the IMP during 
continued administration). 
e) The event can be assumed to be caused by concomitant drug(s). 
f) The event can be assumed to be incidental (such as an accident or 
incidental disease). 
Example:  “Femoral bone fracture” occurring in a traffic accident. 


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g) A relationship with the IMP can be ruled out for other reasons based 
on medical consideration. 
2) Relationship cannot be ruled out 
For reasons such as the following, the possibility of a relationship 
between occurrence of an adverse event and the IMP is reasonably conceivable. 
a) A relationship is predictable from the pharmacological and 
toxicological effects of the IMP. 
Examples: Occurrence of “pancytopenia” when effects on the 
hematopoietic system have been observed in non-clinical studies, or the 
occurrence of “dehydration” when the drug has a diuretic effect. 
b) The event has been observed in previous non-clinical studies and/or 
clinical studies. 
c) A temporal relationship is suspected between IMP administration and onset 
of the adverse event. 
Example: “Allergic dermatitis” occurring several days after the start of 
IMP administration. 
d) A relationship is suspected based on the outcome of an adverse event 
after discontinuation or dose reduction of the IMP. 
Example:  Prompt disappearance of “nausea” after discontinuation of the IMP 
e) A relationship with the IMP cannot be ruled out for other reasons based 
on medical consideration. 
 
8.3.5 
Actions to Be Taken Regarding IMP Administration 
 
Actions to be taken regarding IMP administration following an adverse event will be 
selected from among the following. 
 No change 
 Discontinuation of IMP administration 
Example:  IMP administration was discontinued due to an adverse event 
 Not applicable 
Examples: The adverse event resolved prior to initiation of IMP 
administration or the  adverse event occurred after the end of 
IMP administration 
 
8.3.6 
Actions to Be Taken for Adverse Events 
 
The performance of medical treatments (medications and/or other treatments) for 
adverse events and details of the treatments will be described in the CRF. 


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8.3.7 
Outcome 
 
The outcome of an adverse event will be selected from the following six categories 
(one only). 
If the subject died, the date of death will be recorded in the CRF; if the 
subject’s condition was recovering/resolving, not recovered/not resolved, or unknown, 
the date of outcome confirmation will be recorded in the CRF. 
 Recovered/resolved 
 Recovering/resolving 
 Not recovered/not resolved 
 Recovered/resolved with sequelae 
 Fatal 
 Unknown (for some reason, a follow-up investigation could not be 
performed even once) 
 
8.4 
Follow-up Investigation of Adverse Events 
 
The term “recovered” used below means that a subject who had an adverse event prior 
to the start of IMP administration returned to his or her original condition, or a subject 
who had an adverse event after the start of IMP administration returned to his or her 
condition before the start of IMP administration. 
1) If an adverse event has not resolved by the day of examination 2 weeks after 
the last IMP administration (or the day of last examination if the examination 2 
weeks after the last IMP administration was not performed), the investigator 
or subinvestigator will explain to the subject the need for post-trial follow- 
up investigation and request the subject’s cooperation.  The investigator 
or subinvestigator will conduct a follow-up investigation within 4 weeks after 
the end of the trial, as much as possible, and record information regarding the 
adverse event in the subject’s medical records. If an adverse event has not 
resolved by the day of examination 2 weeks after the last IMP administration (or 
the day of last examination if the examination 2 weeks after the last IMP 
administration was not performed), the investigator or subinvestigator will record 
the outcome in the CRF as “recovering/resolving”, “not recovered/not resolved”, 
or as otherwise appropriate. 
2) If an adverse event has not resolved by the day of the follow-up 
investigation, follow-up investigation will be continued until the event resolves or 
becomes stable, regardless of a causal relationship with the IMP, and information 
regarding the adverse event will be recorded in the subject’s medical records. 
3) If, between the day of examination 2 weeks after the last IMP administration 
(or the day of last examination if the examination 2 weeks after the last 


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IMP administration was not performed) and the day of the follow-up 
investigation, a new serious adverse event for which a causal relationship with the 
IMP cannot be ruled out occurs, or if an adverse event that has not resolved by the 
day of examination 2 weeks after the last IMP administration (or the day of 
last examination if the examination 2 weeks after the last IMP administration was 
not performed) and for which a causal relationship with the IMP cannot be ruled 
out becomes serious, follow-up investigation will be conducted until the adverse 
event resolves or becomes stable and information regarding the adverse event will 
be recorded in the subject’s medical records. 
4) If a serious adverse event for which a relationship with the IMP cannot be 
ruled out is discovered after the day of examination 2 weeks after the last 
IMP administration (or the day of last examination if the examination 2 weeks 
after the last IMP administration was not performed), or after the day of the initial 
follow-up investigation (if performed), follow-up investigation will be conducted 
until the adverse event resolves or becomes stable or until follow-up of the 
subject becomes impossible and information regarding the adverse event will be 
recorded in the subject’s medical records. 
 
8.5 
Pregnancy 
 
If women of childbearing potential or male subjects whose partners are capable 
of becoming pregnant participate in the trial, the investigator or subinvestigator will 
attend to the following. 
 Information on reproductive and developmental toxicity of the IMP 
 Drug interactions between the IMP and hormonal contraceptives 
 Information regarding pregnancy in the informed consent form (ICF) 
 Explanation of contraceptive methods 
 Reporting and follow-up of cases of pregnancy 
 
8.5.1 
Guidance to Subjects Including Contraceptive Methods 
 
1) Before the start of the trial, the investigator or subinvestigator will explain to 
the subjects the importance of using contraception and the risks associated 
with pregnancy of a female subject or partner of a male subject and, after subjects 
have read the written information for subjects and understood it, the investigator 
or subinvestigator will have the subject’s printed name and personal seal or 
signature on the ICF. 
2) If women of childbearing potential or male subjects whose partners are capable 
of becoming pregnant wish to participate in the trial, the investigator or 
subinvestigator will instruct them to practice contraception during the period 
specified in the trial protocol. 


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3) Contraceptive methods include vasectomy, tubal ligation, vaginal diaphragm, 
IUD, birth control pill, and condom with spermicide, and at least 2 of these 
methods have to be employed (double-barrier method). However, if a female 
subject or male subject’s partner is without question unable to become pregnant 
(ie, has undergone bilateral ovariectomy or hysterectomy or has not experienced 
menses for at least 12 consecutive months for whatever other medical reasons, or 
the male subject/partner has undergone bilateral orchidectomy), or if the subject 
and his/her partner remain abstinent, use of contraception is unnecessary. 
4) The investigator or subinvestigator will instruct the subjects that if the 
contraceptive measures fail and evidence of pregnancy of the female subject or 
male subject’s partner such as delay in menstruation is observed, this should be 
promptly reported to the investigator or subinvestigator. 
 
8.5.2 
Actions to Be Taken by the Investigator or Subinvestigator 
When Pregnancy Is Suspected 
 
If the investigator, subinvestigator, or subject suspects that the subject has 
become pregnant before initiation of IMP administration, initiation of IMP administration 
will be withheld and a pregnancy test will be performed. If the test result is positive, the 
trial subject will be withdrawn without receiving IMP administration.  If a pregnancy 
is suspected after initiation of IMP administration, IMP administration will be 
discontinued (refer to Section 9.2, Criteria and Procedures for Withdrawal of Individual 
Subjects). 
8.5.3 
Actions to Be Taken by the Investigator or Subinvestigator When 
a Subject Is Discovered to Be Pregnant 
 
When a female subject is found to be pregnant, the investigator or subinvestigator 
will withdraw the subject from the trial and perform follow-up investigation until 
delivery or end of pregnancy, and report this in writing to the sponsor. 
After discontinuation of IMP administration, the investigator or subinvestigator 
will perform the withdrawal examinations and follow-up observation stipulated in 
the protocol, in so far as they do not affect the pregnancy. 
8.5.4 
Expedited Reporting of Pregnancy 
 
When a female subject or a partner of a male subject is found to be pregnant during 
the trial, the investigator or subinvestigator will promptly (within 24 hours, in principle) 
report this to the sponsor by telephone, facsimile, or e-mail (refer to Annex 1, 
Emergency Contact). The investigator or subinvestigator will then provide any 
additional information requested by the sponsor. 


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8.5.5 
Follow-up Investigation of Pregnancy 
 
If a female subject becomes pregnant, the investigator or subinvestigator will 
perform follow-up investigation of the pregnancy up to delivery or the end of pregnancy 
and report the results of follow-up in writing to the sponsor.  When a subject or 
subject’s partner has delivered, it is best that the neonate be observed for at least 6 
months after delivery. 
 
 
9 
Withdrawal of Individual Subjects From the Trial 
Any subject may discontinue participation in the trial at any time without 
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. 
9.1 
Screen Failure 
 
If a subject is a screen failure, the following information should be recorded in the 
source document and CRF for screen failure subjects. 
Subject number, date of screening examination, date of informed consent, date of 
birth, sex, reason for screen failure, country where the trial was conducted (Japan), race 
(Asian), ethnicity, possibility of pregnancy 
 
 
9.2 
Criteria and Procedures for Withdrawal of Individual Subjects 
 
In any of the events listed below, the investigator or subinvestigator will discontinue  
IMP administration, perform the tests to be performed at withdrawal stipulated in Section 
7.1, Schedule and Procedures” and promptly inform the sponsor of the withdrawal. The 
investigator or subinvestigator will record the date and reason for withdrawal in the CRF. 
If withdrawal is necessitated by problems with safety, such as the occurrence of 
an adverse event or aggravation of an underlying disease, the investigator or 
subinvestigator will promptly take appropriate measures and perform follow-up if 
necessary (refer to Section 8.4, Follow-up Investigation of Adverse Events). 
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 
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3) Occurrence of any adverse event that makes it difficult for the subject to 
continue administration of IMP (including a suspected treatment-related adverse 
event of skin hypersensitivity on the treatment area) 
4) Increase in the total treatment area to more than 40% of BSA 
5) Discovery that the subject is pregnant or suspected to be pregnant 
6) Judgment by the investigator or subinvestigator that it is necessary to 
withdraw the subject from the trial 
 
9.3 
Follow-up Investigation of Subjects Who Do not Visit the Trial Site 
 
If a subject has missed visiting the trial site for an unknown reason, the investigator 
or subinvestigator will promptly contact the subject, family members, or other related 
persons to confirm whether any adverse event has occurred in the subject and 
to encourage the subject to visit the trial site. If the subject keeps missing visits, the 
following issues will be investigated, and the results will be recorded. 
1) The date of investigation 
2) The method of investigation 
3) Whether or not the subject was contacted 
4) Reason why the subject did not (or cannot) visit the trial site 
5) Details of status of IMP administration 
6) Occurrence or absence of adverse events.  If an adverse event has occurred: 
Name of the event, date of onset and date of recovery, severity, relationship to the 
IMP, measures taken regarding IMP administration, treatment of adverse event, 
and outcome 
7) If a follow-up investigation is impossible:  The reason why 
 
10 
Collection of Case Report Form Data and Specification 
of Source Data 
10.1 
Collection of Case Report Form Data 
 
1) Electronic Data Capture (EDC) will be used in the trial. 
2) Subject data will be entered directly into the database from the trial site via a 
Web browser.  These data collected by EDC will constitute the CRF. 
3) Regarding quality assurance of CRFs, the guidelines specified in “Use 
of Electromagnetic Records and Electronic Signatures in Applications for 
Approval or Licensing of Drugs” (PFSB Notification No. 0401022, dated 01 Apr 
2005) and “Guidance on Electronic Capture of Clinical Study Data” (Drug 
Evaluation Committee, Japan Pharmaceutical Manufacturers Association, dated 
01 Nov 2007) will be observed. 


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4) For every subject who provides consent to participate in the trial, a CRF will 
be created on an EDC data entry screen that conforms to the items of CRF 
data collection described in the trial protocol. 
5) The investigator, subinvestigator, or trial associate will create CRFs according to 
the manual provided by the sponsor.  If source documents are available and 
the objectivity of the data can be ensured, then the data may be recorded in a CRF 
by a trial associate. 
6) When entering data into CRFs from the trial site, a predetermined check will 
be automatically performed. The investigator, subinvestigator, or a trial associate 
will make corrections as necessary. 
7) The sponsor will verify CRFs in comparison to source documents and conduct 
data reviews. If additional query is necessary, the sponsor will issue an intra- 
system query, and the investigator, subinvestigator, or a trial associate will 
perform data correction or provide a response to the sponsor’s query as necessary. 
8) A history of all revisions made after the initial data entry is saved on the server 
will be automatically recorded within the system (date of revision, name of 
person making revision, pre- and post-revision data, reason for revision, date of 
query, name of person issuing query, details of query, etc.). 
9) After completion of all CRF data entry and confirmation that the content is 
correct and complete, including confirmation of the audit trail, the investigator 
will attach an electronic signature. 
10) Details concerning data collection will be specified in a separate manual prepared 
in advance. 
 
10.2 
Source Documents 
 
1) Source documents are defined as those documents that are the source of 
data transcribed into CRFs as trial results. 
Medical records and other records (medical records, nursing records, 
prescription records), subject screening list, registration verification forms, ICFs, 
clinical laboratory test and other measurement reports, 12-lead ECG analysis 
reports, IMP management records, administration diaries, VAS sheets, pruritus 
diaries 
2) The investigator or the trial site will retain all trial-related documents and 
records except CRFs in such a manner that enables the sponsor or the regulatory 
authority to have direct access to the documents and records. 
3) The original ICFs will be retained according to the method specified by each 
trial site. 
4) After completion of the trial, the sponsor will retain the original CRFs on CD- 
ROM or some other appropriate electronic medium and the investigator or the 
trial site will retain copies. 
5) The original data regarding drug concentration measurement (eg, original 
bioanalytical reports, chromatograms) will be kept by the bioanalytical 
laboratory. 


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10.3 
Case Report Form Items Treated as Source Data 
 
Not applicable. 
 
 
10.4 
Data to Be Collected by the Sponsor 
 
1) CRFs (data following acquisition of informed consent) 
2) Results of clinical laboratory tests conducted by the central laboratory will 
be directly sent to the sponsor by the central laboratory in the form of electronic 
data. 
3) Results of 12-lead ECG measurement performed by the central ECG 
reading facility will be directly sent to the sponsor by the central ECG reading 
facility in the form of electronic data. 
4) Results of drug concentration measurement conducted by the bioanalytical 
laboratory will be directly sent to the sponsor by the bioanalytical laboratory in 
the form of electronic data. 
 
11 
Statistical Analysis 
The definition of the analysis sets and analysis methods are described below. The 
details of the analysis plan are described separately in a statistical analysis plan. The 
statistical analysis plan will be finalized prior to database lock. 
11.1 
Statistical Analysis Sets 
 
In this trial, a “Full Analysis Set” and “Safety Set” will be established. 
11.1.1 
Full Analysis Set (FAS) 
 
Subjects to whom the IMP has been administered at least once. 
11.1.2 
Safety Set (SS) 
 
Subjects to whom the IMP has been administered at least once. 
 
 
11.2 
Handling of Data 
 
Regarding the incidence of success in IGA, the data will be handled as follows. 
1) Primary analysis 
 Subjects with an IGA score of 0 (clear) or 1 (almost clear) with an 
improvement by at least 2 grades from the baseline are defined as responders. 


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Subjects with missing IGA data at the time of evaluation will be handled as non- 
responders. 
2) Sensitivity analysis 
 Subjects with an IGA score of 0 (clear) or 1 (almost clear) with an 
improvement by at least 2 grades from the baseline are defined as responders. For 
subjects with missing IGA data at the time of evaluation, the last observation 
carried forward (LOCF) will be used. 
 Subjects with an IGA score of 0 (clear) or 1 (almost clear) with an 
improvement by at least 2 grades from the baseline are defined as responders. 
Observed cases (OC) will be used. 
 Subjects with an improvement in IGA score to 0 (clear) or 1 (almost clear) 
are defined as responders. Subjects with missing IGA data at the time of 
evaluation will be handled as non-responders. 
 
11.3 
Analysis Items and Method 
 
11.3.1 
Efficacy Analysis 
 
11.3.1.1 
Primary Variable 
1) Definition 
Incidence of success in IGA at Week 4: percentage of subjects with an IGA 
score of 0 (no response) or 1 (almost no response) with an improvement by at 
least 2 grades (responders) 
2) Analysis set 
FAS 
3) Method of analysis 
The Cochran-Mantel-Haenszel test will be conducted using the baseline IGA 
(mild or moderate) as a stratification factor. In consideration of the issue of 
multiplicity, a comparison between the vehicle group and the 1% OPA-15406 
group will be performed first based on the closed testing procedure. When 
superiority of the 1% OPA-15406 group compared to the vehicle group is 
demonstrated with a two-sided significance level of 0.05, a comparison between 
the vehicle group and the 0.3% OPA-15406 group will be performed. Also, the 
difference in the incidence of success in IGA and its two-sided 95% confidence 
interval will be determined between the vehicle group and the 0.3% OPA-15406 
group or the 1% OPA-15406 group. Also, the sensitivity analysis will be 
performed using the 3 data handling methods in “2) Sensitivity analysis in Section 
11.2 Handling of Data,” under the same analysis procedure described above.  In 
an exploratory manner, a logistic-regression analysis will be conducted, using 
the baseline IGA (mild or moderate) and the treatment group as explanatory 
variables and the incidence of success in IGA at Week 4 as the outcome variable. 


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11.3.1.2 
Secondary Variables 
1) Definition 
 Incidence of success in IGA at Week 1 and Week 8 
 Change from baseline in IGA at Week 1, Week 4, and Week 8 
 Change from baseline in the total score of EASI and each symptom score at Week 
1, Week 4, and Week 8 
 Change from baseline in VAS for pruritus at Week 1, Week 4, and Week 8 
 Change from baseline in VRS for pruritus up to Day 7 
 Change from baseline in the total score of DLQI at Week 1, Week 4, and Week 
8 
 Change from baseline in the total score of POEM at Week 1, Week 4, and Week 
8 
 Change from baseline in the total affected BSA (%) at Week 1, Week 4, 
and Week 8 
 Time to response in IGA and VRS 
2) Analysis set 
FAS 
3) Method of analysis 
 Incidence of success in IGA at Week 1 and Week 8 
The analysis method will be the same as that for the primary variable. 
 Change from baseline in IGA at Week 1, Week 4, and Week 8 
A mixed-model repeated measure (MMRM) analysis with an unstructured 
error covariance matrix will be performed, using the OC data set containing the 
data at baseline, after administration (Week 1, Week 2, Week 4, Week 6, 
and Week 8), and at discontinuation, setting the change from the baseline at Week 
1 through Week 8 as a response variable and the treatment (0.3% OPA-15406, 1% 
OPA-15406, or vehicle), timepoint, baseline IGA (mild or moderate), interaction 
between the treatment (0.3% OPA-15406, 1% OPA-15406, or vehicle) and 
timepoint as factors.  Standard error and degree of freedom for the fixed effect 
will be calculated by the Kenward-Roger method. The least square mean will be 
calculated by treatment group and timepoint. Also, the difference in the least 
square means between the vehicle group and the respective OPA-15406 groups, 
the two-sided 95% confidence interval, and the p value will be calculated at Week 
1, Week 4 and Week 8. Using the OC and LOCF data sets, the analysis of 
covariance (ANCOVA) with treatment (0.3% OPA-15406, 1% OPA-15406, or 
vehicle) and baseline IGA (mild or moderate) as factors will be applied to the 
change from the baseline at the respective timepoints as a response variable. The 
least square mean will be calculated by treatment group and timepoint. Also, the 
difference in the least square means between the vehicle group and the respective 
OPA-15406 groups, the two-sided 95% confidence interval, and the p value will 
be calculated at Week 1, Week 4 and Week 8. Using the OC and LOCF data sets, 
the descriptive statistics will be calculated for measured values and changes from 


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the baseline at the respective timepoints by treatment group and timepoint. For 
the change in IGA at Week 1, Week 4, and Week 8, the frequency distribution 
will also be generated. 
 For the following items, the analysis will be performed in the same manner as 
that of the change from baseline at the respective timepoints in IGA. For the 
MMRM analysis, however, the treatment (0.3% OPA-15406, 1% OPA-15406, or 
vehicle), timepoint, and interaction between the treatment and timepoint will be 
used as factors, and baseline values of the respective variables will be used as 
covariates. For the ANCOVA model, baseline values of the respective variables 
will also be included as covariates, as well as the treatment. For EASI, VAS, and 
DLQI, the percent change from baseline at the respective timepoints will also be 
calculated in the same manner as the amount of change. 
a) Change from baseline in the total score of EASI and each symptom score 
at Week 1, Week 4, and Week 8 
b) Change from baseline in VAS for pruritus at Week 1, Week 4, and Week 8 
c) Change from baseline in the total score of DLQI at Week 1, Week 4, 
and Week 8 
d) Change from baseline in the total score of POEM at Week 1, Week 4, 
and Week 8 
e) Change from baseline in the total affected BSA (%) at Week 1, Week 4, 
and Week 8 
 Change from baseline in VRS for pruritus up to Day 7 
Using the OC and LOCF data sets up to Day 7, the analysis of covariance 
(ANCOVA) with treatment (0.3% OPA-15406, 1% OPA-15406, or vehicle) and 
baseline values as factors will be applied to the change from the baseline at the 
respective timepoints as a response variable. The least square mean will 
be calculated by treatment group and timepoint. Also, the difference in the 
least square means between the vehicle group and the respective OPA-15406 
groups, the two-sided 95% confidence interval, and the p value will be calculated. 
Using the OC and LOCF data sets, the descriptive statistics will be calculated for 
measured values and changes from the baseline at the respective timepoints by 
treatment group and timepoint. Assessments will be made at 4, 8, and 12 hours 
after the start of administration, 1 day after the start of administration (morning 
and night), and thereafter in the same manner up to Day 7 (morning). 
 Time to response in IGA and VRS 
For time to response in IGA and VRS, Kaplan-Meier plots will be generated 
for each treatment group and vehicle group. For IGA, subjects with an IGA score 
of 0 (clear) or 1 (almost clear) with an improvement by at least 2 grades from 
the baseline are defined as responders. For VRS, subjects with VRS score of 0 
(none) or 1 (mild) with an improvement by at least 1 grade from the baseline are 
defined as responders. 


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11.3.2 
Safety Analysis 
 
1) Definition 
Adverse events (Physical findings will be evaluated for reported adverse 
events), vital signs (including body weight), clinical laboratory values, 12-lead 
ECG 
2) Analysis set 
SS 
3) Method of analysis 
 Adverse events 
Based on System Organ Classes and Preferred Terms of the ICH 
Medical Dictionary for Regulatory Activities (MedDRA), the number of subjects 
and incidences will be calculated for the following events occurring after 
IMP administration (treatment-emergent adverse events: TEAEs).  For TEAEs 
for which the relationship to the IMP cannot be ruled out, the number of subjects 
and incidences will also be calculated, in the same manner. 
1. TEAEs 
2. TEAEs resulting in death 
3. Serious TEAEs 
4. TEAEs leading to discontinuation of IMP administration 
5. TEAEs by severity 
6. TEAEs at treatment areas 
 Vital signs (including body weight) 
For each parameter, the descriptive statistics will be calculated for measured 
values and changes from the baseline by treatment group and timepoint. 
 Clinical laboratory tests 
For each parameter (except qualitative urinalysis), the descriptive statistics will 
be calculated for measured values and changes from the baseline by treatment 
group and timepoint. Except for qualitative urinalysis parameters, shift tables will 
be created for predose and postdose values classified into normal, high, and low 
based on the standard value by treatment group. For qualitative urinalysis, shift 
tables will be created for predose and postdose values by each parameter. 
 12-lead ECG 
The descriptive statistics will be calculated for measured values and changes from 
the baseline by treatment group and timepoint. 
 
11.3.3 
Pharmacokinetic Analysis 
 
1) Variables 
 
 Plasma trough concentration of OPA-15406 (prior to IMP administration 
at Week 1, Week 4, and Week 8 of IMP administration; all subjects) 


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 Plasma concentration of OPA-15406 (prior to IMP administration and 2 
hours, 4 hours, and 8 hours postdose on Day 1 and at Week 4; specific sites 
(target of 6 subjects from each group) 
 Pharmacokinetic parameters of OPA-15406: Cmax, tmax, and AUC0-8h on Day 
1 and at Week 4 of IMP administration 
 Accumulation of OPA-15406: Ratio of Cmax and AUC0-8h at Week 4 and on 
Day 1 of IMP administration 
2) Analysis set 
Pharmacokinetics analysis set 
3) Method of analysis 
 Method of calculation 
Plasma concentrations below the lower limit of quantification will be treated 
as zero (0) for calculation of the descriptive statistics. 
 Method of display 
Arithmetic means and standard deviations will be used for figures and tables 
of plasma concentration. 
a) Regarding plasma trough concentration of OPA-15406, the descriptive 
statistics of plasma OPA-15406 concentrations (number of subjects, 
arithmetic mean, standard deviation, coefficient of variation, minimum value, 
median value, and maximum value) will be calculated by treatment group, 
by timepoint, and by baseline affected BSA (≥5% to <10%, ≥10% to <30%, or 
≥30%). Also, the descriptive statistics (number of subjects, arithmetic mean, 
standard deviation, coefficient of variation, minimum value, median value, 
and maximum value) will be calculated by age for each range of affected 
BSA, by affected BSA (%) at the baseline, and by amount of administration 
(g). 
b) Regarding plasma trough concentration of OPA-15406, the descriptive 
statistics of plasma OPA-15406 concentrations by treatment group and 
timepoint, and the descriptive statistics of plasma OPA-15406 concentrations 
(number of subjects, arithmetic mean, standard deviation, coefficient of 
variation, minimum value, median value, and maximum value) adjusted for 
affected BSA at the baseline will be calculated. The subject group for 
pharmacokinetic parameters should be calculated in the same way separately. 
c) Regarding pharmacokinetic parameters of OPA-15406, the descriptive 
statistics (number of subjects, arithmetic mean, standard deviation, coefficient 
of variation, minimum value, median value, and maximum value) by 
treatment group and timepoint will be calculated. 
 
11.3.4 
Demographic and Other Baseline Characteristics 
 
1) Definition 
Baseline data of sex, age, complications, medical history, previous medications 


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(for AD or for other diseases), concomitant medications, severity, IGA, EASI, 
VAS for pruritus, VRS for pruritus, DLQI, POEM, and affected BSA 
2) Analysis set 
SS, FAS 
3) Method of analysis 
The descriptive statistics or frequency distribution will be created by 
treatment groups depending on the characteristics of the respective parameters. 
 
11.3.5 
Subgroup Analysis 
 
For the incidence of success in IGA at Week 1, Week 4, and Week 8, the analysis will 
be performed in the same manner as that for the primary variable by subgroups of 
baseline IGA (mild or moderate). Also, the frequency distribution will be generated by 
the trial sites. 
11.3.6 
Level of Significance and Confidence Coefficient 
 
The two-sided significance level is 5% with a two-sided 95% confidence interval. 
11.3.7 
Multiple Comparison/Multiplicity 
 
For the analysis of the primary variable, a comparison will be performed between 
the vehicle group and the 1% OPA-15406 group and between the vehicle group and the 
0.3% OPA-15406 group. The closed testing procedure will be employed to avoid the 
issue of multiplicity. For variables other than the primary variable, the analysis will be 
performed for reference, and the multiplicity adjustment will not be conducted. 
11.3.8 
Adjustment by Covariates 
The Cochran-Mantel-Haenszel test will be performed, using baseline IGA (mild 
or moderate) as a stratification factor. 
 
 
11.4 
Procedures for Reporting Deviations From the Original Statistical 
Analysis Plan 
 
The statistical analysis plan of this trial will be finalized by the time of data fixation. 
If any content of the analysis methods specified in this protocol are to be changed, 
the detail and reason for the change will be described in the statistical analysis plan 
and clinical study report. 
If any change or addition is made from the statistical analysis plan after 
unblinding, results of the changed or additional analysis will be clearly distinguished 


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from those of the planned analysis, and caution should be taken regarding the possible 
effects on the conclusion. Also, the reason for the change or addition will be stated in the 
clinical study report. 
 
 
11.5 
Rationale for Target Number of Patients 
 
In the phase 2 trial outside Japan (271-12-205), the primary variable of incidence 
of success in IGA was 20.93% and 2.70% in the 1% OPA-15406 group and the 
vehicle group, respectively. In the present trial, with the assumption that the difference in 
the incidence of success in IGA between the vehicle group and the 1% OPA-15406 group 
is similar to that obtained in the foreign trial, a sample size of 54 subjects per group at a 
two-tailed 5% level of significance was calculated with at least an 80% power. In 
consideration of possible discontinuations and dropouts, the number of subjects is 
established as 60 subjects per group. 
 
 
12 
Quality Control and Quality Assurance for the Trial 
To ensure quality of the trial, trial sites, contract research organizations, 
laboratories performing clinical laboratory tests, and the sponsor will perform quality 
control for the trial according to their respective Standard Operating Procedures. 
The audit division of the sponsor company will carry out audits within the company 
and, as necessary, at the trial site and contract research organizations or organizations 
entrusted to perform related activities, and check whether quality control of the trial is 
appropriately performed according to the Standard Operating Procedures. 
 
 
13 
General Items of Caution Pertaining to the Trial 
13.1 
Ethics and GCP Compliance 
 
This clinical trial is to be conducted in compliance with the ethical principles of 
the Declaration of Helsinki, the Pharmaceutical Affairs Law, the Ordinance on Good 
Clinical Practice (Ministry of Health and Welfare Ordinance No. 28 dated 27 Mar 1997), 
relevant notifications, and this trial protocol. 


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13.2 
Institutional Review Board 
 
Prior to performance of this trial, the appropriateness of performance of this trial will be 
reviewed from ethical, scientific, and medical perspectives by the IRB designated by 
the trial site, and this trial will be commenced only after obtaining the approval of the 
IRB. 
 
 
13.3 
Subject Consent 
 
13.3.1 
Procedures for Obtaining Consent 
 
The term “consent” in this protocol is defined as legally established consent that is 
given by the subject or the subject’s legal guardian. 
1) Prior to the start of the screening examination, the investigator or 
subinvestigator will fully explain the matters listed in Section13.3.2 to each 
subject (and the subject’s legal guardian if the subject is under 20 years old) who 
will be included in the trial, using the ICF, and give the ICF to the subject (or to 
the subject’s legal guardian if the subject is under 20 years old). The subject will 
be provided sufficient time to make a decision regarding participation. After 
confirming that the subject has properly understood the explanation, 
the investigator or subinvestigator will obtain written voluntary consent 
for participation in the trial from the subject. If the subject is under 20 years old, 
the relationship between the subject and the subject’s legal guardian will be 
confirmed and recorded. 
2) The investigator or subinvestigator who has provided the explanation to the 
subject (and the subject’s legal guardian if the subject is under 20 years old) will 
put his or her printed name and personal seal or signature on the ICF, and write 
the date on which he or she puts the printed name and personal seal or signature 
on the form. If a trial associate has provided a supplemental explanation of the 
trial, he/she will also put his or her printed name and personal seal or signature on 
the form and write the date on which he or she puts the printed name and personal 
seal or signature on the form. The subject (and the subject’s legal guardian if the 
subject is under 20 years old) will also put his or her printed name and personal 
seal or signature, and the date on the ICF. 
3) The original of the ICF that was marked with the printed name and personal seal 
or signature and dated will be retained by the investigator or subinvestigator 
according to the regulations of the trial site. A copy of the original ICF will be 
given to the subject (or to the subject’s legal guardian if the subject is under 20 
years old). 
4) After obtaining informed consent from the subject (and the subject’s legal 
guardian if the subject is under 20 years old), the investigator or subinvestigator 
will write the date of informed consent acquisition and subject identification code 
in the documents for enrolled subjects. 


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5) If new information becomes available that may influence the willingness of 
the subject to continue participation in the trial, the investigator or subinvestigator 
will promptly inform the subject (and the subject’s legal guardian if the subject is 
under 20 years old) of such information and confirm the willingness of the subject 
to continue participation in the trial, and then record the result in the subject’s 
medical records. If there is guidance regarding the recording of re-consent 
stipulated by the trial site, it will be followed. 
 
13.3.2 
Contents of Informed Consent Form 
 
1) An explanation that the trial involves research 
2) The type of IRB that reviews the appropriateness of trial conduct, matters to 
be reviewed by the IRB, and other relevant descriptions of the activity of the IRB 
3) The objectives of the trial 
4) The trial procedures (including research-related aspects of the trial, inclusion 
criteria for subjects, and, if random allocation is performed, the probability 
of randomization to each treatment arm) 
5) The expected duration of the subject's participation in the trial 
6) The planned number of subjects involved in the trial 
7) The foreseeable IMP-related physical and mental benefits (if no benefits 
are expected, this should be indicated) as well as risks or inconveniences to the 
subject 
8) The existence of alternative treatments for the subject, and their important 
potential benefits and risks 
9) The treatment and compensation available to the subject in the event of trial- 
related injury to health 
10) An explanation that the subject's participation in the trial is voluntary, and that 
the subject can refuse to participate or withdraw from the trial, at any time, 
without penalty or loss of benefits to which he or she would otherwise be entitled 
11) An explanation that the subject will be informed in a timely manner if 
information becomes available that may be relevant to his or her willingness to 
continue participation in the trial 
12) The circumstances or reasons under which the subject's participation in the 
trial should be terminated 
13) An explanation that the monitors, the auditors, the IRB, and the 
regulatory authorities will be granted direct access to the subject's original 
medical records without violating the confidentiality of the subject, and that by 
signing the ICF, the subject is authorizing such access 
14) 1An explanation that if the results of the trial are published, the subject's identity 
will remain confidential 
15) 1The anticipated expenses to the subject for participating in the trial 


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16) The anticipated payment, if any, to the subject for participating in the 
trial (agreements on payment, etc.) 
17) The name, position, and contact address of the investigator or subinvestigator 
18) The persons at the trial site to contact for further information regarding the trial 
and the rights of trial subjects, and whom to contact in the event of trial-related 
injury to health 
19) Matters to be observed by subjects 
 
13.3.3 
Amendments to the Informed Consent Form 
 
If revision of the ICF becomes necessary due to newly obtained information, 
the investigator will promptly revise the ICF to include that information after conferring 
with the sponsor. 
The investigator, when revising the ICF, will report this to the head of the trial site 
and submit the revised document to the IRB designated by the trial site to obtain its 
approval. 
If new information becomes available that may influence the willingness of subjects 
to continue participation in the trial and the ICF has been revised according to the 
new information, the investigator or subinvestigator will again obtain subjects’ 
written informed consent to continue participation in the trial. 
 
 
13.4 
Management of Investigational Medicinal Products 
 
1) The sponsor will issue a “Clinical Operation Manual (COM)” to the 
persons designated by the trial site. 
2) The sponsor will issue the “Document on Investigational Medicinal 
Products Storage Conditions” to the investigator or subinvestigator, trial 
associates, and IMP manager. 
3) The sponsor will deliver the IMPs to the trial site following the start of the 
trial period contracted with the trial site. 
4) The IMP manager will manage the IMPs appropriately according to the 
“COM” prepared by the sponsor. 
5) The IMP manager will prepare and retain the “Record of Management and 
Storage of Investigational Medicinal Products.” 


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13.5 
Direct Access to Source Documents and Monitoring 
 
13.5.1 
Direct Access to Source Documents 
 
The head of the trial site and the investigator must accept monitoring and audits to 
be performed by the sponsor and inspection by the IRB and Japanese and foreign 
regulatory authorities, and must make source documents and all other trial-related records 
available to these agencies for direct access (including copying). Subjects authorize such 
direct access by signing the written ICF. 
13.5.2 
Monitoring 
 
The sponsor bears responsibility for ethical, legal, and scientific conduct of the trial. 
The sponsor will perform monitoring according to the “Procedures for monitoring” 
specified for this trial. Monitoring includes periodic visits, phone calls, or other contact 
with the trial site for the provision, obtaining, and recording of updated trial-related 
information by monitors designated by the sponsor. 
The sponsor may entrust a portion of monitoring activity to a contract 
research organization. 
13.5.3 
Documents to Be Retained by the Investigator 
 
The trial-related documents to be retained by the investigator will be kept in 
the investigator’s file, which will be managed by the investigator. 
 
 
13.6 
Deviations From and Changes or Amendments to the Trial 
Protocol 
 
13.6.1 
Deviations From the Trial Protocol 
 
1) The investigator or subinvestigator should not deviate from the protocol or 
change it without prior written agreement between the investigator and the 
sponsor and the written approval of the IRB of the trial site based on prior review. 
2) In unavoidable medical circumstances such as the need to avoid emergent risk to 
a subject, the investigator or subinvestigator may deviate from the protocol or 
change the protocol without prior written agreement from the sponsor and prior 
approval of the IRB. In such an event, the investigator will promptly submit a 
document providing the details of and reason for the deviation or change to the 
sponsor and the head of the trial site and obtain approval from the IRB. In 
addition, the investigator will obtain written approval from the head of the trial 
site and the written agreement of the sponsor by way of the head of the trial site. 
3) The investigator or subinvestigator will record all deviations from the protocol 


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13.6.2 
Amendments to the Trial Protocol 
 
1) The investigator will promptly submit to the sponsor, the head of the trial site, and 
the IRB by way of the head of the trial site, a written report on any changes in the 
trial that may significantly affect conduct of the trial or increase risks to the trial 
subjects. 
2) The sponsor, after conferring with the investigator, will agree with the 
investigator on the contents of the revised protocol and compliance with the 
revised protocol. 
3) The sponsor will promptly submit the revised protocol to the head of the trial site. 
 
13.7 
Archiving of Records 
 
1) The trial site will retain all the trial-related documents and records for the period 
of time indicated in a) or b) below, whichever is longer.  However, if the 
sponsor requires a longer period of archiving, the head of the trial site will consult 
with the sponsor on the period and procedures of record retention. 
a) The date 2 years after an Application for Approval of a Pharmaceutical 
Product for the IMP is granted; or, if the head of the trial site receives 
notification from the sponsor that development has been terminated or that 
results of the trial will not be submitted with the approval application, the date 
3 years after receipt of such notification. 
b) The date 3 years after termination or completion of the trial. 
2) The investigator will retain the trial-related documents and records as directed 
by the head of the trial site. 
3) If it becomes no longer necessary to retain the trial-related documents and 
records at the trial site, the sponsor will notify the head of the trial site. 
 
13.8 
Termination or Interruption of Part or All of the Trial 
 
13.8.1 
Termination or Interruption of the Trial at Individual Trial Sites 
 
1) In the event of termination or interruption of the trial, the investigator will 
promptly provide the head of the trial site with written notification and a written 
explanation of the details of the termination or interruption of the trial. 
2) When the sponsor has been informed by the head of a trial site that the 
investigator has terminated or interrupted the trial, the sponsor will obtain a 
detailed written explanation of the termination or interruption of the trial from the 
head of the trial site. 


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13.8.2 
Termination or Interruption of the Entire Trial 
 
1) When the entire trial is to be terminated or interrupted by the sponsor, the 
sponsor will promptly provide the heads of all trial sites involved in the trial and 
the regulatory authority with written notification and a detailed written 
explanation of the reason for the termination or interruption of the trial. 
2) When the investigator has received notification of termination or interruption of 
the entire trial by the sponsor from the head of the trial site, the investigator will 
obtain a detailed written explanation of the termination or interruption of the trial 
from the head of the trial site, promptly notify the trial subjects currently 
receiving IMP administration, and take necessary measures such as switching to 
appropriate alternative treatment(s). 
3) When development of the IMP is terminated by the sponsor, the sponsor 
will promptly provide the heads and the investigators of all trial sites involved in 
the trial and the regulatory authority with written notification and a detailed 
written explanation of the reason for the termination of development. 
 
13.9 
Protection of Subjects’ Personal Information 
 
In completion and handling of CRFs, the investigator and subinvestigator will 
take adequate care to ensure protection of the personal information of subjects. 
Individual subjects will be identified by subject numbers. The sponsor will not provide 
the information obtained to any third party. 
 
 
13.10 
Compensation for Injury to Health 
 
Trial subjects will be compensated for health damages according to the criteria 
established by the trial sponsor with reference to the “Guidelines for Health Damage 
Compensation to Trial Subjects” (revised 25 Nov 2009) of the Japan Pharmaceutical 
Industry Legal Affairs Association. 
 
 
13.11 
Agreement on Publication 
 
The sponsor may use the findings obtained from this trial for purposes such as 
an “Application for Approval of a Pharmaceutical Product” for the IMP. 
When the results of this trial and relevant data are to be published in scientific journals 
or at academic meetings, the investigator will obtain prior written approval from the 
sponsor. 


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14 
Trial Administrative Structure 
The administrative structure of this trial is shown in Annex 3. 
 
 
15 
Scheduled Duration of the Trial 
21 Jul 2016 to 31 Jul 2017 
 
 
16 
References 
1 
Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta 
Dermatol Suppl.1980;92:44-7. 
2 
Kato N, Saeki H, Nakahara T, Tanaka A, Kabashima K, Sugaya M, et al. 
Guidelines for Management of Atopic Dermatitis. The Japanese Journal of 
Dermatology. 2016;126(2):121-55. 
3 
Hanifin JM, Butler JM, Chan SC.  Immunopharmacology of the atopic diseases. 
J Invest Dermatol.  1985;85 (1 Suppl):161s-4s 
4 
Mosteller RD. Simplified calculation of body-surface area. N Engl J 
Med. 1987;317:1098. 
5 
Leung DY, Hanifin JM, Pariser DM, Barber KA, Langley RG, Schlievert PM, et al. 
Br J Dermatol. 2009;161:435-43. 
6 
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. Exp Dermatol. 
2001;10:11-8. 
7 
Phan NQ, Blome C, Fritz F, Gers J, Reich A, Toshi Ebata T, et al. Acta Derm 
Venereol.  2011;92:Epub ahead of print. 
8 
Finlay AY, Khan GK.  Clin Exp Dermatol. 1994;19:210-6. 
9 
Charman CR, Venn AJ, Ravenscroft JC, Williams HS. Br J Dermatol. 
2013;169:1326-32. 
10 Kohno Y, supervised by Yamamoto S. Guidelines for the Management of 
Atopic Dermatitis 2008. Available from: 
http://www.jaanet.org/pdf/guideline_skin02.pdf 
11 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. 


271-15-001 
Date 
( 
examination) 
Subject Number  
-S- 
Appendix 1 
Diagnostic Criteria for Atopic Dermatitis 
13 Sep 2016 (Version 3) 
Confidential - Proprietary Information 
 
 
(Hanifin & Rajka) 
 
A. Must have 3 or more basic features described below 
1) Pruritus 
2) Typical morphology and distribution 
Flexural lichenification in adults 
Facial and extensor involvement in infants and children 
3) Chronic or chronically-relapsing dermatitis 
4) Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis) 
B. Must have 3 or more following minor features: 
1) Xerosis 
2) Ichthyosis, palmar hyperlinearity, keratosis pilaris 
3) Immediate (type 1) skin test reaction 
4) Elevated serum IgE 
5) Early age of onset 
6) Tendency toward cutaneous infections (especially Staph. aureus and Herpes simplex)/impaired 
cell-mediated immunity 
7) Tendency toward non-specific hand or foot dermatitis 
8) Nipple eczema 
9) Cheilitis 
10) Recurrent conjunctivitis 
11) Dennie-Morgan infraorbital fold 
12) Keratoconus 
13) Anterior subcapsular cataracts 
14) Orbital darkening 
15) Facial pallor, facial erythema 
16) Pityriasis alba 
17) Anterior neck folds 
18) Itch when sweating 
19) Intolerance to wool and lipid solvents 
20) Perifollicular accentuation 
21) Food intolerance 
22) Course influenced by environmental and emotional factors 
23) White dermographism, delayed blanch 


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Appendix 2 
Visual Analogue Scale (VAS) Sheet for 
Pruritus 
 
 
 
 
 
No Itching 
Maximum Itching 
0 
100 


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Appendix 3 
Dermatology Life Quality Index (DLQI) 
 
The DLQI questionnaire is shown on the next page. 
 
 
© Dermatology Life Quality Index. AY Finlay, GK Khan, April 1992. www.dermatology.org.uk 


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Date 
( 
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Subject Number  
-S- 
 
 
 
Dermatology Life Quality Index (DLQI) 
 
 
Hospital No: 
Date: 
Name: 
Score: 
Address: 
Diagnosis: 
 
The aim of this questionnaire is to measure how much your skin problem has affected your life 
OVER THE LAST WEEK.  Please tick  one box for each question. 
 
1) Over the last week, how itchy, sore, painful or stinging has your skin been? 
□ Very much 
□ A lot 
□ A little 
□ Not at all 
 
2) Over the last week, how embarrassed or self conscious have you been because of your skin? 
□ Very much 
□ A lot 
□ A little 
□ Not at all 
 
3) Over the last week, how much has your skin interfered with you going shopping or looking after  your 
home or going garden? 
□ Very much 
□ A lot 
□ A little 
□ Not at all 
□ Not relevant 
 
4) Over the last week, how much has your skin influenced the clothes you wear? 
□ Very much 
□ A lot 
□ A little 
□ Not at all 
□ Not relevant 
 
5) Over the last week, how much has your skin affected any social or leisure activities? 
□ Very much 
□ A lot 
□ A little 
□ Not at all 
□ Not relevant 
 
6) Over the last week, how much has your skin made it difficult for you to do any sport? 
□ Very much 
□ A lot 
□ A little 
□ Not at all 
□ Not relevant 
 
7) Over the last week, has your skin prevented you from working or studying? 
□ Yes 
□ No 
□ Not relevant 


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Subject Number  
-S- 
 
 
 
 
If "No", over the last week how much has your skin been a problem at work or studying? 
□ A lot 
□ A little 
□ Not at all 
 
8) Over the last week, how much has your skin created problems with your partner or any of your close 
friends or relatives? 
□ Very much 
□ A lot 
□ A little 
□ Not at all 
□ Not relevant 
 
9) Over the last week, how much has your skin caused any sexual difficulties? 
□ Very much 
□ A lot 
□ A little 
□ Not at all 
□ Not relevant 
 
10) Over the last week, how much of a problem has the treatment for your skin been, for example by 
making your home messy, or by taking up time? 
□ Very much 
□ A lot 
□ A little 
□ Not at all 
□ Not relevant 
 
Please check you have answered EVERY question. Thank you. 
Unauthorized copying or replication of the above contents is strictly prohibited. ©DLQI AY Finlay, GK 
Khan, 1992, All rights reserved. 


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Appendix 4 
Patient-Oriented Eczema Measure (POEM) 
 
The POEM questionnaire is shown on the next page. 
 
 
© The University of Nottingham 


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( 
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-S- 
 
 
 
 


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Appendix 5 
Human Body Drawing 
 
 
 
 
 
Total amount of administration  
g 
 
 
 
 
 
Signature of the investigator/subinvestigator 
 
 
Day/ 
Month/20 
Affected site 
Affected area (%) 
Face, neck, and head 
% 
Upper limbs 
% 
Trunk 
% 
Lower limbs 
% 
Administration site 
Treatment area (%) 
Face, neck, and head 
% 
Upper limbs 
% 
Trunk 
% 
Lower limbs 
% 
Total 
% 

SAP_001.pdf: 
 
 
 
 
 
STATISTICAL  ANALYSIS  PLAN 
 
 
A Multicenter, Randomized, Double-blind,  
Vehicle-controlled, Parallel-group Comparison Trial to Assess the 
Efficacy and Safety of 0.3% and 1% OPA-15406 Ointments in 
Patients With Atopic Dermatitis 
(Phase 2) 
 
 
                                                                                                    NCT Number: 02914548 
                                                                                                     PRT NO. ：271-15-001 
                                                                   PRT Version Date: 18 Aug 2017（Version 1） 
 
 
 
 
 
 
 
 
 
 


Protocol 271-15-001 
 
 
2 
 
 
 
A Multicenter, Randomized, Double-blind,  
Vehicle-controlled, Parallel-group Comparison Trial to Assess the 
Efficacy and Safety of 0.3% and 1% OPA-15406 Ointments in 
Patients With Atopic Dermatitis 
(Phase 2) 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
for 
Protocol No. 271-15-001  
(Translated Version) 
 
Confidential 
 
 
 
Otsuka Pharmaceutical Co., Ltd 
 
 
Version 1: 18 Aug 2017   
Date of Translation: 28 Nov 2017 


Protocol 271-15-001 
 
 
3 
 
 
Table of Contents 
Table of Contents ........................................................................................... 3 
List of Abbreviations and Definition of Terms ........................................... 5 
1 
Introduction .......................................................................................... 7 
2 
Trial Objectives .................................................................................... 7 
3 
Trial Design ........................................................................................... 7 
4 
Implementation of Planned Analyses ................................................. 9 
5 
Statistical Analysis Sets ........................................................................ 9 
5.1 
Definitions of Analysis Sets ............................................................................... 9 
6 
Considerations for Data Analysis ..................................................... 10 
6.1 
Software ............................................................................................................ 10 
6.2 
Dictionaries ....................................................................................................... 10 
6.3 
Data Conversion and Calculation ..................................................................... 10 
6.4 
Study Week Windows ...................................................................................... 12 
6.5 
Handling of Missing Values ............................................................................. 13 
6.6 
Significance Level and Confidence Coefficient ............................................... 13 
7 
Disposition of Subjects ....................................................................... 14 
7.1 
Disposition of Subjects ..................................................................................... 14 
7.2 
Statistical Analysis Sets .................................................................................... 14 
7.3 
Protocol Deviations ........................................................................................... 14 
8 
Description of Analysis Dataset ........................................................ 15 
8.1 
Demographics and Baseline Characteristics ..................................................... 15 
8.2 
Medical History/Complications ........................................................................ 15 
8.3 
Prior and Concomitant Medications ................................................................. 15 
8.4 
Concomitant Therapies ..................................................................................... 15 
9 
Efficacy Analyses ................................................................................ 15 
9.1 
Primary Endpoint .............................................................................................. 16 
9.2 
Secondary Endpoints ........................................................................................ 16 
9.3 
Other Efficacy Endpoints .................................................................................. 21 


Protocol 271-15-001 
 
 
4 
 
9.4 
Adjustments for Covariates .............................................................................. 21 
9.5 
Subgroup Analysis ............................................................................................ 22 
10 
Safety Analysis .................................................................................... 22 
10.1 
Exposure to the IMP (Number of Subjects, Duration, and Doses) ................... 22 
10.2 
Adverse Events ................................................................................................. 22 
10.3 
Potentially Drug-related TEAEs ....................................................................... 23 
10.4 
Clinical Laboratory Tests .................................................................................. 23 
10.5 
Vital Signs (Including Body Weight) ............................................................... 23 
10.6 
Electrocardiogram (12-Lead ECG) ................................................................... 24 
11 
Pharmacokinetic Analyses ................................................................. 24 
11.1 
Pharmacokinetics Analysis Set ......................................................................... 24 
11.2 
Pharmacokinetic Endpoints .............................................................................. 24 
11.3 
Method of Calculation of Pharmacokinetic Parameters and Endpoints ........... 25 
11.4 
Method of Display ............................................................................................ 25 
11.5 
Statistical Analysis Methods ............................................................................. 26 
11.6 
Handling of Values ........................................................................................... 26 
12 
Rationale for Target Number of Subjects ........................................ 27 
12.1 
Target Number of Subjects ............................................................................... 27 
12.2 
Rationale for the Number of Subjects ............................................................... 27 
13 
Changes From Analysis Planned in the Protocol ............................ 27 
13.1 
Changes From the Efficacy Analyses Planned in the Protocol ........................ 27 
13.2 
Changes From the Pharmacokinetic Analyses Planned in the Protocol ........... 28 
14 
References ........................................................................................... 28 
15 
Revision History ................................................................................. 29 
16 
Appendix ............................................................................................. 30 
16.1 
Criteria for Potentially Clinically Significant ................................................... 30 
16.2 
Table of Contents .............................................................................................. 31 
 
 
 


Protocol 271-15-001 
 
 
5 
 
List of Abbreviations and Definition of Terms 
List of Abbreviations 
Abbreviation 
Expansion 
AD 
Atopic Dermatitis 
BSA 
Body Surface Area 
DLQI 
Dermatology Life Quality Index 
EASI 
Eczema Area and Severity Index 
FAS 
Full Analysis Set 
IGA 
Investigator’s Global Assessment 
IMP 
Investigational Medicinal Product 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
OC 
Observed Cases 
POEM 
Patient-Oriented Eczema Measure 
QTcB 
QT interval as correlated by Bazett’s formula 
QTcF 
QT interval as correlated by Fridericia’s formula 
SS 
Safety Set 
TEAE 
Treatment-emergent Adverse Event 
VAS 
Visual Analogue Scale 
VRS 
Verbal Rating Scale 
 
List of Pharmacokinetic Parameters 
Abbreviation 
and Term 
Unit 
Expansion or Definition 
AUC8h 
ng∙h/mL 
Area under the plasma concentration-time curve 
from time zero to 8 hours 
AUC8h/Dose 
ng∙h/mL/mg AUC8h normalized by dose  
Cmax 
ng/mL 
Maximum plasma concentration of the drug 
Cmax/Dose 
ng/mL/mg 
Cmax normalized by dose  
R4w,ac(AUC8h) 
 
Ratio of AUC8h 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 
R4w,ac(Cmax) 
 
Ratio of Cmax at Week 4 of multiple administration 
to single administration 
R4w,ac(Cmax/Dose) 
 
Ratio of Cmax/Dose at Week 4 of multiple 
administration to single administration 
tmax 
h 
Time to reach the maximum plasma concentration 
of the drug following administration 
 
 


Protocol 271-15-001 
 
 
6 
 
Definition of Terms 
Term 
Definition 
Descriptive statistics 
Number of subjects, mean, standard deviation, minimum, 
median, and maximum 
Descriptive statistics 
of pharmacokinetic 
parameters 
Number of subjects, arithmetic mean, geometric mean, 
coefficient of variation, standard deviation, minimum, 
median, and maximum  (For tmax, number of subjects, 
minimum, median, and maximum only) 
Descriptive statistics of 
plasma OPA-15406 
concentrations 
Number of subjects, arithmetic mean, coefficient of 
variation, standard deviation, minimum, median, and 
maximum 
Frequency distribution 
Number and percentage of subjects 
 
 
 


Protocol 271-15-001 
 
 
7 
 
1 
Introduction 
This statistical analysis plan (SAP) documents the detailed methodology of 
summarization/analyses and evaluation to provide the trial data required for the 
preparation of a clinical study report of Trial 271-15-001. This document has been 
created based on Protocol No. 271-15-001, Version 4.0, issued on 29 Dec 2016. 
The pharmacokinetic analyses are detailed in Section 11. 
 
2 
Trial Objectives 
Primary Objective: To evaluate Week 4 efficacy of OPA-15406 (0.3% and 1%) 
compared to the vehicle when administered twice daily for 8 weeks using incidence of 
success in Investigator’s Global Assessment (IGA) as the primary endpoint in atopic 
dermatitis (AD) patients 
Secondary Objective: To evaluate the safety of OPA-15406 (0.3% and 1%) 
when administered twice daily for 8 weeks in AD patients  
 
3 
Trial Design 
This is a multicenter, randomized, double-blind, vehicle-controlled, parallel-group, 
comparison trial to evaluate the efficacy and safety of OPA-15406 ointment in patients 
with atopic dermatitis. This trial consists of the 0.3% OPA-15406 group (60 subjects), the 
1% OPA-15406 group (60 subjects), and the vehicle group (60 subjects), and will be 
conducted according to Figure 3-1. 
1) Screening period 
After obtaining informed consent, the investigator or subinvestigator will perform a 
screening examination. The screening period is defined as the period between the day 
of the screening examination and the day of the baseline examination (2-30 days). 
The subjects who meet the inclusion criteria and do not meet the exclusion criteria at 
the baseline examination will be dynamically allocated to the test product (0.3% or 
1% formulation of OPA-15406) or the comparator (vehicle of OPA-15406), using the 
trial site and IGA at the baseline examination as the allocation factors. 
2) Assessment period (treatment period) 
Regarding the subjects who meet the inclusion criteria and do not meet the exclusion 
criteria at the baseline examination, the assessment period is defined as the period 
between the day of the baseline examination and the day of Week 8 examination (or 


Protocol 271-15-001 
 
 
8 
 
the day of discontinuation). The allocated investigational medicinal product (IMP) 
will be administered to the treatment area from the day of the baseline examination 
twice daily for 8 weeks. After the baseline examination, the examinations will be 
performed at Weeks 1, 2, 4, 6, and 8. 
If a subject discontinues the IMP administration between the day of the baseline 
examination and the day of Week 8 examination, a withdrawal examination will be 
performed for that subject. 
3) Post-treatment observation period 
Post-treatment observation period is defined as the period between the end of Week 8 
examination and the day of examination 2 weeks after the last IMP administration. 
The examination will be performed at 2 weeks after the last IMP administration. If 
any adverse event remains not recovered at the examination 2 weeks after the last 
IMP administration (or the day of the last examination if the examination 2 weeks 
after the last IMP administration was not performed), it should be followed up 
according to the specification. 
4) 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 trial discontinuation or completion 
and does not include the follow-up period.  
 
 
 


Protocol 271-15-001 
 
 
9 
 
 
 
Screening  
period 
(2-30 days) 
Assessment period 
Twice daily administration 
(8 weeks) 
Post-treatment 
observation 
 period  
(2 weeks) 
 
 
 
 
0.3% OPA-15406 group 
 
 
 
1% OPA-15406 group 
 
 
 
Vehicle group 
 
 
 
 
 
 
 
 
 
 
 
 
: Treatment period 
 
Figure 3-1 
Trial Design 
 
 
4 
Implementation of Planned Analyses 
The SAP will be finalized prior to database lock, and analyses will be performed using 
the final data. 
 
5 
Statistical Analysis Sets 
5.1 
Definitions of Analysis Sets 
5.1.1 
Full Analysis Set  
The full analysis set (FAS) consists of all subjects who have received the IMP at least 
once. 
 
5.1.2 
Safety Set 
The safety set (SS) consists of all subjects who have received the IMP at least once 
 
Screening examination 
 
Informed consent 
IMP allocation 
Baseline examination 
Week 1 examination 
Week 2 examination 
Week 4 examination 
Examination 2 weeks after 
last IMP administration 
Week 6 examination 
Week 8 examination 


Protocol 271-15-001 
 
 
10 
 
6 
Considerations for Data Analysis 
6.1 
Software 
SAS ver.9.4 (SAS Institute Inc.) 
 
6.2 
Dictionaries 
Coding of adverse events and medical history/complications: Medical Dictionary for 
Regulatory Activities (MedDRA)/J Version 20.0 
Coding of prior and concomitant medications: WHO Drug Dictionary (dated 1 Mar 2016) 
 
6.3 
Data Conversion and Calculation 
6.3.1 
Response in Investigator’s Global Assessment  
Responders and non-responders in investigator’s global assessment (IGA) are defined as 
follows: 
1) Primary analysis 
 Subjects with an IGA score of 0 (clear) or 1 (almost clear) with an improvement 
by at least 2 grades from the baseline are defined as responders. Subjects with 
missing IGA data at the time of evaluation will be handled as non-responders. 
 
2) Sensitivity analysis 
 Subjects with an IGA score of 0 (clear) or 1 (almost clear) with an improvement 
by at least 2 grades from the baseline are defined as responders. For subjects with 
missing IGA data at the time of evaluation, the last observation carried forward 
(LOCF) will be used.  
 Subjects with an IGA score of 0 (clear) or 1 (almost clear) with an improvement 
by at least 2 grades from the baseline are defined as responders. Observed cases 
(OC) will be used. 
 Subjects with an improvement in IGA score to 0 (clear) or 1 (almost clear) are 
defined as responders. Subjects with missing IGA data at the time of evaluation 
will be handled as non-responders. 
 


Protocol 271-15-001 
 
 
11 
 
6.3.2 
Treatment Compliance 
Treatment compliance = (total amount of the IMP applied from the start of administration 
to the assessment point1)/(sum of the specified amounts of the IMP per dose from the 
start of administration to the assessment point2) × 100 
1 [Total amount of the IMP prescribed from the start of administration to the assessment 
point] − [total amount of the IMP returned from the start of administration to the 
assessment point] 
If the total amount of the IMP returned is missing, the total amount of the IMP applied 
from the start of administration to the assessment point will be handled as a missing 
value.  
2 Calculation of “amount of the IMP (g) per dose” 
1) The subject’s body surface area (BSA) (m2) will be calculated based on height 
and body weight at the screening examination, using the following equation. 
3600
)
(
)
(
)
(
2
kg
Wt
cm
Ht
m
BSA


 
2) Based on the subject’s BSA (m2), the amount of administration (g) for 1% of 
BSA will be selected from the table below.  
 
Table 6.3-1 
Amount of Administration (g) for 1% of BSA Based on the 
Subject’s BSA (m2) 
BSA (m2) 
<1.0 
≥1.0 and <1.3 
≥1.3 and <1.6 
≥1.6 and <1.9 
≥1.9 
Amount of 
administration (g) 
for 1% of BSA 
0.1 
0.15 
0.2 
0.25 
0.3 
 
3) [Amount of the IMP (g) per dose] at the assessment point will be calculated as 
[amount of administration (g) for 1% of BSA] × [treatment area (%) at the 
assessment point (including baseline)].  
 
Treatment compliance with the number of administrations will be calculated as follows: 
Treatment compliance with the number of administrations = (number of administrations 
from the start of administration to the assessment point)/(number of days from the start of 
administration to the assessment point × 2) × 100 
 


Protocol 271-15-001 
 
 
12 
 
6.3.3 
Overall Eczema Area and Severity Index Score 
Overall Eczema Area and Severity Index (EASI) total score is the sum of the scores for 4 
body regions (face, neck, and head; upper limbs; trunk; and lower limbs). The score for 
each region will be calculated as shown in Table 6.3-2. 
 
Table 6.3-2 
EASI Score for Each Region 
Body region 
Calculation of the score for each region 
Face, neck, and head 
(E+I+Ex+L) × score of affected BSA × 0.1 
Upper limbs 
(E+I+Ex+L) × score of affected BSA × 0.2 
Trunk 
(E+I+Ex+L) × score of affected BSA × 0.3 
Lower limbs 
(E+I+Ex+L) × score of affected BSA × 0.4 
 
E = severity score of erythema; I = severity score of infiltration/papules; Ex = severity score of 
excoriation; L = severity score of lichenification 
 
Severity score: clear = 0; slight = 0.5; mild = 1; mild-moderate = 1.5; moderate = 2; severe = 2.5; very 
severe = 3 
 
Score of BSA: clear = 0; 1% to 9% = 1; 10% to 29% = 2; 30% to 49% = 3; 50% to 69% = 4; 70% 
to 89% = 5; 90% to 100% = 6 
 
6.3.4 
EASI Symptom Score 
Each EASI symptom score (erythema, infiltration/papules, excoriation, and 
lichenification) will be determined as the sum of the severity scores (Body Regions 
Scores) for 4 regions (face, neck, and head; upper limbs; trunk; and lower limbs) (The 
scores of affected BSA or multipliers will not be used in the calculation). 
 
6.4 
Study Week Windows 
The definitions of timepoints for analysis are described in Table 6.4-1 and Table 6.4-2. 
Timepoints, including unscheduled visits and visit at discontinuation, will be determined 
based on the number of days from the start of IMP administration. However, for Verbal 
Rating Scale (VRS), the timepoint will be determined based on the amount of time that 
has elapsed from the start of IMP administration. For efficacy variables, the data obtained 
between the day of the start of IMP administration and 7 days after the last IMP 
administration will be used in analyses. If multiple data exist within the allowable 
window of the timepoint, the data obtained last will be used for analyses. Data for the 
Last Visit will be defined as the last data obtained between the day of the start of 
IMP administration and 7 days after the last IMP administration (including data obtained 
at discontinuation) for efficacy valuables or as the last data obtained after the start of the 
IMP administration for safety variables. 


Protocol 271-15-001 
 
 
13 
 
In analyses, baseline data will be defined as data obtained on the day or at the date and 
time before and nearest to the start of IMP administration, including the screening data. 
 
Table 6.4-1 
Timepoints and Allowable Windows for Efficacy Variables 
(Except VRS) and Safety Variables 
Timepoint 
Study Day 
Allowable Window (Days After the Start of IMP 
Administration) 
Week 1 
8 
1 
- 
10 
Week 2 
15 
11 
- 
21 
Week 4 
29 
22 
- 
35 
Week 6 
43 
36 
- 
48 
Week 8 
57 
49 
- 
73 
 
Table 6.4-2 
Timepoints and Allowable Windows for VRS 
Timepoint 
Allowable Window (Hours After the Start of 
IMP Administration) 
Hour 4 
1 
- 
< 6 
Hour 8 
6 
- 
< 10 
Hour 12  
10 
- 
< 18 
Hour 24  
18 
- 
< 30 
Hour 36  
30 
- 
< 42 
Hour 48  
42 
- 
< 54 
Hour 60  
54 
- 
< 66 
Hour 72  
66 
- 
< 78 
Hour 84  
78 
- 
< 90 
Hour 96  
90 
- 
< 102 
Hour 108 
102 
- 
< 114 
Hour 120 
114 
- 
< 126 
Hour 132 
126 
- 
< 138 
Hour 144 
138 
- 
< 150 
Hour 156 
150 
- 
< 162 
Hour 168 
162 
- 
< 174 
 
6.5 
Handling of Missing Values 
Missing data for incidence of success in IGA, the primary endpoint, will be handled as 
described in “Section 6.3.1 Response in Investigator’s Global Assessment .” Other 
variables at each timepoint will be analyzed based on the OC and LOCF data sets. 
 
6.6 
Significance Level and Confidence Coefficient 
The two-sided significance level is 5% with a two-sided 95% confidence interval. 


Protocol 271-15-001 
 
 
14 
 
6.6.1 
Multiple Comparisons and Multiplicity 
For the primary analysis of incidence of success in IGA, the primary endpoint, a 
comparison will be performed between the vehicle group and 1% OPA-15406 group and 
between the vehicle group and the 0.3% OPA-15406 group. The closed testing procedure 
will be employed to avoid issue of multiplicity. When superiority of the 1% OPA-15406 
group compared to the vehicle group is demonstrated with a two-sided significance level 
of 0.05, a comparison between the vehicle group and the 0.3% OPA-15406 group will be 
performed. 
For variables other than the primary variable, p-values will also be computed for a 
reference indication of differences between the treatment groups. The multiplicity 
adjustment will not be conducted. 
 
7 
Disposition of Subjects 
7.1 
Disposition of Subjects 
Data will be summarized for the overall population and by age group (<18 or ≥18). The 
numbers of screened and randomized subjects will be provided. The following frequency 
distributions will be provided for overall population and by treatment group, unless 
otherwise specified. The frequency distribution (number and percentage relative to all 
subjects randomized) of subjects treated, those who completed the trial, and those who 
discontinued the trial will be calculated. For subjects who discontinue the trial, the 
frequency distribution will be calculated by reason for discontinuation. 
 
7.2 
Statistical Analysis Sets 
Data will be summarized for the overall population and by age group (<18 or ≥18). For 
the randomized subjects, the number and percentage of subjects included in the FAS, SS, 
and pharmacokinetic analysis set will be provided. 
 
7.3 
Protocol Deviations 
The number and percentage of subjects with major protocol deviations will be provided 
for the overall population and by treatment group. The number and percentage of major 
protocol deviations occurring in each trial site will be provided for the overall population 
and by treatment group. 


Protocol 271-15-001 
 
 
15 
 
 
8 
Description of Analysis Dataset 
8.1 
Demographics and Baseline Characteristics 
Data will be summarized for the overall population and by age group (<18 or ≥18). For 
the randomized subjects, age, gender, duration of AD, body weight, height, BMI, race, 
baseline IGA score, and nation will be summarized for overall population and by 
treatment group using descriptive statistics or frequency distribution. 
Affected BSA at baseline will be categorized as follows and summarized for overall 
population and by treatment group using frequency distribution. 
Affected BSA categories: ≥5% to <10%, ≥10% to <30%, and ≥30%  
 
8.2 
Medical History/Complications 
Medical history and complications will be coded by MedDRA/J system organ class 
(SOC) and preferred term (PT). The medical history and complications will be listed, but 
not summarized. 
 
8.3 
Prior and Concomitant Medications 
For the randomized subjects, the numbers and percentages of subjects who take any 
concomitant medication before the start of IMP administration, during the treatment 
period, and after the last IMP administration will be provided by medication for the 
overall population and by treatment group. The medications will be coded using the 
WHO Drug Dictionary, and summarized by ATC Classification Level 2 and Preferred 
Name. 
 
8.4 
Concomitant Therapies 
The concomitant therapies will be listed, but not summarized. 
 
9 
Efficacy Analyses 
Efficacy analyses will be conducted in the FAS. 


Protocol 271-15-001 
 
 
16 
 
9.1 
Primary Endpoint 
The primary endpoint is incidence of success in IGA at Week 4. 
Comparisons of incidences of success in IGA at Week 4 between the 1% OPA-15406 
group and the vehicle group, and between the 0.3% OPA-15406 group and the vehicle 
group will be conducted using the Cochran-Mantel-Haenszel test stratified by baseline 
IGA score (mild or moderate). The closed testing procedure will be employed to avoid 
issue of multiplicity. When superiority of the 1% OPA-15406 group compared to the 
vehicle group is demonstrated with a two-sided significance level of 0.05, a comparison 
between the vehicle group and the 0.3% OPA-15406 group will be performed. The 
difference in incidence of success in IGA between each OPA-15406 group and the 
vehicle group and its two-sided 95% confidence interval (a Mantel-Haenszel estimator of 
the common risk difference and its two-sided 95% confidence interval) will be computed. 
Additionally, two-sided 95% confidence interval for the incidence of success in IGA 
in each treatment group will also be calculated using Clopper-Pearson method. 
The SAS code to compare the incidence of success in IGA by the 
Cochran-Mantel-Haenszel test and to calculate the difference in incidence of success in 
IGA and its two-sided 95% confidence interval is shown below. 
 
proc freq ; 
   tables BaselineIGA*Treatment*Response/riskdiff(common) cmh ; 
run; 
 
9.1.1 
Sensitivity Analysis 
The analyses described in Section 9.1 will be applied to the 3 assessments defined in 
“Section 6.3.1 Response in Investigator’s Global Assessment , 2) Sensitivity Analysis.” 
 
9.2 
Secondary Endpoints 
9.2.1 
Incidence of Success in IGA at Week 1 and Week 8 
Incidence of success in IGA at Week 1 and Week 8 (as well as Week 2 and Week 6) will 
be analyzed in the same manner as described in Section 9.1. 


Protocol 271-15-001 
 
 
17 
 
The change in incidence of success in IGA (the incidence of success in IGA in the 
primary analysis and the incidence of success in IGA defining responders as subjects 
with an improvement in IGA to 0 [clear] or 1 [almost clear]) will be plotted by timepoint 
for each treatment group. 
 
9.2.2 
Change From Baseline in IGA at Week 1, Week 4, and Week 8 
Based on the OC data set, the change from baseline in IGA (at Week 1, Week 2, Week 4, 
Week 6, and Week 8; if the timing of discontinuation falls within the allowable window 
of a timepoint, the data at discontinuation will be included as the data for the timepoint) 
will be analyzed using the mixed-model repeated measures (MMRM) analysis with 
treatment (0.3% or 1% OPA-15406 groups, and vehicle group), timepoint, and interaction 
between treatment and timepoint as factors and baseline IGA as a covariate. 
An unstructured covariance matrix will be used to model the within-subject errors and 
Kenward-Roger method will be used to calculate the standard error of fixed-effects and 
the degree of freedom. If the MMRM procedure fails to converge under unstructured 
covariance structure, the following structure will be used in the order of 1) heterogeneous 
toeplitz, 2) heterogeneous autoregressive of order 1, 3) heterogeneous compound 
symmetry, and the first (co)variance structure converging to the best fit will be used. 
The least square mean of each treatment group will be calculated by timepoint. The 
difference in the least square mean between the vehicle group and each OPA-15406 
group, and the two-sided 95% confidence interval and p-value will also be calculated at 
Week 1, Week 4, and Week 8 (as well as at Week 2 and Week 6). The least square mean 
and the standard error will be plotted by timepoint for each treatment group. 
The SAS code to conduct the MMRM analysis is shown below. 
proc mixed method = reml ; 
 
class Treatment Visit Subject ; 
 
model Change = Treatment Visit Treatment*Visit Baseline/s ddfm = kr ; 
 
repeated Visit/type = un sub = Subject ; 
 
lsmeans Treatment*Visit/pdiff cl alpha = 0.05 ; 
run; 
“Baseline” represents the IGA at baseline. 
 


Protocol 271-15-001 
 
 
18 
 
The SAS code to use when the MMRM procedure fails to converge under the 
unstructured covariance structure is shown below. (Designate type = TOEPH for 
heterogeneous toeplitz, type = ARH(1) for heterogeneous autoregressive of order 1, and 
type = CSH for heterogeneous compound symmetry). 
proc mixed method = reml empirical ; 
 
class Treatment Visit Subject ; 
 
model Change = Treatment Visit Treatment*Visit Baseline/s ; 
 
repeated Visit/type = TOEPH sub = Subject ; 
 
lsmeans Treatment*Visit/pdiff cl alpha = 0.05 ; 
run; 
 
Based on the OC and LOCF data sets, analysis of covariance (ANCOVA) model with 
treatment (0.3% or 1% OPA-15406 group, and vehicle group) as a factor and baseline 
IGA as a covariate will be applied to the change from baseline up to each timepoint. The 
least square mean of each treatment group will be calculated by timepoint. The difference 
in the least square mean between the vehicle group and each OPA-15406 group, and the 
two-sided 95% confidence interval and p-value will also be calculated at Week 1, Week 
4, and Week 8 (as well as at Week 2 and Week 6). Based on the OC and LOCF data sets, 
measured values and changes from baseline in IGA at Week 1, Week 4, and Week 8 (as 
well as at Week 2 and Week 6) will be summarized by treatment group using descriptive 
statistics. 
The mean with standard error of measured values (in the OC and LOCF data sets) will be 
plotted by timepoint for each group. 
Shift tables will be created for the change from baseline in IGA (−3, −2, −1, ±0, +1, +2) 
at Week 1, Week 4, and Week 8. 
 
9.2.3 
Changes From Baseline in Overall EASI Score and EASI 
Symptom Scores at Week 1, Week 4, and Week 8 
Based on the OC data set, the change from baseline in EASI score (at Week 1, Week 2, 
Week 4, Week 6, and Week 8; If the timing of discontinuation falls within the allowable 
window of a timepoint, the data at discontinuation will be included as the data for the 
timepoint) will be analyzed using the MMRM analysis with treatment (0.3% or 1% 
OPA-15406 group, and vehicle group), timepoint, and interaction between treatment and 


Protocol 271-15-001 
 
 
19 
 
timepoint as factors and baseline EASI score as a covariate. An unstructured covariance 
matrix will be used to model the within-subject errors and Kenward-Roger method will 
be used to calculate the standard error of fixed-effects and the degree of freedom. If the 
MMRM procedure fails to converge under unstructured covariance structure, the 
following structure will be used in the order of 1) heterogeneous toeplitz, 2) 
heterogeneous autoregressive of order 1, 3) heterogeneous compound symmetry, and 
the first (co)variance structure converging to the best fit will be used. 
The least square mean of each treatment group will be calculated by timepoint. For 
overall EASI score, the least square mean and the standard error will be plotted by 
timepoint for each treatment group. The difference in the least square mean between the 
vehicle group and each OPA-15406 group, and the two-sided 95% confidence interval 
and p-value will be calculated at Week 1, Week 4, and Week 8 (as well as at Week 2 and 
Week 6). Based on the OC and LOCF data sets, ANCOVA model with treatment (0.3% 
or 1% OPA-15406 group, and vehicle group) as a factor and baseline EASI score as a 
covariate will be applied to the change from baseline up to each timepoint. The least 
square mean in each treatment group will be calculated by timepoint. The difference in 
the least square mean between the vehicle group and each OPA-15406 group, and the 
two-sided 95% confidence interval and p-value will be calculated at Week 1, Week 4, 
and Week 8 (as well as at Week 2 and Week 6). Based on the OC and LOCF data sets, 
measured values and changes from baseline in IGA at Week 1, Week 4, and Week 8 (as 
well as at Week 2 and Week 6) will be summarized by treatment group using descriptive 
statistics. For the overall EASI score, the mean with standard error of measured values (in 
the OC and LOCF data sets) will be plotted by timepoint for each treatment group. 
EASI scores for body regions (face, neck, and head, upper limbs, trunk, and lower limbs) 
will be analyzed in the same manner as the overall EASI score. 
 
9.2.4 
Change From Baseline in Visual Analogue Scale for Pruritus at 
Week 1, Week 4, and Week 8 
The change from baseline in visual analogue scale (VAS) for pruritus will be analyzed in 
the same manner as that in the overall EASI score or each EASI symptom score. 
 
9.2.5 
Change From Baseline in VRS for Pruritus up to Day 7 
The change from baseline in VRS for pruritus up to Day 7 will be analyzed in the same 
manner as that in overall EASI score or each EASI symptom score. Data will be collected 


Protocol 271-15-001 
 
 
20 
 
at baseline, 4, 8, and 12 hours after the start of administration, 1 day after the start of 
administration (morning and night), and thereafter in the same manner up to Day 7 
(morning). The same analysis will be performed by the time zone of assessment (morning 
or evening). Morning or evening will be determined based on the time label entered in the 
case report form (CRF), not using the timepoints defined in Table 6.4-2, except the 
baseline, which is irrespective of the time zone of assessment. Data will be collected at 
baseline, and the timepoints specified above on Day 1 to Day 7. 
 
9.2.6 
Change From Baseline in Dermatology Life Quality Index Score 
at Week 1, Week 4, and Week 8 
The change from baseline in Dermatology Life Quality Index (DLQI) score will be 
analyzed in the same manner as that in the overall EASI score or each EASI symptom 
score. The DLQI scores will be classified into the following categories and a shift table at 
baseline, Week 1, Week 4, and Week 8 will be created.  
DLQI score categories: 0 to 1, 2 to 5, 6 to 10, 11 to 20, and 21 to 30 
 
9.2.7 
Change From Baseline in Patient-Oriented Eczema Measure 
Score at Week 1, Week 4, and Week 8 
The change from baseline in Patient-Oriented Eczema Measure (POEM) score will be 
analyzed in the same manner as that in the overall EASI score or each EASI symptom 
score. 
 
9.2.8 
Change From Baseline in Overall Percentage Affected BSA at 
Week 1, Week 4, and Week 8 
The change from baseline in overall percentage affected BSA will be analyzed in the 
same manner as that in the overall EASI score or each EASI symptom score. 
 
9.2.9 
Percent Changes From Baseline in Overall EASI Score, EASI 
Symptom Scores, VAS for Pruritus, DLQI, and POEM Scores at 
Week 1, Week 4, and Week 8 
The percent changes from baseline in overall EASI score, EASI symptom scores, EASI 
scores for body regions, VAS for pruritus, DLQI score, and POEM score will be 


Protocol 271-15-001 
 
 
21 
 
analyzed at Week 1, Week 4, and Week 8 (as well as Week 2 and Week 6), in the same 
manner as the changes from baseline in the respective scores. 
 
9.2.10 
Time to Response in IGA 
For the time to response in IGA (days to the first response in IGA in each subject), a 
cumulative response rate will be computed by each treatment group using the 
Kaplan-Meier method and plotted. At each timepoint, the number of subjects (at risk), the 
p-value of the log-rank test comparing the vehicle group and each OPA-15406 group, 
and the time until one half of the subjects have achieved a response (medial survival time 
[MST]) will be provided. Subjects with an IGA of 0 (clear) or 1 (almost clear) with an 
improvement by at least 2 grades from the baseline are defined as responders. The 
starting point is the baseline. Subjects who have failed to achieve a response will be 
treated as censored on the day of the final IGA assessment. 
 
9.2.11 
Time to Response in VRS 
The time to response in VRS (time to the first response in VRS in each subject) will be 
analyzed in the same manner as the time to response in IGA. Subjects with a VRS score 
of 0 (none) or 1 (mild) with an improvement by at least 1 grade from the baseline are 
defined as responders. The starting point is baseline. Subjects who have failed to achieve 
a response will be treated as censored on the day of the final VRS assessment. 
 
9.3 
Other Efficacy Endpoints 
Not applicable. 
 
9.4 
Adjustments for Covariates 
In the analysis of the incidence of success in IGA, the primary analysis, the 
Cochran-Mantel-Haenszel test stratified by baseline IGA (mild or moderate) will be 
conducted. 
 


Protocol 271-15-001 
 
 
22 
 
9.5 
Subgroup Analysis 
Incidence of success in IGA will also be analyzed in the following subgroups in the same 
manner as described in Section 9.1. 
Age: <18 or ≥18 years old 
Gender: Male or female 
Baseline IGA score: 2 (mild) or 3 (moderate) 
 
10 
Safety Analysis  
The following safety endpoints will be analyzed in the safety set (SS). 
10.1 
Exposure to the IMP (Number of Subjects, Duration, and Doses) 
Treatment compliance with the amount of administration and the number of 
administrations, calculated as described in Section 6.3.2, will be classified into the 
following categories, and the number and percentage of subjects will be provided for the 
overall population and by treatment group. The treatment compliance from baseline 
to Week 4 or Week 8 will be provided. The number and percentage of subjects who 
received IMP administration during each week (Week 1, Week 2, Week 3, Week 4, Week 
5, Week 6, Week 7, Week 8, and every week thereafter, if necessary; Any Exposure) will 
be provided. 
Categories of treatment compliance with the amount of administration and the number of 
administrations: <50%, ≥50% to <60%, ≥60% to <70%, ≥70% to <80%, ≥80% to <90%, 
≥90% to <100%, ≥100% to <110%, ≥110% to <120%, ≥120% 
 
10.2 
Adverse Events 
Data will be summarized for the overall population and by age group (<18 or ≥18). All 
AEs will be coded using the MedDRA/J SOC and PT. 
The number and percentage of subjects experiencing the following treatment-emergent 
AEs (TEAEs) will be provided for the overall population and by treatment group. Skin 
and subcutaneous tissue disorders will also be summarized by the grade in the Common 
Terminology Criteria for Adverse Events (CTCAE) v4.0 Japanese JCOG edition. 
1. TEAEs 
2. TEAEs resulting in death 


Protocol 271-15-001 
 
 
23 
 
3. Serious TEAEs 
4. TEAEs leading to discontinuation of IMP administration 
5. TEAEs by severity 
6. TEAEs by CTCAE grade (only skin and subcutaneous tissue disorders) 
7. TEAEs at treatment areas 
For TEAEs and non-serious TEAEs reported in at least 5% of subjects in any treatment 
group, the number and percentage of subjects will be provided for the overall population 
and by treatment group. 
 
10.3 
Potentially Drug-related TEAEs 
Potentially drug-related TEAEs (AEs for which a causal relationship with the IMP cannot 
be ruled out) will be summarized in the same manner as AEs. Serious potentially 
drug-related TEAEs will also be summarized. 
 
10.4 
Clinical Laboratory Tests 
For laboratory parameters (except qualitative urinalysis), measured values and changes 
from baseline at each timepoint will be summarized for the overall population and by 
treatment group using descriptive statistics. Shift tables (except qualitative urinalysis) 
will be created for predose and postdose values classified into normal, high, or low based 
on the reference range by treatment group. For qualitative urinalysis, shift tables will be 
created for predose and postdose values by each parameter. The number and percentage 
of potential Hy’s Law Cases will be provided for the overall population and by treatment 
group. A listing of the potential Hy’s Law Cases will be provided. Potential Hy’s Law 
Cases will be defined as follows: 
Potential Hy’s Law Cases are defined as subjects with AST or ALT ≥ 3 times the 
upper normal limit or whose levels increase ≥ 3 times the initial screening value, and 
with an increase in total bilirubin level ≥ 2 times the upper normal limit or initial 
screening value. 
 
10.5 
Vital Signs (Including Body Weight) 
Measured values and changes from baseline in body weight, body temperature, blood 
pressure (systolic/diastolic), and pulse rate at each timepoint will be summarized for the 


Protocol 271-15-001 
 
 
24 
 
overall population and by treatment group using descriptive statistics. For body 
temperature, blood pressure (systolic/diastolic), and pulse rate, the number and 
percentage of subjects with potentially clinically significant vital sign 
abnormalities (Table 16.1-1) will be computed for the overall population and by 
treatment group. A listing of subjects with potentially clinically significant abnormalities 
will be provided. 
 
10.6 
Electrocardiogram (12-Lead ECG) 
Measured values and changes from baseline in heart rate, PR, QRS, QT, QTc (QT 
interval as correlated by Bazett’s formula [QTcB] and QT interval as correlated by 
Fridericia’s formula [QTcF]), and RR intervals at each timepoint will be summarized for 
the overall population and by treatment group using descriptive statistics. Criteria for 
potentially clinically significant ECG abnormalities in heart rate, PR, QRS, QT, QTcB, 
and QTcF intervals will be set (Table 16.1-2), and the number and percentage of subjects 
who meet the criteria will be provided for the overall population and by treatment group. 
 
11 
Pharmacokinetic Analyses 
11.1 
Pharmacokinetics Analysis Set 
The pharmacokinetic analysis set consists of all subjects who have received the IMP at 
least once and have at least one evaluable plasma drug concentration measured. 
 
11.2 
Pharmacokinetic Endpoints 
 Plasma trough concentration of OPA-15406 (predose at Week 1, Week 4, and 
Week 8): All subjects 
 Plasma concentration of OPA-15406 (predose, and 2, 4, and 8 hours after IMP 
administration on Day 1 and Week 4): PK parameter assessment group (that is 
planned to consist of 6 subjects per group) 
 Pharmacokinetic parameters of OPA-15406: Cmax, Cmax/Dose, tmax, AUC8h, and 
AUC8h/Dose on Day 1 and Week 4 
 Accumulation of OPA-15406: Ratios of the Cmax, Cmax/Dose, AUC8h, and 
AUC8h/Dose at Week 4 to those on Day 1 [R4w,ac(AUC8h), R4w,ac(AUC8h/Dose), 
R4w,ac(Cmax), and R4w,ac(Cmax/Dose)] 
 


Protocol 271-15-001 
 
 
25 
 
11.3 
Method of Calculation of Pharmacokinetic Parameters and 
Endpoints 
1) Pharmacokinetic parameters will be determined by subject using the 
non-compartment analysis. In subjects whose plasma concentration is below the 
lower limit of quantification at all the sampling points, the Cmax and AUC8h will 
be treated as zero (ng/mL or ng∙h/mL) and the tmax not calculable. 
2) Plasma concentration below the lower limit of quantification will be treated as 
zero (ng/mL) for the calculation of pharmacokinetic parameters and descriptive 
statistics. 
3) Plasma trough concentrations will be handled as follows: 
 If the time of the blood sampling was within 6 hours from the last IMP 
administration, the sampling point will be excluded from the analysis. 
 If the treatment area (%) was changed (including non-compliance of IMP) within 
3 days before the sampling point, the sampling point will be excluded from the 
analysis. 
4) The timepoint of the blood sampling for the pharmacokinetic endpoint at 
withdrawal will be handled as follows: If the blood sampling at withdrawal meets 
neither of the exclusion criteria in (3) and falls within the allowable window 
shown below, the sampling point will be included in the analyses. If the sampling 
point at withdrawal coincides with any pharmacokinetic timepoint, the blood 
sampling at withdrawal will not be included in the analyses. 
Timepoint 
Study Day 
Allowable Window (Day) 
Baseline 
1 
 
- 
1 
Week 1 
8 
4 
- 
22 
Week 4 
29 
23 
- 
50 
Week 8 
57 
51 
- 
71 
 
5) In AUC8h/Dose and Cmax/Dose, Dose will be calculated as follows: 
Dose (mg) = [Amount of administration (g) for 1% of BSA per dose just before 
the assessment point] × [treatment area (%)] × [formulation strength (0.3% or 
1%)] × 1000 
6) R4w,ac(AUC8h), R4w,ac(AUC8h/Dose), R4w,ac(Cmax), and R4w,ac(Cmax/Dose) will be 
determined by dividing the AUC8h, AUC8h/Dose , Cmax, and Cmax/Dose values at 
Week 4 by the AUC8h, AUC8h/Dose, Cmax, and Cmax/Dose values on Day 1, 
respectively. 
 
11.4 
Method of Display 
1) When plotting the plasma drug concentration-time profile, arithmetic means and 
standard deviations will be used. 
 


Protocol 271-15-001 
 
 
26 
 
11.5 
Statistical Analysis Methods 
1) Descriptive statistics of the plasma trough concentrations and 
dose(mg)-normalized plasma trough concentrations will be calculated by 
treatment group and pharmacokinetic timepoint. 
2) Descriptive statistics of the total treatment area (%) will be calculated by 
treatment group and pharmacokinetic timepoint. 
3) Among the subjects included in PK parameter assessment group, descriptive 
statistics of the plasma concentrations and pharmacokinetic parameters of 
OPA-15406 will be calculated by treatment group and pharmacokinetic timepoint. 
4) In 1), 2), or 3) above, when the number of analyzed subjects is zero (0), only the 
number of subjects will be calculated; when only one (1) subject is analyzed, only 
the number of subjects, arithmetic mean, and geometric mean will be calculated; 
and when two (2) subjects are analyzed, only the number of subjects, arithmetic 
mean, geometric mean, and maximum and minimum values will be calculated. 
 
11.6 
Handling of Values 
 Values will be rounded off the final step of calculation. Descriptive statistics will be 
calculated as individual values not rounded off. 
 Pharmacokinetic parameters a value of “n + 1” figures will be rounded off to obtain a 
value of “n” figures shown below: 
AUC8h 
3 significant figures 
AUC8h/Dose 
3 significant figures 
Cmax 
3 significant figures 
Cmax/Dose 
3 significant figures 
tmax 
2 decimal places 
R4w,ac(AUC8h), R4w,ac(Cmax) 
3 significant figures 
R4w,ac(AUC8h/Dose), R4w,ac(Cmax/Dose) 
3 significant figures 
 
 Among descriptive statistics, the number of subjects will be displayed in integers, and 
minimum and maximum will be displayed as it is in the same number of digits 
(n-digit) as that of an individual value of the target data. For arithmetic mean, 
geometric mean, median, and standard deviation values, a value of “n + 1” figures 
will be rounded off to obtain a value of “n” figures so that the number of digits will 
be the same number of digits (n-digit) as that of an individual value of the target data. 
For coefficient of variation, 2 decimal places will be rounded to obtain 1 decimal 
place. 
 


Protocol 271-15-001 
 
 
27 
 
12 
Rationale for Target Number of Subjects 
12.1 
Target Number of Subjects 
180 subjects 
 
12.2 
Rationale for the Number of Subjects 
In the phase 2 trial outside Japan (271-12-205), the primary variable of incidence of 
success in IGA was 20.93% in the 1% OPA-15406 group and 2.70% in the vehicle group, 
respectively. In the present trial, with the assumption that the difference in incidence of 
success in IGA between the 1% OPA-15406 group and the vehicle group is similar to that 
obtained in the foreign trial, a sample size of 54 subjects per group at a two-tailed 5% 
level of significance was calculated with at least an 80% power. In consideration of 
possible discontinuations and dropouts, the number of subjects is established as 60 
subjects per group. 
 
13 
Changes From Analysis Planned in the Protocol 
13.1 
Changes From the Efficacy Analyses Planned in the Protocol 
 The factors/covariates included in the MMRM or ANCOVA model were described 
consistently. A categorical variable included in the model was described as a factor, 
and a continuous variable as a covariate. 
Rationale for change: To further clarify the analytical methods  
 The logistic regression with incidence of success in IGA as an outcome variable will 
not be conducted. 
Rationale for change: In the primary analysis, the Cochran-Mantel-Haenszel test 
stratified by baseline IGA will be conducted. In addition, IGA data will be evaluated 
by sensitivity analysis based on the 3 assessments of incidence of success in IGA 
defined in “Section 6.3.1 Response in Investigator’s Global Assessment , 2) 
Sensitivity Analysis,” as well as the summarization of IGA scores by timepoint using 
MMRM and the analysis of time to response in IGA. Thus, it was considered that 
IGA data can be adequately evaluated by these analyses. 
 The frequency distribution of incidence of success in IGA by trial site will not be 
provided. 
Rationale for change: Because many sites will participate in the trial and the number 
of subjects in each group will be limited. 
 


Protocol 271-15-001 
 
 
28 
 
13.2 
Changes From the Pharmacokinetic Analyses Planned in the 
Protocol 
The following pharmacokinetic endpoints were added. 
 Pharmacokinetic parameters of OPA-15406: Cmax/Dose and AUC8h/Dose on Day 1 
and Week 4 
 Accumulation of OPA-15406: Ratios of the Cmax/Dose and AUC8h/Dose at Week 4 to 
those on Day 1 [R4w,ac(AUC8h/Dose), R4w,ac(Cmax/Dose)] 
Rationale for change: The dose (mg) differs among subjects, dose-normalized 
parameters were added. 
 The descriptive statistics of the plasma trough concentrations of OPA-15406 will not 
be calculated by affected BSA at baseline. The plasma trough concentrations of 
OPA-15406 will be normalized by dose (mg), not by affected BSA.  
Rationale for change: Calculation of dose-normalized plasma trough concentration 
was considered adequate, the concentrations will not be computed by or normalized 
by affected BSA. 
 The descriptive statistics for age, treatment area at baseline, and amount of 
administration will not be calculated by the affected BSA. 
Rationale for change: These were considered not necessary for interpretation of the 
data. 
 The descriptive statistics of total treatment area (%) will be calculated by treatment 
group and pharmacokinetic timepoint. 
Rationale for change: These were considered necessary for interpretation of the data. 
 
14 
References 
Not applicable. 


Protocol 271-15-001 
 
 
29 
 
15 
Revision History 
Not applicable. 
Table 15-1 
Revision History 
Version Number 
Date of Revision 
Section 
Original Description 
Revised Description 
Reason for Revision 
− 
− 
− 
− 
− 
− 
 
 


Protocol 271-15-001 
 
 
30 
 
16 
Appendix 
16.1 
Criteria for Potentially Clinically Significant 
Table 16.1-1 
Criteria for Potentially Clinically Significant Vital Sign 
Abnormalities 
TEST 
CRITERIA 1 
CRITERIA 2 
DIASTOLIC BLOOD  
PRESSURE(MMHG) 
DIASTOLIC BLOOD 
PRESSURE (mmHg) < 50 AND 
DECREASE >= 15 
DIASTOLIC BLOOD PRESSURE 
(mmHg) > 105 AND INCREASE 
>= 15 
HEART RATE  
(BEATS/MIN) 
HEART RATE (BPM) < 50 
AND DECREASE >= 15 
HEART RATE (BPM) > 120 
AND INCREASE >= 15 
SYSTOLIC BLOOD  
PRESSURE (MMHG) 
SYSTOLIC BLOOD PRESSURE 
(mmHg) < 90 AND DECREASE >= 20 
SYSTOLIC BLOOD PRESSURE 
(mmHg) > 180 AND INCREASE 
>= 20 
TEMPERATURE (°C) 
- 
TEMPERATURE (°C) >= 37.8 
AND INCREASE >= 1.1°C 
WEIGHT (KG) 
WEIGHT (kg) DECREASE >= 7% 
WEIGHT (kg) INCREASE >= 7% 
 
Table 16.1-2 
Criteria for Potentially Clinically Significant ECG 
Abnormalities 
CLASSIFICATION 
CATEGORY 
CRITERIA 
VENT RATE  
OUTLIERS 
NOTABLE  
INCREASES 
25% INCREASE FROM BASELINE AND 
VENTRICULAR RATE > 100 BPM 
VENT RATE  
OUTLIERS 
NOTABLE  
DECREASES 
25% DECREASE FROM BASELINE AND 
VENTRICULAR RATE < 50 BPM 
PR OUTLIERS 
NOTABLE  
CHANGES 
>= 25% CHANGE FROM BASELINE WHEN PR > 
200 MSEC 
QRS OUTLIERS 
NOTABLE  
CHANGES 
>= 25% CHANGE FROM BASELINE WHEN QRS > 
100 MSEC 
QT 
NEW ONSET  
(>= 450 MSEC) 
NEW ONSET (>=450 MSEC) IN QT MEANS A 
SUBJECT WHO ATTAINS A VALUE >=450 MSEC 
DURING TREATMENT PERIOD BUT NOT AT 
EACH BASELINE 
QTcB 
NEW ONSET  
(>= 450 MSEC) IN 
MALE OR (>= 470 
MSEC) IN FEMALE 
NEW ONSET (>=450 MSEC IN MALE OR >= 470 
MSEC IN FEMALE) IN QTCB MEANS A SUBJECT 
WHO ATTAINS A VALUE >=450 OR >=470 MSEC 
DURING TREATMENT PERIOD BUT NOT AT 
EACH BASELINE 
QTcB 
NEW ONSET  
(>= 450 MSEC) AND 
>= 10% INCREASE 
NEW ONSET (>=450 MSEC) AND >= 10% 
INCREASE IN QTCB MEANS A SUBJECT WHO 
ATTAINS A VALUE >= 450 MSEC AND >= 10% 
INCREASE DURING TREATMENT PERIOD BUT 
NOT AT EACH BASELINE 
QTcB 
INCREASE  
30 - 60 MSEC 
INCREASE IN CHANGE FROM BASELINE VALUE 
>= 30 AND <= 60 MSEC 
QTcB 
INCREASE > 
60 MSEC 
INCREASE IN CHANGE FROM BASELINE VALUE 
> 60 MSEC 
QTcF 
NEW ONSET  
(>= 450 MSEC) IN 
MALE OR (>= 470 
NEW ONSET (>=450 MSEC IN MALE OR >= 470 
MSEC IN FEMALE) IN QTCB MEANS A SUBJECT 
WHO ATTAINS A VALUE >=450 OR >=470 MSEC 


Protocol 271-15-001 
 
 
31 
 
Table 16.1-2 
Criteria for Potentially Clinically Significant ECG 
Abnormalities 
CLASSIFICATION 
CATEGORY 
CRITERIA 
MSEC) IN FEMALE 
DURING TREATMENT PERIOD BUT NOT AT 
EACH BASELINE 
QTcF 
NEW ONSET (>= 
450 MSEC) AND >= 
10% INCREASE 
NEW ONSET (>=450 MSEC) AND >= 10% 
INCREASE IN QTCB MEANS A SUBJECT WHO 
ATTAINS A VALUE >= 450 MSEC AND >= 10% 
INCREASE DURING TREATMENT PERIOD BUT 
NOT AT EACH BASELINE 
QTcF 
INCREASE  
30 - 60 MSEC 
INCREASE IN CHANGE FROM BASELINE VALUE 
>= 30 AND <= 60 MSEC 
QTcF 
INCREASE  
> 60 MSEC 
INCREASE IN CHANGE FROM BASELINE VALUE 
> 60 MSEC 
 
 
16.2 
Table of Contents 
CT-1 Subject Disposition 
CT-2 Reasons for Discontinuation 
CT-3 Demographic Characteristics 
CT-4.1 Concomitant Medications: Medications Taken Prior to Start of Study Therapy 
CT-4.2 Concomitant Medications: Medications Taken During Study Therapy 
CT-4.3 Concomitant Medications: Medications Taken After Study Therapy 
CT-5.1.1 Analysis of Responder Rate for Overall IGA Score 
CT-5.1.2 Sensitivity Analysis of Responder Rate for Overall IGA Score - LOCF 
CT-5.1.3 Sensitivity Analysis of Responder Rate for Overall IGA Score - OC 
CT-5.1.4 Sensitivity Analysis of Responder Rate for Overall IGA Score - Revised 
Responder Definition 
CT-5.1.5 Shift Tables of Overall IGA Score - OC 
CT-5.1.6 Shift Tables of Overall IGA Score - LOCF 
CT-5.2.1 Analysis of Baseline and Change from Baseline in Overall IGA Score - 
MMRM 
CT-5.2.2 Analysis of Baseline and Change from Baseline in Overall IGA Score - 
ANCOVA OC 


Protocol 271-15-001 
 
 
32 
 
CT-5.2.3 Analysis of Baseline and Change from Baseline in Overall IGA Score - 
ANCOVA LOCF 
CT-5.3.1.1 Analysis of Baseline and Change from Baseline in Overall EASI Score - 
MMRM 
CT-5.3.1.2 Analysis of Baseline and Change from Baseline in Overall EASI Score - 
ANCOVA OC 
CT-5.3.1.3 Analysis of Baseline and Change from Baseline in Overall EASI Score - 
ANCOVA LOCF 
CT-5.3.1.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score - MMRM 
CT-5.3.1.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score - ANCOVA OC 
CT-5.3.1.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score - ANCOVA LOCF 
CT-5.3.2.1 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Erythema - MMRM 
CT-5.3.2.2 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Erythema - ANCOVA OC 
CT-5.3.2.3 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Erythema - ANCOVA LOCF 
CT-5.3.2.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Erythema - MMRM 
CT-5.3.2.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Erythema - ANCOVA OC 
CT-5.3.2.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Erythema - ANCOVA LOCF 
CT-5.3.3.1 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Induration/Papulation - MMRM 
CT-5.3.3.2 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Induration/Papulation - ANCOVA OC 
CT-5.3.3.3 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Induration/Papulation - ANCOVA LOCF 


Protocol 271-15-001 
 
 
33 
 
CT-5.3.3.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Induration/Papulation - MMRM 
CT-5.3.3.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Induration/Papulation - ANCOVA OC 
CT-5.3.3.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Induration/Papulation - ANCOVA LOCF 
CT-5.3.4.1 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Excoriation - MMRM 
CT-5.3.4.2 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Excoriation - ANCOVA OC 
CT-5.3.4.3 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Excoriation - ANCOVA LOCF 
CT-5.3.4.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Excoriation - MMRM 
CT-5.3.4.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Excoriation - ANCOVA OC 
CT-5.3.4.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Excoriation - ANCOVA LOCF 
CT-5.3.5.1 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Lichenification - MMRM 
CT-5.3.5.2 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Lichenification - ANCOVA OC 
CT-5.3.5.3 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
Lichenification - ANCOVA LOCF 
CT-5.3.5.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Lichenification - MMRM 
CT-5.3.5.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Lichenification - ANCOVA OC 
CT-5.3.5.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, Lichenification - ANCOVA LOCF 
CT-5.3.6.1 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
HEAD/NECK - MMRM 


Protocol 271-15-001 
 
 
34 
 
CT-5.3.6.2 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
HEAD/NECK - ANCOVA OC 
CT-5.3.6.3 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
HEAD/NECK - ANCOVA LOCF 
CT-5.3.6.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, HEAD/NECK - MMRM 
CT-5.3.6.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, HEAD/NECK - ANCOVA OC 
CT-5.3.6.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, HEAD/NECK - ANCOVA LOCF 
CT-5.3.7.1 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
UPPER LIMBS - MMRM 
CT-5.3.7.2 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
UPPER LIMBS - ANCOVA OC 
CT-5.3.7.3 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
UPPER LIMBS - ANCOVA LOCF 
CT-5.3.7.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, UPPER LIMBS - MMRM 
CT-5.3.7.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, UPPER LIMBS - ANCOVA OC 
CT-5.3.7.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, UPPER LIMBS - ANCOVA LOCF 
CT-5.3.8.1 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
TRUNK - MMRM 
CT-5.3.8.2 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
TRUNK - ANCOVA OC 
CT-5.3.8.3 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
TRUNK - ANCOVA LOCF 
CT-5.3.8.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, TRUNK - MMRM 
CT-5.3.8.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, TRUNK - ANCOVA OC 


Protocol 271-15-001 
 
 
35 
 
CT-5.3.8.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, TRUNK - ANCOVA LOCF 
CT-5.3.9.1 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
LOWER LIMBS - MMRM 
CT-5.3.9.2 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
LOWER LIMBS - ANCOVA OC 
CT-5.3.9.3 Analysis of Baseline and Change from Baseline in Overall EASI Score, 
LOWER LIMBS - ANCOVA LOCF 
CT-5.3.9.4 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, LOWER LIMBS - MMRM 
CT-5.3.9.5 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, LOWER LIMBS - ANCOVA OC 
CT-5.3.9.6 Analysis of Baseline and Percent Change from Baseline in Overall EASI 
Score, LOWER LIMBS - ANCOVA LOCF 
CT-5.4.1 Analysis of Baseline and Change from Baseline in VAS for Pruritus Score - 
MMRM 
CT-5.4.2 Analysis of Baseline and Change from Baseline in VAS for Pruritus Score - 
ANCOVA OC 
CT-5.4.3 Analysis of Baseline and Change from Baseline in VAS for Pruritus Score - 
ANCOVA LOCF 
CT-5.4.4 Analysis of Baseline and Percent Change from Baseline in VAS for Pruritus 
Score - MMRM 
CT-5.4.5 Analysis of Baseline and Percent Change from Baseline in VAS for Pruritus 
Score - ANCOVA OC 
CT-5.4.6 Analysis of Baseline and Percent Change from Baseline in VAS for Pruritus 
Score - ANCOVA LOCF 
CT-5.5.1 Analysis of Baseline and Change from Baseline in Overall Percentage 
Affected Body Surface Area - MMRM 
CT-5.5.2 Analysis of Baseline and Change from Baseline in Overall Percentage 
Affected Body Surface Area - ANCOVA OC 
CT-5.5.3 Analysis of Baseline and Change from Baseline in Overall Percentage 
Affected Body Surface Area - ANCOVA LOCF 


Protocol 271-15-001 
 
 
36 
 
CT-5.6.1 Analysis of Baseline and Change from Baseline in POEM Score - MMRM 
CT-5.6.2 Analysis of Baseline and Change from Baseline in POEM Score - 
ANCOVA OC 
CT-5.6.3 Analysis of Baseline and Change from Baseline in POEM Score - 
ANCOVA LOCF 
CT-5.6.4 Analysis of Baseline and Percent Change from Baseline in POEM Score - 
MMRM 
CT-5.6.5 Analysis of Baseline and Percent Change from Baseline in POEM Score - 
ANCOVA OC 
CT-5.6.6 Analysis of Baseline and Percent Change from Baseline in POEM Score - 
ANCOVA LOCF 
CT-5.7.1 Analysis of Baseline and Change from Baseline in VRS for Pruritus Score - 
MMRM 
CT-5.7.2 Analysis of Baseline and Change from Baseline in VRS for Pruritus Score - 
ANCOVA OC 
CT-5.7.3 Analysis of Baseline and Change from Baseline in VRS for Pruritus Score - 
ANCOVA LOCF 
CT-5.7.4 Analysis of Baseline and Change from Baseline in VRS for Pruritus Score 
(Morning / Evening) - MMRM 
CT-5.7.5 Analysis of Baseline and Change from Baseline in VRS for Pruritus Score 
(Morning / Evening) - ANCOVA OC 
CT-5.8.1 Analysis of Baseline and Change from Baseline in DLQI Score - MMRM 
CT-5.8.2 Analysis of Baseline and Change from Baseline in DLQI Score - ANCOVA 
OC 
CT-5.8.3 Analysis of Baseline and Change from Baseline in DLQI Score - ANCOVA 
LOCF 
CT-5.8.4 Analysis of Baseline and Percent Change from Baseline in DLQI Score - 
MMRM 
CT-5.8.5 Analysis of Baseline and Percent Change from Baseline in DLQI Score - 
ANCOVA OC 
CT-5.8.6 Analysis of Baseline and Percent Change from Baseline in DLQI Score - 
ANCOVA LOCF 


Protocol 271-15-001 
 
 
37 
 
CT-5.9.1 Subgroup Analysis of Responder Rate for Overall IGA Score - by Age 
CT-5.9.2 Subgroup Analysis of Responder Rate for Overall IGA Score - by Gender 
CT-5.9.3 Subgroup Analysis of Responder Rate for Overall IGA Score - by IGA 
Score at Baseline 
CT-6.1 Change/Shift from Baseline in Dermatology Life Quality Index (DLQI) 
CT-7.1.1 Summary of Treatment Compliance 
CT-7.1.2 Summary of Treatment Compliance for Number of Administrations 
CT-7.2 Extent of Exposure to Trial Medication 
CT-8.1.1 Adverse Events (All Causalities) 
CT-8.1.2 Adverse Events According to Application Site (All Causalities) 
CT-8.2.1.1 Incidence of Treatment-emergent Adverse Events by System Organ Class 
CT-8.2.1.2 Incidence of Treatment-emergent Adverse Events by System Organ Class 
CT-8.2.1.3 Incidence of Treatment-emergent Adverse Events by System Organ Class 
CT-8.2.2.1 Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term 
CT-8.2.2.2 Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term 
CT-8.2.2.3 Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term 
CT-8.2.3.1 Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Severity 
CT-8.2.3.2 Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Severity 
CT-8.2.3.3 Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Severity 
CT-8.2.4.1 Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and CTCAE Grade 
CT-8.2.4.2 Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and CTCAE Grade 


Protocol 271-15-001 
 
 
38 
 
CT-8.2.4.3 Incidence of Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and CTCAE Grade 
CT-8.3.1.1 Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class 
CT-8.3.1.2 Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class 
CT-8.3.1.3 Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class 
CT-8.3.2.1 Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class and Preferred Term 
CT-8.3.2.2 Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class and Preferred Term 
CT-8.3.2.3 Incidence of Potentially Drug-Related Treatment-emergent Adverse 
Events by System Organ Class and Preferred Term 
CT-8.3.3.1 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class, Preferred Term and Severity 
CT-8.3.3.2 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class, Preferred Term and Severity 
CT-8.3.3.3 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class, Preferred Term and Severity 
CT-8.3.4.1 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class, Preferred Term and CTCAE Grade 
CT-8.3.4.2 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class, Preferred Term and CTCAE Grade 
CT-8.3.4.3 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class, Preferred Term and CTCAE Grade 
CT-8.4.1.1 Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class 
CT-8.4.1.2 Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class 
CT-8.4.1.3 Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class 


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CT-8.4.2.1 Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class and Preferred Term 
CT-8.4.2.2 Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class and Preferred Term 
CT-8.4.2.3 Incidence of Deaths due to Treatment-emergent Adverse Events by 
System Organ Class and Preferred Term 
CT-8.5.1.1 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class 
CT-8.5.1.2 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class 
CT-8.5.1.3 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class 
CT-8.5.2.1 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class and Preferred Term 
CT-8.5.2.2 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class and Preferred Term 
CT-8.5.2.3 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class and Preferred Term 
CT-8.5.3.1 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and Severity 
CT-8.5.3.2 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and Severity 
CT-8.5.3.3 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and Severity 
CT-8.5.4.1 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and CTCAE Grade 
CT-8.5.4.2 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and CTCAE Grade 
CT-8.5.4.3 Incidence of Serious Treatment-emergent Adverse Events by System 
Organ Class, Preferred Term and CTCAE Grade 
CT-8.6.1.1 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class 


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CT-8.6.1.2 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class 
CT-8.6.1.3 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class 
CT-8.6.2.1 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.6.2.2 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.6.2.3 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.6.3.1 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.6.3.2 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.6.3.3 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.6.4.1 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.6.4.2 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.6.4.3 Incidence of Treatment-emergent Adverse Events Resulting in 
Discontinuation from Study by System Organ Class and Preferred Term 
CT-8.7.1.1 Incidence of Treatment-emergent Adverse Events Greater Than or Equal 
to 5% in Any Group by System Organ Class and Preferred Term 
CT-8.7.1.2 Incidence of Treatment-emergent Adverse Events Greater Than or Equal 
to 5% in Any Group by System Organ Class and Preferred Term 
CT-8.7.1.3 Incidence of Treatment-emergent Adverse Events Greater Than or Equal 
to 5% in Any Group by System Organ Class and Preferred Term 
CT-8.8.1.1 Incidence of Non-Serious Treatment-emergent Adverse Events Greater 
Than or Equal to 5% in Any Group by System Organ Class and Preferred Term 
CT-8.8.1.2 Incidence of Non-Serious Treatment-emergent Adverse Events Greater 
Than or Equal to 5% in Any Group by System Organ Class and Preferred Term 


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CT-8.8.1.3 Incidence of Non-Serious Treatment-emergent Adverse Events Greater 
Than or Equal to 5% in Any Group by System Organ Class and Preferred Term 
CT-8.9.1.1 Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term According to Application Site 
CT-8.9.1.2 Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term According to Application Site 
CT-8.9.1.3 Incidence of Treatment-emergent Adverse Events by System Organ Class 
and Preferred Term According to Application Site 
CT-8.10.1.1 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class and Preferred Term According to Application Site 
CT-8.10.1.2 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class and Preferred Term According to Application Site 
CT-8.10.1.3 Incidence of Potentially Drug-related Treatment-emergent Adverse 
Events by System Organ Class and Preferred Term According to Application Site 
CT-9.1 Listing of Deaths 
CT-9.2 Listing of Serious Adverse Events 
CT-9.3 Listing of Study Drug Discontinuations Due to Adverse Events 
CT-9.4 Incidence of Potential Hy's Law Cases 
CT-9.5 Listing of Potential Hy's Law Cases - by Subject 
CT-10.1.1 Mean Change From Baseline in Laboratory Test Values: Serum Chemistry 
CT-10.1.2 Mean Change From Baseline in Laboratory Test Values: Hematology 
CT-10.2.1 Shift Tables of Clinical Laboratory Test Results: Serum Chemistry 
CT-10.2.2 Shift Tables of Clinical Laboratory Test Results: Hematology 
CT-10.2.3 Shift Tables of Clinical Laboratory Test Results: Urinalysis 
CT-11.1 Mean Change From Baseline in Vital Sign Parameters 
CT-11.2 Listing of Vital Signs Abnormalities 
CT-11.3 Incidence of Potential Clinical Significance in Vital Signs 
CT-11.4 Criteria for Vital Signs Potential Clinical Significance 
CT-12.1 Mean Change From Baseline in ECG Evaluations 
CT-12.2 Incidence of Categorical Changes in ECG Evaluations 


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CT-12.3 Listing of Categorical Changes in ECG Evaluations 
CT-12.4 Criteria for Categorical Changes in ECG Evaluations 
 
CF-1.1 Incidence of Responder Rate for Overall IGA Score by Visit 
CF-1.2 Incidence of Responder Rate for Overall IGA Score by Visit - Revised 
Responder Definition 
CF-2.1.1 Least Square Means of Change from Baseline in Overall IGA Score by Visit 
- MMRM 
CF-2.1.2 Means of Overall IGA Score by Visit - OC 
CF-2.1.3 Means of Overall IGA Score by Visit - LOCF 
CF-2.2.1 Least Square Means of Change from Baseline in Overall EASI Score by 
Visit - MMRM 
CF-2.2.2 Means of Overall EASI Score by Visit - OC 
CF-2.2.3 Means of Overall EASI Score by Visit - LOCF 
CF-3.1 Kaplan-Meier Plot of Time to Improvement in Overall IGA Score 
CF-3.2 Kaplan-Meier Plot of Time to Improvement in VRS for Pruritus Score 
 
PKT-1.1 Individual and Summary of OPA-15406 Plasma Concentrations Following 
Topical Administration of 0.3% OPA-15406 Ointment to Adult Subjects With Atopic 
Dermatitis (Group for Which PK Parameters are Evaluated) 
PKT-1.2 Individual and Summary of OPA-15406 Plasma Concentrations Following 
Topical Administration of 1% OPA-15406 Ointment to Adult Subjects With Atopic 
Dermatitis (Group for Which PK Parameters are Evaluated) 
PKT-2.1 Individual and Summary of OPA-15406 Plasma Trough Concentrations 
Following Topical Administration of 0.3% OPA-15406 Ointment to Adult Subjects 
With Atopic Dermatitis 
PKT-2.2 Individual and Summary of OPA-15406 Plasma Trough Concentrations 
Following Topical Administration of 1% OPA-15406 Ointment to Adult Subjects 
With Atopic Dermatitis 


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PKT-3 Individual and Summary of OPA-15406 Plasma Pharmacokinetic Parameters 
Following Topical Administration of OPA-15406 Ointment to Adult Subjects With 
Atopic Dermatitis 
PKT-4 Individual and Summary of OPA-15406 Accumulation Parameters Following 
Topical Administration of OPA-15406 Ointment to Adult Subjects With Atopic 
Dermatitis 
PKT-5.1 Individual and Summary of Normalized OPA-15406 Plasma Trough 
Concentrations by Dose Derived From % BSA Treated Following Topical 
Administration of 0.3% OPA-15406 Ointment to Adult Subjects With Atopic 
Dermatitis 
PKT-5.2 Individual and Summary of Normalized OPA-15406 Plasma Trough 
Concentrations by Dose Derived From % BSA Treated Following Topical 
Administration of 1% OPA-15406 Ointment to Adult Subjects With Atopic 
Dermatitis 
 
PKF-1.1 Mean OPA-15406 Plasma Trough Concentrations Following Topical 
Administration of OPA-15406 Ointment to Adult Subject With Atopic Dermatitis 
PKF-1.2 Mean Normalized OPA-15406 Plasma Trough Concentrations by Dose 
Derived From % BSA Treated Following Topical Administration of OPA-15406 
Ointment to Adult Subjects With Atopic Dermatitis 
PKF-2 Mean OPA-15406 Plasma Concentrations Following Topical Administration 
of OPA-15406 Ointment to Adult Subject With Atopic Dermatitis (Group for Which 
PK Parameters are Evaluated) 
PKF-3 Individual OPA-15406 Plasma Concentrations Following Topical 
Administration of OPA-15406 Ointment to Adult Subject With Atopic Dermatitis 
(Group for Which PK Parameters are Evaluated) 
 
PDATA-1.1 Inclusion and Exclusion Criteria 
PDATA-1.2 Subject Disposition 
PDATA-2.1 Medical History 
PDATA-2.2 History of Atopic Dermatitis 


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PDATA-3.1 Concomitant Medications: Medications Taken Prior to Start of Study 
Therapy 
PDATA-3.2 Concomitant Medications: Medications Taken During Study Therapy 
PDATA-3.3 Concomitant Medications: Medications Taken After Study Therapy 
PDATA-4.1 Exposure to Trial Medication 
PDATA-4.2 Listing of Trial Medication by Subject 
PDATA-5.1 Physical Examination 
PDATA-6 Adverse Events 
PDATA-7 Vital Signs 
PDATA-8 Electrocardiogram Results 
PDATA-9 Blood Sampling for Pharmacokinetics 
PDATA-10 Screening Failures 
PDATA-11 Protocol Deviations (Major) - CRF 
PDATA-12 Patch Application and Removal 
PDATA-13 Eczema Area and Severity Index 
PDATA-14 Visual Analog Scale for Pruritus 
PDATA-15 Verbal Rating Scale 
PDATA-16 Overall Investigator's Global Assessment of Disease Severity 
PDATA-17 Patient-Oriented Eczema Measure 
PDATA-18 Affected Body Surface Area 
PDATA-19 Treatment Area 
PDATA-20 Dermatology Life Quality Index 
 
DREAS-1 Discontinued Subjects and Reasons for Discontinuations 
 
DEMOG-1 Demographic Characteristics 
DEMOG-2 Informed Consent 
 


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AE-1 Adverse Events 
 
SMED-1 Investigational Medicinal Product Compliance 
SMED-2 Actual Exposure to Study Medication 
SMED-3 Investigational Medicinal Product Compliance for Number of 
Administrations 
 
EFF-1 Change from Baseline in IGA Score and Response with Overall IGA Score 
EFF-2 Change from Baseline in Total EASI Score 
EFF-3 Change from Baseline in EASI Score, Erythema 
EFF-4 Change from Baseline in EASI Score, Induration/Papulation 
EFF-5 Change from Baseline in EASI Score, Excoriation 
EFF-6 Change from Baseline in EASI Score, Lichenification 
EFF-7 Change from Baseline in EASI Score, HEAD/NECK 
EFF-8 Change from Baseline in EASI Score, UPPER LIMBS 
EFF-9 Change from Baseline in EASI Score, TRUNK 
EFF-10 Change from Baseline in EASI Score, LOWER LIMBS 
EFF-11 Change from Baseline in VAS Score 
EFF-12 Change from Baseline in Overall Percentage Affected Body Surface Area 
EFF-13 Change from Baseline in POEM Score 
EFF-14 Change from Baseline in VRS Score 
EFF-15 Change from Baseline in DLQI Score 
 
LAB-1 Laboratory Test Results: Serum Chemistry 
LAB-2 Laboratory Test Results: Hematology 
LAB-3 Laboratory Test Results: Urinalysis 
 
PDEV-1 Summary of Subjects with Major Protocol Deviations by Type of Deviation 


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SUBEX-1 Subjects Excluded From Analysis Set