Clinical trial NCT03703102
Conditions: Atopic Dermatitis
Keywords: AD eczema skin diseases biologics
Sponsor: Kyowa Kirin, Inc.
Start date: 2018-10-22; Completion date: 2020-11-12
Enrollment: 274 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 2, multicenter, randomized, placebo-controlled, double-blind, parallel-group study for subjects with moderate to severe AD whose disease cannot be adequately controlled with topical medications or for whom topical treatment is medically inadvisable.

Detailed description:

Arms: arm 1: Subcutaneous administration of placebo arm 2: Subcutaneous administration of KHK4083 (dose level 1, dosing regimen 2) arm 3: Subcutaneous administration of KHK4083 (dose level 2, dosing regimen 1) arm 4: Subcutaneous administration of KHK4083 (dose level 3, dosing regimen 1) arm 5: Subcutaneous administration of KHK4083 (dose level 3, dosing regimen 2)
Interventions: intervention 1: KHK4083 intervention 2: Placebo
Intervention descriptions: intervention 1: Anti-OX40 Monoclonal Antibody KHK4083 intervention 2: Matching placebo

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
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CLINICAL PROTOCOL 
 
A Phase 2, Multicenter, Randomized, Double-blind, Parallel-group, 
Placebo-controlled Study of an Anti-OX40 Monoclonal Antibody (KHK4083) 
in Subjects with Moderate to Severe Atopic Dermatitis (AD) 
 
Protocol Number: 
4083-006 
Date: 
11 June 2020 
Version: 
3.0 
 
 
Test Drug: 
KHK4083 
Phase: 
2 
 
 
US IND Number: 
138069 
EudraCT Number: 
2018-000998-72 
Sponsor: 
Kyowa Kirin Co., Ltd 
1-9-2, Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan 
 
Confidentiality Statement 
The information contained in this document is the confidential information owned by Kyowa Kirin Co., Ltd and 
affiliated companies, the Sponsor of this clinical study, and is only provided to those who are directly involved 
in the study such as Investigators, sub-Investigators (including study staff such as clinical research 
coordinators, investigational product managers, the study administrative office, the Institutional Review Boards 
(IRBs), and where applicable, the directors of investigative sites). Therefore, it is understood that this 
information will not be disclosed or leaked to any third party not involved in the study. You shall not duplicate, 
cite, or publish this information without prior written authorization from Kyowa Kirin Co., Ltd.


Clinical Protocol: 4083-006 
 
 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Protocol Title: A Phase 2, Multicenter, Randomized, Double-blind, Parallel-group, 
Placebo-controlled Study of an Anti-OX40 Monoclonal Antibody (KHK4083) in Subjects 
with Moderate to Severe Atopic Dermatitis 
Protocol Number: 4083-006 
Version: 3.0 
This protocol contains confidential information that is proprietary to Kyowa Kirin Co., Ltd. 
and affiliated companies. This information is being provided to you for the purpose of 
conducting a clinical study on behalf of Kyowa Kirin Co., Ltd. You may disclose the contents 
of this protocol to the study personnel under your supervision and to your Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC). As an Investigator 
participating in this study, you agree to not disclose the contents of this protocol to any other 
parties (unless such disclosure is required by government regulations or laws) without the 
prior written permission of Kyowa Kirin Co., Ltd. 
Any supplemental information (e.g., protocol amendment, Investigator’s Brochure, and study 
manuals) that may accompany this document are also proprietary to Kyowa Kirin Co., Ltd. 
and should be handled consistent with the terms stated above. 
I, the undersigned, have reviewed this protocol, including appendices. I will conduct the 
clinical study in compliance with the protocol, study manuals, Good Clinical Practice (GCP), 
and the applicable regulatory requirements. 
Principal Investigator: 
________________________________________  
 
 
 
 
 
Signature 
 
 
 
 
 
Date 
 
________________________________________  
 
 
 
 
 
Printed Name  
 
 
 
 
Title  
 
________________________________________  
 
 
 
 
 
Institution Address 
 
 
 
 
Telephone Number 


Clinical Protocol: 4083-006 
 
 
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PROTOCOL SIGNATURE PAGE 
Protocol Title: A Phase 2, Multicenter, Randomized, Double-blind, Parallel-group, 
Placebo-controlled Study of an Anti-OX40 Monoclonal Antibody (KHK4083) in Subjects 
with Moderate to Severe Atopic Dermatitis 
Protocol Number: 4083-006 
Version: 3.0 
 
 
Tadahiro Kakuno 
Manager, Clinical Development Department 
Kyowa Kirin Co., Ltd. 
Otemachi Financial City Grand Cube, 1-9-2 Otemachi, 
Chiyoda-ku, Tokyo 100-0004, Japan 
 
Date 


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CLINICAL STUDY PROTOCOL SYNOPSIS 
I 
Study Title 
A Phase 2, Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled Study 
of an Anti-OX40 Monoclonal Antibody (KHK4083) in Subjects with Moderate to Severe 
Atopic Dermatitis (AD)  
II 
Study Objectives and Endpoints 
Primary Objective 
Endpoint 
To assess the efficacy of four dose regimens of 
KHK4083 compared to placebo as measured by the 
change from baseline in Eczema Area and Severity 
Index (EASI) score following multiple subcutaneous 
(SC) injections for 16 weeks in subjects with moderate 
to severe AD. 
• 
Percent change from baseline to Week 16 in EASI 
score 
Secondary Objectives 
Endpoints 
To evaluate the effects on skin symptoms following 
multiple SC injections of KHK4083 for 16 weeks in 
comparison with placebo in subjects with moderate to 
severe AD. 
 
• 
Achievement of 50%, 75%, or 90% reduction 
from baseline in EASI score (EASI-50, EASI-75, 
or EASI-90) at Week 16 
• 
Change from baseline to Week 16 in EASI score 
• 
Change and percent change from baseline to 
Week 16 in Severity Scoring of Atopic Dermatitis 
(SCORAD) score 
• 
Achievement of an Investigator’s Global 
Assessment (IGA) score of 0 or 1 and a reduction 
from baseline of ≥2 points at Week 16 
• 
Change from baseline to Week 16 in percent body 
surface area of involvement of AD (BSA)  
To evaluate the effects on itching and sleeping 
following multiple SC injections of KHK4083 for 
16 weeks in comparison with placebo in subjects with 
moderate to severe AD. 
• 
Change and percent change from baseline to 
Week 16 in pruritus Numerical Rating Scale 
(NRS) score 
• 
Change and percent change from baseline to 
Week 16 in sleep disturbance NRS score 
To evaluate the effects on quality of life (QoL) 
following multiple SC injections of KHK4083 for 
16 weeks in comparison with placebo in subjects with 
moderate to severe AD. 
• 
Change from baseline to Week 16 in Dermatology 
Life Quality Index (DLQI)  


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To evaluate the effects on skin symptoms following 
multiple SC injections of KHK4083 for 36 weeks in 
subjects with moderate to severe AD. 
• 
Change and percent change from baseline in 
EASI score at each time point 
• 
Achievement of EASI-50, EASI-75, or EASI-90 
at each time point 
• 
Change and percent change from baseline in 
SCORAD score at each time point 
• 
Achievement of an IGA score of 0 or 1 and a 
reduction from baseline of ≥2 points at each time 
point  
• 
Change from baseline in percent BSA at each 
time point 
To evaluate the effects on itching and sleeping 
following multiple SC injections of KHK4083 for 
36 weeks in subjects with moderate to severe AD. 
• 
Change and percent change from baseline in 
pruritus NRS score at each time point 
• 
Change and percent change from baseline sleep 
disturbance NRS score at each time point 
To evaluate the effects on QoL following multiple SC 
injections of KHK4083 for 36 weeks in subjects with 
moderate to severe AD. 
• 
Change from baseline in DLQI at each time point 
Safety Objective 
Endpoints 
To evaluate the safety of multiple SC injections of 
KHK4083 in subjects with moderate to severe AD. 
• 
Treatment-emergent adverse events (TEAEs) 
• 
Laboratory values 
• 
Vital signs 
• 
Standard 12-lead electrocardiogram (ECG) 
Exploratory Objectives 
Endpoints 
To investigate pharmacokinetics and immunogenicity 
following multiple SC injections of KHK4083 in 
subjects with moderate to severe AD. 
• 
Pharmacokinetic assessment 
– 
Serum KHK4083 concentration 
– 
Pharmacokinetic parameters (e.g., Cmax, 
Ctrough) 
• 
Anti-KHK4083 antibody 
To assess pharmacodynamics following multiple SC 
injections of KHK4083 in subjects with moderate to 
severe AD. 
• 
Pharmacodynamic assessment 
– 
Serum disease markers (thymus and 
activation-regulated chemokine [TARC], 
serum total IgE) 
III 
Summary of Study Design 
This is a Phase 2, multicenter, randomized, placebo-controlled, double-blind, parallel-group 
study consisting of a screening period of at least 2 weeks (a maximum 6 weeks), an 18-week 
placebo-controlled treatment period (Treatment A period), followed by an 18-week treatment 
period (Treatment B period), and a 20-week follow-up period. 


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Subjects will receive SC doses of investigational product (IP) every 2 weeks under double-
blind conditions (Weeks 0 [Day 1], 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 
and 34). The last dose will be administered at Week 34, and subjects will complete the 
treatment period at Week 36 (end of treatment [EOT]). Subsequently, subjects will be 
followed up at Weeks 40, 44, 48, 52, and 56. The study period will be a maximum of 
60 weeks. 
1) Screening Period 
The Investigator will register subjects who provide written informed consent in an interactive 
web response system (IWRS) to start screening those subjects within 4 weeks after the date 
of subject’s signature on informed consent. Subjects will undergo baseline assessments at 
least 2 weeks but not later than 6 weeks after the start of screening.  
A total of approximately 250 subjects who are considered eligible as a result of the screening 
and baseline assessments will be enrolled. 
Subjects will be required to apply a topical emollient, as a rule, twice daily for at least 1 week 
before baseline visit through the end of the study. The use of topical corticosteroids will be 
prohibited from at least 1 week before baseline visit through Week 36 assessment. 
2) Treatment Period (Day 1 to Week 36) 
Randomization will be performed within 3 days after baseline visit. 
Subjects will start study treatment on the day of or the day after randomization (date of the 
first dose of IP will be regarded as Day 1). The treatment period is defined as the period 
between Day 1 and the end of the Week 36 assessment. 
The study consists of 2 treatment periods. 
Treatment A period (last dose at Week 16) 
All subjects who meet the inclusion criteria and none of the exclusion criteria during the 
screen phase will be randomized to one of the treatment groups (placebo, KHK4083 150 mg 
Q4W, 300 mg Q2W, 600 mg Q2W, or 600 mg Q4W). In the 150 mg Q4W group and the 
600 mg Q4W group, placebo will be administered between KHK4083 injections to ensure 
blinding. 


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Treatment A period is defined as the period between Day 1 and Week 18 pre (before IP 
administration at Week 18).  
In order to ensure the study blind, the efficacy data until Week 16 shall be entered into the 
electronic Clinical Outcome Assessment (eCOA). 
Treatment B period (last dose at Week 34) 
Treatment B period is an extension phase where all subjects will receive KHK4083 for an 
additional 18 weeks under double-blind conditions (from Week 18 post [IP administration at 
Week 18] through Week 36). 
In Treatment B period, subjects randomized to the placebo group in Treatment A period will 
receive SC injections of 600 mg KHK4083 every 2 weeks starting at Week 18. Subjects 
randomized to any of the KHK4083 groups in Treatment A period will receive KHK4083 at 
the same dose and dosing interval as in Treatment A period. 
Subjects who meet withdrawal criterion 5) (Section 4.4.1) based on the IGA score at 
Week 26 will discontinue IP administration at Week 26, undergo end-of-study assessments, 
and then be withdrawn from the study.  
Subjects receiving rescue treatment (See Section 6.3.3) during the period between the start of 
IP administration and the end of the Week 36 assessment will discontinue IP, undergo end-
of-study assessments, and subsequently be withdrawn from the study. 
3) Follow-up Period (up to Week 56) 
Subjects will enter the follow-up period after the end of the Week 36 assessment and will be 
followed up every 4 weeks until Week 56. Subjects who received rescue treatment after 
Week 36 will not be withdrawn from the study and will be observed until the end of the study 
up to Week 56. 
4) Other Potential Study Assessments (optional) 
Sampling for exploratory biomarkers: Exploratory biomarkers to characterize KHK4083 
pharmacodynamic activity will be assessed. At selected investigative sites in the United 
States and Canada, blood and skin samples will be collected from subjects who voluntarily 
provide consent to undergo both serum analyses (including but not limited to serum cytokines 


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and chemokines) and skin biopsy. At all investigative sites in Japan, blood and skin samples 
will be collected from subjects who voluntarily provide consent to undergo both flow 
cytometry (OX40-positive T cell and cutaneous lymphocyte-associated antigen [CLA]-
positive T memory cell) and skin biopsy. 
Pharmacogenetic testing: The purpose of this assessment is to explore the association 
between individual differences in responses to KHK4083 and mutations in DNA sequence. 
Blood samples will be collected before IP injection at Week 0 from subjects who voluntarily 
provide consent. 
IV 
Number of Subjects 
A total of approximately 250 subjects will be randomly assigned by a 1:1:1:1:1 ratio to 
4 active treatment groups (50 subjects in each group) and one placebo group (50 subjects) in 
Treatment A period.  
V 
Target Subjects 
Subjects with moderate to severe AD whose disease cannot be adequately controlled with 
topical medications or for whom topical treatment is medically inadvisable. 
To allow efficacy and safety assessments in subjects without previous use of biological 
products, enrollment of subjects who have received previous treatment with biological 
products for treatment of AD will be limited to not more than 50% of total enrollment. 
VI 
Inclusion Criteria 
Subjects who meet all of the following criteria will be enrolled in this study: 
1) Voluntarily signed informed consent to participate in the study; 
2) Men and women ≥18 years at the time of informed consent; 
3) Chronic AD, according to American Academy of Dermatology Consensus Criteria 
(Eichenfield et al, 2014) or the local diagnostic criteria, that has been present for at least 
1 year before screening; 
4) EASI score ≥16 at screening and baseline; 
5) IGA score ≥3 (moderate) at both screening and baseline; 
6) BSA ≥10% at both screening and baseline; 


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7) Documented recent history (within 1 year prior to screening visit) of inadequate response 
to treatment with topical medications or for whom topical treatments are otherwise 
medically inadvisable (e.g., because of important side effects or safety risks); 
Note:  
• Inadequate response is defined as failure to achieve and maintain remission or a low disease activity 
state (comparable to IGA 0 = clear to 2 =mild) despite treatment with a daily regimen of topical 
corticosteroid of medium to higher potency (± topical calcineurin inhibitors as appropriate), applied 
for at least 28 days or for the maximum duration recommended by the product prescribing information 
(e.g., 14 days for super-potent topical corticosteroids), whichever is shorter. 
• Patients with documented systemic treatment for AD in the past 1 year are also considered as 
inadequate responders to topical treatments and are potentially eligible for treatment with KHK4083 
after appropriate washout. 
• Important side effects or safety risks are those that outweigh the potential treatment benefits and 
include intolerance to treatment, hypersensitivity reactions, significant skin atrophy, and systemic 
effects, as assessed by the Investigator or by the patient’s treating physician. 
8) Women of childbearing potential (WOCBP) and fertile men must agree to use highly 
effective contraceptive methods per the approved local guidance in each country from the 
time of informed consent to 6 months after the last dose of IP (for women) or from the 
start of IP administration to 6 months after the last dose of IP (for men). WOCBP must 
have a negative serum pregnancy test result at screening and a negative urinary pregnancy 
test result at baseline assessments. 
For the United States and Canada, WOCBP who have sexual intercourse with a non-
surgically sterilized male partner must agree and commit to the use one of the following 
highly effective methods of contraception (Clinical Trials Facilitation Group, 2014) from 
the time of informed consent to 6 months after the last dose of IP. Contraceptive methods 
considered acceptable for use in this study include:  
a) Established use (≥2 months prior to the screening visit) of oral, injected, transdermal 
or implanted combined estrogen-progestogen hormonal methods of contraception. 
Subjects who have used such methods for less than 2 months at the screening visit are 
required to use one of the methods described under b) or c) until the establishment of 
hormonal contraception methods.  
b) Double barrier contraception: use of occlusive diaphragm (cap or cervical/vault caps) 
with spermicidal foam/gel/film/cream/suppository. In countries where spermicidal 
condoms are not allowed ordinary condoms could be used in combination with 
spermicidal creams. Appropriate measures are to be determined by the investigator 
together with the subject, in accordance with the standard of care in the country where 
treatment is administered. A female condom and a male condom should not be used 
together as friction between the two can result in either, or both product(s) failing.  
c) An intrauterine device or system. 
For Germany, WOCBP and fertile men must agree to use highly effective contraceptive 
methods that can achieve a failure rate of less than 1% per year from the time of informed 
consent to 6 months after the last dose of IP (for women) or from the start of IP 
administration to 6 months after the last dose of IP (for men). WOCBP must have a 


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negative serum pregnancy test result at screening and a negative urinary pregnancy test 
result at baseline assessments and at each dose interval. 
Birth control methods considered highly effective used consistently and correctly include: 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation 
– oral 
– intravaginal 
– transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
– oral 
– injectable 
– implantable 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
• 
Vasectomised partner 
• 
Sexual abstinence (Sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period of the 
study treatments). 
Note:  
• WOCBP exclude women who have undergone permanent sterilization, those who are postmenopausal 
[defined as the absence of menstruation for at least 12 consecutive months without any other medical 
reason (or in postmenopausal range per local laboratory standards)], and those anatomically having 
no childbearing potential. 
VII 
Exclusion Criteria 
Subjects must be excluded from the study if they meet any of the following criteria. 
1) Current or past history of clinically significant illness(es) deemed by the Investigator to 
be likely to affect the study conduct and assessments. Examples include, but are not 
limited to, clinically significant cardiovascular (e.g., New York Heart Association 
[NYHA] Class III or IV), uncontrolled diabetes (HbA1c ≥9%), liver (e.g., Child-Pugh 
class B or C), renal, respiratory, hematologic, central nervous system, psychiatric, or 
autoimmune diseases/disorders; 
2) Any of the following laboratory abnormalities at screening: 
• 
Serum creatinine: >1.5 mg/dL 
• 
AST or ALT: ≥2.5 times the upper limit of normal 
• 
Neutrophil count: <1.5×103/μL 


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• 
Other laboratory abnormalities that may affect the completion or evaluation of the 
study, as judged by the Investigator; 
3) Active malignancies, or onset or a history of treatment of malignancies within 5 years 
prior to informed consent (except curatively treated in situ cervical carcinoma, cutaneous 
basal cell carcinoma, or cutaneous squamous cell carcinoma); 
4) Past history of alcohol or substance abuse within 1 year before screening visit; active 
alcohol dependence or drug dependence; 
5) Current or past history of any suicidal behavior; 
6) History of major immunologic reaction (e.g., serum sickness, anaphylaxis, or 
anaphylactic reaction) to any other biologic product or any excipient of KHK4083; 
7) History of ≥3 systemic infections requiring systemic administration (excluding oral 
administration) of antimicrobials, antifungals, or antivirals within 1 year prior to baseline 
visit; 
8) Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, 
antiparasitics, antiprotozoals, or antifungals within 4 weeks before the baseline visit, or 
superficial skin infections within 2 weeks before the baseline visit; 
9) Treatment with live vaccination (e.g., BCG, polio, measles, or rubella) within 12 weeks 
prior to baseline visit. Inactivated vaccination (e.g., hepatitis, pneumococcal, 
meningococcal, tetanus, diphtheria toxoid, acellular pertussis, inactivated polio, human 
papilloma and influenza-except intranasal influenza) is allowed; 
10) Treatment with any biological product (including an IP) within 12 weeks (16 weeks for 
Japan) or 5 half-lives, whichever is longer, prior to baseline visit; 
11) Treatment with 3 or more biological products (including an IP) within 2 years before the 
baseline visit; 
12) Participation in a clinical or equivalent study and use of an IP (other than biologics) or 
unapproved medical device within 4 weeks (16 weeks for Japan) or 5 half-lives, 
whichever is longer, prior to baseline visit; 
13) Treatment with any of the following medications or therapies within 4 weeks or 5 half-
lives, whichever is longer, prior to baseline visit; 
• 
Systemic corticosteroids (inhaled corticosteroids, eye, ear, or nasal drops containing 
corticosteroids are allowed, suppositories or enemas containing corticosteroids are not 
allowed) 
• 
Systemic treatment with methotrexate, mycophenolate, calcineurin inhibitors, 
thalidomide, or other immunosuppressants 
• 
Phototherapy (e.g., psoralen ultraviolet A [PUVA] therapy, ultraviolet B [UVB] 
therapy, narrow-band UVB therapy, ultraviolet A1 [UVA1] therapy , excimer light) 
for the treatment of AD 
• 
Janus kinase inhibitors 


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14) Treatment with any of the following medications for the treatment of AD within 1 week 
prior to baseline visit; 
• 
Topical corticosteroids 
• 
Topical calcineurin inhibitors or other immunosuppressive agents 
• 
Topical agents including crotamiton, Eucrisa®/crisaborole 
• 
Combination topical agents containing a corticosteroid or a calcineurin-inhibiting 
component or other immunosuppressive agents 
• 
Chinese herbal medicines (e.g., jumi-haidoku-to, shofu-san, saiko-seikan-to, hochu-
eki-to) 
15) Any planned surgical treatment or invasive procedure (for instance dental implant 
installation or non-emergency low invasive intra-cardiac manipulation) during the study; 
16) Any conditions not allowing for discontinuation of prohibited concomitant drugs or 
therapies; 
17) Pregnant or breastfeeding women, or women willing to become pregnant; 
18) Evidence of HIV infection or are positive for HIV antibodies at screening; or current 
acquired, common variable or inherited, primary or secondary immunodeficiency; 
19) Positive test for active hepatitis B (HB) infection at screening defined as: 
• 
Positive for HB surface antigen; 
• 
Positive for anti-HB core antibody or positive for HBV-DNA; or 
• 
For subjects enrolled in Japan, positive for anti-HB core antibody and/or positive for 
anti-HB surface antibody, and positive for HBV-DNA. However, HBV-DNA 
measurement will not be required for subjects who are positive for antibodies 
produced after HB vaccination and who are not affected with hepatitis B at screening. 
If any of HB tests has an indeterminate or the result cannot be interpreted with 
certainty, confirmatory testing as per local guidelines will be performed. 
20) Positive for anti-hepatitis C (HC) virus antibody at screening, and confirmed infection 
with HC virus by RNA or other confirmation test. If the HC test has an indeterminate 
result, confirmatory testing will be performed by an alternative method that is locally 
accepted; 
21) Evidence or history of active tuberculosis (TB), either treated or untreated; or latent TB 
(defined as a positive purified protein derivative [PPD] or interferon-gamma release assay 
[IGRA] test without evidence of clinically manifested active TB), the treatment of which 
was completed more than 12 months before baseline visit or untreated. Evaluation for TB 
will be conducted according to the local standards of care or as determined by local 
guidelines and will include PPD or IGRA tests and may consist of history, physical 
examinations and chest X-ray. 
Subjects with latent TB who meet either of the following conditions can be enrolled: 


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• 
Subjects with latent TB who have completed an appropriate course of anti-TB 
treatment as per local guidelines or standards of care within 12 months before 
baseline visit. 
• 
Subjects with latent TB who have been receiving appropriate anti-TB treatment as per 
local guidelines or standards of care (for instance isoniazid) for at least 28 days 
(21 days in Japan) before baseline visit. 
22) Previous participation in a study of KHK4083 and use of an IP; 
23) Other conditions unsuitable for participation in the study in the opinion of the 
Investigator. 


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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ........................................................................................3 
CLINICAL STUDY PROTOCOL SYNOPSIS .....................................................................4 
TABLE OF CONTENTS .......................................................................................................14 
LIST OF IN-TEXT TABLES ................................................................................................22 
LIST OF IN-TEXT FIGURES ..............................................................................................22 
LIST OF TERMS ...................................................................................................................23 
1 
INTRODUCTION .......................................................................................................27 
1.1 
Medical Background ..................................................................................................27 
1.2 
Atopic Dermatitis .......................................................................................................28 
1.3 
KHK4083 ...................................................................................................................29 
1.3.1 
Non-Clinical Studies ...............................................................................................30 
1.3.2 
Clinical Studies .......................................................................................................30 
1.4 
Risks and Benefits ......................................................................................................32 
1.4.1 
Risks ........................................................................................................................32 
1.4.2 
Benefits ...................................................................................................................32 
1.5 
Rationale for Conducting the Study ...........................................................................32 
2 
STUDY OBJECTIVES AND ENDPOINTS .............................................................33 
3 
STUDY DESIGN..........................................................................................................35 
3.1 
Study Design and Duration ........................................................................................35 
3.1.1 
Screening Period .....................................................................................................37 
3.1.2 
Treatment Period (Day 1 to Week 36) ....................................................................37 
3.1.3 
Follow-up Period (up to Week 56) .........................................................................38 
3.1.4 
Other Potential Study Assessments (optional) ........................................................38 


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3.2 
Rationale for Study Design ........................................................................................39 
3.3 
Enrollment ..................................................................................................................39 
3.4 
Randomization and Blinding ......................................................................................40 
3.4.1 
Randomization ........................................................................................................40 
3.4.2 
Blinding ..................................................................................................................41 
3.4.2.1 
Creation and Storage of Allocation Table ...........................................................41 
3.4.2.2 
Blinding Method ..................................................................................................41 
3.4.2.3 
Measures Taken to Maintain Blindness Assignment Based on 
Known Information on KHK4083 .......................................................................42 
3.4.2.4 
Unblinding ...........................................................................................................42 
3.5 
Safety Monitoring Plan...............................................................................................43 
3.5.1 
Injection Reaction ...................................................................................................43 
3.5.2 
Contraception ..........................................................................................................44 
4 
SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA ..............................44 
4.1 
Target Subjects ...........................................................................................................44 
4.2 
Inclusion Criteria ........................................................................................................45 
4.3 
Exclusion Criteria .......................................................................................................47 
4.4 
Criteria and Procedure for Removal from Study ........................................................49 
4.4.1 
Subject Removal .....................................................................................................49 
4.4.2 
Premature Termination or Suspension of the Entire Study or the Study 
at Individual Investigative Site ...............................................................................51 
5 
INVESTIGATIONAL PRODUCTS ..........................................................................52 
5.1 
Investigational Drug and Comparator ........................................................................52 
5.1.1 
Investigational Drug ...............................................................................................52 
5.1.2 
Comparator .............................................................................................................52 


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5.2 
Packaging and Labelling ............................................................................................53 
5.2.1 
Packaging ................................................................................................................53 
5.2.2 
Labeling ..................................................................................................................53 
5.3 
Storage ........................................................................................................................53 
5.4 
Delivery, Storage, Accountability, and Return of Investigational Product ................53 
6 
TREATMENT PLAN AND CONCOMITANT THERAPY ...................................54 
6.1 
Dose and Duration of Treatment ................................................................................54 
6.2 
Mode of Administration .............................................................................................54 
6.2.1 
KHK4083 or Placebo ..............................................................................................54 
6.2.2 
Dose Modification ..................................................................................................56 
6.2.3 
Measures to be taken for Acute Reactions ..............................................................57 
6.2.4 
Rationale for Route of Administration, Dosing Regimen, and 
Treatment Duration .................................................................................................58 
6.3 
Concomitant Medications and Therapies ...................................................................60 
6.3.1 
Concomitant Medications .......................................................................................60 
6.3.2 
Prohibited Concomitant Medications and Therapies ..............................................61 
6.3.3 
Rescue Treatments ..................................................................................................62 
6.4 
Treatment Compliance ...............................................................................................62 
7 
STUDY PROCEDURES .............................................................................................63 
7.1 
Overall Schedule ........................................................................................................63 
7.2 
Investigation Items .....................................................................................................70 
7.2.1 
Demographics .........................................................................................................70 
7.2.2 
Exposure .................................................................................................................70 
7.3 
Efficacy Assessments .................................................................................................70 
7.3.1 
Eczema Area and Severity Index (EASI) ...............................................................71 


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7.3.2 
SCORing Atopic Dermatitis (SCORAD) ...............................................................71 
7.3.3 
Investigator’s Global Assessment (IGA) ................................................................72 
7.3.4 
Body Surface Area of Involvement of AD (BSA) ..................................................72 
7.3.5 
Pruritus Numerical Rating Scale (NRS) .................................................................72 
7.3.6 
Sleep Disturbance Numerical Rating Scale (NRS) .................................................73 
7.3.7 
Dermatology Life Quality Index (DLQI) ...............................................................73 
7.3.8 
Photograph (Optional) ............................................................................................73 
7.4 
Pharmacodynamic Assessments .................................................................................74 
7.4.1 
Serum Disease Markers ..........................................................................................74 
7.4.2 
Serum IL-22 ............................................................................................................74 
7.5 
Pharmacokinetic 
Concentrations 
and 
Immunogenicity 
Specimen 
Assessment .................................................................................................................74 
7.5.1 
Serum KHK4083 Concentration .............................................................................74 
7.5.2 
Anti-KHK4083 Antibody .......................................................................................75 
7.6 
Exploratory Biomarker Measurement (Optional) ......................................................75 
7.6.1 
Skin Biopsy (To be Performed at the Selected Investigative Sites in the 
United States and Canada and the Investigative Sites in Japan) .............................75 
7.6.2 
Serum Cytokines and Chemokines (To be Performed at the Selected 
Investigative Sites in the United States and Canada Only) ....................................76 
7.6.3 
Flow Cytometry (To be Performed in Japan Only) ................................................76 
7.7 
Pharmacogenetics .......................................................................................................77 
7.8 
Safety Assessments ....................................................................................................78 
7.8.1 
Clinical Laboratory Evaluation ...............................................................................78 
7.8.2 
Physical Examination .............................................................................................79 
7.8.3 
Height and Weight ..................................................................................................80 
7.8.4 
Vital Signs ...............................................................................................................80 


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7.8.5 
Standard 12-Lead Electrocardiogram .....................................................................80 
7.9 
Adverse Events ...........................................................................................................81 
7.9.1 
Definitions ..............................................................................................................81 
7.9.2 
Actions for Subjects ................................................................................................82 
7.9.3 
Urgent Safety Measures ..........................................................................................82 
7.9.4 
Reporting of Adverse Events ..................................................................................82 
7.9.4.1 
Assessment of Intensity .......................................................................................84 
7.9.4.2 
Assessment of Relationship to Study Treatment .................................................84 
7.9.5 
Definition of Serious Adverse Events ....................................................................84 
7.9.5.1 
Reporting of Serious Adverse Events..................................................................85 
7.9.5.2 
Notification of Serious Adverse Events to Institutional Review 
Board or Ethics Committee .................................................................................86 
7.9.6 
Definition of Treatment-Emergent Adverse Events ...............................................87 
7.9.7 
Definition of Other Significant Treatment-Emergent Adverse Events...................87 
7.9.8 
Other Significant Treatment-Emergent Adverse Events Requiring 
Special Handling .....................................................................................................87 
7.9.8.1 
Reporting of Injection Reactions .........................................................................87 
7.9.8.2 
Overdose ..............................................................................................................88 
7.9.8.3 
Pregnancy Reporting ...........................................................................................88 
7.9.9 
Other Handling .......................................................................................................89 
8 
DATA MANAGEMENT .............................................................................................89 
8.1 
Source Documents (Source Data) ..............................................................................89 
8.2 
Access to Data ............................................................................................................89 
8.3 
Electronic Case Report Forms (eCRFs) .....................................................................89 
8.4 
Data Collection Using eCOA System ........................................................................90 


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8.4.1 
Other Instructions Related to Creation of eCOA ....................................................91 
8.5 
Record Keeping and Archiving ..................................................................................92 
8.6 
Study Monitoring........................................................................................................92 
9 
STATISTICAL ANALYSIS .......................................................................................92 
9.1 
Statistical Methods .....................................................................................................92 
9.1.1 
Primary Efficacy Analysis ......................................................................................93 
9.1.2 
Secondary Efficacy Analyses .................................................................................93 
9.1.2.1 
Efficacy Endpoints at Week 16 ...........................................................................93 
9.1.2.2 
Efficacy Endpoints at Each Time Point...............................................................94 
9.1.3 
Safety Analyses .......................................................................................................94 
9.1.3.1 
Adverse Events ....................................................................................................95 
9.1.3.2 
Laboratory Values ...............................................................................................95 
9.1.3.3 
Vital Signs ...........................................................................................................95 
9.1.3.4 
Standard 12-lead Electrocardiogram ...................................................................95 
9.1.4 
Exploratory Analyses ..............................................................................................95 
9.1.4.1 
Pharmacokinetics .................................................................................................95 
9.1.4.2 
Pharmacodynamics ..............................................................................................96 
9.1.4.3 
Other Testing .......................................................................................................96 
9.2 
Target Number of Subjects .........................................................................................97 
9.2.1 
Rationale for Target Number of Subjects ...............................................................97 
9.3 
Significance Level ......................................................................................................98 
9.4 
Early Termination Criteria .........................................................................................98 
9.5 
Handling of Missing, Unused, and Abnormal Data ...................................................98 
9.6 
Development of Statistical Analysis Plan and Procedure for Reporting 
Deviations from the Original Statistical Analysis Plan ..............................................98 


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9.7 
Selection of Subjects to be Included in Analyses .......................................................99 
9.7.1 
Full Analysis Set (FAS) ..........................................................................................99 
9.7.2 
Per Protocol Set (PPS) ............................................................................................99 
9.7.3 
Safety Analysis Set .................................................................................................99 
9.7.4 
Pharmacokinetic Analysis Set ................................................................................99 
9.8 
Interim Analysis .......................................................................................................100 
10 
ETHICAL AND REGULATORY CONSIDERATIONS ......................................101 
10.1 
Compliance with GCP, the Protocol, and Other Applicable Regulatory 
Requirements ............................................................................................................101 
10.2 
Institutional Review..................................................................................................101 
10.3 
Deviations from or Changes to the Protocol ............................................................102 
10.4 
Investigator’s Responsibilities ..................................................................................102 
10.4.1 
Selection of Subjects to be enrolled in the Study and Assurance of 
Their Safety ...........................................................................................................102 
10.4.2 
Protection of Subjects’ Personal Information and Privacy ...................................103 
10.4.3 
Subject Informed Consent ....................................................................................103 
10.5 
Audit and Inspection.................................................................................................104 
10.5.1 
Investigator Information .......................................................................................104 
10.5.2 
Compliance with Law, Audit, and Debarment .....................................................105 
10.5.3 
Financial Disclosure .............................................................................................106 
10.6 
Expenses Related to the Study .................................................................................106 
10.7 
Compensation for Health Injury ...............................................................................106 
10.8 
Publication Policy .....................................................................................................107 
11 
STUDY ADMINISTRATIVE STRUCTURE .........................................................107 
11.1 
Sponsor .....................................................................................................................107 


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11.2 
Clinical Trial Manager (Sponsor Signatory) ............................................................107 
11.3 
Medical Monitor .......................................................................................................108 
12 
REFERENCES...........................................................................................................109 
13 
APPENDICES/ATTACHMENTS ...........................................................................113 
 


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List of In-text Tables 
Table 6.2.1-1 
Dosing Schedule for Randomized Treatment Groups ................... 56 
Table 7.1-1 
Study Schedule of Events - Screening, Baseline, and Treatment 
A period ......................................................................................... 64 
Table 7.1-2 
Study Schedule of Events - Treatment B period ........................... 66 
Table 7.1-3 
Study Schedule of Events - Follow-up Period and Early 
Termination ................................................................................... 68 
Table 7.8.1-1 
Clinical Laboratory Assessments .................................................. 79 
 
List of In-text Figures 
Figure 3.1-1 
Overall Study Design .................................................................... 36 
Figure 6.2.4-1 
Comparison of serum concentration between Population 
Analysis Results and Observed Values in Study 4083-004 .......... 58 
Figure 6.2.4-2 
Simulation of Serum Concentrations at Each Dosing Regimen.... 59 
 


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LIST OF TERMS 
List of Abbreviations 
Abbreviation 
Expanded Form 
AD 
Atopic dermatitis 
ADCC 
Antibody-dependent cellular cytotoxicity 
AE 
Adverse event 
BSA 
Body surface area of involvement of AD 
CFR 
Code of Federal Regulations 
CLA 
Cutaneous lymphocyte-associated antigen 
CRO 
Contract research organization 
DLQI 
Dermatology Life Quality Index 
EASI 
Eczema Area and Severity Index 
eCOA 
electronic Clinical Outcome Assessment 
eCRF 
electronic Case Report Form 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
FAS 
Full analysis set 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ID 
Identifier 
IEC 
Independent Ethics Committee 
IGA 
Investigator’s global assessment 
IRB 
Institutional Review Board 
IP 
Investigational product 
IV 
Intravenous 
IWRS 
Interactive web response system 
JAK 
Janus kinase 
KKD 
Kyowa Kirin Pharmaceutical Development, Inc. 
mAb 
Monoclonal antibody 
MACE 
Major adverse cardiovascular events 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numerical rating scale 
NYHA 
New York Heart Association  
PK 
Pharmacokinetic(s) 
PT 
Preferred term 
PPD 
Purified protein derivative 
PPS 
Per protocol set 
PUVA 
Psoralen ultraviolet A 
Q2W, Q4W 
every 2 weeks, every 4 weeks 
 


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Abbreviation 
Expanded Form 
QoL 
Quality of life 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SCORAD 
Severity scoring of atopic dermatitis 
SOC 
System organ class  
TARC (CCL17) 
Thymus and activation-regulated chemokine 
TB 
Tuberculosis 
TCS 
Topical corticosteroid 
TEAE 
Treatment-emergent adverse event 
Th 
T-helper 
TNFR 
Tumor necrosis factor receptor 
TSLP 
Thymic stromal lymphopoietin 
UC 
Ulcerative colitis 
US 
United States 
UVA1 
Ultraviolet A1 
UVB 
Ultraviolet B 
WOCBP 
Women of childbearing potential 
List of Definitions 
Term 
Definition 
ANCOVA 
Analysis of covariance 
Cmax 
Maximum observed serum concentration 
CTCAE 
Common terminology criteria for adverse events 
Ctrough 
Serum trough concentration 
DNA 
Deoxyribonucleic acid 
EASI-50, -75, -90 
50%, 75%, or 90% reduction from baseline in EASI score 
FcRIIIa 
Receptors group III encoded by gene A recognizing the Fc portion of IgG mAbs 
HBc 
Hepatitis B virus core 
HBs 
Hepatitis B virus surface 
HBV-DNA 
Hepatitis B virus DNA 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HTLV-1 
Human T-cell lymphotropic virus type-1 
Injection reaction 
Any systemic injection-related reaction 
Injection site reaction 
Any local injection-related reaction 
IgE 
Immunoglobulin E 
Investigator 
Principal Investigator or sub-Investigator 
RNA 
Ribonucleic acid 
tmax 
Time of maximum observed serum concentration 
List of Clinical Laboratory Assessments (clinical laboratory evaluation, standard 12-
lead electrocardiogram) 
Term 
Clinical Laboratory Assessment 
WBC 
Leukocytes 
RBC 
Erythrocytes 


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Term 
Clinical Laboratory Assessment 
Ht 
Hematocrit 
Hb 
Hemoglobin 
PLT 
Platelets 
Baso 
Basophils/Leukocytes 
Eosino 
Eosinophils/Leukocytes 
Neutro 
Neutrophils/Leukocytes 
Mono 
Monocytes/Leukocytes 
Lymph 
Lymphocytes/Leukocytes 
CRP 
C Reactive Protein  
γ-GTP 
Gamma Glutamyl Transferase 
AST 
Aspartate Aminotransferase 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
Alb 
Albumin 
K 
Potassium 
Ca 
Calcium 
Cre 
Creatinine 
Cl 
Chloride 
BUN 
Blood Urea Nitrogen 
Glu 
Glucose 
T-Cho 
Cholesterol 
T-Bil 
Bilirubin 
TP 
Protein 
TG 
Triglycerides 
Na 
Sodium 
LDH 
Lactate Dehydrogenase 
UA 
Urate 
P 
Phosphate 
HbA1c 
Hemoglobin A1c 
HR 
Heart rate 
PR interval 
The time from the onset of the P wave to the start of the QRS complex. 
QRS interval 
The time from the start of the Q wave to the end of the S wave. 
QT interval 
The time from the start of the Q wave to the end of the T wave. 
QTc interval 
The corrected QT interval 
Study Participation Period 
The study participation period for each subject in this study is defined as the period from the 
date of obtaining informed consent through the completion of the last protocol-specified 
assessment. 
Time points for Investigational Product Administration, Observation, and 
Examinations 


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The date of the first dose of investigational product (IP) is defined as Day 1 (the start date of 
IP administration). The date that is Xth day of IP administration is regarded as Day X. The 
day before the start of IP administration is defined as Day −1. The week in which IP 
administration is started is defined as Week 0. The week that is Y weeks after Week 0 is 
regarded as Week Y.


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1 
INTRODUCTION  
1.1 
Medical Background 
OX40 (CD134, TNFR superfamily 4), a tumor necrosis factor receptor (TNFR) family 
member, represents a novel target molecule. OX40 costimulatory signaling has been shown 
to play a key role in maintaining late T-cell proliferation and survival and in inducing T-cell 
memory formation (Salek-Ardakani et al, 2006; Croft, 2010; Croft [a], 2009). Survival is 
increased by suppression of apoptosis (Song et al, 2005; Rogers et al, 2001). OX40 is mostly 
expressed on activated, but not naïve, CD4 and CD8 T cells such as T-helper (Th)1, Th2, and 
Th17 lymphocytes (Croft, 2010). The OX40 transient expression pattern is unique, increasing 
only after antigen-specific major histocompatibility complex-induced T cell receptor (TCR) 
activation and decreasing quickly after activation.  
The OX40 ligand is a transmembrane glycoprotein that belongs to the TNF superfamily and 
its expression is induced on antigen-presenting cell including activated B cells, mature 
conventional dendritic cells, Langerhans cells, and macrophages. OX40 ligand is also 
inducible on some activated CD4 and CD8 T cells, NK cells, mast cells and during conditions 
of inflammation, on vascular endothelial and smooth muscle cells (Croft, 2010; Croft [b], 
2009). Blocking OX40 signaling has resulted in inhibition of T cell responses and pathogenic 
symptoms in animal models of autoimmune diseases (Salek-Ardakani et al, 2006; Croft [a], 
2009). 
In humans, OX40 expression has been observed on T cells in diseased, but not in non-
diseased, areas in psoriasis, multiple sclerosis, rheumatoid arthritis, and atopic dermatitis 
(AD) (Matsumura et al, 2003; Cavanagh and Hussel, 2008). OX40 expression has been also 
observed on human T cells in several immune-based diseases including inflammatory bowel 
disease (IBD), type 1 diabetes, myasthenia gravis, systemic lupus erythematosus (Dolff et al, 
2010), lupus nephritis (Farres et al, 2011), bone marrow transplants, skin allografts, and heart 
disease (acute myocarditis and dilated cardiomyopathy) (Salek-Ardakani et al, 2006; Croft, 
2010). The infiltration of OX40+ T cells is enhanced in the gastrointestinal tissue of patients 
with ulcerative colitis (UC), Crohn’s disease, and celiac disease (Stüber et al, 2000). 


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1.2 
Atopic Dermatitis 
AD is defined as pruritic, eczematous dermatitis with symptoms that chronically fluctuate 
with remissions and relapses. Pathologically, AD is accompanied by the cutaneous 
physiological dysfunction of dry and barrier-disrupted skin due to abnormalities of the 
epidermis, especially the horny cell layers, and follows a chronic course with eczema 
characterized by inflammation due to the intervention of various unspecific stimulation or 
specific allergens. Most patients with AD have atopic diathesis (personal or family history 
[one or more of asthma, allergic rhinitis or conjunctivitis, and AD], or predisposition to 
overproduction of immunoglobulin [Ig] E antibodies) (Bieber, 2010). 
For the diagnosis of AD, the diagnostic criteria defined by Hanifin and Rajka in 1980 are 
frequently used for the diagnosis of AD in the world (Hanifin and Rajka, 1980). A revision of 
the diagnostic criteria was accomplished by Williams (Williams et al, 1994). 
The atopic dermatitis severity classifications that are mainly used are the Severity Scoring of 
Atopic Dermatitis (SCORAD) established by the European Task Force on Atopic Dermatitis 
(European Task Force on Atopic Dermatitis, 1993) and the Eczema Area and Severity Index 
(EASI) (Hanifin et al, 2001). In addition to these severity classifications, measurements such 
as peripheral blood eosinophil count, serum total IgE, lactate dehydrogenase, and thymus and 
activation regulated chemokine (TARC) are used as reference indicators of severity or 
disease activity of AD. 
AD is a disease due to multiple causes including gene factors. At present, there are no drugs 
that can completely heal the disease. Therefore, all available drug therapies are symptomatic 
and focus on the improvement or relief of symptoms. The main drug therapy for skin 
inflammation is topical treatment primarily with topical corticosteroids (TCSs) or tacrolimus 
ointment (Saeki et al, 2016). TCS of appropriate potency is selected for use according to the 
severity of each eruption. Tacrolimus ointment is used for eruptions that are difficult to treat 
with existing therapies such as TCSs because of an inadequate response or side effects and 
are applied to eruption areas except for ulcers and erosions with obvious plaque formation. 
Topical agents that improve eruptions are available; however, since AD is a long-standing 
disease, discomfort associated with some types of ointment bases and burden for patients and 
their family of applying topical agents to wide areas of skin every day, which takes more time 
and trouble than taking oral corticosteroids, lead to low treatment compliance (Ohya et al, 
2001). Side effects caused by TCSs include vasodilatation, skin atrophy, and induction of 
skin infections, and the higher the potency of the TCS, the more attention is required to side 


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effects. Oral corticosteroids and oral cyclosporine are used against symptoms of skin 
inflammation in patients with severe or very severe AD (Saeki et al, 2016). Oral 
corticosteroids are used at the time of acute flare or for patients with severe or very severe 
AD as induction therapy. However, the use of oral corticosteroids should be minimized, 
considering systemic side effects due to long-term use such as adrenal function suppression 
and rebound phenomenon after discontinuation of treatment (Saeki et al, 2016). Oral 
cyclosporine is indicated only for adult patients with severe AD who have inadequately 
responded to existing therapies such as TCSs or tacrolimus ointment and have 30% or more 
skin involvement by eruption with severe inflammation. Although the efficacy of oral 
cyclosporine on eruptions has been demonstrated, the target patients and treatment duration 
are limited because of its side effects such as renal impairment, hepatic impairment, and 
infections. 
1.3 
KHK4083  
KHK4083 is a fully human, non-fucosylated IgG1 monoclonal antibody (mAb) developed by 
Kyowa Kirin Co., Ltd (formerly, Kyowa Hakko Kirin Co., Ltd). KHK4083 binds to OX40 
and blocks the action. It is known that the removal of the core fucose from the biantennary 
complex-type oligosaccharides attached to the Fc region of the antibody therapeutics 
dramatically enhances the antibody-dependent cellular cytotoxicity (ADCC) activity 
mediated by binding to FcγRIIIa. The mechanism of action of KHK4083 includes the 
selective depletion of activated T cells by ADCC and the antagonistic suppression of clonal T 
cell expansion.  
OX40 is known to have an important role in the signaling and induction of Th2 cells in AD 
(Guttman-Yassky et al, 2013). KHK4083, selectively depleting OX40+ activated T cells by 
ADCC, is expected to improve AD, which is a disease caused by activated Th2 cells (Leung 
and Guttman-Yassky, 2014; Malajian and Guttman-Yassky, 2015). 
Allergy is induced by a series of immune cascades consisting of generation of multiple 
cytokines, induction of lymphocyte activation including IgE-producing B cells, and activation 
of multiple immune cells including eosinophils and mast cells. As one of the triggers of the 
immune activation cascades, myeloid dendritic cells are activated by thymic stromal 
lymphopoietin (TSLP) of epithelial origin and express OX40 ligands and CCL17 (TARC). It 
activates the activation and sustained growth of effector Th2 cells, causing induction and 
exacerbation of allergic inflammation (Ito et al, 2005; Wang et al, 2006). Immune responses 
induced by TSLP in the skin (e.g., Th2 inflammatory cell infiltration, cytokine secretion, and 


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IgE production) were inhibited in mice with OX40L-blocking (Seshasayee et al, 2007). These 
findings indicate that the anti-OX40 antibody KHK4083 may contribute to establish a new 
treatment strategy for AD. 
1.3.1 
Non-Clinical Studies 
The generation of the KHK4083 mAb and its in vitro characterization as well as the 
nonclinical pharmacology, pharmacokinetics (PK), and toxicology study reports are 
thoroughly described in the Investigator’s Brochure. All nonclinical safety studies were 
conducted in Japan, a country which is one of the members of the Organisation for Economic 
Co-operation and Development Mutual Acceptance of Data Program, and were also 
conducted in compliance with Good Laboratory Practice (GLP). The 
nonclinical/toxicological program includes two pivotal GLP studies in cynomolgus monkeys: 
a 4-week intravenous (IV) study (SBL303-081) and a 26-week subcutaneous (SC) study 
(SBL303-104). 
In Study SBL303-081, no toxicologically significant changes were observed at doses up to 
100 mg/kg when KHK4083 (0, 3, 10, 30, or 100 mg/kg) was intravenously administered to 
male and female cynomolgus monkeys once weekly for 4 weeks. In Study SBL303-104, 
KHK4083 (0, 0.3, 3, or 30 mg/kg) was subcutaneously administered to male and female 
cynomolgus monkeys once every 2 weeks for 26 weeks. An IV group given 30 mg/kg 
KHK4083 was included to compare toxicity with the SC group. There were no toxicological 
changes in any groups including the IV group, and the no-observed-adverse-effect level 
(NOAEL) of KHK4083 was 30 mg/kg (both SC and IV) in males and females. A 4-week 
toxicological study of SC doses of KHK4083 (0, 10, 30, or 100 mg/kg) administered every 
2 weeks was conducted by using a highly concentrated IP formulation (Process 2 
formulation), which was expected to be used in clinical studies. The study was conducted for 
determination of local tolerance, toxicokinetic assessments, measurement of anti-KHK4083 
antibodies, and supplemental toxicological examinations. In this study, neither systemic 
toxicity nor local irritation was observed at the site of administration up to 100 mg/kg. 
1.3.2 
Clinical Studies 
The Phase 1a (single ascending dose)/Phase 1b (double-blind, placebo-controlled, single 
ascending dose) study of KHK4083 in subjects with mild to moderate plaque-type psoriasis 
was conducted in Canada by Kyowa Kirin Pharmaceutical Development, Inc. (KKD), the 
Sponsor, and completed in December 2014 (Study 4083-001). In this study, a total of 


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55 subjects received 0.003 to 10 mg/kg KHK4083 (IV dose at 0.003, 0.01, 0.03, 0.1, 0.3, 1.0, 
3.0, or 10 mg/kg and SC dose at 1 mg/kg) (Papp et al, 2017). No dose-limiting toxicity was 
identified at any dose, and KHK4083 was well-tolerated. 
Currently, a Phase 2a (double-blind, placebo-controlled, multiple ascending dose, long-term 
extension) study of multiple IV doses of 1 to 10 mg/kg KHK4083 or placebo is ongoing in 
66 subjects randomized with moderately active UC in Europe and the United States (Study 
4083-002). No dose-limiting toxicities were identified in that trial, as per the cut off date (Oct 
2018). KHK4083 had demonstrated reasonable safety and tolerability in subjects with UC. 
In Japan, a Phase 1 (Study 4083-003), single-blind, randomized, placebo-controlled, single-
dose or open-label multiple-dose study of KHK4083 in healthy male adults and subjects with 
moderately active UC was conducted by KHK, the Sponsor, and completed the last protocol-
specified examination in February 2018. In Part 1 of the study, 32 Japanese subjects (8 
subjects [KHK4083, 6 subjects; placebo, 2 subjects] per cohort × 4) or 16 Caucasian subjects 
(8 subjects [KHK4083, 6 subjects; placebo, 2 subjects] per cohort × 2) received a single IV 
infusion (1, 3, or 10 mg/kg) or SC injection (3 mg/kg) of KHK4083 in a placebo-controlled, 
single-blind manner. In Part 2 of the study, 8 subjects with UC received multiple IV infusions 
of 10 mg/kg KHK4083 in an open-label manner. No dose-limiting toxicity was observed 
during a 6-week open-label treatment period when 3 IV doses were administered every 2 
weeks at dose of 10 mg/kg and during a 16-week follow-up period. In this study, the safety 
and tolerability of KHK4083 were demonstrated in healthy men and subjects with moderately 
active UC, and the efficacy of KHK4083 was demonstrated in subjects with UC. 
In addition, a Phase 1 (Study 4083-004), open-label, repeated-dose study of KHK4083 in 
subjects with moderate to severe AD was conducted in Japan by KHK, the Sponsor, and 
completed the last protocol-specified examination in February 2018. In Study 4083-004, a 
total of 22 subjects received multiple IV doses of 10 mg/kg KHK4083. In this study, the 
safety and tolerability of KHK4083 were demonstrated during a 6-week open-label treatment 
period when 3 IV doses (10 mg/kg) were administered every 2 weeks. Despite the low 
number of patients the efficacy of KHK4083 was demonstrated in these subjects over the 
course of the treatment and 16-week follow-up periods. 


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1.4 
Risks and Benefits 
1.4.1 
Risks 
As a result of an overall evaluation of safety data obtained from the clinical studies of 
KHK4083, “infusion/injection-related reactions” were defined as identified risks of 
KHK4083 and “reactivation of latent infections and development of new infections” were 
defined as potential risks of KHK4083. 
1.4.2 
Benefits 
AD is a chronic inflammatory disease, whose symptoms mainly appear on the skin. Moderate 
to severe AD is characterized by rash, which is accompanied by continuous intense, 
intractable itching, dry skin, skin cracks, erythema, scabs, and capillary hemorrhage. Itching 
is the wasting symptom representing the greatest burden for patients and may affect the 
various aspects of patients’ daily life such as sleep (Zuberbier et al, 2006). 
The potential benefit of treatment with KHK4083 is to improve skin symptoms in patients 
with AD, which is mainly caused by Th2 cells (Leung and Guttman-Yassky, 2014; Malajian 
and Guttman-Yassky, 2015). Continuation of therapy is expected to sustain improved skin 
symptoms and also improve other symptoms of AD. 
1.5 
Rationale for Conducting the Study 
Study 4083-004 was conducted to evaluate the safety, tolerability, and PK of repeated IV 
doses of 10 mg/kg KHK4083 in Japanese subjects with moderate to severe AD. In Study 
4083-004, the safety and tolerability of multiple doses of 10 mg/kg KHK4083 were 
demonstrated. Clinical symptoms (EASI) and itching score (NRS) were also assessed in an 
exploratory manner and showed a trend toward improvement. Further safety and efficacy of 
KHK4083 will be evaluated in this large scale international Phase 2 clinical study in subjects 
with moderate to severe AD.  


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2 STUDY OBJECTIVES AND ENDPOINTS 
The primary, secondary, safety, and exploratory objectives of the study are as follows: 
1) Primary Objective 
Primary Objective 
Endpoint 
To assess the efficacy of four dose regimens of 
KHK4083 compared to placebo as measured by the 
change from baseline in EASI score following 
multiple subcutaneous (SC) injections for 16 weeks in 
subjects with moderate to severe AD. 
• 
Percent change from baseline to Week 16 in EASI 
score 
2) Secondary Objectives 
Secondary Objectives 
Endpoints 
To evaluate the effects on skin symptoms following 
multiple SC injections of KHK4083 for 16 weeks in 
comparison with placebo in subjects with moderate to 
severe AD. 
 
• 
Achievement of 50%, 75%, or 90% reduction 
from baseline in EASI score (EASI-50, EASI-75, 
or EASI-90) at Week 16 
• 
Change from baseline to Week 16 in EASI score 
• 
Change and percent change from baseline to 
Week 16 in SCORAD score 
• 
Achievement of an Investigator’s Global 
Assessment (IGA) score of 0 or 1 and a reduction 
from baseline of ≥2 points at Week 16 
• 
Change from baseline to Week 16 in percent body 
surface area of involvement of AD (BSA) 
To evaluate the effects on itching and sleeping 
following multiple SC injections of KHK4083 for 
16 weeks in comparison with placebo in subjects with 
moderate to severe AD. 
• 
Change and percent change from baseline to 
Week 16 in pruritus NRS score 
• 
Change and percent change from baseline to 
Week 16 in sleep disturbance NRS score 
To evaluate the effects on quality of life (QoL) 
following multiple SC injections of KHK4083 for 
16 weeks in comparison with placebo in subjects with 
moderate to severe AD. 
• 
Change from baseline to Week 16 in Dermatology 
Life Quality Index (DLQI) 


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To evaluate the effects on skin symptoms following 
multiple SC injections of KHK4083 for 36 weeks in 
subjects with moderate to severe AD. 
• 
Change and percent change from baseline in 
EASI score at each time point 
• 
Achievement of EASI-50, EASI-75, or EASI-90 
at each time point 
• 
Change and percent change from baseline in 
SCORAD score at each time point 
• 
Achievement of an IGA score of 0 or 1 and a 
reduction from baseline of ≥2 points at each time 
point 
• 
Change from baseline in percent BSA at each 
time point 
To evaluate the effects on itching and sleeping 
following multiple SC injections of KHK4083 for 
36 weeks in subjects with moderate to severe AD. 
• 
Change and percent change from baseline in 
pruritus NRS score at each time point 
• 
Change and percent change from baseline in sleep 
disturbance NRS score at each time point 
To evaluate the effects on QoL following multiple SC 
injections of KHK4083 for 36 weeks in subjects with 
moderate to severe AD. 
• 
Change from baseline in DLQI at each time point 
3) Safety Objective 
Safety Objective 
Endpoints 
To evaluate the safety of multiple SC injections of 
KHK4083 in subjects with moderate to severe AD. 
• 
Treatment-emergent adverse events (TEAEs) 
• 
Laboratory values 
• 
Vital signs 
• 
Standard 12-lead electrocardiogram (ECG) 
4) Exploratory Objectives 
Exploratory Objectives 
Endpoints 
To investigate PK and immunogenicity following 
multiple SC injections of KHK4083 in subjects with 
moderate to severe AD. 
• 
PK assessment 
– 
Serum KHK4083 concentration 
– 
PK parameters (e.g., Cmax, Ctrough) 
• 
Anti-KHK4083 antibody 
To assess pharmacodynamics following multiple SC 
injections of KHK4083 in subjects with moderate to 
severe AD. 
• 
Pharmacodynamic assessment 
– 
Serum disease markers (TARC, serum total 
IgE) 
 


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3 
STUDY DESIGN 
3.1 
Study Design and Duration 
This is a Phase 2, multicenter, randomized, placebo-controlled, double-blind, parallel-group 
study consisting of a screening period of at least 2 weeks (a maximum 6 weeks), an 18-week 
placebo-controlled treatment period (Treatment A period), followed by an 18-week treatment 
period (Treatment B period), and a 20-week follow-up period. 
Subjects will receive SC doses of IP every 2 weeks under double-blind conditions (Weeks 0 
[Day 1], 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, and 34). The last dose will be 
administered at Week 34, and subjects will complete the treatment period at Week 36 (end of 
treatment [EOT]). Subsequently, subjects will be followed up at Weeks 40, 44, 48, 52, and 56. 
The study period will be a maximum of 60 weeks. 
The study is expected to start in the third quarter of 2018 and end by the first quarter of 2021. 
The study design is outlined in Figure 3.1-1. 


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Figure 3.1-1 Overall Study Design 
 
1: Randomization will be performed within 3 days after baseline visit.  2: Subjects will start study treatment on the day of or the day after randomization.  3: Subjects will 
apply a topical emollient by the simple method from at least 1 week before baseline visit through Week 36. Subjects may continue using the emollient throughout the study.  
4: Subjects receiving rescue treatment (See Section 6.3.3) before the end of the Week 36 assessment will discontinue IP, undergo end-of-study assessments, and then be 
withdrawn from the study.  5: The study will be blinded to all study personnel/consultants, investigative site personnel, and study subjects. At the time when all subjects 
(excluding withdrawn subjects) have reached Week 16 and Week 36, the study will be unblinded to selected personnel to conduct interim analyses.  6: Subject who are 
randomized to the KHK4083 150 mg Q4W group and 600 mg Q4W group will receive KHK4083 alternating every 2 weeks with placebo.  7: Subjects who meet withdrawal 
criterion 5) (Section 4.4.1) based on the IGA score at Week 26 will discontinue IP administration at Week 26, undergo end-of-study assessments, and then be withdrawn from 
the study. 
 
-2 to -6 weeks
(Screening)
W02
(D1)
W165
Emollient (twice daily)3
-1 week
Screening period1
Treatment B period
Treatment A period
Subjects who receive rescue treatment before the end of the Week 36 assessment 
will permanently discontinue IP4
Follow-up period 
KHK4083 150 mg SC Q4W6
KHK4083 300 mg SC Q2W
KHK4083 600 mg SC Q2W
W365
(End of Treatment)
W56
(End of Study)
Randomization 
on Day -1 or Day 1 
(1:1:1:1:1) 
IP=investigational product, SC=subcutaneous, Q2W=every 2 weeks, Q4W=every 4 weeks, W=Week, D=Day, Day 1= the date of the first dose of IP, ♦: IP administration
W18
(D127)
KHK4083 600 mg SC Q2W
Follow-up visit  
at W40, 44, 48, 52 and 56 
KHK4083 150 mg SC Q4W6
KHK4083 300 mg SC Q2W
KHK4083 600 mg SC Q2W
Placebo
KHK4083 600 mg SC Q4W6
KHK4083 600 mg SC Q4W6
Baseline
visit
W267


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3.1.1 
Screening Period 
The Investigator will register subjects who provide written informed consent in an interactive 
web response system (IWRS) to start screening those subjects within 4 weeks after the date 
of subject’s signature on informed consent. Subjects will undergo baseline assessments at 
least 2 weeks but not later than 6 weeks after the start of screening.  
A total of approximately 250 subjects who are considered eligible as a result of the screening 
and baseline assessments will be enrolled. 
Subjects will be required to apply a topical emollient, as a rule, twice daily for at least 1 week 
before baseline visit through the end of the study. The use of TCSs will be prohibited from at 
least 1 week before baseline visit through Week 36 assessment. 
3.1.2 
Treatment Period (Day 1 to Week 36) 
Randomization will be performed within 3 days after baseline visit. 
Subjects will start study treatment on the day of or the day after randomization (date of the 
first dose of IP will be regarded as Day 1). The treatment period is defined as the period 
between Day 1 and the end of the Week 36 assessment. 
The study consists of 2 treatment periods.  
Treatment A period (last dose at Week 16) 
All subjects who meet the inclusion criteria and none of the exclusion criteria during the 
screen phase will be randomized to one of the treatment groups (placebo, KHK4083 150 mg 
Q4W, 300 mg Q2W, 600 mg Q2W, or 600 mg Q4W). In the 150 mg Q4W group and the 
600 mg Q4W group, placebo will be administered between KHK4083 injections to ensure 
blinding. 
Treatment A period is defined as the period between Day 1 and Week 18 pre (before IP 
administration at Week 18).  
In order to ensure the study blind, the efficacy data until Week 16 shall be entered into the 
electronic Clinical Outcome Assessment (eCOA).  


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Treatment B period (last dose at Week 34) 
Treatment B period is an extension phase where all subjects will receive KHK4083 for an 
additional 18 weeks under double-blind conditions (from Week 18 post [IP administration at 
Week 18] through Week 36). 
In Treatment B period, subjects randomized to the placebo group in Treatment A period will 
receive SC injections of 600 mg KHK4083 every 2 weeks starting at Week 18. Subjects 
randomized to any of the KHK4083 groups in Treatment A period will receive KHK4083 at 
the same dose and dosing interval as in Treatment A period. 
Subjects who meet withdrawal criterion 5) (Section 4.4.1) based on the IGA score at 
Week 26 will discontinue IP administration at Week 26, undergo end-of-study assessments, 
and then be withdrawn from the study.  
Subjects receiving rescue treatment (See Section 6.3.3) during the period between the start of 
IP administration and the end of the Week 36 assessment will discontinue IP, undergo end-
of-study assessments, and subsequently be withdrawn from the study. 
3.1.3 
Follow-up Period (up to Week 56) 
Subjects will enter the follow-up period after the end of the Week 36 assessment and will be 
followed up every 4 weeks until Week 56. Subjects who received rescue treatment after 
Week 36 will not be withdrawn from the study and will be observed until the end of the study 
up to Week 56. 
3.1.4 
Other Potential Study Assessments (optional) 
Sampling for exploratory biomarkers: Exploratory biomarkers to characterize KHK4083 
pharmacodynamic activity will be assessed. At selected investigative sites in the United 
States and Canada, blood and skin samples will be collected from subjects who voluntarily 
provide consent to undergo both serum analyses (including but not limited to serum cytokines 
and chemokines) and skin biopsy. At all investigative sites in Japan, blood and skin samples 
will be collected from subjects who voluntarily provide consent to undergo both flow 
cytometry (OX40-positive T cell and cutaneous lymphocyte-associated antigen [CLA]-
positive memory T cell) and skin biopsy. 


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Pharmacogenetic testing: The purpose of this assessment is to explore the association 
between individual differences in responses to KHK4083 and mutations in DNA sequence. 
Blood samples will be collected before IP injection at Week 0 from subjects who voluntarily 
provide consent. 
3.2 
Rationale for Study Design 
This is a multicenter, Phase 2 study to evaluate the efficacy and safety of SC doses of 
KHK4083 300 mg or 600 mg administered every 2 weeks, or 150 mg or 600 mg administered 
every 4 weeks compared with placebo in subjects with moderate to severe AD. 
In order to assess improvement of skin symptoms, the percent change from baseline in EASI 
score at Week 16 is selected as the primary endpoint. TCSs, which may significantly affect 
the efficacy, will be prohibited from 1 week before the start of IP administration until the end 
of the treatment period. During this period, an emollient will be used instead of TCSs. 
In a Phase 1 study (Study 4083-004), a total of 3 doses of 10 mg/kg KHK4083 were 
intravenously administered every 2 weeks to subjects with moderate to severe AD, the same 
population as this study. The results indicated that a trend toward improvement of skin 
symptoms was sustained even in a 16-week follow-up period after the end of treatment with 
KHK4083. On the basis of this finding, a placebo-controlled treatment phase (Treatment A) 
will be followed by an 18-week extension phase (Treatment B period) in this study so as to 
evaluate the efficacy and safety of the long-term administration of KHK4083 after the 
primary efficacy evaluation at Week 16. In addition, as with Study 4083-004, Study 4083-
006 includes a 20-week follow-up period, the duration of which may be sufficient to evaluate 
the sustained of efficacy and safety of KHK4083 after the end of the treatment period. 
Interim analyses will be conducted at the time when all subjects have completed assessments 
at Week 16 and Week 36 to obtain preliminary information for planning a future study of 
KHK4083 for the treatment of AD. 
3.3 
Enrollment 
A total of approximately 250 subjects with moderate to severe AD will be enrolled in this 
study.  
The Investigator will enroll subjects according to the following procedure. 


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1) Before starting the study-specific procedures, written informed consent (or assent, if 
applicable) should be obtained from potentially eligible subjects. 
2) At each investigative site, a subject identifier (ID) will be assigned through the IWRS to 
each subject who provides consent, according to the following rule. The same ID will be 
used from the time of informed consent through the end of the study. 
ID: 4083-006-XX-YY-ZZ 
XX: Country code (e.g., JP, Japan, US, the United States, CA, Canada, GE, Germany) 
YY: Investigative site code 
ZZ: Sequential number for subjects providing consent at the investigative site 
For example, the subject ID of the first subject who provides consent at ### hospital 
(investigative site code: 01) in Japan is 4083-006-JP-01-01. 
3) Subjects will be assessed for eligibility.  
4) Eligible subjects will be registered as an enrolled subject in the IWRS. 
5) A subject who is not eligible may be re-screened at the discretion of the Investigator after 
re-obtaining written informed consent. Subjects will be permitted to be re-screened only 
once. Chest X ray (or CT scan) at re-screening may be omitted upon consultation with the 
Sponsor only if there are no findings suggestive of tuberculosis (TB) at the initial 
screening. The subject ID of re-screened subjects will be the same as that initially 
assigned. 
Details of the subject enrollment method are specified in separate written procedures. 
3.4 
Randomization and Blinding  
3.4.1 
Randomization 
Randomization will be performed through the IWRS in the order of enrollment. Subjects who 
meet all of the eligibility criteria will be randomly assigned to receive 150 mg Q4W, 300 mg 
Q2W, 600 mg Q2W, or 600 mg Q4W KHK4083 or placebo in a 1:1:1:1:1 ratio by the IWRS 
according to a dynamic allocation procedure. Randomization will be performed within 3 days 
after baseline assessments. The severity of AD (moderate, IGA=3; severe, IGA=4) at baseline, 
region (Japan, rest of world), and previous use of biological products (Yes, No) for the 
treatment of AD at baseline will be used as stratification factors for randomization by 
prioritizing them. Detailed written procedures for randomization will be provided separately 
from the protocol. 


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Randomization transaction of IWRS would decide each subject treatment arm allocation and 
at the same time indicated drug number (Kit No.) to be dispensed. The Kit No. shall be 
entered into the electronic Case Report Form (eCRF). 
3.4.2 
Blinding 
3.4.2.1 
Creation and Storage of Allocation Table 
PAREXEL International Inc., Japan will prepare a drug randomization list and allocate IP to 
each subject with the IWRS according to separate written procedures. 
The drug randomization will be adaptive based on separate written procedures. The subject 
treatment group will be allocated by the IWRS according to the separate written procedures. 
PAREXEL International Inc., Japan will create treatment assignment list that will be 
provided at the interim analysis following separate written procedures and will provide a 
record of emergency unblinding from the IWRS as required. 
3.4.2.2 
Blinding Method 
The study will be blinded to all study personnel/consultants, investigative site personnel, and 
study subjects. However, the study will be unblinded to selected personnel as follows. 
In this study, a pharmacist who is unblinded to treatment assignment (“unblinded 
pharmacist”) (or qualified designee) will be registered at each investigative site beforehand. 
The unblinded pharmacist (or qualified designee) will prepare the IP dose for SC injection 
according to the assigned treatment. Details are specified in the Pharmacy Manual, which is 
separately provided. 
Persons to be unblinded from the start of this study include unblinded pharmacist (or 
qualified designee), unblinded drug supply managers responsible for managing IP logistics 
and unblinded monitor responsible for monitoring the IP is stored, controlled and prepared 
according to the procedures of the Contract Research Organization (CRO), and safety 
personnel of the Sponsor who reports certain serious adverse events (SAEs) to the regulatory 
authorities; and persons to be unblinded after the interim analysis at Week 16 include 
personnel at interim analysis center of CRO and person responsible for PK and biomarkers of 
the Sponsor. The individuals will be identified in the separate document of Blinding Plan and 
Unblinding Processes.  


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The allocation of IP to the subject will be managed by the IWRS, the unblinded pharmacist 
(or qualified designee) will be given information on the IP allocation electronically via the 
IWRS. 
3.4.2.3 
Measures Taken to Maintain Blindness Assignment Based on 
Known Information on KHK4083 
Test results on serum KHK4083 concentrations, anti-KHK4083 antibodies, TARC, serum 
total IgE, OX40-positive cells in skin and peripheral blood, and CLA-positive memory T 
cells in peripheral blood (Japan only) may unblind the subject treatment group based on 
serum drug concentration, immune response or KHK4083 mechanism of action. Therefore, 
those results must not be provided to the Investigator or site staff, who are involved in 
treatment or clinical assessments of subjects, or Sponsor/CRO personnel (except personnel at 
interim analysis center of CRO and person responsible for PK and biomarkers of the 
Sponsor) until the study is unblinded by the Sponsor, with the exception of when the 
knowledge of the test result is necessary to ensure subject safety or to submit an expedited 
report of a Suspected Unexpected Serious Adverse Reaction (SUSAR) to the Regulatory 
agencies. The Investigator must notify the Sponsor if they become aware of any test result 
regardless of the reason. 
3.4.2.4 
Unblinding 
The Sponsor reserves the right to unblind an individual subject's treatment for the purposes of 
fulfilling regulatory requirements for expedited reporting of adverse events (AEs) and/or 
subject safety. A subject’s treatment assignment should only be unblinded by the Investigator 
or Sponsor when knowledge of the treatment is essential for the further management of the 
subject or may impact the safety of subjects in current and/or subsequent cohorts. The 
emergency unblinding process will be identified in the separate document of Emergency 
Unblinding Procedure. 
In the following cases, the Investigator will immediately notify the Sponsor and withdraw the 
relevant subject from the study. 
• 
Any study staff (the Principal Investigator, sub-Investigator, or clinical research 
coordinator) other than the unblinded pharmacist becomes aware of the treatment 
assignment of the subject. 
• 
The knowledge of the treatment group of the subject is necessary to take measures 
against a TEAE. (The Investigator should report to the Sponsor before disclosing the 
emergency key code.) 


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After all subjects have completed the scheduled assessments and the database has been 
locked, the study will be unblinded to all study personnel. 
3.5 
Safety Monitoring Plan 
The Sponsor and CRO will monitor subjects’ safety and compliance with the protocol (e.g., 
inclusion and exclusion criteria, concomitant medications, and study visits) according to the 
procedures of the Sponsor. 
The Sponsor has primary responsibility for the ongoing medical review of safety data 
throughout the study. 
Recommendations will be made with the input of the Medical Monitor to the Principal 
Investigator and other appropriate designated staff regarding further conduct of the study.  
Currently, based on safety observations from existing clinical trials, the infusion or injection 
reactions are identified as AE of special interest for KHK4083. However, the following 
safety events will also be considered as AEs of special interest. Detailed written procedures 
for the follow-up AEs of special interest will be provided separately from the protocol. 
• 
Malignancy 
• 
Infections (particularly TB, serious infections, opportunistic infections, or infections 
requiring systemic antibiotic therapy) 
• 
Injection site reactions 
• 
Major adverse cardiovascular events (MACE) 
• 
Hypersensitivity reactions (including anaphylactic and serum sickness-like reactions) 
• 
Neuropsychiatric events (including suicidal ideation and behavior) 
3.5.1 
Injection-related Reaction 
The Investigator should monitor subjects for acute drug reactions at the investigative site for 
at least 2 hours after IP administration for visits at Day 1, Weeks 2, 4, 18, 20, and 22. At all 
other visits subjects will be monitored for acute drug reactions at the investigative site for at 
least 30 minutes after IP administration. However, subjects will stay longer at the site for 
observation whenever it is clinically required and at the discretion and clinical judgment of 
the Investigator. Refer to Section 6.2.3 for detail on measures to be taken for acute reactions. 
No pre-medication (e.g., acetaminophen, anti-emetic; 5HT3 blocker; histamine H1 and/or H2 
blocker[s]) is planned to be routinely/prophylactically administered prior to IP administration 


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in this study. However, pre-medication may be used prior to IP administration as per the 
decision of the Investigator upon approval of the Sponsor; or the Sponsor may recommend 
the pretreatment of subjects to the Principal Investigator if consistent mild (Grade 1) and/or 
moderate (Grade 2) injection reactions are observed during the course of the study. Refer to 
Section 7.9.8.1 for reporting an injection-related reaction including descriptions of specific 
symptoms observed or reported by the subject. 
Each investigative site must have trained staff and immediate access to emergency supplies 
and equipment including, but are not limited to, drugs needed to treat a subject in case of a 
life threatening emergency. 
3.5.2 
Contraception 
The Investigator will instruct subjects to use highly effective contraceptive methods per the 
approved local guidance in each country from the day of providing informed consent through 
6 months after the last dose of IP for women of childbearing potential (WOCBP) and from 
the start day of IP administration through 6 months after the last dose of IP for men with 
reproductive capability. The Investigator will thoroughly explain the risks in pregnancy and 
the effective contraceptive methods to the subjects. 
Actions will be taken according to Section 7.9.8.3, if a female subject becomes pregnant after 
providing informed consent, or if a partner of a male subject becomes pregnant after the start 
of IP administration until 6 months after the last dose of IP. 
4 
SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA 
4.1 
Target Subjects 
Subjects with moderate to severe AD whose disease cannot be adequately controlled with 
topical medications or for whom topical treatment is medically inadvisable. 
To allow efficacy and safety assessments in subjects without previous use of biological 
products, enrollment of subjects who have received previous treatment with biological 
products for the treatment of AD will be limited to not more than 50% of total enrollment. 


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4.2 
Inclusion Criteria 
Subjects who meet all of the following criteria will be enrolled in this study: 
1) Voluntarily signed informed consent to participate in the study; 
2) Men and women ≥18 years at the time of informed consent; 
3) Chronic AD, according to American Academy of Dermatology Consensus Criteria 
(Eichenfield et al, 2014) or the local diagnostic criteria, that has been present for at least 
1 year before screening; 
4) EASI score ≥16 at screening and baseline; 
5) IGA score ≥3 (moderate) at both screening and baseline; 
6) BSA ≥10% at both screening and baseline; 
7) Documented recent history (within 1 year prior to screening visit) of inadequate response 
to treatment with topical medications or for whom topical treatments are otherwise 
medically inadvisable (e.g., because of important side effects or safety risks); 
Note:  
• Inadequate response is defined as failure to achieve and maintain remission or a low disease activity 
state (comparable to IGA 0 = clear to 2 =mild) despite treatment with a daily regimen of TCS of 
medium to higher potency (± topical calcineurin inhibitors as appropriate), applied for at least 28 days 
or for the maximum duration recommended by the product prescribing information (e.g., 14 days for 
super-potent TCSs), whichever is shorter. 
• Patients with documented systemic treatment for AD in the past 1 year are also considered as 
inadequate responders to topical treatments and are potentially eligible for treatment with KHK4083 
after appropriate washout. 
• Important side effects or safety risks are those that outweigh the potential treatment benefits and 
include intolerance to treatment, hypersensitivity reactions, significant skin atrophy, and systemic 
effects, as assessed by the Investigator or by the patient’s treating physician. 
8) WOCBP and fertile men must agree to use highly effective contraceptive methods per the 
approved local guidance in each country from the time of informed consent to 6 months 
after the last dose of IP (for women) or from the start of IP administration to 6 months 
after the last dose of IP (for men). WOCBP must have a negative serum pregnancy test 
result at screening and a negative urinary pregnancy test result at baseline assessments. 
For the United States and Canada, WOCBP who have sexual intercourse with a non-
surgically sterilized male partner must agree and commit to the use one of the following 
highly effective methods of contraception (Clinical Trials Facilitation Group, 2014) from 
the time of informed consent to 6 months after the last dose of IP. Contraceptive methods 
considered acceptable for use in this study include:  
a) Established use (≥2 months prior to the screening visit) of oral, injected, transdermal 
or implanted combined estrogen-progestogen hormonal methods of contraception. 
Subjects who have used such methods for less than 2 months at the screening visit are 


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required to use one of the methods described under b) or c) until the establishment of 
hormonal contraception methods.  
b) Double barrier contraception: use of occlusive diaphragm (cap or cervical/vault caps) 
with spermicidal foam/gel/film/cream/suppository. In countries where spermicidal 
condoms are not allowed ordinary condoms could be used in combination with 
spermicidal creams. Appropriate measures are to be determined by the investigator 
together with the subject, in accordance with the standard of care in the country where 
treatment is administered. A female condom and a male condom should not be used 
together as friction between the two can result in either, or both product(s) failing.  
c) An intrauterine device or system. 
For Germany, WOCBP and fertile men must agree to use highly effective contraceptive 
methods that can achieve a failure rate of less than 1% per year from the time of informed 
consent to 6 months after the last dose of IP (for women) or from the start of IP 
administration to 6 months after the last dose of IP (for men). WOCBP must have a 
negative serum pregnancy test result at screening and a negative urinary pregnancy test 
result at baseline assessments and at each dose interval. 
Birth control methods considered highly effective used consistently and correctly include: 
• 
Comb Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation 
– oral 
– intravaginal 
– transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
– oral 
– injectable 
– implantable 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
• 
Vasectomised partner 
• 
Sexual abstinence (Sexual abstinence is considered a highly effective method only 
if defined as refraining from heterosexual intercourse during the entire period of the 
study treatments). 
Note:  
• WOCBP exclude women who have undergone permanent sterilization, those who are postmenopausal 
[defined as the absence of menstruation for at least 12 consecutive months without any other medical 
reason (or in postmenopausal range per local laboratory standards)], and those anatomically having 
no childbearing potential. 


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4.3 
Exclusion Criteria 
Subjects must be excluded from the study if they meet any of the following criteria. 
1) Current or past history of clinically significant illness(es) deemed by the Investigator to 
be likely to affect the study conduct and assessments. Examples include, but are not 
limited to, clinically significant cardiovascular (e.g., New York Heart Association 
[NYHA] Class III or IV), uncontrolled diabetes (HbA1c ≥9%), liver (e.g., Child-Pugh 
class B or C), renal, respiratory, hematologic, central nervous system, psychiatric, or 
autoimmune diseases/disorders; 
2) Any of the following laboratory abnormalities at screening: 
• 
Serum creatinine: >1.5 mg/dL 
• 
AST or ALT: ≥2.5 times the upper limit of normal (ULN) 
• 
Neutrophil count: <1.5×103/μL 
• 
Other laboratory abnormalities that may affect the completion or evaluation of the 
study, as judged by the Investigator; 
3) Active malignancies, or onset or a history of treatment of malignancies within 5 years 
prior to informed consent (except curatively treated in situ cervical carcinoma, cutaneous 
basal cell carcinoma, or cutaneous squamous cell carcinoma); 
4) Past history of alcohol or substance abuse within 1 year before screening visit; active 
alcohol dependence or drug dependence; 
5) Current or past history of any suicidal behavior; 
6) History of major immunologic reaction (e.g., serum sickness, anaphylaxis, or 
anaphylactic reaction) to any other biologic product or any excipient of KHK4083; 
7) History of ≥3 systemic infections requiring systemic administration (excluding oral 
administration) of antimicrobials, antifungals, or antivirals within 1 year prior to baseline 
visit; 
8) Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, 
antiparasitics, antiprotozoals, or antifungals within 4 weeks before the baseline visit, or 
superficial skin infections within 2 weeks before the baseline visit; 
9) Treatment with live vaccination (e.g., BCG, polio, measles, or rubella) within 12 weeks 
prior to baseline visit. Inactivated vaccination (e.g., hepatitis, pneumococcal, 
meningococcal, tetanus, diphtheria toxoid, acellular pertussis, inactivated polio, human 
papilloma and influenza-except intranasal influenza) is allowed; 
10) Treatment with any biological product (including an IP) within 12 weeks (16 weeks for 
Japan) or 5 half-lives, whichever is longer, prior to baseline visit; 
11) Treatment with 3 or more biological products (including an IP) within 2 years before the 
baseline visit; 


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12) Participation in a clinical or equivalent study and use of an IP (other than biologics) or 
unapproved medical device within 4 weeks (16 weeks for Japan) or 5 half-lives, 
whichever is longer, prior to baseline visit; 
13) Treatment with any of the following medications or therapies within 4 weeks or 5 half-
lives, whichever is longer, prior to baseline visit; 
• 
Systemic corticosteroids (inhaled corticosteroids, eye, ear, or nasal drops containing 
corticosteroids are allowed, suppositories or enemas containing corticosteroids are not 
allowed) 
• 
Systemic treatment with methotrexate, mycophenolate, calcineurin inhibitors, 
thalidomide, or other immunosuppressants 
• 
Phototherapy (e.g., psoralen ultraviolet A [PUVA] therapy, ultraviolet B [UVB] 
therapy, narrow-band UVB therapy, ultraviolet A1 [UVA1] therapy, excimer light) 
for the treatment of AD 
• 
Janus kinase (JAK) inhibitors 
14) Treatment with any of the following medications for the treatment of AD within 1 week 
prior to baseline visit: 
• 
TCSs 
• 
Topical calcineurin inhibitors or other immunosuppressive agents 
• 
Topical agents including crotamiton, Eucrisa®/crisaborole 
• 
Combination topical agents containing a corticosteroid or a calcineurin-inhibiting 
component or other immunosuppressive agents 
• 
Chinese herbal medicines (e.g., jumi-haidoku-to, shofu-san, saiko-seikan-to, hochu-
eki-to)  
15) Any planned surgical treatment or invasive procedure (for instance dental implant 
installation or non-emergency low invasive intra-cardiac manipulation) during the study; 
16) Any conditions not allowing for discontinuation of prohibited concomitant drugs or 
therapies; 
17) Pregnant or breastfeeding women, or women willing to become pregnant; 
18) Evidence of HIV infection or a positive result for HIV antibodies at screening; or current 
acquired, common variable or inherited, primary or secondary immunodeficiency; 
19) Positive test for active hepatitis B (HB) infection at screening defined as: 
• 
Positive for HB surface antigen; 
• 
Positive for anti-HB core antibody or positive for HBV-DNA; or 
• 
For subjects enrolled in Japan, positive for anti-HB core antibody and/or positive for 
anti-HB surface antibody, and positive for HBV-DNA. However, HBV-DNA 
measurement will not be required for subjects who are positive for antibodies 
produced after HB vaccination and who are not affected with hepatitis B at screening. 


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If any of HB tests has an indeterminate or the result cannot be interpreted with 
certainty, confirmatory testing as per local guidelines will be performed. 
20) Positive for anti-hepatitis C (HC) virus antibody at screening, and confirmed infection 
with HC virus by RNA or other confirmation test. If the HC test has an indeterminate 
result, confirmatory testing will be performed by an alternative method that is locally 
accepted; 
21) Evidence or history of active TB, either treated or untreated; or latent TB (defined as a 
positive purified protein derivative [PPD] or interferon-gamma release assay [IGRA] test 
without evidence of clinically manifested active TB), the treatment of which was 
completed more than 12 months before baseline visit or untreated. Evaluation for TB will 
be conducted according to the local standards of care or as determined by local guidelines 
and will include PPD or IGRA tests and may consist of history, physical examinations 
and chest X-ray. 
Subjects with latent TB who meet either of the following conditions can be enrolled: 
• 
Subjects with latent TB who have completed an appropriate course of anti-TB 
treatment as per local guidelines or standards of care within 12 months before 
baseline visit. 
• 
Subjects with latent TB who have been receiving appropriate anti-TB treatment as per 
local guidelines or standards of care (for instance isoniazid) for at least 28 days 
(21 days in Japan) before baseline visit. 
22) Previous participation in a study of KHK4083 and use of an IP; 
23) Other conditions unsuitable for participation in the study in the opinion of the 
Investigator. 
4.4 
Criteria and Procedure for Removal from Study 
4.4.1 
Subject Removal 
If a subject’s treatment is discontinued due to safety concerns such as AEs, the Investigator 
will take appropriate actions for the subject to be withdrawn from the study after appropriate 
follow-up. The Investigator will examine the safety of each subject who has discontinued 
treatment and promptly perform early termination assessments. Subjects who meet 
withdrawal criterion 4) or 5) will be performed the end-of-study assessments. 
A subject who stops visiting the investigative site after exposure to IP but before completing 
planned assessment will be followed and assessed safety to the extent possible, in a way that 
will protect the subject’s human rights. In the absence of a medical contraindication or 
significant protocol violation, every effort will be made by the Investigator to keep the 
subject in the study. However, if the Investigator concludes that it is in the best interest of the 


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subject to discontinue IP administration or should the subject decide to discontinue study 
treatment, all efforts will be made to complete and report the observations as thoroughly as 
possible.  
Subject will be withdrawn from the study if any of the following events occur: 
1) Subject is found to be ineligible after the start of the study, not meeting the eligibility 
criteria. This may include, but is not limited to, the following events: 
• 
Diagnosis of a malignancy during study 
• 
Active TB or opportunistic infection 
2) Subject experiences a serious, acute injection reaction despite administration of a 
prophylactic regimen or subject experiences anaphylaxis regardless of having received a 
pre-medication regimen or not; 
3) Two consecutive doses of IP are not administered as scheduled or 3 or more doses are 
skipped during the treatment period. However, the subject who meets this criterion due to 
the logistical issue caused by the COVID-19 outbreak such as restriction on traveling, 
isolation etc., is allowed to remain in the study by the Investigator’s discretion. Once the 
subject is able to make visits, he or she continues with IP administration and other 
procedures required by this protocol. However, missed visits may not be repeated. For 
example, if a subject missed Week 26 and 28 visits, and then makes a visit to the site 
again on the scheduled date for Week 30, assessments for Week 30 should be conducted 
instead of Week 26 assessments. If a subject returns to the site on Week 36 or later, no IP 
administration should occur; 
4) Subject receives rescue treatment (See Section 6.3.3) during the treatment period; 
5) IGA score at Week 26 remains unchanged or has worsened from both baseline (Week 0) 
and Week 18; 
6) Subject experiences an AE, and the Investigator determines that treatment should be 
discontinued and the subject should be withdrawn from the study after follow-up. This 
may include, but is not limited to, the following events: 
• CTCAE v4.0 Grade 2 or higher cardiovascular AE 
• Any MACE 
• CTCAE v4.0 Grade 2 or higher Blood and Lymphatic System Disorders (System 
Organ Class [SOC]) 
• Any CTCAE v4.0 Grade 3 or higher AEs, such as: 
– Severe pulmonary, kidney, liver, neurologic or systemic disorders including but 
not limited to central nervous system hemorrhage or thrombosis/embolism or 
renal failure 
– Hypersensitivity reactions (including anaphylactic and serum sickness-like 
reactions) 


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– Neuropsychiatric events (including suicidal ideation and behavior) 
• Severe laboratory abnormalities, such as: 
– Neutrophil count ≤0.5 × 103/μL 
– Platelet count ≤50 × 103/μL 
– ALT and/or AST values >3 × ULN with total bilirubin >2 × ULN (unless elevated 
bilirubin is related to confirmed Gilbert’s Syndrome) 
– Confirmed AST and/or ALT >5 × ULN 
7) Subject or his/her legally acceptable representative decides to withdraw consent to 
participate the study in the absence of a medical need for withdrawal as determined by the 
Investigator; 
8) Subject cannot undergo necessary observations and examinations anymore due to 
inconvenience to the subject; 
9) Subject becomes pregnant, or wishes to become pregnant; 
10) The emergency key code for the subject is opened during the study period; 
11) The Investigator determines that the subject should be withdrawn from the study for a 
reason other than above (e.g., if use of any of the prohibited medications defined in 1) to 
3) of Section 6.3.2 is considered necessary); 
12) The Sponsor determines that this study should be terminated. 
The Investigator will identify the date of withdrawal and the reason for withdrawal and will 
record the information on the eCRF. 
In addition, subjects who discontinued IP administration due to an AE will be followed up 
until the AE is recovered/resolved. For the subject, safety follow up should be conducted 
under the Investigator's responsibility. However, no further eCRF entry is required other than 
AE data. The subject is followed up to 28 days (+14 days) after the last dose of the IP or until 
the date of early termination/end of study assessments, whichever is later, and if the AE is not 
recovered/resolved by then, the subject’s current AE data will be recorded on the eCRF. After 
that, the subject will be followed up until AE is resolved unless medical judgment is obtained, 
but without further recording of the data on the eCRF. 
4.4.2 
Premature Termination or Suspension of the Entire Study or the Study 
at Individual Investigative Site 
The Sponsor reserves the right to terminate or suspend the entire study or the study at 
individual investigative sites at any time. Reasons for study termination include, but may not 
be limited to, manufacturing problems, a request to discontinue the study from a regulatory 


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authority, a corporate decision to discontinue development of KHK4083, AE incidence or 
severity not consistent with the potential benefit of the drug, poor enrollment, or inadequate 
adherence to ICH-GCP guidelines.  
In terminating the study, the Sponsor and the Principal Investigator will ensure that adequate 
consideration is given to the protection of the subjects’ interest. 
If the study is terminated prematurely, the IEC/IRB and regulatory authorities (if required) 
will be notified. Should the Principal Investigator choose to prematurely discontinue 
participation in the study, the site must promptly notify the Sponsor and IRB/IEC in 
accordance with local GCP guidelines. 
5 
INVESTIGATIONAL PRODUCTS 
5.1 
Investigational Drug and Comparator 
5.1.1 
Investigational Drug 
Company code: KHK4083 
Non-proprietary name: TBD 
Strength and dosage form:  
KHK4083 IP, 100 mg/vial (100 mg/mL, 1 mL label fill), is supplied as a single-use, 
preservative-free solution. The KHK4083 IP is a sterile, non-pyrogenic, clear to slightly 
opalescent, colorless to slightly brownish-yellow solution essentially free of visible 
particulates. The product is formulated at a concentration of 100 mg/mL in L-histidine, 
D-sorbitol, L-methionine, Polysorbate 80, and hydrochloric acid, pH 5.5. The 
100 mg/vial presentation is contained in 3 mL clear, United States Pharmacopoeia Type 
I glass vials that are stoppered with rubber stoppers and sealed with aluminum seals. A 
volume of 1.3 mL of KHK4083 IP is filled per vial. A 0.3 mL over-fill is included in 
each vial to account for vial, needle, and syringe holdup. 
5.1.2 
Comparator 
Placebo 


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Strength and dosage form:  
Placebo for KHK4083 is supplied in the same container closure system and contains the 
same deliverable volume and excipients as KHK4083 IP without the active ingredient. 
5.2 
Packaging and Labelling 
5.2.1 
Packaging 
Seven vials (KHK4083 and/or placebo) per box 
5.2.2 
Labeling 
Labels will bear the appropriate text as required by local regulatory requirements. 
5.3 
Storage 
The IPs (KHK4083 and placebo) should be stored in a secure, limited access area at a 
temperature of 2°C to 8°C (36°F to 46°F) and protected from light. The vials should not be 
shaken. 
Guidance of the recommended storage conditions for IPs can be found in the Pharmacy 
Manual. 
5.4 
Delivery, Storage, Accountability, and Return of Investigational Product 
After signing a Clinical Trial Agreement, the Sponsor will dispense IP to each investigative 
site through a carrier company with which the Sponsor appropriately concludes a contract. 
Separate written procedures will be followed for dispensing IP. The Sponsor will develop 
written procedures for controlling IP and provide it to each investigative site. 
The IP manager at each investigative site (unblinded pharmacist or qualified designee) will 
properly store and control IP according to the procedures and will document the status of IP 
such as inventory, use, return, and disposal. All IPs (used and unused) should be stored until 
the record is finalized after verification of the unblinded monitor of CRO. The IP manager 
will properly check unused and used IP supplies (including empty vials and boxes) against 
the IP management record. All unused or expired drugs after accountability will be either 
destroyed at site or returned to the depot upon authorization by the Sponsor and/or the CRO 


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according to the investigative site’s biohazards waste procedures and local regulations. After 
study completion or at the delivery of a new batch, the IP manager will seal all unused 
supplies. 
It will be the Principal Investigator’s responsibility to arrange for disposal of all IPs with 
containers, provided that procedures for proper disposal have been established according to 
applicable regulations and institutional guidelines and procedures, and provided that 
appropriate records of disposal are kept. 
A copy of the certificate of destruction must be placed in the Sponsor’s Trial Master File. 
Refer to the Pharmacy Manual for additional details on the destruction of IP. 
6 
TREATMENT PLAN AND CONCOMITANT THERAPY 
6.1 
Dose and Duration of Treatment 
Dose: KHK4083 at 150 mg or 600 mg every 4 weeks, 300 mg or 600 mg every 2 weeks, or 
placebo. 
Duration of treatment: 36 weeks (a total of 18 visits for injections) 
6.2 
Mode of Administration 
6.2.1 
KHK4083 or Placebo 
To maintain the double blind and randomization schedule, the following treatment 
administration schedule will be followed (Table 6.2.1-1). 
Subjects who are randomized to the KHK4083 150 mg or 600 mg Q4W group will receive 
150 mg or 600 mg KHK4083 at Weeks 0 (Day 1), 4, 8, 12, 16, 20, 24, 28, and 32, and will 
receive placebo at Weeks 2, 6, 10, 14, 18, 22, 26, 30, and 34. 
Subjects who are randomized to the KHK4083 300 mg or 600 mg Q2W group will receive 
300 mg or 600 mg KHK4083 at Weeks 0 (Day 1), 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 
28, 30, 32, and 34. 


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Subjects who are randomized to the placebo group will receive placebo at Weeks 0 (Day 1), 2, 
4, 6, 8, 10, 12, 14, and 16, and will receive KHK4083 600 mg at Weeks 18 (Day 127), 20, 22, 
24, 26, 28, 30, 32, and 34. 


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Table 6.2.1-1 
Dosing Schedule for Randomized Treatment Groups 
 
Treatment A period 
Treatment B period 
Weeks 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
Placebo 
P 
P 
P 
P 
P 
P 
P 
P 
P 
600 600 600 600 600 600 600 600 600 
150 mg 
Q4W 
150 
P 
150 
P 
150 
P 
150 
P 
150 
P 
150 
P 
150 
P 
150 
P 
150 
P 
300 mg 
Q2W 
300 300 300 300 300 300 300 300 300 300 300 300 300 300 300 300 300 300 
600 mg 
Q2W 
600 600 600 600 600 600 600 600 600 600 600 600 600 600 600 600 600 600 
600 mg 
Q4W 
600 
P 
600 
P 
600 
P 
600 
P 
600 
P 
600 
P 
600 
P 
600 
P 
600 
P 
P = Placebo, 150 = KHK4083 150 mg, 300 = KHK4083 300 mg, 600 = KHK4083 600 mg 
 
The volume of SC injection will be 6 mL (divided into three syringes) per dose regardless of 
treatment assigned to subject. Each subject will receive three SC injections of 2 mL each at 
every dosing visit. For subjects who complete all 18 dosing visits from Week 0 until Week 34, 
the total number of injections during the study will be 54. The procedure for preparing the 
KHK4083 dose for SC injection is provided in the Pharmacy Manual. 
A designated unblinded pharmacist (or qualified designee) at each investigative site will 
withdraw the required amount of IP from designated 7 vials into syringes. The method of IP 
administration is specified in the Pharmacy Manual. 
The Principal Investigator, sub-Investigator, clinical research coordinator (nurse), or other 
healthcare professional will administer IP subcutaneously in the abdomen, thigh, upper arm, 
or other appropriate sites. The site of injection should be rotated so that IP is not injected into 
the same site consecutively. Before IP administration, the Investigator should make sure that 
there are no skin disorders such as erythema, redness, pain, or swelling in the area for 
injection. 
6.2.2 
Dose Modification 
No dose modifications of IP will be permitted in this study. 
IP administration may be suspended only if dose interruption is considered necessary because 
of an AE. IP administration may be resumed if the symptom has resolved and the Investigator 
determines that the subject can be rechallenged with IP. Subjects will discontinue IP 
according to the withdrawal criteria, as indicated in Section 4.4.1, if two consecutive doses 


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are not administrated or a total of 3 or more doses are skipped during the treatment period 
(both A and B) due to the reason other than the logistical issues caused by the COVID-19 
outbreak. 
6.2.3 
Measures to be taken for Acute Reactions 
Fully human antibodies such as KHK4083 may be associated with acute reactions, especially 
with the first injection. Therefore, the Investigator must carefully monitor subjects for 
injection-related reactions or other TEAEs occurring after each IP administration to confirm 
the safety of each subject after injection as specified below. 
Day 1, Weeks 2, 18, and 20: Vital signs will be measured before IP administration. Subjects 
will remain and be monitored at the investigative site for at least 2 hours after IP 
administration. In addition, vital signs will be measured 2 hours (±10 minutes) after IP 
administration.  
Weeks 4 and 22: Vital signs will be measured before IP administration. Subjects will remain 
and be monitored at the investigative site for at least 2 hours after IP administration. 
Administration time points other than above: Vital signs will be measured before IP 
administration. Subjects will remain and be monitored at the investigative site for at least 
30 minutes after IP administration. However, subjects will stay longer at the site for 
observation whenever it is clinically required and at the discretion and clinical judgment of 
the Investigator. 
No pre-medication (e.g., acetaminophen, anti-emetic; 5HT3 blocker; histamine H1 and/or H2 
blocker[s]) is planned to be routinely/prophylactically administered prior to KHK4083 
injection in this study. However, appropriate measures should be selected to treat individual 
subjects at the discretion of the Investigator upon approval of the Sponsor. If consistent mild 
(Grade 1) and/or moderate (Grade 2) injection reactions are observed, the Sponsor may 
recommend the pretreatment of subjects to the Principal Investigator. 
Any subject experiencing an acute reaction must receive immediate medical assessment and 
indicated supportive management according to the institutional standard of care and local 
Principal Investigator judgment until the signs/symptoms of the reaction have resolved. Refer 
to Section 7.9.8.1 for reporting an injection-related reaction including descriptions of specific 
symptoms observed or reported by the subjects. 


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6.2.4 
Rationale for Route of Administration, Dosing Regimen, and 
Treatment Duration 
The inhibitory activity of KHK4083 against OX40 was saturated at approximately 10 μg/mL 
(see Section 4.1.2.3 of the Investigator’s Brochure Edition 07). The ADCC activity of 
KHK4083 almost reached the maximum at approximately 1 μg/mL (see Section 4.1.2.5 of the 
Investigator’s Brochure Edition 07). In Study 4083-004, the amount of unoccupied OX40 
recovered from around Week 14, and the serum concentration at the same time point was also 
around 10 μg/mL (Figure 6.2.4-1). The effective serum concentration in patients with AD 
was thus estimated to be 10 μg/mL. The comparison of serum concentration between 
observed values and the median of a 1000-subject simulation (solid line; dotted line = 5 and 
95 percentiles) is shown in Figure 6.2.4-1. 
Figure 6.2.4-1 Comparison of serum concentration between Population Analysis 
Results and Observed Values in Study 4083-004 
 
Preliminary results based on the clinical database as of 13 Mar 2018. 
 


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The trough concentration following multiple SC doses of KHK4083 every 2 or 4 weeks was 
simulated using the population PK parameters in patients with AD and the PK parameters of 
absorption phase after SC dosing in Study 4083-003 (Figure 6.2.4-2). The trough 
concentration at week 16 was expected to reach the estimated effective serum concentration 
(10 µg/mL) in almost all patients with AD at 300 mg Q2W, 600 mg Q4W, and 600 mg Q2W. 
On the other hand, the serum trough concentration of KHK4083 at week 16 was estimated to 
exceed 10 µg/mL in only 20% of the patients at 150 mg Q4W. Given that the tissue 
distribution of most antibodies is approximately 10% (Lobo et al, 2004; Wang et al, 2008), 
when the serum concentration of KHK4083 exceeded 100 µg/mL, the estimated effective 
concentration was expected to be achieved also in the skin, which is the site of the disease, 
providing an additional pharmacological effect. The serum trough concentration at week 16 
was estimated to exceed 100 µg/mL in 50% of the patients at 600 mg Q2W.  
Figure 6.2.4-2 Simulation of Serum Concentrations at Each Dosing Regimen 
 
Solid line, median; dot lines 5 percentile and 95 percentile  
 
In summary, KHK4083 is expected to be highly effective against activated T cells in patients 
with AD at 300 mg Q2W, 600 mg Q4W, and 600 mg Q2W, and provide an additional effect 
1
10
100
0
28
56
84
112
140
168
196
224
Time (day)
Concentration (ug/mL)
150  mg/body SC Q4W ,Conc@112d= 4.9  ug/mL
1
10
100
0
28
56
84
112
140
168
196
224
Time (day)
Concentration (ug/mL)
600  mg/body SC Q2W ,Conc@112d= 99.6  ug/mL
1
10
100
0
28
56
84
112
140
168
196
224
Time (day)
Concentration (ug/mL)
300  mg/body SC Q2W ,Conc@112d= 45.7  ug/mL
1
10
100
0
28
56
84
112
140
168
196
224
Time (day)
Concentration (ug/mL)
600  mg/body SC Q4W ,Conc@112d= 33.8  ug/mL


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at the site of the disease at 600 mg Q2W. The effect of dosing interval could be investigated 
by comparing the 600 mg Q4W regimen and the 300 mg Q2W regimen, in which the total 
dose is almost equivalent to that of the 600 mg Q4W regimen. In addition, the relationship 
between exposure and response could be extensively investigated by including the 150 mg 
Q4W group, in which the serum trough concentration at week 16 is expected to reach the 
estimated effective serum concentration in approximately 20% of patients with AD. 
6.3 
Concomitant Medications and Therapies 
The following information will be recorded on the eCRF, if a subject receives any medication 
or therapy during the period from day of informed consent until the end (early termination) of 
the study:  
• 
Generic name of medication or therapy 
• 
Route of administration 
• 
Start date and end date of medication 
• 
Reason for use (indication) 
Regarding the name of medicine, the generic names are preferred. For combination drugs, the 
brand names are allowed. 
6.3.1 
Concomitant Medications 
In this study, an emollient prescribed by the Investigator will be used concomitantly as 
background treatment during the study period between at least 1 week before baseline visit 
and the end of the study. If the subject is using any emollient as prior medication, the dosing 
regimen of the emollient must be switched to that prescribed by the Investigator at least 
1 week before baseline visit. If the subject is not using any emollients as prior medication, an 
emollient designated by the Investigator will be newly prescribed at least 1 week before 
baseline visit. Subjects will be required to apply a topical emollient, as a rule, twice daily 
during the study period. The application of the emollient must be continued at the same 
regimen throughout the study period even after improvement of AD symptoms.  
In the United States, Canada, and Germany, over-the-counter emollients can be used instead 
of prescription emollients from at least l week before baseline visit through the end of the 
study with approval from the Investigator. 


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6.3.2 
Prohibited Concomitant Medications and Therapies 
1) The following medication will be prohibited from 12 weeks (16 weeks for Japan) or 
5 half-lives, whichever is longer, before baseline visit through the end of study (or early 
termination) 
• 
Biological products (including IPs) 
2) The following medication will be prohibited from 4 weeks (16 weeks for Japan) or 5 half-
lives, whichever is longer, before baseline visit through the end of study (or early 
termination) 
• 
Other IPs (excluding biological products) 
3) The following medication will be prohibited from 12 weeks before baseline visit through 
the end of study (or early termination) 
• 
Vaccination with live vaccines (e.g., BCG, oral polio, measles, rubella) 
4) The following medications and therapies will be prohibited from 4 weeks or 5 half-lives, 
whichever is longer, before baseline visit through the end of study (or early termination) 
• 
Systemic corticosteroids (inhaled corticosteroids, eye, ear, or nasal drops containing 
corticosteroids are allowed, suppositories or enemas containing corticosteroids are not 
allowed) 
• 
Systemic treatment with methotrexate, mycophenolate, calcineurin inhibitor, 
thalidomide, or other immunosuppressants 
• 
Phototherapy (e.g., PUVA therapy, UVB therapy, narrow-band UVB therapy, UVA1 
therapy, excimer light) for the treatment of AD 
• 
JAK inhibitors 
5) The following medications for the treatment of AD will be prohibited from 1 week before 
baseline visit through the end of study (or early termination). Subjects who received 
rescue treatment after Week 36 will not be withdrawn from the study and will be 
observed until the end of the study up to Week 56. 
• 
TCSs 
• 
Topical calcineurin inhibitors or other immunosuppressive agents 
• 
Topical agents including crotamiton, Eucrisa®/crisaborole 
• 
Combination topical agents containing a corticosteroid or a calcineurin-inhibiting 
component or other immunosuppressive agents 
• 
Chinese herbal medicines (e.g., jumi-haidoku-to, shofu-san, saiko-seikan-to, hochu-
eki-to) 


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6.3.3 
Rescue Treatments 
Rescue treatment is defined as the use of any of the prohibited medications or therapies 
defined in 4) and 5) of Section 6.3.2 for exacerbation of AD. Subjects who have received 
rescue treatment until Week 36 assessment will discontinue further IP administration and will 
be withdrawn from the study. The use of a prohibited concomitant medication or therapy for 
rescue treatment will not be regarded as a protocol deviation. Subjects who received rescue 
treatment after Week 36 will not be withdrawn from the study and will be observed until the 
end of the study up to Week 56. 
6.4 
Treatment Compliance 
IP should be administered within the allowable window for each visit specified in Section 7.1. 
The dose should be skipped if IP cannot be administered within the specified allowable 
window. Study treatment should be discontinued if the scheduled dosing is skipped twice 
consecutively or three times in total during the treatment period. Details are described in 
Section 4.4.1. 


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7 
STUDY PROCEDURES 
7.1 
Overall Schedule 
The Investigator will assign subject IDs to subjects who provide written informed consent 
followed by a transaction within the IWRS to start screening those subjects within 4 weeks 
after the date of subject’s signature on informed consent. The Investigator will register 
eligible subjects in the IWRS and randomize them. Subsequently, subjects will start study 
treatment and undergo observation, investigations, and examinations according to the 
schedule provided in Table 7.1-1 to Table 7.1-3. Detailed study procedures are described in 
Section 7.2 to Section 7.8.  
Day 1 will be the starting point when scheduling study visits and examinations during the 
study. Examinations and observations for efficacy assessment must be performed before 
IP administration of the study visit.


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Table 7.1-1 Study Schedule of Events - Screening, Baseline, and Treatment A period 
STUDY PROCEDURE 
SCREENING 
TREATMENT A PERIOD : Day 1 to Week 18 pre (Last dose at Week 16) 
Screening Baseline 
Week 0 Week 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Week 14 Week 15 Week 16 Week 18 
pre 
Day 1 
Day 8 
±3 days 
Day 15 
±3 days 
Day 29 
±3 days 
Day 43 
±3 days 
Day 57 
±3 days 
Day 71 
±3 days 
Day 85 
±3 days 
Day 99 
±3 days 
Day 106 
±3 days 
Day 113 
±3 days 
Day 127 
±3 days 
SCREENING/BASELINE: 
Written Informed Consent 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration on IWRS 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Training on eCOA1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT: 
IP Administration3 
 
 
X2 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Prior/Concomitant 
Medications 
X4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EFFICACY: 
EASI, SCORAD, IGA, BSA 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pruritus NRS5 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sleep disturbance NRS5 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DLQI5 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Photograph of AD area 
(optional)6 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAFETY: 
Weight 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination7 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Brief Physical Examination8 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Sign9 
X 
X 
X3 
X 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*:  The Investigator will start screening subjects providing written informed consent within 4 weeks after the date of informed consent. 


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Table 7.1-1 Study Schedule of Events - Screening, Baseline, and Treatment A period (Continued) 
STUDY PROCEDURE 
SCREENING 
TREATMENT A PERIOD : Day 1 to Week 18 pre (Last dose at Week 16) 
Screening Baseline 
Week 0 Week 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Week 14 Week 15 Week 16 Week 18 
pre 
Day 1 
Day 8 
±3 days 
Day 15 
±3 days 
Day 29 
±3 days 
Day 43 
±3 days 
Day 57 
±3 days 
Day 71 
±3 days 
Day 85 
±3 days 
Day 99 
±3 days 
Day 106 
±3 days 
Day 113 
±3 days 
Day 127 
±3 days 
LABORATORY: 
Infection Test10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV-DNA11 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
TB test12 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinary Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinary Pregnancy13 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
Urinalysis 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
Chemistry 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Hematology 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TARC, Serum total IgE 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum IL-22 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
PK/DRUG CONCENTRATION and ANTI-DRUG ANTIBODY SAMPLING: 
Serum KHK4083 concentration 
sample14 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-KHK4083 antibody 
sample15 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
OTHER POTENTIAL STUDY ASSESSMENTS (optional): 
Serum cytokines and 
chemokines (at only selected 
US and Canada sites)16 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
Skin biopsy(at only selected US 
and Canada sites, and all Japan 
sites)17 
 
X 
(NL, L) 
 
 
 
 
 
X 
(L) 
 
 
 
 
X 
(NL, L) 
 
Flow cytometry (at only Japan 
sites)18 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Stored blood for 
pharmacogenetics19 
 
X 
 
 
 
 
 
 
 
 
 
 
 


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Table 7.1-2 Study Schedule of Events - Treatment B period 
STUDY PROCEDURE 
TREATMENT B PERIOD : Weeks 18 post to 36 (Last dose at Week 34) 
 
 
 
 
 
 
 
 
 
End of 
Treatment 
Week 18 
post 
Week 20 
Week 22 
Week 24 
Week 26 
Week 28 
Week 30 
Week 32 
Week 34 
Week 36 
Day 127 
±3 days 
Day 141 
± 3 days 
Day 155 
± 3 days 
Day 169 
± 3 days 
Day 183 
± 3 days 
Day 197 
± 3 days 
Day 211 
± 3 days 
Day 225 
± 3 days 
Day 239 
± 3 days 
Day 253 
± 3 days 
TREATMENT: 
IP Administration3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EFFICACY: 
EASI, SCORAD, IGA, BSA 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pruritus NRS5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sleep disturbance NRS5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DLQI5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Photograph of AD area (optional)6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAFETY: 
Weight 
 
 
 
 
 
 
 
 
 
X 
Height 
 
 
 
 
 
 
 
 
 
 
Physical Examination7 
 
 
 
 
 
 
 
 
 
X 
Brief Physical Examination8 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Sign9 
X3 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
 
 
 
X 
 
 
 
X 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Table 7.1-2 Study Schedule of Events - Treatment B period (Continued) 
STUDY PROCEDURE 
TREATMENT B PERIOD : Weeks 18 post to 36 (Last dose at Week 34) 
 
 
 
 
 
 
 
 
 
End of 
Treatment 
Week 18 
post 
Week 20 
Week 22 
Week 24 
Week 26 
Week 28 
Week 30 
Week 32 
Week 34 
Week 36 
Day 127 
±3 days 
Day 141 
± 3 days 
Day 155 
± 3 days 
Day 169 
± 3 days 
Day 183 
± 3 days 
Day 197 
± 3 days 
Day 211 
± 3 days 
Day 225 
± 3 days 
Day 239 
± 3 days 
Day 253 
± 3 days 
LABORATORY: 
Infection Test10 
 
 
 
 
 
 
 
 
 
 
HBV-DNA11 
 
X 
 
X 
 
X 
 
X 
 
X 
TB test 12 
 
 
 
 
 
 
 
 
 
X 
Urinary Drug Screen 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy13 
 
 
 
 
 
 
 
 
 
 
Urinary Pregnancy13 
 
X 
 
X 
 
X 
 
X 
 
X 
Urinalysis 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TARC, Serum total IgE 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum IL-22 
 
 
 
 
 
 
 
 
 
X 
PK/DRUG CONCENTRATION and ANTI-DRUG ANTIBODY SAMPLING: 
Serum KHK4083 concentration 
sample14 
 
X 
X 
X 
X 
X 
 
X 
 
X 
Anti-KHK4083 antibody sample15 
 
X 
 
 
 
X 
 
 
 
X 
OTHER POTENTIAL STUDY ASSESSMENTS (optional): 
Serum cytokines and chemokines (at 
only selected US and Canada sites) 16 
 
 
 
 
 
 
 
 
 
X 
Skin biopsy (at only selected US and 
Canada sites, and all Japan sites) 17  
 
 
 
 
 
 
 
 
 
X 
(L) 
Flow cytometry (at only Japan sites)18 
 
 
 
 
 
 
 
 
 
X 
 


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Table 7.1-3 Study Schedule of Events - Follow-up Period and Early Termination 
STUDY PROCEDURE 
FOLLOW-UP 
Early 
Termination 
(if applicable) 
 
 
 
 
End of Study 
Week 40 
Week 44 
Week 48 
Week 52 
Week 56 
Day 281 
± 3 days 
Day 309 
± 7 days 
Day 337 
± 7 days 
Day 365 
± 7 days 
Day 393 
± 7 days 
TREATMENT: 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
EFFICACY20: 
EASI, SCORAD, IGA, BSA 
X 
X 
X 
X 
X 
X 
Pruritus NRS5 
X 
X 
X 
X 
X 
X 
Sleep disturbance NRS5 
X 
X 
X 
X 
X 
X 
DLQI5 
X 
X 
X 
X 
X 
X 
Photograph of AD area (optional)6 
X 
X 
X 
X 
X 
X 
SAFETY: 
Weight 
 
X 
 
 
X 
X 
Brief Physical Examination8 
X 
X 
X 
X 
X 
X 
Vital Sign9 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
X 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
LABORATORY: 
HBV-DNA11 
X 
X 
X 
X 
X 
 
TB test 12 
 
 
 
 
X 
X 
Urinary Pregnancy13 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
Chemistry 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
TARC, Serum total IgE 
X 
X 
X 
X 
X 
 
Serum IL-22 
X 
X 
X 
X 
 
 
PK/DRUG CONCENTRATION and ANTI-DRUG ANTIBODY SAMPLING: 
Serum KHK4083 concentration 
sample 
X 
X 
X 
X 
X 
X 
Anti-KHK4083 antibody sample 
X 
 
X 
 
X 
X 
OTHER POTENTIAL STUDY ASSESSMENTS (optional): 
Serum cytokines and chemokines 
(optional, at only selected US and 
Canada sites) 16 
 
 
 
X 
 
 
Skin biopsy (optional, at only 
selected US and Canada, and all 
Japan sites)17 
 
 
 
X 
(L) 
 
 
Flow cytometry (optional, at only 
Japan sites)18 
X 
X 
X 
X 
 
 


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Footnotes to Table 7.1-1 to Table 7.1-3 
Week 18 pre: Before IP administration at Week 18. 
Week 18 post: After IP administration at Week 18. 
 
1: Subjects will be trained on how to use an eCOA device at the screening visit and complete pruritus NRS, sleep 
disturbance NRS, SCORAD (part C), and DLQI and record of emollient use on the eCOA device. 
2: The first dose of IP will be administered on the day of or the day after randomization.  
3: All subjects are required to remain at the investigative site to be carefully monitored for injection reactions, injection site 
reactions or other TEAEs after each injection. The safety of subjects after injection will be confirmed as specified below. 
Day 1, Weeks 2, 18, and 20:  Vital signs will be measured before the IP administration and 2 hours (±10 minutes) after 
injection. Subjects will remain and be monitored at the site for at least 2 hours after injection. 
Weeks 4 and 22:  Vital signs will be measured before the IP administration. Subjects will remain and be monitored at the 
site for at least 2 hours after injection. 
Weeks 6, 8, 10, 12, 14, 16, 24, 26, 28, 30, 32, and 34:  Vital signs will be measured before the IP administration. 
Subjects will remain and be monitored at the site for at least 30 minutes after injection. However, subjects will stay 
longer at the site for observation whenever it is clinically required and at the discretion and clinical judgment of the 
Investigator. 
4: For all subjects, information on the use of concomitant medications will be obtained by visit or phone etc. on Day −7. 
5: Pruritus NRS, sleep disturbance NRS, SCORAD (part C), and DLQI should be completed before the assessments of EASI, 
SCORAD (part A and B), IGA, and BSA. 
6: Photographs of AD lesions will be obtained only from subjects who provide separate consent. The sites to be 
photographed are the front and back sides of the body (from the neck down) in principle, but may be determined by the 
Investigator. 
7: Complete physical examination includes general appearance, examination of the HEENT (head, eyes, ears, nose, and 
throat) and body systems (including, but not limited to, cardiovascular, respiratory, abdominal, musculoskeletal, 
extremities, lymph nodes, and skin). 
8: Brief physical examination only includes the HEENT, cardiovascular, respiratory, abdominal, and skin examinations. 
9: Blood pressure, pulse, respiration rate, and body temperature will be measured. 
10: Infection tests include HBs antigen/antibody, HBc antibody, HCV antibody, HIV antigen/antibody, and HTLV-1 
antibody. 
11: HBV-DNA will be measured every 4 weeks in subjects who test negative for HBs antigen but positive for HBc and/or 
HBs antibodies. 
12: Chest X-ray (or chest CT scan) and/or a test according to the local guideline (e.g., QuantiFERON, T-Spot, PPD test) will 
be conducted at screening. TB risk assessment questionnaire provided in Appendix 8 may be conducted at Weeks 16, 36, 
and 56, and at early termination. 
13: Only WOCBP will undergo urinary pregnancy test. 
14: PK samples must be collected before IP administration. 
15: Samples for anti-KHK4083 antibodies must be collected before IP administration, at the same time as PK samples. 
16: Blood samples will be collected from subjects providing consent (optional) to undergo both skin biopsy and serum 
analyses at the selected investigative sites in the United States and Canada. 
17: Skin samples will be collected from subjects providing consent (optional) at the selected investigative sites in the United 
States and Canada, and all investigative sites in Japan. NL = non-lesion, L = lesion 
18: At all investigative sites in Japan, blood samples for flow cytometry will be collected from subjects providing consent 
(optional) to undergo both skin biopsy and flow cytometry analysis. OX40-positive T cells and CLA-positive memory T 
cells in peripheral blood will be measured by flow cytometry. 
19: Blood samples will be collected from subjects providing consent (optional) to pharmacogenetic testing. 
20: In the follow-up period, efficacy assessments may be omitted for subjects who have received rescue treatment for 
exacerbation of AD, at the time points (including early termination) after receiving the rescue treatment. 


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7.2 
Investigation Items 
7.2.1 
Demographics 
The following demographic information of subjects will be recorded on the eCRF: 
• 
Date of informed consent 
• 
Sex 
• 
Year of birth/age 
• 
Race/Ethnicity 
• 
Current medical history 
• 
Past medical history 
• 
Previous use of biological products for the treatment of AD (Yes/No); if Yes, generic 
name of the biological product and reason for discontinuation of treatment 
• 
Time of diagnosis of AD 
Time points: screening. 
7.2.2 
Exposure 
The following information on the status of IP administration will be collected in the eCRF: 
• 
Kit No. 
• 
Date and time of administration 
• 
Status of administration (per protocol/not per protocol) 
• 
Location sites of administration 
• 
Reason for dose interruption (if applicable) 
Time points: Week 0 (Day 1), Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18 (Day 127), 20, 22, 24, 26, 
28, 30, 32, and 34. 
7.3 
Efficacy Assessments 
Examinations and observations must be performed before IP administration. However, in the 
follow-up period, efficacy assessments may be omitted for subjects who have received any of 
the medications or therapies specified in items 1) to 5) of Section 6.3.2 for exacerbation of 
AD, at the time points (including early termination) after receiving the medication or therapy. 


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7.3.1 
Eczema Area and Severity Index (EASI) 
In the EASI assessment, the severity of 4 elements of eczema (erythema, 
induration/papulation, excoriation, and lichenification) at each of 4 body regions (head and 
neck, trunk, upper extremities, and lower extremities) will be assessed on a scale of 0 to 3 
(0 = None , 1 = Mild, 2 = Moderate, 3 = Severe). Half scores (1.5 and 2.5) are allowed, with 
the exception of 0.5. Any signs must be at least 1 (mild) in severity (see Appendix 1). In 
addition, the extent of eczema at each of the 4 body regions will be assessed on a scale of 0 to 
6 (0 = 0%, 1 = 1% to 9%, 2 = 10% to 29%, 3 = 30% to 49%, 4 = 50% to 69%, 5 = 70% to 
89%, 6 = 90% to 100%). 
Scores calculated according to the expression “total score of 4 elements of eczema × area 
score of eczema” will be multiplied by 0.1 for head and neck, 0.2 for upper extremities, 0.3 
for trunk, and 0.4 for lower extremities. The 4 region scores obtained will then be summed up 
(maximum score: 72) as EASI score. To ensure consistent evaluation, individual subjects 
should be evaluated by the same assessor (whenever possible) at baseline and all subsequent 
visits. The Investigator will complete the EASI assessment on the eCOA device at each visit. 
Time points: screening, baseline, Week 1 to 56, early termination. 
7.3.2 
SCORing Atopic Dermatitis (SCORAD) 
In the SCORAD assessment, the extent of AD will be calculated as the sum of the percentage 
of each defined body area, with a maximum score of 100% (assigned as “A” in the overall 
SCORAD calculation). The severity of 6 specific symptoms of AD will be assessed using the 
following scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe, with a maximum score of 
18 (assigned as “B” in the overall SCORAD calculation). Itch and sleeplessness will be 
assessed by subjects on a visual analogue scale (VAS), where 0 is no itch (or sleeplessness) 
and 10 is the worst imaginable itch (or sleeplessness), with a maximum score of 20 (assigned 
as “C” in the overall SCORAD calculation). The SCORAD score is calculated as A/5 + 7B/2 
+ C. 
Refer to Appendix 2 for the SCORAD assessment tool. Subjects will complete SCORAD (C) 
on the eCOA device at each visit before the assessments of EASI, SCORAD (A and B), IGA, 
and BSA. To ensure consistent evaluation, individual subjects should have the same 
representative area evaluated by the same assessor (whenever possible) at baseline and at all 


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subsequent visits. The Investigator will complete the SCORAD assessment on the eCOA 
device at each visit. 
Time points: screening, baseline, Week 1 to 56, early termination. 
7.3.3 
Investigator’s Global Assessment (IGA) 
In the IGA, the Investigator will evaluate the overall skin symptoms of subjects at each visit 
on a 5-point scale ranging from 0 (clear) to 4 (severe).  
Refer to Appendix 3 for the IGA assessment tool. To ensure consistent evaluation, individual 
subjects should be evaluated by the same assessor (whenever possible) at all visits. The 
Investigator will complete IGA on the eCOA device at each visit. 
Time points: screening, baseline, Week 1 to 56, early termination. 
7.3.4 
Body Surface Area of Involvement of AD (BSA) 
The Investigator will calculate the percentage (%) of the total body surface area affected by 
AD and complete BSA on the eCOA device at each visit. To ensure consistent evaluation, 
individual subjects should be evaluated by the same assessor (whenever possible) at all visits. 
Time points: screening, baseline, Week 1 to 56, early termination. 
7.3.5 
Pruritus Numerical Rating Scale (NRS) 
The worst degree of itch experienced during 24 hours before the time point will be assessed 
on a NRS (see Appendix 4). The degree of itch will be scored on an 11-point scale, with 0 
being “no itch” and 10 being the “worst itch imaginable.” 
Subjects will complete pruritus NRS on the eCOA device at each visit before the assessments 
of EASI, SCORAD (A and B), IGA, and BSA. 
Time points: screening, baseline, Week 1 to 56, early termination. 


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7.3.6 
Sleep Disturbance Numerical Rating Scale (NRS) 
Daily sleep disturbance in the last 24 hours before the relevant time point will be assessed on 
a NRS (see Appendix 5). Subjects will score the degree of their sleep disturbance on an 11-
point scale ranging from ‘no sleep loss’ (0) to ‘I cannot sleep at all’ (10). 
Subjects should complete the sleep disturbance NRS on the eCOA device at each visit before 
the assessments of EASI, SCORAD (A and B), IGA, and BSA. 
Time points: screening, baseline, Week 1 to 56, early termination. 
7.3.7 
Dermatology Life Quality Index (DLQI) 
The effects of skin symptoms on daily living in the last 1 week will be assessed by DLQI (see 
Appendix 6). DLQI consists of 6 subscales (symptoms and feelings, daily activities, leisure, 
work and school, personal relationships, and treatment), which are scored on the basis of 
10 questions. The scoring of each question is as follows: 
Response 
Score 
very much 
scored 3 
a lot 
scored 2 
a little 
scored 1 
not at all / not relevant / question unanswered 
scored 0 
Question 7: “prevented work or studying” 
scored 3 
The DLQI is calculated by summing the score of each question resulting in a maximum of 30 
and a minimum of 0. The higher the score, the more QoL is impaired.  
Subjects will complete DLQI on the eCOA device at each visit before the assessments of 
EASI, SCORAD (A and B), IGA, and BSA.  
Time points: screening, baseline, Week 1 to 56, early termination. 
7.3.8 
Photograph (Optional) 
Photographs will be obtained only from subjects who provide separate consent. The sites to 
be photographed are the front and back sides (from the neck down) in principle but may be 
determined by the Investigator. Photographs involving the face should be taken with due 
consideration so that the subject is not identifiable. Photograph data will be submitted to the 
Sponsor according to separate written procedures. 


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Time points: screening, baseline, Week 1 to 56, early termination. 
7.4 
Pharmacodynamic Assessments 
7.4.1 
Serum Disease Markers 
TARC and serum total IgE will be measured as serum disease markers. Blood should be 
collected before IP injection if the administration of IP is scheduled at the same time. Details 
are specified in a separate Laboratory Manual provided to the investigative sites. Residual 
samples, after measurement, may be utilized for the improvement of serum biomarker assay. 
The date of blood collection will be entered into the eCRF. 
Time points: screening, baseline, Weeks 1, 2, 4, 6, 8, 10, 12, 14, 15, 16, 18 pre, 20, 22, 24, 26, 
28, 30, 32, 34, 36, 40, 44, 48, 52, and 56.  
7.4.2 
Serum IL-22 
Blood samples for measuring serum IL-22 should be collected before IP injection if the 
administration of IP is scheduled at the same time. Details are specified in a separate 
Laboratory Manual provided to the investigative sites. Residual samples, after measurement, 
may be utilized for the improvement of serum biomarker assay. The date of blood collection 
will be entered into the eCRF. 
Time points: baseline, Weeks 1, 8, 16, 36, 40, 44, 48, and 52.  
7.5 
Pharmacokinetic Concentrations and Immunogenicity Specimen 
Assessment 
7.5.1 
Serum KHK4083 Concentration 
Drug concentrations will be measured by a PK bioanalytical laboratory. Serum samples 
should be collected prior to IP injection if the administration of IP is scheduled at the same 
time. Details of the collection, storage, and shipment of samples are described in the 
Laboratory Manual. The date and time of blood collection and IP administration will be 
entered into the eCRF. 


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Residual samples after measurement may be removed from the study and utilized for the 
improvement of serum KHK4083 concentration assay. 
Time points: baseline, Weeks 1, 2, 4, 6, 8, 10, 12, 14, 15, 16, 18 pre (Day 127), 20, 22, 24, 26, 
28, 32, 36, 40, 44, 48, 52, and 56, early termination.  
7.5.2 
Anti-KHK4083 Antibody 
Anti-KHK4083 antibodies will be measured by a PK bioanalytical laboratory. Evaluation of 
neutralizing activity may also be measured by a PK bioanalytical laboratory, if necessary. 
Serum samples should be collected prior to IP administration, at the same time as PK 
sampling. Details of the collection, storage, and shipment of samples are described in the 
Laboratory Manual. The date and time of blood collection will be entered into the eCRF. 
Residual samples after measurement may be removed from the study and utilized to improve 
anti-KHK4083 antibody assay. 
Time points: baseline, Weeks 4, 8, 12, 16, 20, 28, 36, 40, 48, and 56, early termination.  
7.6 
Exploratory Biomarker Measurement (Optional) 
7.6.1 
Skin Biopsy (To be Performed at the Selected Investigative Sites in 
the United States and Canada and the Investigative Sites in Japan) 
At the selected investigative sites in the United States and Canada, skin samples will be 
collected from subjects providing additional consent to undergo both skin biopsy and serum 
cytokines and chemokines, as described in Section 7.6.2. Samples should be collected before 
IP injection if the administration of IP is scheduled at the same time. Gene expression tests 
(excluding gene sequence analysis), pathological staining, and immunohistochemical staining 
will be conducted using the samples collected. The tests will be performed at a facility 
working with the Sponsor. Details of the collection, storage, and shipment of samples are 
described in the Laboratory Manual and Punch Biopsy Procedure provided separately. The 
date of consent, the date of skin biopsy collection and the location of skin biopsy collection 
will be entered into the eCRF. The laboratory reports will be provided to the Sponsor. The 
results of this exploratory biomarker research may be reported separately and may not form 
part of the Clinical Study Report. 


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At the investigative sites in Japan, skin samples will be collected from subjects providing 
additional consent to undergo both skin biopsy and flow cytometry, as described in Section 
7.6.3. Samples should be collected before IP injection if the administration of IP is scheduled 
at the same time. Gene expression tests (excluding gene sequence analysis) and 
immunohistochemical staining will be conducted using the samples collected. The tests will 
be performed at a facility working with the Sponsor. Details of the collection, storage, and 
shipment of samples are described in the Laboratory Manual. The date of consent, the date of 
skin biopsy collection and the location of skin biopsy collection will be entered into the eCRF. 
The laboratory reports will be provided to the Sponsor. The results of this exploratory 
biomarker research may be reported separately and may not form part of the Clinical Study 
Report. 
Time of sampling: baseline (non-lesions and lesions), Week 8 (lesions), Week 16 (non-
lesions and lesions), Week 36 (lesions), and Week 52 (lesions). 
7.6.2 
Serum Cytokines and Chemokines (To be Performed at the Selected 
Investigative Sites in the United States and Canada Only) 
At the selected investigative sites in the United States and Canada, blood samples for serum 
cytokines and chemokines will be collected from subjects providing additional consent to 
undergo both skin biopsy and serum cytokines and chemokines, as indicated in Section 7.6.1. 
Samples should be collected before IP injection if the administration of IP is scheduled at the 
same time. Serum cytokines and chemokines will be measured by a facility working with the 
Sponsor. Details of the collection, storage, and shipment of samples are described in the 
Laboratory Manual. The date of consent and the date of blood collection will be entered into 
the eCRF. The laboratory reports will be provided to the Sponsor. The results of this 
exploratory biomarker research may be reported separately and may not form part of the 
Clinical Study Report. 
Time of sampling: baseline, Weeks 8, 16, 36, and 52. 
7.6.3 
Flow Cytometry (To be Performed in Japan Only) 
At the investigative sites in Japan, blood samples for flow cytometry will be collected from 
subjects providing additional consent to undergo both skin biopsy and flow cytometry, as 
indicated in Section 7.6.1. Samples should be collected before IP injection if the 
administration of IP is scheduled at the same time. OX40+ cell counts and CLA+ memory T 


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cell counts will be determined. Analysis will be performed by a facility working with the 
Sponsor. Details of the collection, storage, and shipment of samples are described in the 
Laboratory Manual. The date of consent and the date of blood collection will be entered into 
the eCRF. The laboratory reports will be provided to the Sponsor. The results of this 
exploratory biomarker research may be reported separately and may not form part of the 
Clinical Study Report. 
Time points: screening, baseline, Weeks 1, 8, 16, 36, 40, 44, 48, and 52. 
7.7 
Pharmacogenetics 
The purpose of the pharmacogenetic testing is to explore the association between individual 
differences in responses to KHK4083 (e.g., efficacy, adverse drug reactions, 
pharmacokinetics, and pharmacodynamics) and mutations in DNA sequence (e.g., genetic 
polymorphism). Only subjects who provide additional consent to participation in the study 
and to the collection, storage, and use of blood samples for pharmacogenetic testing will be 
involved in this exploratory assessment. 
Blood sampling for the pharmacogenetic testing should be completed before IP 
administration at Day 1. The blood samples will be anonymized with subject IDs and stored 
at a sample-archiving facility. The date of consent and the date of blood collection will be 
entered into the eCRF.  
If a subject withdraws consent to the collection, storage, and use of blood samples for the 
pharmacogenetic testing, the investigative site should immediately notify the Sponsor of the 
withdrawal. The Sponsor will instruct the sample-archiving facility to destroy the relevant 
samples. The sample-archiving facility will destroy the samples and submit a certificate of 
destruction to the Sponsor. The Sponsor will designate a biobanking manager. 
The pharmacogenetic testing using archived samples will be conducted only if the Sponsor 
considers it useful to explore mutations in DNA sequence (e.g., genetic polymorphism) that 
are associated with responses to KHK4083. Candidate genes may include, but are not limited 
to, IL-4R, FLG, IL-4, IL-13, SPINK5, and STAT6. 
When the schedule or contents of pharmacogenetic testing using samples is specified, a 
“Pharmacogenetic Testing Protocol” will also be prepared before the testing is initiated. 
Measurement of pharmacogenetics will be conducted by the Sponsor or a company working 


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with the Sponsor. The results of this pharmacogenetics may be reported separately and may 
not form part of the Clinical Study Report. 
The scientific reliability, such as accuracy or certainty, of results obtained from 
pharmacogenetic testing using archived samples is unknown at present. Therefore, any 
obtained results (e.g., pharmacogenetic test results) will not be disclosed to subjects. 
However, the obtained information will be disclosed to subjects (1) when the subject requests 
disclosure of test results according to laws related to personal information protection and the 
claim is considered to meet relevant requirements; or (2) when an ethics review committee 
established by the Sponsor determines after its deliberations that the disclosure of the 
information is necessary. As a general rule, the information will be disclosed only to the 
subject in both cases. 
The samples derived from the subjects who have provided consent for the storage and use of 
samples for pharmacogenetics will be stored for 15 years after the completion of scheduled 
assessments of the last subject, until the research is considered unnecessary, or until the 
subject withdraws consent for the storage and use of samples, whichever is the earliest. The 
samples will then be discarded after being treated appropriately so that they cannot be used 
by other persons for other research. 
7.8 
Safety Assessments 
7.8.1 
Clinical Laboratory Evaluation 
All prespecified laboratory tests, except for the investigative site controls will be performed 
by a central laboratory. The central laboratory will provide the required materials for 
processing the samples, and will also provide details of the collection, storage, and shipment 
of samples as the Laboratory Manual. The Investigator will receive a laboratory report for 
information on a per visit basis. Clinical significance will be reported as AEs including any 
related comments. 
Clinical laboratory parameters are shown in Table 7.8.1-1. Each test will be performed 
according to the test schedule provided in Section 7.1. Samples should be collected before IP 
injection if the administration of IP is scheduled at the same time.  


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Table 7.8.1-1 Clinical Laboratory Assessments 
Hematology 
WBC, RBC, Ht, Hb, PLT, differential WBC (Baso, Eosino, Neutro, Mono, 
Lymph) 
Chemistry 
T-Bil, ALP, LDH, AST, ALT, γ-GTP, TP, Alb, Glu, T-Cho, TG, BUN, Cre, UA, 
Na, K, Cl, Ca, P, CRP, HbA1ca 
 a: To be measured only at screening. 
Urinalysis 
Specific gravity, pH, qualitative parameters (glucose, protein, bilirubin, 
urobilinogen, occult blood, ketone body) 
Urinary drug screen 
Phencyclidine, benzodiazepine, cocaine, psychostimulants, cannabis, morphine, 
barbiturates, tricyclic antidepressants 
Infection test (blood test) 
HBs 
antigen, 
HBs 
antibody, 
HBc 
antibody, 
HCV 
antibody, 
HIV 
antigen/antibody, HTLV-1 antibody 
Any indeterminate result should be confirmed by a local alternative test method. 
HBV-DNA (blood test) 
 
HBV-DNA will be measured if the subject is negative for HBs antigen and 
positive for HBc antibody and/or HBs antibody at screening. Subjects enrolled 
with an HBV-DNA level below the limit of detection will undergo measurement 
of HBV-DNA according to the schedule specified in the protocol.  
TB test 
Chest X-ray (or chest CT scan) and/or a test according to the local guideline (e.g., 
QuantiFERON, T-Spot, PPD test) will be conducted at screening. TB risk 
assessment questionnaire provided in Appendix 8 may be conducted at Weeks 16, 
36, and 56, and at early termination. 
Pregnancy test (blood or 
urinary test) 
Information such as the presence or absence of menstruation, menstrual cycle, 
and surgical history will be obtained through interview. WOCBP (excluding 
women who have undergone permanent contraception, post-menopausal women 
[defined as the absence of menstruation for at least 12 months without any other 
medical reason], or women who anatomically have no childbearing potential) will 
undergo pregnancy test. The reason for not undergoing pregnancy test should be 
described in source documents, if applicable. 
Urinary hCG (serum hCG at screening) 
7.8.2 
Physical Examination 
The Investigator will observe subjects for any changes in symptoms or finding and for any 
new symptoms or findings after the start of IP administration according to the schedule 
provided in Section 7.1. At each visit, the Investigator will observe subjects for skin disorders 
(including late responses) such as erythema, redness, pain, and swelling at the sites of 
injection. 
Complete physical examinations include general appearance, examination of the HEENT 
(head, eyes, ears, nose, and throat) and body systems (including, but not limited to, 
cardiovascular, respiratory, abdominal, musculoskeletal, extremities, lymph nodes, and skin) 
at screening, baseline, Weeks 18 and 36. 


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Brief physical examinations only include the HEENT, cardiovascular, respiratory, abdominal, 
and skin examinations at Weeks 1, 2, 4, 6, 8, 10, 12, 14, 15, 16, 20, 22, 24, 26, 28, 30, 32, 34, 
40, 44, 48, 52, and 56 and at early termination. 
If there are any unfavorable or unintended signs or symptoms, they will be reported as AEs. 
7.8.3 
Height and Weight 
Body weight will be measured at screening, baseline, Weeks 2, 8, 18, 36, 44, and 56, and 
early termination. Body weight should be measured before IP injection if the administration 
of IP is scheduled at the same time. Height will be measured only at screening. 
7.8.4 
Vital Signs 
Vital signs include systolic and diastolic blood pressure, pulse, respiration rate, and body 
temperature and should be measured in the supine or semi-supine position after at least 5-
minute rest. Vital signs will be measured at all study visits for screening and during the 
treatment period and the follow-up period. Vital signs should be measured before IP injection 
if the administration of IP is scheduled at the same time. In addition, on Day 1 and at 
Weeks 2, 18, and 20, vital signs should be measured 2 hours (±10 minutes) after IP 
administration. 
Additional vital sign measurements will be performed at the discretion of the Investigator if 
any clinically significant signs or symptoms occur. Refer to Section 6.2.3 for detail on 
measures to be taken for acute reactions.  
Time points: screening, baseline, Week 0 (Day 1) to 56, early termination 
Note: If baseline visit and Day 1 are same day, one measurement can be allowed for baseline assessment 
and Day 1 assessment before IP administration. 
7.8.5 
Standard 12-Lead Electrocardiogram 
Standard 12-lead ECG parameters include heart rate, PR interval, QRS interval, QT interval, 
and QTc interval (QTcB, QTcF), which will be recorded after the subject has rested in a 
supine position for at least 5 minutes, but before blood collection for drug concentration 
measurement.  


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The Investigator will check for any clinically abnormal findings and if any, determine 
whether the abnormality is clinically significant or not (Interpretation: normal or abnormal, 
not clinically significant/abnormal, clinically significant).  The interpretation will be recorded 
on the eCRF. 
Time points: screening, baseline, Weeks 2, 8, 16, 24, 32, 40, 48, and 56, early termination 
7.9 
Adverse Events 
7.9.1 
Definitions 
An AE is defined as any untoward medical occurrence in a clinical study subject and does not 
necessarily have a causal relationship with the study treatment. An AE can therefore be any 
unfavorable and/or unintended sign (e.g., an abnormal laboratory finding), symptom or 
disease whether or not considered related to the product. 
An AE includes but is not limited to: 
• 
Any clinically significant* worsening of a pre-existing condition;  
• 
A clinically significant* new/worsened laboratory abnormality; 
• 
Any clinically important changes noted during interim or final physical examinations, 
12-lead ECGs, X-rays, or any other potential safety assessments, whether or not these 
procedures are required by the protocol; 
• 
An AE occurring from overdose (i.e., a dose higher than that prescribed by a 
healthcare professional for clinical reasons, or a dose higher than that described on the 
marketed product label) of an investigational or marketed product, whether accidental 
or intentional; 
• 
An AE occurring from abuse (e.g., use for non-clinical reasons) of an investigational 
or marketed product. 
*Clinically significant may include, but is not limited to, abnormalities that meet the 
definition of “serious” (see Section 7.9.5), or an event that leads to an intervention such as 
premature discontinuation of IP or the addition of concomitant/corrective therapy. 
The collection of AE and SAE information commences following the subject’s written 
consent to participate in the study. The Investigator will inquire about AEs at all subject visits 
by asking the subject a non-leading question such as: “How have you been feeling since your 
last visit?” All AEs, whether observed by the Investigator or reported by the subject, must be 
collected. If a subject experiences an AE or SAE, the subject will receive appropriate 
treatment and supportive care as necessary, and the Investigator will continue to follow up 


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until there is a return to the subject’s baseline condition, or until a clinically satisfactory 
resolution is achieved. 
In addition to the Investigator’s own description of the AEs, each AE will be coded by the 
Sponsor according to the Medical Dictionary for Regulatory Activities (MedDRA). 
7.9.2 
Actions for Subjects 
If an AE occurs, the Investigator will take appropriate actions as needed, such as providing a 
proper medical intervention or withdrawal from the study, to ensure the safety of the subject. 
If it is necessary to identify the treatment (drug) received by the subject, the emergency key 
code for the subject will be opened according to the procedure provided in Section 3.4.2.4. 
7.9.3 
Urgent Safety Measures 
In accordance with the principles of ICH E6-GCP, the Investigator(s) has/have primary 
responsibility for assuring subject safety throughout the performance of study procedures. An 
urgent safety measure is defined as any measure which an Investigator may need to 
implement, which is a deviation from, or a change in, the protocol to eliminate an immediate 
hazard(s) to study subjects without prior IEC/IRB approval/favorable opinion. 
The Investigator may take appropriate urgent safety measures in order to protect the subjects 
of the clinical study against any immediate hazards to their health or safety. However, the 
Investigator must inform the Sponsor within 24 hours of having taken such measures, 
and the AE resulting in the Urgent Safety Measure must also be reported within 24 hours, 
following the SAE reporting instruction in Section 7.9.5.1. 
7.9.4 
Reporting of Adverse Events 
The following information will be recorded on the eCRF from the subject’s written consent to 
participate in the study through the end of the study. However, information on AEs leading to 
discontinue of IP administration will be collected in accordance with Section 4.4.1. The 
Sponsor retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
 


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1) Reported AE term: Events of injection reaction or injection site reaction with study 
treatment will be entered for ‘Yes: Was this an injection reaction/ this an injection site 
reaction associated with Study Treatment?’ in addition to AE term. 
2) Start date/time of AE: The date and time of onset will be entered for injection reactions or 
injection site reactions. Only the date of onset will be entered for other AEs. 
3) Severity, as indicated in Section 7.9.4.1; 
4) Serious event 
• 
Serious (Y): AEs defined in Section 7.9.5. 
• 
Non-serious (N): AEs other than those defined in Section 7.9.5. 
5) Action taken with study treatment 
• 
Dose not changed 
• 
Drug interrupted 
• 
Drug withdrawn 
• 
Not applicable 
6) Other action taken 
• 
None 
• 
Other drug taken 
• 
Other therapy received 
• 
Other 
7) Outcome of AE 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered/resolved with sequelae 
• 
Fatal 
• 
Unknown 
8) End date/time of AE: The date and time of outcome identification will be entered for 
injection reactions or injection site reactions. Only the date of outcome identification will 
be entered for other AEs. 
9) Relationship to study treatment: Causal relationships to the IP will be classified into 
3 categories, as indicated in Section 7.9.4.2. 
• 
Related 
• 
Not related 


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• 
Unknown 
7.9.4.1 
Assessment of Intensity 
All AEs will be classified either as Grade 1 to 5 in intensity as defined below:  
• 
Grade 1 (Mild) − Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• 
Grade 2 (Moderate) − Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL) (e.g., preparing meals, 
shopping for groceries or clothes, using the telephone, managing money). 
• 
Grade 3 − Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL (bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden). 
• 
Grade 4 − Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 − Death related to an AE (fatal). 
The Investigator will be instructed to closely monitor each subject who experiences an AE 
(whether ascribed to the IP or not) until the outcome of the AE has been determined. The AE 
must be monitored until the return to the subject’s baseline condition or until clinically 
satisfactory resolution is achieved (e.g., Grade 1 or stable). 
7.9.4.2 
Assessment of Relationship to Study Treatment 
The causal relationship to study treatment should be assessed as one of the following: 
• 
Related − There is a reasonable causal relationship between the IP administration and 
the AE. The term “reasonable causal relationship” means there is evidence to suggest a 
causal relationship. 
• 
Not related − There is not a reasonable causal relationship between the IP administration 
and the AE. 
• 
Unknown − The causal relationship cannot be determined. 
7.9.5 
Definition of Serious Adverse Events 
An SAE is an event defined as below. 
• 
Death 
• 
Life-threatening − The term “life-threatening” as part of the definition of “serious” 
refers to an event in which the subject was at risk of immediate death at the time of the 


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event; it does not refer to an event that hypothetically might have caused death if it were 
more severe; 
• 
Hospitalization or prolongation of existing hospitalization − Hospitalizations for 
procedures planned prior to study entry are not considered SAEs; 
• 
Persistent or significant disability 
• 
Congenital anomaly or birth defect 
• 
Other medically important are those that may not result in death, be life threatening, or 
require hospitalization, but may be considered an SAE when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical intervention 
to prevent one of the outcomes listed above. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
or blood dyscrasias that does not result in in-patient hospitalization, or the development 
of drug dependency or drug abuse. 
All AEs, whether non-serious or serious, must be recorded on the AE page of the eCRF. In 
addition, any AE that is initially considered serious or becomes serious must be reported on 
the SAE form. The SAE information entered on the eCRF must be consistent with the 
information entered on the SAE form. 
7.9.5.1 
Reporting of Serious Adverse Events 
SAEs require expeditious handling to comply with regulatory requirements. Any SAE 
occurring in a clinical study and follow-up must be reported to the Sponsor or designee 
within 24 hours of the Investigator having knowledge of the SAE.  
The Investigator or other qualified individual at the investigative site must complete the SAE 
form, sign it, and fax or e-mail it to the Sponsor or designee. If the Investigator is unable to 
sign the form that is initially submitted within 24 hours, the form must be resubmitted with 
signature within 72 hours. All telephone communication regarding an SAE must be followed 
by a written report. 


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Serious Adverse Event Contacts 
Countries other than Japan 
FAX:  +1-800 209-2251 
e-mail:  KKD.SAESOURCE@kyowakirin.com 
Japan 
e-mail:  4083-006.sae.t5@kyowakirin.com 
or 
BELLSYSTEM24, Inc. 
TEL:  0120-49-2934    FAX:  0120-49-2935 
Hours:  24 hours a day, every day of the year 
The Investigator will ensure that information reported immediately by telephone or other 
means and information entered on the SAE report form are accurate and consistent. For all 
SAEs, the Investigator is obligated to pursue and provide information as requested by the 
Sponsor in addition to that requested on the SAE report form. Information must include a 
description of the AE in sufficient detail to allow for a complete, independent medical 
assessment of the case and independent determination of causality. Supporting 
documentation such as hospital discharge summaries or pertinent laboratory reports should 
also be sent to the Sponsor. In the case of a subject death, a summary of available autopsy 
findings must be submitted as soon as possible to the Sponsor. 
Within 7 days of being aware of the SAE, the Principal Investigator will submit a detailed 
written report using the SAE report form (Detailed Report) to the Sponsor. For Japan sites 
only, the SAE report form must also be submitted to the director of the investigative site. 
Serious, unexpected drug-related AEs should be identified when reporting to the director of 
the investigative site. 
7.9.5.2 
Notification of Serious Adverse Events to Institutional Review Board 
or Ethics Committee 
The Investigator must comply with the applicable regulatory requirements related to the 
reporting of SAEs and the Sponsor’s safety information to the IRB/IEC as per standard 
operating procedures.  
The Investigator will provide additional information upon request from the Sponsor, 
IRB/IEC, and where applicable, the director of the investigative site in Japan. 


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The investigative site will consult with the IRB/IEC and Sponsor whether to continue the 
subject in the study. For Japan only, the director of the investigative site will consult with the 
IRB/IEC whether to continue the study at the site. 
7.9.6 
Definition of Treatment-Emergent Adverse Events 
A treatment-emergent adverse event (TEAE) is herein defined as any untoward medical 
occurrence in a subject who received an IP (KHK4083 or placebo). A TEAE can therefore be 
any unfavorable or unintended signs (including any abnormal laboratory findings), symptoms, 
or disease that occurred after treatment with the IP, whether or not considered related to the 
IP.  
A TEAE of which causal relationship to IP is assessed as “related” or “unknown” is defined 
as a drug-related TEAE.  
Results of laboratory tests will be checked against the normal range for any deviations 
(abnormal test results) and any abnormal test results will be compared with those obtained 
prior to treatment with the IP to determine whether such a change is clinically significant 
(abnormal change).  
Any abnormal changes in signs, symptoms, and laboratory data associated with a disease 
(diagnosis) are regarded as an AE whose name is consistent with the diagnosis. If an injection 
reaction occurs, the presenting signs or symptoms of the reaction will be regarded as TEAEs 
(Section 7.9.8.1). Any individual atypical or extremely severe signs or symptoms of the 
disease will be regarded as independent AEs, separately from the diagnosis. 
7.9.7 
Definition of Other Significant Treatment-Emergent Adverse Events 
Other significant TEAEs are defined as any non-serious TEAEs that lead to interruption or 
discontinuation of IP. 
7.9.8 
Other Significant Treatment-Emergent Adverse Events Requiring 
Special Handling 
7.9.8.1 
Reporting of Injection-related Reactions  
The signs and symptoms of an injection reaction usually develop shortly after drug injection 
and generally resolved completely within 24 hours of completion of the injection. The 


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presenting sign or symptom should be reported as TEAE term(s). Acute injection 
reactions should not be classified as anaphylaxis unless symptomatic bronchospasm and/or 
allergy-related edema/angioedema is/are the principal clinical manifestation(s). Refer to 
Appendix 7 for the clinical criteria for diagnosis of anaphylaxis. 
The time of onset of the injection reaction or injection site reaction and the time of outcome 
identification should be entered into the eCRF. 
7.9.8.2 
Overdose 
Overdoses should be reported, whether or not the overdose was associated with an AE/SAE, 
using an SAE form within 24 hours of the Investigator having knowledge of the error. Follow 
the SAE reporting instructions in Section 7.9.5.1. 
7.9.8.3 
Pregnancy Reporting 
Pregnancy in a female subject or partner of a male subject must be avoided. 
When a female study subject reports a pregnancy: The subject must be advised by the 
Investigator immediately if she suspects she may be pregnant. The Investigator is obligated to 
immediately report to the Sponsor or designee any pregnancy occurring at any time after the 
subject signs the Informed Consent Form (ICF) and within 6 months after the last dose of IP. 
When a male study subject reports a pregnancy of a female partner: The subject must be 
advised by the Investigator immediately if he suspects his partner became pregnant after the 
subject received IP. The Investigator is obligated to immediately report to the Sponsor or 
designee any pregnancy occurring at any time after the start of IP administration and within 
6 months after the last dose of IP. 
When a female study subject reports a pregnancy (or a male study subject reports a 
pregnancy of a female partner), IP administration should be stopped immediately for the 
female subject and a pregnancy test should be arranged for the female subject/female partner 
by the Investigator within seven (7) days of the pregnancy being reported. In the case of 
pregnancy, the Investigator must immediately notify the Sponsor of this event and report the 
pregnancy on the Pregnancy Surveillance Form. This includes a study subject as well as the 
partner of a study subject who becomes pregnant while the subject was receiving IP. If a 
partner of a male subject becomes pregnant, voluntary written informed consent (a separate 
ICF will be provided) should be obtained from the partner before conducting necessary 


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follow-up. Every attempt will be made to follow the pregnancy to conclusion to obtain 
information regarding the outcome. 
7.9.9 
Other Handling 
Safety data will be summarized and reported as required by regulatory authorities. 
8 
DATA MANAGEMENT 
8.1 
Source Documents (Source Data) 
Subjects’ data are obtained from source documents, where data are first recorded. These 
include, but are not limited to, hospital records (from which medical history and previous and 
concurrent medication may be summarized into the eCRF), clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, radiographs, and correspondence. 
All documents will be stored safely in confidential conditions. On all trial-specific documents, 
other than the signed consent, the subject will be referred to by the subject ID, not by name. 
8.2 
Access to Data 
By signing this protocol, the Principal Investigator agrees to treat all subject data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations, including all applicable provisions of the Personal Information Protection 
Law, the Health Insurance Portability and Accountability Act (HIPAA), the General Data 
Protection Regulation (GDPR), and their implementing regulations. During the Sponsor’s 
monitoring and auditing, the IRB/IEC’s review, and inspections by domestic and foreign 
regulatory authorities, the Investigator and the investigative site should allow them direct 
access to (and copying of, if required) all study-related records including source documents. 
8.3 
Electronic Case Report Forms (eCRFs) 
An electronic data capture (EDC) system will be used for collecting data in this study. The 
EDC system allows each investigative site to enter data in the eCRF, check the input data, 
and respond to the Sponsor’s inquiries on the input data, as well as to append electronic 
signatures. The entered data will be encrypted and transferred to the EDC server via the 
Internet. This EDC system is designed to meet requirements and guidelines of regulatory 


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agencies (Food and Drug Administration [FDA], Code of Federal Regulations [CFR], Title 
21, ICH GCP, European Medicines Agency [EMA] and Ministry of Health, Labour and 
Welfare [MHLW]). 
The Principal Investigator will fill out an eCRF for each subject and, after ascertaining that 
all data are accurate and complete, append his/her electronic signature through the EDC 
system. If an eCRF is filled out by a sub-Investigator or clinical research coordinator, the 
Principal Investigator will check the accuracy and completeness of data prior to appending 
his/her electronic signature. The Guide for Changes or Corrections to an Electronic Case 
Report Form, which will be supplied by the Sponsor, must be followed to fill out the eCRF. 
In this study, the subject data stored in the EDC server will be regarded as the original eCRF. 
In this regard, however, once the eCRF data are relocated to a non-rewritable medium (e.g., 
DVD), or to the electronic document control system, the data in such medium/system will be 
handled as the original. Data should be migrated to the electronic document control system 
according to prespecified written procedures. 
The Sponsor will provide a copy of eCRFs and change or correction histories to each 
investigative site. 
By signing this protocol, the Principal Investigator agrees to treat all subject data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules, 
and regulations. In addition for the investigative sites in the United States, compliance is 
required with all applicable provisions of the HIPAA and its implementing regulations. 
The Principal Investigator, sub-Investigator, or clinical research coordinator will change or 
correct entries in the eCRF according to the Guide for Changes or Corrections to an 
Electronic Case Report Form provided by the Sponsor. The change or correction history to 
the eCRF is automatically recorded on the EDC system. 
8.4 
Data Collection Using eCOA System 
An eCOA system will be used to collect data on EASI, IGA, BSA, SCORAD, pruritus NRS, 
sleep disturbance NRS, DLQI, and record of emollient use in this study. Since data collected 
by eCOA system will be regard as source data, paper instruments will not be used and will 
not be available as source documents. 
The eCOA system consists of an eCOA device and an eCOA server. 


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The eCOA device, which will be used by subjects and Investigator, provides functions such 
as entering data, checking entered data, and obtaining audit trails on entered data. Data that 
are entered are transferred to and saved on the eCOA server. In addition, the investigative 
sites and the Sponsor are allowed to access data through the eCOA system on the eCOA 
server. 
The eCOA device will be provided to each investigative site. The Investigator will complete 
EASI, IGA, BSA and SCORAD (A and B) data on the eCOA device at each visit. Subjects 
will complete pruritus NRS, sleep disturbance NRS, SCORAD (C), and DLQI data and 
record emollient use on the eCOA device at each visit. Written procedures provided by the 
Sponsor will be followed for data entry into the eCOA system. Data cannot be changed or 
corrected by subjects once they are saved on the eCOA device or the eCOA server. 
If any change or correction is required for data saved on the eCOA server, the Principal 
Investigator, sub-Investigator, or clinical research coordinator will change or correct the 
relevant data according to written procedures provided by the Sponsor. Histories of changes 
or corrections on the eCOA system will be obtained by the system. 
If the eCOA is filled out by a sub-Investigator, the Principal Investigator have to check the 
accuracy and completeness. 
Since the eCOA system uses the device, data (including audit trails) saved on the eCOA 
device will be regarded as source data from data entry into the device until data transfer to the 
eCOA system, and data on the eCOA server will be regarded as source data after data transfer 
to the eCOA system. If data (including audit trails) on the eCOA server are migrated to a 
non-rewritable medium (e.g., CD-R, DVD-R), data on the medium will be regarded as source 
data and provided to the investigative site. The Sponsor will retain a copy of the source data. 
8.4.1 
Other Instructions Related to Creation of eCOA 
The following data obtained until Week 16 from subjects who have completed the Week 16 
assessment should be immediately entered into the eCOA. The data entered must be reviewed 
by the Sponsor and the CRO by the day before Week 18. 
• 
EASI score 
• 
SCORAD score 
• 
IGA score 
• 
BSA 


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• 
Pruritus NRS 
• 
Sleep disturbance NRS 
• 
DLQI score 
8.5 
Record Keeping and Archiving  
The investigative site and the Sponsor will retain the clinical trial master file and medical 
files of subjects for at least 25 years after the end of the study. If the investigative site's 
situation is such that retaining can no longer be ensured, the investigative site must inform the 
Sponsor and the relevant records will be transferred to mutually agreed-upon destination. 
8.6 
Study Monitoring  
The monitor will check and ensure that the study has been conducted in compliance with the 
ICH E6-GCP, the protocol, applicable local regulations, and written procedures for this study 
and that the entries of eCRF coincide with the source data. Detailed procedures will be given 
in a monitoring plan document or alternative written procedures. 
9 
STATISTICAL ANALYSIS  
9.1 
Statistical Methods 
Subjects will be summarized according to randomized treatment group.  Subjects in the 
placebo group will be summarized as a treatment group of 'Placebo in Treatment A period 
and 600 mg Q2W in Treatment B period' and never combined with 600 mg Q2W group. 
Unless otherwise specified, categorical data will be summarized with frequency and 
percentage. Continuous variables will be summarized with descriptive statistics including 
number of subjects, mean, standard deviation, minimum, median, and maximum. In addition 
to these descriptive statistics for PK parameters, coefficient of variation and geometric mean 
will also be calculated.  


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9.1.1 
Primary Efficacy Analysis 
Percent Change from Baseline to Week 16 in EASI Score 
The primary analysis will be performed in the percent change from baseline to Week 16 in 
EASI score, by applying ANCOVA with treatment, EASI score at baseline, and the following 
stratification factors: 
• 
Severity of AD (IGA = 3, IGA = 4) at baseline 
• 
Region (Japan, rest of world) 
• 
Previous use of biological products (Yes, No) for the treatment of AD at baseline 
The percent change from baseline is defined as below, 
Percent change from baseline (%) = 100 × (Post-dosing value − Value at baseline) / Value 
at baseline. 
The adjusted mean (least squares [LS] mean) and the corresponding 95% confidence interval 
will be calculated from the ANCOVA model for each treatment group. A two-sided t-test 
with a significance level of 5% will be performed on the difference of LS mean between each 
KHK4083 group and the placebo group. A closed test procedure will be used to maintain 
overall type I error rate. The test will be performed in sequence, starting with 600 mg Q2W 
vs. placebo and continue in the order of 300 mg Q2W vs. placebo, 600 mg Q4W vs. placebo, 
and 150 mg Q4W vs. placebo, from the highest dose to lowest dose until statistical 
significance at 5% is not achieved. 
9.1.2 
Secondary Efficacy Analyses 
9.1.2.1 
Efficacy Endpoints at Week 16 
Continuous endpoints will be analyzed by ANCOVA model with treatment, the relevant 
baseline value and the stratification factors. The LS mean and the corresponding 95% 
confidence interval will be calculated from the ANCOVA model for each treatment group. 
The difference between the placebo group and each KHK4083 group and the corresponding 
95% confidence intervals will also be calculated.  
Categorical endpoints will be summarized by treatment group by number and percentage of 
subjects achieving the endpoint and their exact 95% confidence intervals. The difference 


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between the placebo group and each KHK4083 group and the corresponding 95% confidence 
intervals will also be calculated. The following secondary endpoints will be analyzed: 
• 
Achievement of 50%, 75%, or 90% reduction from baseline in EASI score (EASI-50, 
EASI-75, or EASI-90) at Week 16 
• 
Change from baseline to Week 16 in EASI score 
• 
Change and percent change from baseline to Week 16 in SCORAD score 
• 
Achievement of an IGA score of 0 or 1 and a reduction from baseline of ≥2 points at 
Week 16 
• 
Change from baseline to Week 16 in percent BSA 
• 
Change and percent change from baseline to Week 16 in pruritus NRS score 
• 
Change and percent change from baseline to Week 16 in sleep disturbance NRS score 
• 
Change from baseline to Week 16 in DLQI 
9.1.2.2 
Efficacy Endpoints at Each Time Point 
The following endpoints will be analyzed at each time point (scheduled visit until Week 56) 
by treatment group: 
• 
Percent change from baseline in EASI score at each time point 
• 
Achievement of EASI-50, EASI-75, or EASI-90 at each time point 
• 
Change and percent change from baseline in SCORAD score at each time point 
• 
Achievement of an IGA score of 0 or 1 and a reduction from baseline of ≥2 points at 
each time point 
• 
Change from baseline in percent BSA at each time point 
• 
Change and percent change from baseline in pruritus NRS score at each time point 
• 
Change and percent change from baseline sleep disturbance NRS score at each time 
point 
• 
Change from baseline in DLQI at each time point 
9.1.3 
Safety Analyses 
TEAEs will be summarized for Treatment A period and the whole study period. For the 
placebo group, TEAEs that occur after the start of administration of KHK4083 will be 
presented along with TEAEs that occur after the start of administration of IP in the whole 
study period. 
As for safety assessments other than TEAEs, they will be presented for each treatment group.  


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9.1.3.1 
Adverse Events 
All TEAEs will be summarized for each treatment group. The incidence of TEAEs will be 
summarized by frequency and percentage using MedDRA, by SOC and Preferred Term (PT). 
Multiple occurrences of TEAEs of the same term and classification in the same subject will 
be counted only once. The latest version of MedDRA at the time of database lock will be 
used for coding TEAEs. 
9.1.3.2 
Laboratory Values 
Laboratory test values will be listed. Descriptive statistics of continuous variables at each 
time point (scheduled visit until Week 56) will be presented by treatment group. Categorical 
variables before and after administration will be presented in a shift table. 
9.1.3.3 
Vital Signs 
Vital sign data will be listed. Descriptive statistics of continuous variables at each time point 
(scheduled visit until Week 56) will be presented by treatment group. 
9.1.3.4 
Standard 12-lead Electrocardiogram 
Standard 12-lead ECG data will be listed. 
9.1.4 
Exploratory Analyses 
9.1.4.1 
Pharmacokinetics 
The following analyses will be conducted in the PK analysis set. 
9.1.4.1.1 Serum KHK4083 Concentration 
The descriptive statistics of serum KHK4083 concentrations at each blood sampling point 
will be presented by treatment group. Plots of serum KHK4083 concentration-time profiles 
will be prepared.  
9.1.4.1.2 Pharmacokinetics Parameters Calculated from Serum KHK4083 
Concentrations 
PK parameters (e.g., Cmax, Ctrough) will be calculated from serum KHK4083 concentrations for 
4 treatment groups (KHK4083 150 mg Q4W, 300 mg Q2W, 600 mg Q2W, or 600 mg Q4W) 


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and will be presented by treatment group. For the Q2W treatment groups (KHK4083 300 mg 
Q2W and 600 mg Q2W), the Cmax will be calculated only after administration of KHK4083 
on Week 1 and Week 14. Following a single SC administration of KHK4083, the mean tmax 
was approximately 1 week (5.2 day, 7.0 day: minimum, maximum) in Study 4083-001 and 
Study 4083-003 (preliminary unaudited data), thus the Cmax for Week 1 and Week 14 
administrations will be defined as observed KHK4083 concentration at Week 1 (Day 8) and 
Week 15 (Day 106) within the acceptable ranges (±3 days), respectively. The Ctrough will be 
defined as the observed KHK4083 concentrations at Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 
22, 24, 26, 28, 32, and 36. Accumulation ratio based on Cmax and Ctrough will be calculated 
using each PK parameters in Week 1 and Week 14 administrations. For the Q4W  treatment 
groups (KHK4083 150 mg Q4W and 600 mg Q4W), the Cmax for Week 1 and Week 14 
administrations will be defined as observed maximum KHK4083 concentration after 
administration. The Ctrough will be defined as the observed KHK4083 concentrations at Weeks 
4, 8, 12, 16, 20, 24, 28, 32, and 36. 
9.1.4.1.3 Anti-KHK4083 Antibody 
All anti-KHK4083 antibody test values will be listed for each subject. 
9.1.4.2 
Pharmacodynamics 
Pharmacodynamic analysis will be conducted using safety analysis set. 
9.1.4.2.1 Serum Disease Markers 
Changes in TARC and serum total IgE over time will be presented in a graph. The descriptive 
statistics of TARC and serum total IgE at each blood sampling point will be presented by 
treatment group. 
9.1.4.3 
Other Testing 
9.1.4.3.1 Serum IL-22 
Changes in serum IL-22 over time will be presented in a graph. The descriptive statistics of 
serum IL-22 at each blood sampling point will be presented by treatment group. 


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9.2 
Target Number of Subjects 
A total of approximately 250 subjects will be randomly assigned in a 1:1:1:1:1 ratio to 
4 active treatment groups (50 subjects in each group) or one placebo group (50 subjects) in 
Treatment A period. 
9.2.1 
Rationale for Target Number of Subjects 
Given that the mean percent change in EASI score at Week 16 is −60% in the KHK4083 dose 
group and −35% in the placebo group and the common standard deviation is 40%, the 
number of subjects required to obtain a statistically significant difference with a significance 
level of 5% (two-sided) and a power of over 80% is calculated to be 42 per group. Taking 
into account the possibility of fluctuation of allocation to each treatment group and subjects 
who excluded from the primary analysis set, the target number of subjects is determined to be 
50 per group as randomized (250 in total). 
The mean percent changes in EASI score at Week 16 in the KHK4083 group and the placebo 
group were assumed on the basis of the following study results: 
• 
Mean percent change in EASI score 
KHK4083 group: The mean percent change was assumed to be −60% as the mean 
percent change in EASI score at Week 18 in a Phase 1, open-label, multiple-dose study 
in subjects with AD (Study 4083-004) was −62.1% (last observation carrier forward 
[LOCF]) (as of 07 Feb 2018). 
Placebo group: The mean percent change was assumed to be −35% since the LS mean 
of the percent change in EASI score at Week 16 in a Phase 2b clinical study (Study 
R668-AD-1021) and Phase 3 clinical studies (SOLO1 and SOLO2) of Dupixent® 
(dupilumab), which has been approved for the treatment of AD in the United States, 
Europe, and Japan, was −18.1%, −37.6%, and −30.9%, respectively. 
• 
Common standard deviation 
The common standard deviation was conservatively determined to be 40% on the basis 
of the maximum standard deviation of the percent change in EASI score among those at 
each time point in Study 4083-004 and the standard deviation of it for placebo in a Phase 
2b clinical study (Study R668-AD-1021) of Dupixent® (dupilumab). 


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9.3 
Significance Level 
The significance level for the primary efficacy endpoint will be 5% (two-sided). The 
statistical test for the primary efficacy endpoint will be conducted only at the first interim 
analysis as the final result. A closed test procedure will be used to maintain overall type I 
error rate. 
9.4 
Early Termination Criteria 
No criteria for early termination of the study based on statistical evidence will be specified. 
9.5 
Handling of Missing, Unused, and Abnormal Data 
Any efficacy data obtained after prohibited concomitant medications and therapies will be 
deemed as missing.  
Any missing data of the primary endpoint and other continuous endpoints at Week 16 will be 
imputed by the LOCF method. For dropout subjects (including subjects who receive rescue 
treatment), data at the last assessment point will be defined as data obtained prior to dropout 
or receiving rescue treatment, while Week 16 data will be used for all other subjects. Subjects 
with any missing data of categorical endpoints at Week 16 will be counted as non-responder. 
Sensitivity analysis such as complete case analysis and multiple imputation will be performed 
to assess the robustness of primary endpoint analysis results. 
If it is necessary to discuss how to handle data of a particular subject because of an event 
unexpected at study initiation, handling of such data to be used in the interim analysis 
(Section 9.8) should be decided before database is frozen (The "Freeze" status in EDC will be 
used) and the other data handling should be decided before database lock. 
9.6 
Development of Statistical Analysis Plan and Procedure for Reporting 
Deviations from the Original Statistical Analysis Plan 
Details of the final analysis plan should be established in a statistical analysis plan that will 
be finalized before the database is frozen for the primary analysis. Major changes to the 
analysis plan will be described in the clinical study report. 


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9.7 
Selection of Subjects to be Included in Analyses 
The following populations are defined as analysis sets. Subjects included in the full analysis 
set (FAS) should be determined before the primary analysis and those include in other 
analysis sets should be determined before database lock. 
9.7.1 
Full Analysis Set (FAS) 
The primary analysis set for the efficacy endpoints will be the FAS. The FAS is defined as a 
population of randomized subjects excluding those who meet either of the following 
conditions: 
• 
Subjects who are not exposed to IP 
• 
Subjects without any evaluable EASI score after the start of IP administration until 
Week 16 
9.7.2 
Per Protocol Set (PPS) 
The per protocol set (PPS) will consist of all the FAS subjects excluding those who meet 
either of the following conditions. This analysis set has been selected to confirm the 
robustness of the result in the primary analysis. 
• 
Subjects who failed to meet any major eligibility criteria 
• 
Subjects with a major deviation from the protocol that may affect the primary 
endpoint 
9.7.3 
Safety Analysis Set 
The safety analysis set is defined as a population of randomized subjects excluding those who 
meet the following condition. Analysis will be conducted according to the randomized 
treatment received by subjects. 
• 
Subjects who are not exposed to IP 
9.7.4 
Pharmacokinetic Analysis Set 
The PK analysis set is defined as a population of subjects excluding those who meet either of 
the following conditions: 
• 
Subjects who are not exposed to KHK4083 


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• 
Subjects who do not undergo PK blood sampling at all after the administration of 
KHK4083 
9.8 
Interim Analysis 
Interim analyses will be conducted at two time points: when all subjects (excluding early 
withdrawn subjects) have reached Week 16 and Week 36. All data for the interim analysis 1 
should be frozen (The “Freeze” status in EDC will be used). However, only frozen efficacy 
data and SDVed safety data will be included in the interim analysis 2 (The “Verified” status 
in EDC will be used). The primary analysis will be performed in the FAS. The purpose of 
each interim analysis is as described below.  
• 
Interim analysis 1, Week 16: To confirm a clinically significant difference in 
efficacy between KHK4083 and placebo and to obtain preliminary information for 
planning a future study. 
• 
Interim analysis 2, Week 36: To obtain preliminary safety and efficacy information 
of KHK4083 for planning a future study. 
The interim analysis 1 will be conducted for efficacy endpoints with the FAS after the 
database is frozen. The interim analysis 2 will be conducted for efficacy and safety (also 
including study withdrawal, demography). The cutoff date will be the date when the data is 
provided for the analysis after all subjects (excluding early withdrawn subjects) have reached 
Week 36 visit. However, only efficacy data that have been frozen as of the cutoff date and 
safety data that have been SDVed as of the cutoff date will be included in the interim analysis 
2. The efficacy and safety analyses of the interim analysis 2 will be conducted with the FAS 
and the safety analysis set, respectively. These analyses will be performed for only pre-
specified efficacy and safety analyses by a separate group which is different from the group 
for final analysis to maintain the blind at the subject level until final database lock. This 
group will share with the Sponsor only the summarized results (tables or figures) but not 
individual data listings. Further details of the interim analyses will be described in the 
statistical analysis plan that will be finalized before the database is frozen for the primary 
analysis conducted at the interim analysis 1. In addition, these interim analyses will be 
conducted for pre-specified exploratory endpoints, serum IL-22, and exploratory biomarkers 
with existing data at the time of interim analysis. 


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10 
ETHICAL AND REGULATORY CONSIDERATIONS  
10.1 Compliance with GCP, the Protocol, and Other Applicable Regulatory 
Requirements 
The Principal Investigator and sub-Investigator are responsible for conducting the study in 
full accordance with US FDA CFR21, Parts 50, 56, and 312, the October 2013 revision of the 
Declaration of Helsinki, the GCP Guideline, approved by the ICH, and any applicable 
national and local laws and regulations. The Principal Investigator and sub-Investigator will 
comply with the protocol on which the Principal Investigator and the Sponsor have agreed 
and which has been approved in writing by the IRB/IEC. 
If the IRB/IEC approves the collection, storage, and use of biological samples, a research 
protocol will be developed, and the research will be conducted in compliance with ethical 
principles based on the Declaration of Helsinki, any applicable laws and regulations in each 
country and related notifications, the protocol for this study, and the research protocol. 
10.2 Institutional Review 
Before starting this study, the protocol (authorized by the Sponsor) will be submitted to the 
regulatory/local health authorities (in accordance with local regulations) in the countries 
involved in the study and to the IRB/IEC for evaluation. The protocol will also be signed by 
the Principal Investigator before submission to the IRB/IEC. The study will not start before 
the IRB/IEC gives written approval or a favorable opinion in accordance with ICH E6-GCP 
and all applicable regulatory/local health authorities give approval or a favorable opinion as 
required. 
When the Sponsor amends the protocol, the Sponsor will fully inform each Investigator using 
the amended version of the protocol or a written description of the amendment to obtain 
his/her agreement. The Principal Investigator will conduct the study according to the 
amended protocol after receiving the written approval of the IRB/IEC based on its prior 
review. Protocol amendments should be submitted to the IRB/IEC without delay. Any 
significant deviation from the protocol when no approved amendment exists will be regarded 
as a protocol violation, and will be addressed as such during the reporting of the study. 
However, this does not apply to amendments that only involve administrative issues (e.g., 
changes in affiliation, job title, address, or telephone number). 


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At least once a year or upon request, the site must submit a brief summary of the study 
progress to the IRB/IEC in accordance with local regulations. 
10.3 Deviations from or Changes to the Protocol 
The Investigator must not deviate from or change the protocol without obtaining the 
Sponsor’s prior written agreement and the IRB/IEC’s written approval based on its prior 
review. In the event of a deviation from or change to the protocol, the Investigator will make 
a record of all of the relevant actions regardless of the reason. 
For medical reasons such as the need to eliminate immediate hazards to the subjects, the 
Investigator may deviate from or change the protocol without the Sponsor’s prior written 
agreement or the IRB/IEC’s prior written approval. In such a case, a document describing the 
nature of and the reason for the deviation or change should be submitted to the Sponsor. The 
site will also submit the document to the IRB/IEC for its approval, and in addition, will 
obtain the written approval from the Sponsor. For Japan sites only, written approval must also 
be obtained from the director of the investigative site. 
10.4 Investigator’s Responsibilities 
10.4.1 
Selection of Subjects to be enrolled in the Study and Assurance of 
Their Safety 
In order to protect the human rights of all subjects, the Investigator must carefully examine 
the eligibility of each subject. For example, individuals who may be put at a disadvantage in 
case of refusal to participate (socially vulnerable people) should not be coerced into 
participating in the study. 
The Investigator will determine whether each subject is eligible for enrollment according to 
the inclusion and exclusion criteria to ensure that the study will not include any subjects 
whose safety cannot be secured. 
Throughout the study, the Investigator will keep track of the subject’s condition by ensuring 
emergency contact or any other method, and will collect and share information that may be 
relevant to the safety of IP. If a TEAE occurs, the Investigator will ensure the safety of the 
subject by taking such measures as providing appropriate treatment to the subject and 
discontinuing IP administration, if necessary. 


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10.4.2 
Protection of Subjects’ Personal Information and Privacy 
In filling out the eCRF, the Investigator will identify each subject with his/her subject ID to 
ensure that the subject’s personal information is protected. 
No individual who belongs to the Sponsor’s units involved in the study may disclose, without 
a valid reason, confidential information on a subject to which he/she has access in the 
performance of his or her duties. 
10.4.3 
Subject Informed Consent 
The Investigator will fully inform each subject before enrollment who is considered 
appropriate for the study about the description of the study based on Information for Subjects/ 
ICF as provided separately in a language understandable by the subject. The subject will be 
given sufficient time to decide whether or not to participate in the study, and the Investigator 
will obtain written consent (using the ICF provided separately) from the subject on a 
voluntary basis before the screening examinations.  
After the subject signs and dates the ICF, the Investigator who has conducted the informed 
consent discussion will also sign and date it.  
The Investigator will provide the subject with a copy of the signed ICF and the Information 
for Subjects. The Investigator will retain the original for the investigative site’s record in 
accordance with the policy of each site. 
Information for Subjects/ICF must contain the information specified by the local GCP 
guidelines and any applicable laws and regulations in the region. 
When any new information that may influence the subject’s willingness to continue 
participation in the study becomes available, the Investigator will promptly provide the 
subject with the updated information, confirm his/her willingness to continue the study, and 
document the details of the explanation given, the date of explanation, the name of person 
who confirmed the subject’s decision, and the content of the subject’s decision in medical 
records. 
If the Information for Subjects/ICF needs revising in terms of the explanation given to the 
subject, the Principal Investigator will promptly revise it and obtain the IRB/IEC’s approval. 
The Investigator will again give an explanation to the subject using the revised Information 


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for Subjects/ICF, and obtain written informed consent from the subject or his/her legally 
acceptable representative for further participation in the study in the same manner as in the 
case of the initial consent. 
10.5 Audit and Inspection 
The Sponsor or designee will verify, through monitoring and auditing, that the study, data 
generation, recording, and reporting are conducted in compliance with the protocol and ICH 
E6-GCP. According to ICH E6-GCP, the Sponsor or regulatory authorities may audit the 
investigative site. The Quality Assurance Unit of the Sponsor, independent of the Clinical 
Research and Development Department, is responsible for auditing the study. 
The Principal Investigator must accept that domestic and foreign regulatory authorities may 
conduct an inspection to verify compliance of the study with GCP. 
The management and quality assurance of data will be conducted according to the Sponsor’s 
standard operating procedures for clinical studies and auditing. 
10.5.1 
Investigator Information 
By agreeing to this protocol, the Principal Investigator recognizes that certain personal 
identifying information with respect to the Principal Investigator, and all sub-Investigators 
and study investigative site personnel, may be used and disclosed for study management 
purposes, as part of regulatory submissions, and as required by law. This information may 
include: 
• 
name, address, telephone number, and email address; 
• 
hospital or clinic address and telephone number; 
• 
curriculum vitae or other summary of qualifications and credentials; 
• 
other professional documentation. 
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, affiliates, and agents of the Sponsor, in the country of the Investigator or other 
countries, including those that do not have laws protecting such information. Additionally, 
the Principal Investigator’s name and business contact information may be included when 
reporting certain SAEs to regulatory agencies in the countries involved in the study or to 
other Principal Investigators. By agreeing to this protocol, the Principal Investigator 
expressly consents to these uses and disclosures. 


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In order to facilitate contact between Principal Investigators, the Sponsor may share a 
Principal Investigator’s name and contact information with other participating Principal 
Investigators upon request. 
10.5.2 
Compliance with Law, Audit, and Debarment 
By agreeing to this protocol, the Principal Investigator agrees to:  
1) Conduct the study in an efficient and diligent manner and in compliance with this 
protocol, GCP, and all applicable regulatory requirements. 
2) Complete, and/or update the FDA Form 1572 (or any other forms as equivalent) in a 
timely manner, and conduct the study in accordance with ICH GCP. 
3) Allow monitoring, audits, IRB/IEC review, and inspection by domestic and foreign 
regulatory agencies of study-related documents and procedures; and provide for direct 
access to all study related source data and documents. 
• 
Promptly and fully disclose to the Sponsor, and make available all source 
documentation at their investigative site upon the request for inspection by 
representatives of the Sponsor, IRB/IEC, or any regulatory agencies.  
• 
Promptly inform the Sponsor of any regulatory agency inspection conducted for this 
study. 
• 
Promptly take any reasonable steps that are requested by the Sponsor as a result of an 
audit to cure deficiencies in the study documentation and worksheets/case report 
forms.  
4) Upon completion of the protocol-specified dosing and observation in all the subjects at an 
investigative site, the Investigator will promptly notify the IRB/IEC and the Sponsor of 
the completion of the study in writing in accordance with local procedures and any 
applicable laws and regulations. 
5) For Japan sites only, upon completion of the protocol-specified dosing and observation of 
all the subjects at an investigative site, the Principal Investigator will report to the director 
of the investigative site on study-completion information and outline study results in 
writing. 
6) Immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the 
best of the Principal Investigator’s knowledge, threatened. Persons debarred from 
conducting or working on clinical studies by any court or regulatory agency will not be 
allowed to conduct or work on the Sponsor’s studies. 
7) Provide to the Sponsor accurate financial information to allow the Sponsor to submit 
complete and accurate certification and disclosure statements as required by US FDA 
regulations (CFR, Title 21, Part 54), and other financial regulatory agencies. The 
Principal Investigator further agrees to provide this information on a Financial 


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Disclosure/Certification Form that is provided. This requirement extends to sub-
Investigators. This may involve the transmission of information to countries that do not 
have laws protecting personal data. Refer to Section 10.5.3 for additional details. 
The ICH E6-GCP guidelines recommend that the Principal Investigator inform the subject’s 
primary physician about the subject’s participation in the study, if the subject has a primary 
physician and if the subject agrees to the primary physician being informed. 
In the event the Sponsor prematurely terminates a particular investigative site, the Sponsor 
will promptly notify that investigative site’s IRB/IEC. 
10.5.3 
Financial Disclosure  
According to US FDA CFR, Title 21, Part 54, the Sponsor is required to completely and 
accurately disclose or certify information concerning the financial interests of an Investigator 
(or investigative site) who is not a full-time or part-time employee to the FDA. Therefore, the 
Principal Investigators and sub-Investigators (or investigative site) must provide the Sponsor 
with sufficient, accurate financial certification that none of the financial arrangements 
described in US FDA CFR, Title 21, Part 54.2 exist with the Sponsor or fully disclose the 
nature of the arrangement. This financial disclosure also applies to any financial 
arrangements that exist between the Sponsor and the Investigator’s spouse(s) or dependent 
children. 
10.6 Expenses Related to the Study 
The details related to the expenses during the study treatment period for examinations and 
medical treatment such as administration or injection of pharmaceutical products with similar 
indications or therapeutic effects to those of IP are specified in the Clinical Trial Agreement. 
In order to reduce the burden to subjects resulting from participation in the study, the Sponsor 
will bear the compensation/reimbursements for incurred expenses to the subjects through the 
relevant investigative site, in accordance with the applicable rules of each investigative site. 
10.7 Compensation for Health Injury 
In the event of any study-related disease or health injury in a subject, appropriate therapeutic 
measures will be taken in accordance with the clauses on compensation in the Information for 
Subjects/ICF or the Clinical Trial Agreement. An information leaflet containing essential 


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information about the compensation can be provided upon request of the subject (or attached 
to the ICF in Japan). 
10.8 Publication Policy 
The study is part of a multicenter study; accordingly, the investigative site and the Principal 
Investigator agree that the first publication of the results of the study shall be made in 
conjunction with the presentation of a joint, multicenter publication of the study results with 
the Principal Investigators and the investigative sites from all appropriate sites contributing 
data, analyses and comments. However, if such a multicenter publication is not submitted 
within 12 months after the database has been locked, abandonment or termination of the 
study at all sites, or after Sponsor confirms there will be no multicenter study publication, the 
investigative site and/or such Principal Investigator may publish the results from the 
institution site individually in accordance with the Sponsor’s publication policy. Prior to 
submission of any materials for publication or presentation, the investigative site will provide 
such materials or manuscript to the Sponsor for review and approval. Details of the Sponsor’s 
publication policy can be found in the Clinical Trial Agreement. 
11 
STUDY ADMINISTRATIVE STRUCTURE 
11.1 Sponsor 
Masashi Miyamoto 
Chief Executive Officer and President 
Kyowa Kirin Co., Ltd. 
Otemachi Financial City Grand Cube, 1-9-2 Otemachi, Chiyoda-ku, Tokyo 100-0004, 
Japan  
11.2 Clinical Trial Manager (Sponsor Signatory) 
Tadahiro Kakuno 
Manager, Clinical Development Center 
Kyowa Kirin Co., Ltd. 
Otemachi Financial City Grand Cube, 1-9-2 Otemachi, Chiyoda-ku, Tokyo 100-0004, 


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Japan 
Phone: +81 90-2459-8011 
11.3 Medical Monitor 
Masutaka Furue, MD, PhD  
Department of Dermatology, Kyushu University 
3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan 
Phone: +81-92-642-5581 
Richard L Leff, MD 
Medical Sciences 
Kyowa Kirin Pharmaceutical Development, Inc. 
212 Carnegie Center, Suite 400, Princeton, NJ, 08540 U.S.A 
E-mail: richard.leff@kyowakirin.com 
Phone: +1-609-216-5236 
Back-up Medical Monitor: 
Ehsanollah Esfandiari MD, PhD 
Medical Sciences 
Kyowa Kirin Pharmaceutical International plc. 
UK London (Marlow) office, 2 Globeside, SL7 1HZ 
E-mail: ehsanollah.esfandiari@kyowakirin.com 
Phone: +44-7741-666423 
For further information on the study administrative structure, refer to other study documents 
and vendors’ procedures that are provided separately. 


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12 
REFERENCES  
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Cavanagh MM and Hussell T. Is it wise to target the late costimulatory molecule OX40 as a 
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Clinical Trials Facilitation Group (CTFG) [Internet]. Recommendations related to 
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About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
Croft M [a], So T, Duan W, Soroosh P. The significance of OX40 and OX40L to T cell 
biology and immune disease. Immunol Rev. 2009 May;229(1):173-91. 
Croft M [b]. The role of TNF superfamily members in T cell function and diseases. Nat Rev 
Immunol. 2009 Apr;9(4):271-85. 
Croft M. Control of immunity by the TNFR-related molecule OX40 (CD134). Annu Rev 
Immunol. 2010;28:57-78. 
Dolff S, Quandt D, Wilde B, Feldkamp T, Hua F, Cai X, et al. Increased expression of 
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Eichenfield LF, Tom WL, Chamlin SL, Feldman SR, Hanifin JM, Simpson EL, et al. 
Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and 
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European Task Force on Atopic Dermatitis. Severity scoring of atopic dermatitis: the 
SCORAD index, Dermatology. 1993;186:23-31. 
Farres MN, Al-Zifzaf DS, Aly AA, Abd Raboh NM. OX40/OX40L in systemic lupus 
erythematosus: association with disease activity and lupus nephritis. Ann Saudi Med. 
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Furue M, Ebata T, Ikoma A, Takeuchi S, Kataoka Y, Takamori K, et al. Verbalizing 
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Guttman-Yassky E, Dhingra N, Leung DY. New era of biological therapeutics in atopic 
dermatitis. Expert Opin Biol Ther. 2013;13(4):549-61. 
Hanifin JM and Rajka G. Diagnostic features of atopic eczema. Acta Dermatol Venereol 
(Stockh). 1980;92:44-7. 
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and 
severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. 
Exp Dermatol. 2001;10:11-8. 
Ito T, Wang YH, Duramad O, Hori T, Delespesse GJ, Watanabe N, et al. TSLP-activated 
dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J 
Exp Med. 2005;202(9):1213-23. 
Leung DY and Guttman-Yassky E. Deciphering the complexities of atopic dermatitis: 
shifting paradigms in treatment approaches. J Allergy Clin Immunol. 2014;134(4):769-79. 
Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J 
Pharm Sci. 2004;93(11):2645-68. 
Malajian D and Guttman-Yassky E. New pathogenic and therapeutic paradigms in atopic 
dermatitis. Cytokine. 2015;73:311-8. 
Matsumura Y, Hori T, Nishigori C, Shirogane K, Toda KI, Uchiyama T, et al. Expression of 
CD134 and CD134 ligand in lesional and nonlesional psoriatic skin. Arch Dermatol Res. 
2003;294(12):563-6. 
Mousavi SF, Soroosh P, Takahashi T, Yoshikai Y, Shen H, Lefrançois L, et al. OX40 
costimulatory signals potentiate the memory commitment of effector CD8+ T cells. J 
Immunol. 2008;181(9):5990-6001. 
Ohya Y, Williams H, Steptoe A, Saito H, Iikura Y, Anderson R, et al. Psychosocial factors 
and adherence to treatment advice in childhood atopic dermatitis. J Invest Dermatol. 
2001;117(4):852-7. 
Papp KA, Gooderham MJ, Girard G, Raman M, Strout V. Phase I randomized study of 
KHK4083, an anti-OX40 monoclonal antibody, in patients with mild to moderate plaque 
psoriasis. J Eur Acad Dermatol Venereol. 2017;31(8):1324-32. 


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Rogers PR, Song J, Gramaglia I, Killeen N, Croft M. OX40 promotes Bcl-xL and Bcl-2 
expression and is essential for long-term survival of CD4 T cells. Immunity. 2001;15(3):445-
55. 
Ruby CE, Montler R, Zheng R, Shu S, Weinberg AD. IL-12 is required for anti-OX40-
mediated CD4 T cell survival. J Immunol. 2008;180(4):2140-8. 
Saeki H, Furue M, Furukawa F, Hide M, Ohtsuki M, Katayama I, et al.; Committee for 
Guidelines for the Management of Atopic Dermatitis of Japanese Dermatological Association. 
Guidelines for Management of Atopic Dermatitis. J Dermatol. 2009;36(10):563-77. 
Saeki H, Nakahara T, Tanaka A, Kabashima K, Sugaya M, Murota H, et al.; Committee for 
Guidelines for the Management of Atopic Dermatitis of Japanese Dermatological Association. 
Clinical Practice Guidelines for the Management of Atopic Dermatitis. J Dermatol. 
2016;43(10):1117-45. 
Salek-Ardakani S, Song A, Humphrey IR, Croft M. OX-40:OX40L Axis: Emerging targets 
for immunotherapy of human disease. Current Immunol. Rev. 2006;2:37-53. 
Seshasayee D, Lee WP, Zhou M, Shu J, Suto E, Zhang J, et al. In vivo blockade of OX40 
ligand inhibits thymic stromal lymphoietin driven atopic inflammation. J Clin invest. 
2007;117(12):3868-78. 
Song A, Tang X, Harms KM, Croft M. OX40 and Bcl-xL promote the persistence of CD8 T 
cells to recall tumor-associated antigen. J Immunol. 2005;175(6):3534-41. 
Stüber E, Büschenfeld A, Lüttges J, von Freier A, Arendt T, Fölsch UR. The expression of 
OX40 in immunologically mediated diseases of the gastrointestinal tract (celiac disease, 
Crohn’s disease, ulcerative colitis). Eur J Clin Invest. 2000;30(7):594-9. 
Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and 
pharmacodynamics. Clin Phalmaco Ther. 2008;84(5):548-58. 
Wang YH, Ito T, Wong YH, Homey B, Watanabe N, Martin R, et al. Maintenance and 
polarization of human TH2 central memory T cells by thymic stromal lymphopoietin-
activated dendritic cells. Immunity. 2006;24:827-38. 


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Williams HC, Burney PG, Hay RJ, Archer CB, Shioley MJ, Hunter JJ, et al. The U.K. 
Working Party’s Diagnostic Criteria for Atopic Dermatitis.  I. Derivation of a minimum set of 
discriminators for atopic dermatitis. Br J Dermatol 1994;131:383-96. 
Zuberbier T, Orlow SJ, Paller AS, et al. Patient perspectives on the management of atopic 
dermatitis. J Allergy Clin Immunol. 2006;118:226-232. 


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13 APPENDICES/ATTACHMENTS 


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Appendix 1 Eczema Area and Severity Index (EASI) 
 
Body region 
EASI score1, 2 
Head/Neck (H) 
(E + I + Ex + L) × Area × 0.1 
Upper limbs (UL) 
(E + I + Ex + L) × Area × 0.2 
Trunk (T) 
(E + I + Ex + L) × Area × 0.3 
Lower limbs (LL) 
(E + I + Ex + L) × Area × 0.4 
EASI = 
Sum of the above 4 body region scores 
E = erythema, I = induration/papulation, Ex = excoriation, L = lichenification 
 
1 The average degree of severity of each sign in each of the four body regions is 
assigned a score of 0 to 3 (0: none, 1: mild, 2: moderate, and 3: severe, 
respectively) with half-steps allowed. 
2 The percentage of area involved for each of the four body regions is assigned a 
proportional score from 0 to 6 during the analysis: 0 = no eruption; 1 = <10%; 2 = 
10% to 29%; 3= 30% to 49%; 4 = 50% to 69%; 5 = 70% to 89%; and 6 = 90% to 
100%. 
Reference: Hanifin et al, 2001 
 
Note that the data will be recorded on the eCOA device. 
 


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Appendix 2 Severity Scoring of Atopic Dermatitis (SCORAD) 
Extent Criteria (A): 
To determine the area, on a drawing of a body shade the sites affected by atopic 
dermatitis. Lesions assessed must only include inflammatory lesions and not 
dryness. 
1. Head and neck 9% 
2. Upper limbs 9% each 
3. Lower limbs 18% each 
4. Anterior trunk 18% 
5. Back 18% 
6. 1% each for genitals, each palm and the back of each hand (the area for the 
palms and back of hands is included in the upper limbs). 
 
Intensity (B): 
To determine the intensity, select a representative area of dermatitis and assess the 
intensity of each of the following signs as absence (0), mild (1), moderate (2), or 
severe (3): 
7. Erythema 
8. Edema/papulation 
9. Oozing/crusting 
10. Excoriations 
11. Lichenification 
12. Dryness (this is assessed in an area where there is no inflammation and 
without prior application of emollients/moisturizers). 


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Subjective Symptoms (C): 
Subjective symptoms of pruritus and sleeplessness over the last 3 days, will be 
scored by the patient using a visual analogue scale where 0 is no itch (or no 
sleeplessness) and 10 is the worst imaginable itch (or sleeplessness). 
 
SCORAD = A/5 + 7B/2 + C 
Reference: European Task Force on Atopic Dermatitis, 1993 
 
Note that the data will be recorded on the eCOA device. 
 


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Appendix 3 Investigator Global Assessment (IGA) scale 
 
Score 
Morphological Description 
0 - Clear 
No inflammatory signs of atopic dermatitis (no erythema, no 
induration/papulation, no lichenification, no oozing/crusting). Post-
inflammatory hyperpigmentation and/or hypopigmentation may be 
present. 
1 - Almost clear 
Barely perceptible erythema, barely perceptible induration/papulation, 
and/or minimal lichenification. No oozing or crusting. 
2 - Mild 
Slight 
but 
definite 
erythema 
(pink), 
slight 
but 
definite 
induration/papulation, and/or slight but definite lichenification. No oozing 
or crusting. 
3 - Moderate 
Clearly 
perceptible 
erythema 
(dull 
red), 
clearly 
perceptible 
induration/papulation, and/or clearly perceptible lichenification. Oozing 
and crusting may be present. 
4 - Severe 
Marked erythema (deep or bright red), marked induration/papulation, 
and/or marked lichenification. Disease is widespread in extent. Oozing 
or crusting may be present. 
 
Notes: 
1. In indeterminate case, please use extent to differentiate between scores. 
For example: 
• 
Patient with marked erythema (deep or bright red), marked papulation and/or marked 
lichenification that is limited in extent, will be considered “3 - Moderate”. 
2. Excoriations should not be considered when assessing disease severity. 
 
Copyright ©2017 Eli Lilly and Company – Used with the permission of Eli Lilly and Company under a Creative Commons 
Attribution-NoDerivatives 4.0 International License - https://creativecommons.org/licenses/by-nd/4.0/ 
Note that the data will be recorded on the eCOA device. 
 


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Appendix 4 Pruritus Numerical Rating Scale (NRS) 
 
Please rate how bad your itching has been in the last 24 hours on the following scale 
by selecting your worst degree of itching. 
No itch 
 
Worst itch 
imaginable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
 
 
Note that the data will be recorded on the eCOA device. 
 


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Appendix 5 Sleep Disturbance Numerical Rating Scale (NRS) 
 
Please rate how much of a problem sleep has been for you in the last 24 hours on 
the following scale by selecting your worst degree of sleep disturbance. 
No sleep 
loss 
 
I cannot sleep 
at all 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
 
 
Note that the data will be recorded on the eCOA device. 
 
 
 


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Appendix 6 Dermatology Life Quality Index (DLQI) 
Hospital No: 
Date: 
 
DLQI 
Subject ID: 
Diagnosis: 
Score: 
 
 
 
 
 
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 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       
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       
 
 


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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.  
©AY Finlay, GK Khan, April 1992 www.dermatology.o©rg.uk, this must not be copied without the permission of the authors. 
 
Note that the data will be recorded on the eCOA device. 
 


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Appendix 7 Diagnosis of Anaphylaxis 
Diagnosis of Anaphylaxis 
The diagnosis of anaphylaxis is based on the following three clinical criteria, with 
anaphylaxis considered as highly likely when one of these criteria is fulfilled (Sampson et al, 
2006): 
a) Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen 
lips-tongue-uvula), and at least one of the following: 
• 
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia) 
• 
Reduced blood pressure or associated symptoms of end-organ dysfunction 
(e.g., hypotonia [collapse], syncope, incontinence) 
b) Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
• Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula)  
• Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow, hypoxemia) 
• Reduced blood pressure or associated symptoms (e.g., hypotonia [collapse], 
syncope, incontinence)  
• Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
c) Reduced blood pressure after exposure to known allergen for that patient (minutes to 
several hours): 
• Infants and children: low systolic blood pressure (age specific) or greater than 
30-percent decrease in systolic blood pressure 
• Adults: systolic blood pressure of less than 90 mm Hg or greater than 30-percent 
decrease from that person’s baseline 
Although none of the clinical criteria provide 100-percent sensitivity and specificity, it is 
believed that these criteria are likely to capture more than 95-percent of cases of anaphylaxis 
(Sampson et al, 2006). 
Laboratory tests for evaluating anaphylaxis: 
At present, there are no sensitive and specific laboratory tests to confirm the clinical 
diagnosis of anaphylaxis.  Skin testing and in vitro diagnostic tests to determine the level of 
specific IgE antibodies directed against the therapeutic protein product, mediator release, or 
basophil activation may be useful for characterizing the underlying pathophysiology and may 


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provide insight into potential mitigation strategies (Simons, 2010; Lee and Vadas, 2011).  
However, the results of unvalidated tests should be interpreted with caution; and the clinical 
relevance of positive results from unvalidated tests may be uncertain during product 
development. 
Reference 
Lee JK, Vadas P.  Anaphylaxis: mechanisms and management. Clin Exp Allergy. 
2011;41(7):923-38. 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report--
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7. 
Simons KJ, Simons FE. Epinephrine and its use in anaphylaxis: current issues [abstract]. 
Current Opin Allergy Clin Immunol. 2010;10(4):354-61. 


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Appendix 8 Tuberculosis (TB) Risk Assessment Questionnaire 
 
Hospital No: 
 
Date of risk assessment: 
Subject ID: 
 
Investigator’s signature:  
 
TB testing will be performed on a country-by-country basis, according to local 
guidelines if required by regulatory authorities or ethics boards.  
Below are suggested questions: 
If there is a “Yes” response to any of the questions 1−3 below, then the local clinical 
practice guideline should be followed, or a tuberculin skin test (TST) or Interferon 
Gamma Release Assay (IGRA) should be performed.  
Risk Factors 
1. One or more signs and symptoms of TB (prolonged cough, 
coughing up blood, fever, night sweats, weight loss, excessive 
fatigue) 
Note: A chest X-ray and/or sputum examination may be necessary 
to rule out infectious TB. 
Yes 
No 
2. Close contact with someone with infectious TB disease 
Yes 
No 
3. Travel to high TB - prevalence country for more than 1 month 
Yes 
No