Clinical trial NCT02647866
Conditions: Ulcerative Colitis Digestive System Diseases Colitis, Ulcerative Colitis Gastrointestinal Diseases Inflammatory Bowel Diseases Intestinal Diseases Colonic Diseases Autoimmune Disease Abdominal Pain
Keywords: 4083-002 Intestinal Diseases Ulcerative Colitis UC Mayo Clinic Scoring Gastrointestinal Tract
Sponsor: Kyowa Kirin, Inc.
Start date: 2016-06-01; Completion date: 2018-10-01
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to determine the safety and tolerability of administration of multiple ascending doses of KHK4083 and to select the highest dose tolerated by subjects with moderately active Ulcerative Colitis (UC) followed by a Long-term Extension Therapy (LTE) phase for eligible subjects with a clinical response.

Detailed description:
A Phase 2, double-blind clinical study of multiple ascending doses of KHK4083 (or placebo) with an Long-term Extension Therapy (LTE) phase will be conducted in approximately 60 randomized adult subjects with moderately active UC who have a documented unsuccessful previous treatment.

The Treatment Period includes double-blind Induction Therapy (12 weeks) and Open-label Therapy (OLE) phase (40 weeks) for eligible subjects at Week 12. Subjects already enrolled in the double-blind, long-term extension (LTE) under preceding versions of the protocol who worsen may be eligible to transition to the OLE up to Week 28.

The Follow Up Period after the last administration will be for up to 16 weeks.

Arms: arm 1: Subjects received one 1.0 mg/kg IV infusion treatment of KHK4083 every two weeks from Week 0 to Week 10 of Induction Therapy. Subjects who chose to continue into extension therapy and were eligible received one IV infusion every 4 weeks (at the same dose as Induction Therapy) from Week 12 to Week 48. arm 2: Subjects received one 3.0 mg/kg IV infusion treatment of KHK4083 every two weeks from Week 0 to Week 10 of Induction Therapy. Subjects who chose to continue into extension therapy and were eligible received one IV infusion every 4 weeks (at the same dose as Induction Therapy) from Week 12 to Week 48. arm 3: Subjects received one 10.0 mg/kg IV infusion treatment of KHK4083 every two weeks from Week 0 to Week 10 of Induction Therapy. Subjects who chose to continue into extension therapy and were eligible received one IV infusion every 4 weeks (at the same dose as Induction Therapy) from Week 12 to Week 48. arm 4: Subjects received one maximum tolerated dose (10.0 mg/kg) IV infusion treatment of KHK4083 every two weeks from Week 0 to Week 10 of Induction Therapy. Subjects who chose to continue into extension therapy and were eligible received one IV infusion every 4 weeks (at the same dose as Induction Therapy) from Week 12 to Week 48. arm 5: Subjects received one IV infusion treatment of Placebo every two weeks from Week 0 to Week 10 of Induction Therapy. Subjects who chose to continue into extension therapy and were eligible received one IV infusion every 4 weeks (at the same dose as Induction Therapy) from Week 12 to Week 48. Subjects who participated in Open-Label Therapy received KHK4083 instead of placebo.
Interventions: intervention 1: KHK4083 intervention 2: Placebo
Intervention descriptions: intervention 1: IV Infusion intervention 2: IV Infusion

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
1 
 
CLINICAL PROTOCOL 
A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Multiple 
Ascending Dose Study (Induction Therapy) and Long-term Extension Therapy of an 
Anti-OX40 Monoclonal Antibody (KHK4083) in Subjects with Moderately 
Active Ulcerative Colitis 
REVISED TO INCORPORATE AMENDMENT 2 
Protocol Number: 
4083-002 
Original Protocol: 
14AUG2015 
Amendment 1 
15OCT2015 
Amendment 2 
04OCT2016 
Phase: 
2 
US IND Number: 
124049 
EudraCT Number: 
2015-001555-69 
Sponsor: 
Kyowa Kirin Pharmaceutical Development, Inc. 
212 Carnegie Center, Suite 101 
Princeton, NJ  08540 USA 
 
 
 
 
Confidentiality Statement 
The information contained in this document is the property of or under the control of Kyowa Kirin 
Pharmaceutical Development, Inc. (KKD) and its affiliated companies. This information is provided to you in 
confidence as an Investigator, potential Investigator or consultant, for review by you, your staff and applicable 
Institutional Review Board/Ethics Committee. You shall not disclose this information to others without prior 
written authorization from KKD, except to the extent necessary to obtain informed consent from those persons 
to whom the drug may be administered, and except as may be required by federal, state, or local laws or 
regulations. 
 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
2 
 
Principal Investigator Signature Page 
Protocol Title:  A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled 
Multiple Ascending Dose Study (Induction Therapy) and Long-term Extension Therapy of an 
Anti-OX40 Monoclonal Antibody (KHK4083) in Subjects with Moderately 
Active Ulcerative Colitis 
Protocol Number:  4083-002, Amendment 2  
This protocol contains information that is proprietary to Kyowa Kirin Pharmaceutical 
Development, Inc. (KKD). This information is being provided to you for the purpose of 
conducting a clinical study on behalf of KKD. 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 KKD. 
Any supplemental information (e.g., protocol amendment, Investigator’s Brochure, and study 
manuals) that may accompany this document are also proprietary to KKD 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 
______________________________________________ 
Institution 
______________________________________________ 
Address 
______________________________________________ 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
3 
 
Protocol Signature Page  
 
Protocol Title:  A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled 
Multiple Ascending Dose Study (Induction Therapy) and Long-term Extension Therapy of an 
Anti-OX40 Monoclonal Antibody (KHK4083) in Subjects with Moderately 
Active Ulcerative Colitis 
Protocol Number:  4083-002, Amendment 2 
 
 
Signature 
 
Stephen Letrent, PharmD, PhD, BCPS 
Senior Vice President, Drug Development  
Kyowa Kirin Pharmaceutical Development, Inc. 
212 Carnegie Center, Suite 101 
Princeton, NJ 08540 USA 
 
Date 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
4 
 
Summary of Changes 
REASON FOR THE AMENDMENT: 
The changes that were made to the protocol are listed in the following table, along with the 
rationale for each change: 
Section 
Change 
Rationale 
Section 5 OBJECTIVES 
Revised objectives to include 
the open-label extension. 
Revised in accordance with changes in the 
study design. 
Section 6.1 Overall Study Design 
and Plan 
The study plan was revised 
to: 
1) Convert the post induction 
phase of the study from a 
blinded long-term extension 
to an open-label extension. 
2) Add investigative sites in 
the Czech Republic. 
 
1) The protocol was amended to allow all 
eligible subjects to receive KHK4083 after 
the 12-week, double-blind induction 
phase.  Subjects currently enrolled in the 
long-term extension who are receiving 
study medication but who are 
non-responders up to the Week 28 visit 
will be eligible to receive KHK4083 in the 
open-label study extension.  
2) Sites in the Czech Republic will be 
added to the study to ensure complete 
accrual. 
Section 6.1.3 Open-label 
Extension Therapy:  Week 12 
(First Dose) to Week 52 
Section added 
Revised in accordance with changes in the 
study design. 
Section 6.1.4 Transitioning from 
the Long-term Extension to the 
Open-label Extension 
Section added 
Revised in accordance with changes in the 
study design. 
Section 6.3 Study Safety 
Monitoring Plan 
1) The Safety Monitoring 
Committee will evaluate the 
cumulative safety data 
available after the first 4 
subjects in a cohort at 
Week 6 for the 3.0 and 
10 mg/kg dose cohorts 
instead of Week 8.  
2) The Safety Monitoring 
Committee and Sponsor may 
dose-reduce cohorts or not 
escalate to the planned doses 
based upon review of safety 
data. 
3) The dose administered 
during the open-label 
extension will be the same as 
the dose for that cohort 
during the induction therapy, 
1) KHK4083 concentrations in serum at 
Week 6 are estimated to be approximately 
10% lower than those at Week 8 based on 
the elimination half-life of the drug. This 
small difference in drug exposure at Week 
6 and Week 8 is not expected to affect the 
detection of safety signals and will allow 
for an earlier review of the safety data. 
2) To clarify how dose reductions for a 
cohort will occur. 
3) To clarify how the dose for the open-
label extension will be selected. 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
5 
 
Section 
Change 
Rationale 
unless dose-reduction is 
recommended by the Safety 
Monitoring Committee and 
Sponsor. 
Section 7.3 Exclusion Criterion 2) 
Subjects with well-controlled 
immunologic, autoimmune or 
chronic inflammatory 
disorders, other than 
ulcerative colitis, or 
autoimmune connective 
tissue diseases may be 
included, after consulting 
with the medical monitor.  
Ulcerative colitis is often accompanied by 
involvement of organs besides the colon 
and/or other autoimmune or chronic 
inflammatory diseases.  Including subjects 
with stable, well-controlled disease 
outside of the colon will result in inclusion 
of a more representative population of 
subjects with ulcerative colitis. 
Section 7.3 Exclusion Criterion 3) 
The definition of biologic 
treatment history has been 
revised from “failed to 
respond to more than one 
biologic treatment” to “failed 
to respond to two or more 
biologic treatments with 
different mechanism of 
action” 
Clarification of criteria.  Note that some 
patients with moderate ulcerative colitis 
receive two or more anti-TNF monoclonal 
antibodies, and failure to respond to drugs 
with similar mechanisms of action is not 
felt to impact the assessment of efficacy or 
safety. 
Section 7.3 Exclusion Criterion 4) 
Modified to allow subjects 
receiving stable doses of oral 
budenoside ≤ 9 mg/day to 
participate. 
Amended to harmonize this criterion with 
Inclusion Criterion #6 
Section 7.3 Exclusion Criterion 
23) 
(see also Section 7.1Procedures 
for Enrollment) 
A subject who was 
considered a screen failure 
and not dosed with 
investigational product is 
permitted to be re-screened 
once due to failure to meet 
the Inclusion/Exclusion 
Criteria, whereas subjects 
with other reasons for lack of 
randomization may be re-
screened twice. 
To allow for re-screening in cases where a 
subject fails screening because all 
assessments were not completed within 
the 28-day screening window 
Section 7.4 Additional Criteria to 
Enroll in Open-label Extension 
Therapy 
Criteria to participate in the 
long-term extension have 
been replaced with criteria to 
enroll in the open-label 
extension 
Revised in accordance with changes in the 
study design. 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
6 
 
Section 
Change 
Rationale 
Section 7.5.3 Criteria for Subject 
Removal from Treatment and the 
Study 
 
A subject who has two 
consecutive visits during 
Induction Therapy with a 
worsening from Baseline, in 
partial Mayo Clinic score of 
≥ 3 points (e.g., partial Mayo 
Clinic score of 3 at baseline, 
6 at Week 2, and 6 at Week 
4) or two consecutive visits 
during maintenance therapy 
with a worsening from Week 
12 in partial Mayo Clinic 
score of ≥ 3 points at a visit 
and ≥ 5 points at the next 
visit may continue to receive 
study medication if the 
Investigator, with agreement 
from the Sponsor, determines 
that there has not been 
clinically significant 
worsening.  
As the patient-reported stool frequency 
and bloodiness for the Partial Mayo 
clinical score is the average of the last 2 to 
3 days prior to a visit, the diaries may not 
always reflect the subject’s and 
physician’s perception of the UC disease 
activity.  This permits an additional dose 
of study medication to be administered on 
a case-by-case basis for subjects who may 
not have clinically significant worsening. 
Section 7.5.4 End-of-Treatment 
Visit 
Section added. Assessments 
have been amended as 
follows: If the subject 
discontinues during Induction 
Therapy, a sigmoidoscopy 
will be performed at End-of-
Treatment/Week 12 if the 
subject discontinues more 
than 8 weeks after Baseline 
visit; the sigmoidoscopy may 
be performed up to 4 weeks 
after the last dose of study 
medication.  If the subject 
discontinues during 
OLE/LTE therapy, a 
sigmoidoscopy will be 
performed at End-of-
Treatment/Week 52 if the 
subject discontinues more 
than 8 weeks after the Week 
12 visit; the sigmoidoscopy 
may be performed up to 8 
weeks after the last dose of 
study medication. 
The section was added to clarify the End-
of-Treatment procedures.  
The timing of the End-of-Treatment 
sigmoidoscopy for subjects who 
discontinue prematurely was changed, as 
the primary analysis for endoscopic 
findings is at 12 weeks after 
administration of 5 of 6 doses of study 
medication. This clarifies when a 
sigmoidoscopy should occur and which 
timeframe is considered too short for the 
purposes of this study for an End-of-
treatment sigmoidoscopy. 
 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
7 
 
Section 
Change 
Rationale 
7.5.5 End-of-Study Visit 
Section added 
The section was added to clarify the End-
of-Study procedures. 
Section 8.1.2 Investigational 
Product Destruction 
Removed the mandate for 
destruction of investigational 
product at the site.  
Sites participating in the study that have 
been unable to destroy the investigational 
product on site have contacted the 
Sponsor and alternate destruction 
arrangements have been made. 
Section 8.1.3.4 Dose 
Modifications 
Clarified that dose reduction 
is not permitted for an 
individual subject.  Doses 
chosen for each cohort, as 
determined by the Safety 
Monitoring Committee and 
Sponsor, may result in dose 
reduction for all subjects 
enrolled in a cohort. 
In order to determine the safety profile for 
KHK4083, individual subjects are not 
permitted to dose reduce. Dose reduction 
for a cohort may occur based upon 
evaluation of safety by the Safety 
Monitoring Committee and Sponsor. 
Section 9.1 Screening Period (Day 
−28 to Day −1) 
For subjects who are 
rescreened, the original 
screening sigmoidoscopy can 
be used to satisfy the entry 
criteria if obtained within 42 
days prior to the first dose. 
To obviate the need for a second 
sigmoidoscopy during re-screening, if 
performed up to 42 days prior to Day 1. 
Section 10.4.1 Pharmacokinetic 
and Pharmacodynamic 
Assessments 
The visit schedule for Part A 
has been revised to eliminate 
study visits on Days 3 and 4 
in Weeks 0, 10, and 48. The 
pharmacokinetic timepoints 
on Day 3 and Day 4 in Week 
0, Week 10 and Week 48 
were removed. The PD 
timepoint was moved from 
Day 4 to Day 2 because of 
elimination of the Day 4 
visit. 
Considering the characteristics of the PK 
profile for KHK4083 following 
intravenous administration, the PK 
sampling timepoints on Day 3 and Day 4 
are deemed not critical in determination of 
the PK disposition of KHK4083. The 
revised PK sampling schedule is 
considered adequate to assess the PK of 
KHK4083 in this study. The PD timepoint 
is moving from Day 4 to Day 2 to 
coincide with the change in the visit 
schedule. 
Appendix 6 
Follow-up and 
End-of-Study for Subjects who 
Discontinued During the Study 
Added study diagram 
To clarify the End-of-Study and Follow-
up visits 
 
Additional revisions include updating the company name from Kyowa Hakko Kirin Pharma, 
Inc. to Kyowa Kirin Pharmaceutical Development, Inc. (a.k.a. the Sponsor or KKD 
throughout the document) and the list of Adverse Event Contacts. 
Cross-referencing has been used to represent the changes listed above and edits have been 
made in all sections of the protocol, as applicable.  


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
8 
 
Adverse Event Contacts 
Email for SERIOUS ADVERSE EVENTS (SAEs):  
SAESource@kyowa-kirin-pharma.com 
 
Richard L. Leff, MD 
Medical Monitor 
Kyowa Kirin Pharmaceutical Development, Inc. 
212 Carnegie Center, Suite 101 
Princeton, NJ 08540 USA 
 
Phone (mobile):  +1 484-947-6189 
Fax:  +1 609-919-1111 
24-Hour Contact Phone:  +1 484-947-6189 
24-Hour Contact Email:  RichardLLeff@verizon.net 
 
Rebecca Monroe  
Clinical Trial Manager 
Kyowa Kirin Pharmaceutical Development, Inc. 
212 Carnegie Center, Suite 101 
Princeton, NJ 08540 USA 
 
Phone:  +1 609-919-1100 
Fax:  +1 609-919-1111 
 
Jennifer Sheller, MPH 
Executive Director 
Clinical Operations/Clinical Supplies 
Kyowa Kirin Pharmaceutical Development, Inc. 
212 Carnegie Center, Suite 101 
Princeton, NJ 08540 USA 
 
Phone:  +1 609-919-1100 
Fax:  +1 609-919-1111 
 
John Hanna, MD 
Drug Safety Surveillance 
Kyowa Kirin Pharmaceutical Development, Inc. 
212 Carnegie Center, Suite 101 
Princeton, NJ 08540 USA 
 
Phone:  +1 609-919-1100 
Fax:  +1 609-919-1111 
 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
9 
 
1 
SYNOPSIS 
Name of Sponsor/Company: 
Kyowa Kirin Pharmaceutical 
Development, Inc. 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
KHK4083 
Name of Active Ingredient: 
KHK4083 
 
Title of Study:  A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Multiple Ascending 
Dose Study (Induction Therapy) and Long-term Extension Therapy of an Anti-OX40 Monoclonal Antibody 
(KHK4083) in Subjects with Moderately Active Ulcerative Colitis  
Protocol Number:  4083-002, Amendment 2 
Investigators and Study Center(s):  Multicenter at approximately 40 investigative sites in the United States 
(US), Russia, Hungary, Poland, Romania, Serbia and Czech Republic; other countries may be included as 
needed. 
Phase of Development:  Phase 2 
Objectives: 
Primary:  
• 
Induction Therapy - Part A:  To determine the safety and tolerability of administration of multiple ascending 
doses of KHK4083 and to select the highest dose tolerated by subjects with moderately active ulcerative 
colitis (UC) to recommend for use in Part B; 
• 
Induction Therapy - Part B:  To determine if the recommended dose of KHK4083 identified in Part A 
improves the mucosa in subjects with moderately active UC at Week 12 as measured by the modified Mayo 
endoscopy subscore (mMES).  
Secondary:   
• 
To determine if KHK4083 at dose levels different than the recommended dose improve the mucosa based on 
the mMES;  
• 
To determine if any dose level of KHK4083 administered as Induction Therapy will meet the following 
objectives at Week 12 (or as noted): 
– 
Improve the mucosa based on the modified Baron endoscopic score; 
– 
Improve the mucosa based on the Ulcerative Colitis Endoscopic Index of Severity (UCEIS); 
– 
Induce mucosal healing based on the mMES; 
– 
Improve clinical signs and symptoms based on total Mayo Clinic score; 
– 
Improve clinical signs and symptoms based on partial Mayo Clinic scores (Week 2 through Week 12, 
excludes endoscopy subscores);  
– 
Induce a clinical response based on a reduction in the total Mayo Clinic score (i.e., reduction of at least 
3 points and a decrease of at least 30% from Baseline [Week 0] to Week 12) and rectal bleeding 
subscale (i.e., reduction of at least 1 point from Baseline [Week 0] to Week 12) (or a defined absolute 
rectal bleeding score of 0 or 1 at Week 12);  
– 
Induce clinical remission based on a total Mayo Clinic score (i.e., score of ≤ 2) and subscores (i.e., no 
subscores > 1).  
• 
To characterize the pharmacokinetics (PK) of KHK4083 in subjects with moderately active UC following 
multiple dose administration; 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
10 
 
Name of Sponsor/Company: 
Kyowa Kirin Pharmaceutical 
Development, Inc. 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
KHK4083 
Name of Active Ingredient: 
KHK4083 
 
• 
To evaluate the development of antibodies against KHK4083 (immunogenicity). 
Exploratory:  
• 
To determine if multiple doses of KHK4083 administered during Open-label Extension (OLE) or Long-term 
Extension (LTE) Therapy will meet the following objectives at Week 52 (or as noted) when compared with 
Baseline (Week 0) scores (or subscores) or assessments: 
– 
Improve clinical signs and symptoms based on total Mayo Clinic score; 
– 
Improve clinical signs and symptoms based on partial Mayo Clinic scores (excludes endoscopy 
subscores) at Week 16 through Week 52, and the OLE/LTE Therapy Follow-up Period (Week 56 
through Week 64); 
– 
Induce a clinical response based on a reduction in the total Mayo Clinic score and rectal bleeding 
subscale (or a defined absolute rectal bleeding score); 
– 
Induce clinical remission based on a total Mayo Clinic score and subscores; 
– 
Induce durable clinical responses and durable clinical remissions (present at both Weeks 12 and 52), and 
glucocorticoid-free clinical remission;  
– 
Induce mucosal healing based on the mMES; 
– 
Improve the mucosa based on the mMES, UCEIS, and/or modified Baron endoscopic score; 
– 
Induce a remission (Week 12; Week 52) based on modified Mayo endoscopy, stool frequency, and 
rectal bleeding subscores (defined as an mMES of 0 or 1, stool frequency subscore of 0 or 1, and rectal 
bleeding subscore of 0). 
• 
To evaluate the activity of KHK4083 on health-related quality of life, which will be based on the subject’s 
completed Inflammatory Bowel Disease Questionnaires (IBDQs) in comparison with Baseline assessments; 
• 
To measure changes from Baseline in corticosteroid (glucocorticoid) dosages; 
• 
To determine the percentage of subjects who are glucocorticoid-free from Week 16 through Week 52, and 
the OLE/LTE Therapy Follow-up Period (Week 56 through Week 64); 
• 
To evaluate the pharmacodynamic (PD) profile of KHK4083; 
• 
To explore the PK-PD relationships. 
Study Design:  
This Phase 2, double-blind clinical study of multiple ascending doses of KHK4083 (or placebo) with an 
OLE Therapy phase will be conducted in approximately 60 randomized adult subjects with moderately active UC 
who have a documented unsuccessful previous treatment. The study will include a 4-week Screening Period, 
followed by a total of up to 64 weeks (treatment and follow-up) on study from the time of randomization to study 
completion. The Treatment Period includes double-blind Induction Therapy (12 weeks) and OLE Therapy 
(40 weeks) for eligible subjects at Week 12. Subjects already enrolled in the double-blind, long-term extension 
(LTE) under preceding versions of the protocol who worsen may be eligible to transition to the OLE up to 
Week 28.  Selected Sponsor personnel will be unblinded after the last subject completes Induction Therapy. 
Post-treatment assessments will continue for 16 weeks after the last infusion associated with the subject’s 
treatment period. The doses selected for this study are based on a Phase 1a/1b single-ascending dose study, 
which showed that KHK4083 was well tolerated and there were no dose-limiting adverse effects up to 10 mg/kg, 
the highest dose studied.  
 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
11 
 
Name of Sponsor/Company: 
Kyowa Kirin Pharmaceutical 
Development, Inc. 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
KHK4083 
Name of Active Ingredient: 
KHK4083 
 
Screening Period (Day −28 to Day −1):  
At the Screening visit, the Investigator will review the written informed consent form (ICF) with each subject to 
ensure that the subject understands the study and the study procedures. The subject will read, sign, and date the 
ICF and other locally applicable documents. Screening evaluations used to determine the subject’s study 
eligibility must be completed within the Screening Period (Day −28 to Day −1) prior to starting treatment on 
Day 1 (Week 0), and include a baseline sigmoidoscopy with biopsy being completed within 7 to 28 days prior to 
Day 1. For subjects who are rescreened, the original screening sigmoidoscopy can be used to satisfy the entry 
criteria if obtained within 42 days prior to Day 1. All sigmoidoscopy procedures will be performed using a 
flexible sigmoidoscope. 
Double-blind Treatment Period (Weeks 0 to 12/52): 
Each subject must be carefully monitored at the investigative site for signs of acute, potential dose-limiting 
toxicity infusion reactions during and for at least 3 hours following the completion of the first and second 
intravenous (IV) infusions of investigational product, and for at least 1 hour following all other IV infusions. In 
addition, a phone call to each subject will be conducted at approximately 48 to 72 hours following the 
completion of the first and second infusions for any subject who does not return for a visit at the investigative 
site. 
Induction Therapy:  Week 0 to Week 12 (Last Dose at Week 10) 
Double-blind Induction Therapy is separated into Part A for administration of multiple ascending IV doses of 
KHK4083 (or placebo) to subjects in Cohorts 1 - 3 and Part B for administration of the recommended IV dose 
(one of three dose levels identified in Part A) of KHK4083 (or placebo) to subjects in Cohort 4. Subjects in each 
cohort will be randomly assigned in a 3:1 ratio to receive KHK4083 or placebo by IV infusion over 60 minutes 
(± 10 minutes).  
Induction Therapy - Part A:  
In the first 3 cohorts, 27 subjects (9 subjects/cohort) will receive KHK4083 and 9 subjects (3 subjects/cohort) 
will receive placebo once every 2 weeks (Weeks 0 to 10) as follows:  
Cohort 1:  1.0 mg/kg or placebo  
Cohort 2:  3.0 mg/kg or placebo  
Cohort 3:  10 mg/kg or placebo  
The cumulative safety data available after the first 8 of 12 subjects randomized in Cohort 1 will be evaluated by 
the Safety Monitoring Committee at Week 4 (~Day 29) to assess whether dosing will continue for subjects within 
Cohort 1 and if investigational product will be administered at the next higher dose level for subjects in Cohort 2. 
For Cohorts 2 and 3, the cumulative safety data available after the first 8 subjects in each cohort at Week 4 
(~Day 29) with the first 4 subjects in each cohort at Week 6 (~Day 43) will be evaluated for continuation of all of 
the subjects and for dose escalation in the next cohort, i.e., Cohort 3 in Part A and Cohort 4 in Part B, 
respectively. The Safety Monitoring Committee and Sponsor may dose-reduce cohorts or not escalate to the 
planned doses based upon review of safety data. 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
12 
 
Name of Sponsor/Company: 
Kyowa Kirin Pharmaceutical 
Development, Inc. 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
KHK4083 
Name of Active Ingredient: 
KHK4083 
 
Induction Therapy - Part B:   
The recommended dose (one of three dose levels in Cohorts 1 - 3 selected based on the safety data from Part A) 
will be administered once every 2 weeks (Weeks 0 to 10) to additional subjects (18 subjects to receive 
KHK4083, 6 subjects to receive placebo) in Cohort 4 who did not participate in Part A.  
For subjects in all cohorts, a sigmoidoscopy with biopsy is scheduled at Week 12 to assess improvement in the 
mucosa from Baseline (Week 0) to Week 12. It is highly recommended that the sigmoidoscopy with biopsy be 
performed within 7 to 13 days prior to the Week 12 visit. 
Long-term Extension Therapy:  Week 12 (First Dose) to Week 52 
The LTE is only active for subjects who entered it prior to approval of Amendment 2. Subjects who sign an ICF 
under Amendment 2 are eligible for the OLE. 
Subjects who completed double-blind Induction Therapy (i.e., at least five of six treatments) and had a clinical 
response or mucosal healing were eligible to continue in double-blind LTE Therapy. A clinical response is 
defined as a reduction in the total Mayo Clinic score of at least 3 points and a decrease of at least 30% from 
Baseline (Week 0) to Week 12, and a reduction in the rectal bleeding subscale of at least 1 point from Baseline 
(Week 0) to Week 12 or an absolute rectal bleeding score of 0 or 1 at Week 12. Mucosal healing is defined as a 
mMES of 0 or 1. 
All subjects who qualified were to have been given two options: 
1) To receive no further treatment and proceed directly to the Induction Therapy Follow-up Period 
(Week 16 through Week 26); or  
2) To continue in double-blind LTE Therapy and receive 10 additional treatments of KHK4083 (at the 
same dose administered to that subject during Induction Therapy) or placebo as maintenance 
therapy. Each subject will receive one IV infusion every 4 weeks from Week 12 to Week 48 
followed by an End-of-LTE Therapy visit at Week 52, and then proceed to the LTE Therapy 
Follow-up Period (Week 56 through Week 64).  
Note:   Subjects who already started treatments in the double-blind LTE therapy will continue to 
receive KHK4083 or placebo during LTE Therapy. If their UC worsens or flares up to the Week 28 
visit, they may transition to the OLE 
Subjects who did not qualify were to have received no further treatment and entered the Induction Therapy 
Follow-up Period.  
Subjects in the double-blind LTE may enter the OLE up to the Week 28 visit if their UC worsens or flares. 
Open-label Extension Therapy:  Week 12 (First Dose) to Week 52 
Subjects who complete double-blind Induction Therapy (i.e., at least five of six treatments) are eligible to 
continue in open-label treatment OLE Therapy (refer to Section 7.4 for specific eligibility criteria).  
 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
13 
 
Name of Sponsor/Company: 
Kyowa Kirin Pharmaceutical 
Development, Inc. 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
KHK4083 
Name of Active Ingredient: 
KHK4083 
 
All subjects who qualify will be given two options: 
1) To receive no further treatment and proceed directly to the Induction Therapy Follow-up Period 
(Week 16 through Week 26); or  
2) To receive 10 treatments of open-label KHK4083 (at the same dose administered to that subject 
during Induction Therapy) as maintenance therapy. Each subject will receive one IV infusion every 
4 weeks from Week 12 to Week 48 followed by an End-of-OLE Therapy visit at Week 52, and then 
proceed to the OLE Therapy Follow-up Period (Week 56 through Week 64). 
Subjects who do not qualify will receive no further treatment and will enter the Induction Therapy Follow-up 
Period. 
Each subject must be carefully monitored at the investigative site for signs of acute, potential dose-limiting 
toxicity infusion reactions during and for at least 3 hours following the completion of the first and second 
intravenous (IV) infusions of the open-label, investigational product, and for at least 1 hour following all other 
IV infusions. In addition, a phone call to each subject will be conducted at approximately 48 to 72 hours 
following the completion of the first and second infusions for any subject who does not return for a visit at the 
investigative site. 
End-of-Treatment Visit 
An End-of-Treatment visit must be conducted for all subjects who discontinue from treatment. This visit must 
occur within 2 weeks or 4 weeks after the last dose of investigational product of Induction Therapy or OLE/LTE 
Therapy, respectively. If the subject discontinues during Induction Therapy, a sigmoidoscopy will be performed 
at End-of-Treatment/Week 12 if the subject discontinues more than 8 weeks after Baseline visit; the 
sigmoidoscopy may be performed up to 4 weeks after the last dose of study medication.  
If the subject discontinues during OLE/LTE therapy, a sigmoidoscopy will be performed at End-of-
Treatment/Week 52 if the subject discontinues more than 8 weeks after the Week 12 visit; the sigmoidoscopy 
may be performed up to 8 weeks after the last dose of study medication.  
End-of-Study Visit 
If the subject is withdrawn from the study, and thus no subsequent visits are planned, then the Investigator must 
complete all applicable final visit procedures. 
Post-treatment Follow-up Period: 
Three on-site follow-up visits for post-treatment assessments will be conducted at Weeks 16, 20, and 26 for 
subjects who only receive Induction Therapy or at Weeks 56, 60, and 64 for subjects who receive both Induction 
and OLE/LTE Therapies. Subjects removed from the study for adverse events (AEs) will be followed until there 
is a return to the subject’s baseline condition, or until a clinically satisfactory resolution is achieved.  
Primary Endpoints: 
Subjects with moderately active UC will primarily be evaluated for an improvement in the mucosa determined by 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
14 
 
Name of Sponsor/Company: 
Kyowa Kirin Pharmaceutical 
Development, Inc. 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
KHK4083 
Name of Active Ingredient: 
KHK4083 
 
their mMES (subscores from 0 to 3, with modified endoscopy finding scoring, i.e., by excluding mild friability 
from a subscore of 1) at completion of double-blind Induction Therapy. The primary efficacy endpoint will be 
the mean change in the mMES from Baseline (Week 0) to Week 12 for all subjects who receive the 
recommended dose in Parts A and B. 
The safety and tolerability of KHK4083 will be determined by physical examination, vital signs, body weight, 
12-lead electrocardiograms (ECGs), and clinical laboratory findings; and the number and percentage of subjects 
reporting AEs, serious adverse events (SAEs), and treatment discontinuation due to AEs.  
Selection of Subjects:  
Subjects may be included in the study if they meet all of the following Inclusion Criteria: 
1) Subject is able and willing to comply with study procedures, and to adhere to dosing and visit 
schedules and follow-up procedures as described in the protocol and ICF; 
2) Subject voluntarily signs/dates an Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)-approved ICF in accordance with regulatory and institutional guidelines; 
Note:  Written informed consent must be obtained prior to performing any study-related procedure. 
3) Male and female subjects  18 years of age at the time of enrollment; 
4) Subject has UC that was diagnosed at least 6 months prior to the Screening visit; 
5) Subject has moderately active UC, defined as: 
a) Total Mayo Clinic score of 4 to 9 (range:  0 to 12, with higher scores indicating more disease 
activity); 
b) Endoscopy subscore (mMES determined by a central reader) of at least 2; and 
c) Disease that extends  15 cm from the anal verge. 
6) Subject has had previous treatment (within 5 years prior to Screening) with one or more of the 
following:  corticosteroids, immunosuppressive medications, or tumor necrosis factor (TNF) 
antagonist therapy that was unsuccessful because of a lack of efficacy response or AEs, as defined 
below: 
a) corticosteroids for induction therapy of at least prednisolone-equivalent of 20 mg (or oral 
budesonide 9 mg) oral daily for 2 weeks or injectable for 1 week, or for maintenance therapy at 
least two failed attempts to reduce to less than prednisolone-equivalent 10 mg (or oral 
budesonide 3 mg) oral daily, or a history of intolerance to corticosteroids (including but not 
limited to hypertension, insomnia, osteopenia, osteoporosis, hyperglycemia, infection or 
Cushing’s syndrome); 
b) Azathioprine or 6-mercaptopurine of at least 1.5 mg/kg/day or 0.75 mg/kg/day, respectively, 
for 8 weeks, or a history of intolerance to either agent (including but not limited to nausea, 
vomiting, abdominal pain, aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) elevations, thiopurine methyltransferase genetic mutation, or infection); 
c) tumor necrosis factor-alpha antagonists for induction therapy with approved anti-TNF products 
including, but not limited to, infliximab 5 mg/kg IV for 2 doses at least 2 weeks apart, 
adalimumab 160 mg SC followed by at least 80 mg SC at least 2 weeks apart, and golimumab 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
15 
 
Name of Sponsor/Company: 
Kyowa Kirin Pharmaceutical 
Development, Inc. 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
KHK4083 
Name of Active Ingredient: 
KHK4083 
 
200 mg SC followed by at least 100 mg at least 2 weeks apart and anti-TNF biosimilar 
products with approved dosages for 2 doses at least 2 weeks apart; or as maintenance therapy 
for recurrence of symptoms despite continued dosing, or history of intolerance (including but 
not limited to infusion or injection reactions, demyelination or infection).  
7) Female subjects who are considered to be women of childbearing potential (WOCBP) must have a 
negative pregnancy test at Screening and Baseline. WOCBP must agree to use effective 
contraception, defined as oral contraceptives with one barrier method, or tubal ligation with one 
barrier method or double barrier method (condom plus spermicide or diaphragm plus spermicide) 
during the study and for at least 6 months after the last dose of investigational product. Subjects are 
considered to not be of childbearing potential if they are ≥ 50 years of age and without menses for 
24 consecutive months and have a follicle-stimulating hormone level > 25 mIU/mL (or in 
postmenopausal range per local laboratory standards); or have undergone a hysterectomy and/or a 
bilateral salpingo-oophorectomy.  
Egg donation is not permitted while on study medication and for at least 6 months after the last dose 
of study medication. 
8) Male subjects (including those who have had a vasectomy) must use adequate contraception (e.g., 
latex condom, non-latex condom not made of natural animal membrane such as polyurethane 
condom) during the study and for at least 6 months after the last dose of investigational product. 
Sperm donation is not permitted while on study medication and for at least 6 months after the last 
dose of study medication. 
Subjects must be excluded from participating in this study if they meet any of the following Exclusion Criteria: 
1) Subject, who, for any reason, is judged by the Investigator to be inappropriate for this study, 
including a subject who is unable to communicate or cooperate with the Investigator, who has/had a 
psychiatric illness, disability or social situation that may compromise the safety of the subject 
during the study or affect the ability of the subject to adhere to study procedures; 
2) Subject has a medical history of clinically significant (as determined by the Investigator or the 
Sponsor) cardiac, renal, hepatic/biliary (e.g., sclerosing cholangitis), pulmonary, or other medical 
conditions or is not generally in good health. 
Subjects with the history of immunologic, autoimmune or chronic inflammatory disorders (e.g., 
uveitis, rheumatoid arthritis, ankylosing spondylitis or spondyloarthritis, psoriasis) other than UC or 
autoimmune connective tissue diseases (e.g., systemic lupus erythematosus, systemic sclerosis) and 
are well controlled may be included into the trial after consultancy with medical monitor. Subjects 
with thyroid disorders, vitiligo, or alopecia are eligible for inclusion. 
3) Subject’s UC had failed to respond to:  
a) Two or more biologic treatments with different mechanisms of action (e.g., infliximab and 
vedolizumab), or  
b) Three or more anti-TNF biologics (e.g. infliximab, adalimumab, and golimumab).  
4) Subject requires prescription treatment for UC, except for the stable, oral treatment of UC, as 
follows: 
a) Aminosalicylates (5-aminosalicylic acid [5-ASA] or mesalamine ≤ 4.8 g/day; sulfasalazine 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
16 
 
Name of Sponsor/Company: 
Kyowa Kirin Pharmaceutical 
Development, Inc. 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
KHK4083 
Name of Active Ingredient: 
KHK4083 
 
≤ 3 g/day) for at least 14 days prior to the Screening visit; and/or 
b) Glucocorticoids (≤ 20 mg/day prednisolone or the equivalent, or budenoside ≤ 9 mg/day) for at 
least 14 days prior to the Screening visit (or for 4 weeks if a course of corticosteroids had 
started at less than 8 weeks prior to Screening visit); and/or 
c) Azathioprine up to 3 mg/kg/day or 6-mercaptopurine up to 1.5 mg/kg/day for a total treatment 
period of at least 12 weeks, including 4 weeks of stable treatment, prior to the Screening visit. 
5) Subject has received any of the following prior treatments or treatments within the specified time: 
a) Natalizumab, efalizumab or rituximab or other lymphocyte-depleting treatments, including but 
not limited, to alkylating agents (such as cyclophosphamide or chlorambucil) and total 
lymphoid irradiation at any time prior to randomization (Baseline visit);  
b) TNF antagonists within 8 weeks, or 5 half-lives (based on maximum duration but not 
exceeding 12 weeks), prior to randomization (Baseline visit); 
c) Vedolizumab within 16 weeks prior to randomization (Baseline visit);  
d) Methotrexate, cyclosporine, mycophenolate, tacrolimus, thalidomide, or other immune altering 
drugs within 4 weeks prior to randomization (Baseline visit) (ophthalmologic preparations are 
permitted); 
e) 5-ASA enema, or steroid enema or suppository use within 2 weeks prior to randomization 
(Baseline visit); and/or 
f) 
Investigational agents within 8 weeks or 5 half-lives (if pharmacology information is available) 
prior to randomization (Baseline visit), whichever is longer. 
6) Subject with recent (within 1 year prior to Screening), suspected or confirmed symptomatic stenosis 
of the colon, abdominal abscess, or ischemic colitis based on clinical or radiographic data; or who 
has suspected, confirmed or a history of toxic megacolon; or with any colonic resection, subtotal or 
total colectomy, ileostomy, or colostomy; or who had any previous surgery for UC or an anticipated 
requirement for surgery for UC; 
7) Subject with known colonic dysplasia, adenomas or polyposis; 
8) Subject had major surgery within 4 weeks prior to Screening or an anticipated requirement for 
major surgery; 
9) Subject with enteric pathogens (including Clostridium difficile) detected on stool analysis; or 
Clostridium difficile infection within 8 weeks prior to Screening; or intestinal pathogen infection 
detected within 4 weeks prior to Screening; 
10) Subject with any of the following hematological and chemistry laboratory values: 
a) Platelet count < 100,000/mm3; 
b) Neutrophils < 1500/mm3; 
c) Serum creatinine ≥ 1.6 mg/dL (≥ 144.4 μmol/L); 
d) Alkaline phosphatase > 3 times the upper limit of normal (ULN); 
e) Aspartate aminotransferase or ALT > 2 times ULN; 
f) 
Total bilirubin > 2 mg/dL, unless due to Gilbert’s Syndrome; 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
17 
 
Name of Sponsor/Company: 
Kyowa Kirin Pharmaceutical 
Development, Inc. 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
KHK4083 
Name of Active Ingredient: 
KHK4083 
 
g) Serum albumin < 3 g/dL; 
h) Hemoglobin < 9 g/dL; 
i) 
Glycated serum hemoglobin A1c ≥ 9%. 
11) Subject has a clinically significant cardiac disease (class II, III, or IV of the New York Heart 
Association classification) (The Criteria Committee of the New York Heart Association 
Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels, 1994); 
unstable angina pectoris; myocardial infarction within 6 months or is post angioplasty or stenting 
within 6 months; uncontrolled hypertension; or clinically significant abnormality, such as cardiac 
arrhythmia, on a 12-lead ECG at Screening; 
12) Subject is pregnant or breastfeeding; 
13) Subject has had a major immunologic reaction (e.g., serum sickness, anaphylaxis, or anaphylactoid 
reaction); 
14) Subject is Hepatitis B core antibody or surface antigen positive at Screening and/or Hepatitis C 
antibody positive with detectable RNA at Screening; 
15) Subject has a history of human immunodeficiency virus (HIV) positivity, tests positive for HIV at 
Screening, or has congenital or acquired immunodeficiency; 
16) Subject has or has had active tuberculosis (TB), suspected extra-pulmonary TB, a history of 
incompletely treated TB, or latent TB or other latent infection. Subjects with latent TB (purified 
protein derivative [PPD] or interferon gamma release assay [IGRA]) may be included in the study if 
prophylactic therapy for latent TB is started at least 4 weeks prior to Screening. Subjects with a 
potentially untreated other infection (clinical findings) are to be excluded.  
Note:  Performing of both IGRA and PPD tests in the same subject should be avoided as screening 
procedures. Positivity of one of the tests cannot be voided by negativity of the other, i.e., subjects 
with positive PPD and negative IGRA test performed as a part of Screening will be considered TB 
positive and will be required to start prophylactic anti-TB therapy prior to infusion of 
investigational product according to local treatment standards. All safety laboratory tests may be 
repeated. Screening procedures may be extended by 2 weeks. 
17) Subject has bacterial infections requiring treatment with oral or parenteral antibiotics (topical 
antibiotics are allowed), within 2 and 4 weeks, respectively, of the Screening period;  
18) Subject has a history of systemic opportunistic infection or recurrent infections; 
19) Subject has malignancy or history of malignancy, except for adequately treated basal cell skin 
cancer or adequately treated carcinoma in-situ of the cervix without recurrence, and treatment must 
have been completed at least 5 years before the Screening Period; 
20) Subject who received a bacille Calmette-Guérin (BCG) vaccine within 6 months of randomization 
or live vaccination (e.g., measles, mumps, rubella [MMR]; herpes zoster; varicella; intranasal 
influenza; and oral poliomyelitis) within 4 weeks of randomization is to be excluded. Subject is 
allowed vaccinations of inactivated vaccines (e.g., hepatitis, pneumococcal, meningococcal, 
tetanus, diphtheria toxoid, acellular pertussis, inactivated polio, human papilloma and influenza – 
except intranasal influenza); 
21) Subject with a history of substance abuse within 1 year of Screening; or active marijuana 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
18 
 
Name of Sponsor/Company: 
Kyowa Kirin Pharmaceutical 
Development, Inc. 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
KHK4083 
Name of Active Ingredient: 
KHK4083 
 
(medicinal or recreational) use or active substance abuse; 
22) Subject has other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational product 
administration, or may interfere with the interpretation of study results, as determined by the 
Investigator; 
23) Subject who previously participated in a study of KHK4083. 
Note:  A subject who was considered a Screen failure and not dosed with investigational product in 
the current study (4083-002) is permitted to be re-screened once due to failure to meet the 
Inclusion/Exclusion Criteria, whereas subjects with other reasons for lack of randomization may be 
re-screened twice.  
Additional Criteria to Enroll in OLE Therapy: 
Prior to receiving one infusion every 4 weeks of KHK4083 in the OLE, subjects must meet the following criteria: 
1) Subjects must have completed double-blind Induction Therapy, i.e., at least five of six double-blind 
treatments, or the subject is already in the double-blind LTE and not beyond Week 28 with a clinical 
worsening or a flare of disease as defined by the Investigator); 
2) Subjects must have evaluable total Mayo Clinic scores at baseline and Week 12;  
3) Subjects must have been compliant with the protocol (including concomitant medication restrictions); 
and 
4) Subjects may have no clinically significant additional risks, as determined by the Investigator or the 
Sponsor, of treatment with KHK4083. 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
19 
 
Name of Sponsor/Company: 
Kyowa Kirin Pharmaceutical 
Development, Inc. 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
KHK4083 
Name of Active Ingredient: 
KHK4083 
 
Number of Subjects Planned:  Assuming a 15% dropout rate, it is anticipated that approximately 60 subjects 
will be required to be randomized in order to achieve 51 evaluable subjects in the Full Analysis Set.  
Treatment of Subjects:  
Duration of Treatment:  A total of up to 52 weeks of double-blind treatment includes 12 weeks of Induction 
Therapy (Part A and Part B) and 40 weeks of OLE/LTE Therapy.  
Induction Therapy (12 weeks): 
• 
Part A (Cohorts 1 - 3):  Each subject will be administered one IV infusion of KHK4083 or placebo once 
every 2 weeks for a total of 6 treatments, i.e., on Day 1 (Week 0), Day 15 (Week 2), Day 29 (Week 4), 
Day 43 (Week 6), Day 57 (Week 8), and Day 71 (Week 10).  
• 
Part B (Cohort 4):  Each subject will be administered an IV infusion of the recommended KHK4083 dose 
selected in Part A (one of three dose levels in Cohorts 1 - 3) or placebo once every 2 weeks for a total of 
6 treatments.  
Investigational Product:  
• 
Part A (Cohorts 1 - 3):  KHK4083 1.0 mg/kg (Cohort 1); 3.0 mg/kg (Cohort 2); and 10 mg/kg (Cohort 3).  
• 
Part B (Cohort 4):  KHK4083 recommended dose (one of three dose levels in Cohorts 1 - 3). 
Control (Cohorts 1 - 4):  Placebo IV infusion as treatment during Induction Therapy.  
Open-label / Long-term Extension Maintenance Therapy:  Week 12 (First Dose) to Week 52 
All subjects who qualify and continue double-blind LTE or start open-label maintenance therapy will be 
administered one KHK4083 or placebo (LTE) or one KHK4083 (OLE) IV infusion at Weeks 12, 16, 20, 24, 28, 
32, 36, 40, 44, and 48 for a total of 10 additional treatments. Some subjects in the LTE may transition to the OLE 
after Week 12 and up to Week 28. The treatment at Week 12 will be administered at the scheduled visit or within 
7 days after Week 12.  
Efficacy, Pharmacokinetics, Pharmacodynamics, Immunogenicity, and Safety Variables 
Efficacy: 
The efficacy variables include mMES, UCEIS score, modified Baron endoscopic score, total Mayo Clinic score, 
partial Mayo Clinic score (without sigmoidoscopy), and an IBDQ score.  
Pharmacokinetics: 
The PK variables include maximum observed serum concentration (Cmax), time of maximum observed serum 
concentration (tmax), trough concentration at the end of the dosing interval (Cmin), area under the serum 
concentration-time curve (AUC0-t, AUC0-τ, AUC0-∞), terminal elimination half-life (t1/2), systemic serum 
clearance (CLs), volume of distribution at steady state (Vss), volume of distribution at terminal phase (Vz), and 
accumulation ratio (Rac). 
Pharmacodynamics: 
The PD variables include the measurement of fecal calprotectin and C-reactive protein (using wr-CRP assay) 
concentrations. Other PD assessments include delayed-type hypersensitivity skin testing with the Candida 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
20 
 
Name of Sponsor/Company: 
Kyowa Kirin Pharmaceutical 
Development, Inc. 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
KHK4083 
Name of Active Ingredient: 
KHK4083 
 
albicans antigen (at all investigative sites in the US and in other selected countries), immunohistochemical 
staining on all endoscopic biopsy samples, and flow cytometry analyses on whole blood or peripheral blood 
mononuclear cells for the measurement of specific immune-related cells. 
Immunogenicity: 
For immunogenicity, the development of anti-KHK4083 antibodies will be assessed.  
Safety: 
The safety variables include AEs (including SAEs), physical examinations, vital signs, body weight, 12-lead 
ECGs, and clinical laboratory evaluations (serum chemistry, hematology, coagulation profile, multiplex-31 
assays, and urinalysis).  
Safety Management and Monitoring: 
Kyowa Kirin Pharmaceutical Development, Inc. 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. The Safety Monitoring Committee will 
evaluate the cumulative safety data available after the first 8 subjects (1.0 mg/kg dose cohort) at Week 4. For 
subsequent dose escalation, the Safety Monitoring Committee will evaluate the cumulative safety data available 
and after the first 8 subjects in a cohort at Week 4 and with the first 4 subjects in a cohort at Week 6 for the 3.0 
and 10 mg/kg dose cohorts. At each of the timepoints, the committee will assess whether dosing will continue for 
all subjects and if the investigational product will be administered at the next higher dose level for subjects in the 
next cohort in Part A or for Cohort 4 in Part B. A separate Safety Monitoring Committee Charter will identify the 
membership and define the specific procedures of the committee. 
Statistical Methods and Planned Analysis:  
All categorical variables will be summarized by counts and percentages. Descriptive statistics (mean, standard 
deviation, median, minimum, and maximum) for continuous variables will be utilized. All summaries and 
analyses conducted will be by treatment cohort (KHK4083 dose levels; combined KHK4083; and placebo) and 
by visit. The last pre-administration observation will be used as the Baseline value for calculating post-
administration changes from Baseline. All data obtained on the electronic case report form and entered into the 
database will be provided in separate data listings showing individual subject values. 
The following analysis sets will be used in the study: 
Safety Analysis Set:  Includes all subjects who received any investigational product (even a partial dose); 
Full Analysis Set:  Includes all subjects who receive at least one full dose of investigational product and who 
have Baseline data and at least one post-treatment assessment of the primary efficacy variable.  
Treatment-emergent adverse events (TEAEs) will be grouped and tabulated by the Medical Dictionary for 
Regulatory Activities Preferred Term and System Organ Class. All TEAEs will be summarized showing the 
number and percentage of subjects for each event with a start time within the Treatment Period (i.e., Induction 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
21 
 
Name of Sponsor/Company: 
Kyowa Kirin Pharmaceutical 
Development, Inc. 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
KHK4083 
Name of Active Ingredient: 
KHK4083 
 
Therapy and LTE or OLE Therapy) and by cohort (KHK4083 versus placebo) during Induction Therapy, OLE or 
LTE Therapy. 
The overall safety and tolerability of KHK4083 compared to placebo administered in multiple IV doses will be 
determined for all safety variables.  
All efficacy analyses will be performed in the FAS unless otherwise specified. All statistical analyses in this 
Phase 2 study will be descriptive or exploratory, and no adjustment to control Type I error will be performed. 
Pharmacokinetic, Pharmacodynamic, and Immunogenicity Methods: 
The PK parameters (i.e., Cmax, tmax, Cmin, AUC0-t, AUC0-τ, AUC0-∞, t1/2, CLs, Vss, Vz, and Rac) for KHK4083 will 
be summarized by dose level and Treatment Period. The dose proportionality of KHK4083 PK exposure 
parameters will be assessed using the Power Model for Cohorts 1 - 3 (Induction Therapy - Part A and LTE 
Therapy). The PK exposure parameters include Cmax, AUC0-t, and AUC0-∞, as appropriate.  
The PD parameters will be determined and summarized by dose level and Treatment Period. The PK-PD 
relationships will be explored using graphic tools or modeling as needed.  
The immunogenicity of KHK4083 will be determined and the percentage of subjects with confirmed 
anti-KHK4083 antibodies will be summarized by dose level and Treatment Period, visit (week), and overall. The 
effect of positive anti-KHK4083 antibodies on the PK, and possibly efficacy and safety, will be explored. 
Serum samples, which will be collected at specified times throughout the study, will be assessed using 
multiplex-31 assays at four sample collection timepoints:  Baseline (Week 0), Week 2, Week 12 
(End-of-Induction Therapy), and Week 52 (End-of-OLE/LTE Therapy) or at a follow-up visit if the subject does 
not continue in OLE/LTE Therapy. For other potential study assessments (e.g., exploratory biomarker analyses), 
whole blood samples will be collected and stored (frozen) for future analysis.  


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
22 
 
2 
TABLE OF CONTENTS 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE .........................................................2 
PROTOCOL SIGNATURE PAGE ........................................................................................3 
SUMMARY OF CHANGES ...................................................................................................4 
ADVERSE EVENT CONTACTS ...........................................................................................8 
1 
SYNOPSIS ......................................................................................................................9 
2 
TABLE OF CONTENTS ............................................................................................22 
LIST OF IN-TEXT TABLES ................................................................................................27 
LIST OF IN-TEXT FIGURES ..............................................................................................27 
LIST OF APPENDICES ........................................................................................................27 
3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................28 
4 
BACKGROUND INFORMATION ...........................................................................30 
4.1 
Ulcerative Colitis ........................................................................................................30 
4.2 
Current Treatment of Ulcerative Colitis and Associated Benefit/Risks .....................32 
4.3 
KHK4083 - Investigational Product ...........................................................................33 
4.3.1 
KHK4083 Development .........................................................................................33 
4.3.2 
Nonclinical Development .......................................................................................34 
4.3.3 
Clinical Program .....................................................................................................35 
5 
OBJECTIVES ..............................................................................................................35 
6 
STUDY DESIGN..........................................................................................................37 
6.1 
Overall Study Design and Plan...................................................................................37 
6.1.1 
Induction Therapy:  Week 0 to Week 12 (Last Dose at Week 10) .........................40 
6.1.2 
Long-term Extension Therapy:  Week 12 (First Dose) to Week 52 .......................40 
6.1.3 
Open-label Extension Therapy:  Week 12 (First Dose) to Week 52 ......................41 
6.1.4 
Transitioning from the Long-term Extension to the Open-label 
Extension ................................................................................................................41 
6.2 
Study Rationale ..........................................................................................................42 
6.3 
Study Safety Monitoring Plan ....................................................................................42 
6.4 
Study Timeframe ........................................................................................................44 
6.5 
Risks and Benefits to Subjects ...................................................................................44 
6.5.1 
Risks ........................................................................................................................44 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
CONFIDENTIAL 
23 
 
6.5.2 
Benefits ...................................................................................................................45 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................45 
7.1 
Procedures for Enrollment ..........................................................................................45 
7.2 
Inclusion Criteria ........................................................................................................46 
7.3 
Exclusion Criteria .......................................................................................................47 
7.4 
Additional Criteria to Enroll in Open-label Extension Therapy ................................50 
7.5 
Withdrawal and Termination Criteria ........................................................................51 
7.5.1 
Subject Withdrawal .................................................................................................51 
7.5.2 
Study or Investigative Site Termination .................................................................52 
7.5.3 
Criteria for Subject Removal from Treatment and the Study .................................52 
7.5.4 
End-of-Treatment Visit ...........................................................................................54 
7.5.5 
End-of-Study Visit ..................................................................................................54 
7.6 
Replacement of Subjects ............................................................................................55 
8 
TREATMENT OF SUBJECTS ..................................................................................55 
8.1 
Investigational Product(s) ...........................................................................................55 
8.1.1 
Recommended Storage and Use Conditions ...........................................................55 
8.1.2 
Investigational Product Destruction ........................................................................56 
8.1.3 
Dosage and Administration ....................................................................................56 
8.1.3.1 
Selection of Doses ...............................................................................................56 
8.1.3.2 
Administration .....................................................................................................58 
8.1.3.3 
Infusion Reactions ...............................................................................................58 
8.1.3.4 
Dose Modifications .............................................................................................60 
8.1.4 
Treatment Period (Weeks 0 to 52) ..........................................................................60 
8.1.4.1 
Induction Therapy: Weeks 0 to 12 (Last Dose:  Week 10) .................................60 
8.1.4.2 
Open-label/Long-term Extension Maintenance Therapy:  Week 12 
(First Dose) to Week 52 ......................................................................................61 
8.1.5 
Post-treatment Follow-up Period ............................................................................62 
8.2 
Method of Numbering Subjects and Assigning Subjects to Treatment 
Cohorts or Randomization ..........................................................................................62 
8.3 
Blinding During the Double-blind Treatment Period (Induction Therapy 
and Long-term Extension Therapy) ............................................................................62 
8.4 
Unblinding During the Treatment Period and After Induction Therapy 
and Long-term Extension Therapy .............................................................................63 


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8.5 
Prior and Concurrent Therapy ....................................................................................64 
8.5.1 
Prohibited Treatment ..............................................................................................65 
8.6 
Treatment Compliance ...............................................................................................65 
8.6.1 
Study Visit Outside of Planned Scheduled - Delay in Dosing ...............................65 
9 
STUDY PROCEDURES .............................................................................................66 
9.1 
Screening Period (Day −28 to Day −1) ......................................................................75 
9.2 
Baseline Visit (Week 0, Day 1) ..................................................................................76 
9.3 
Double-blind Treatment Period (Induction Therapy and Long-term 
Extension Therapy) and Open-label Extension Therapy ............................................78 
9.4 
Post-treatment Follow-up Period ................................................................................79 
10 
EFFICACY, 
PHARMACOKINETIC, 
PHARMACODYNAMIC, 
IMMUNOGENICITY, SAFETY, AND OTHER VARIABLES .............................80 
10.1 
Primary Endpoints ......................................................................................................81 
10.1.1 
Efficacy ...................................................................................................................81 
10.1.2 
Safety ......................................................................................................................81 
10.2 
Secondary Efficacy Endpoints ...................................................................................81 
10.3 
Exploratory Endpoints ................................................................................................82 
10.4 
Pharmacokinetic, Pharmacodynamic, Immunogenicity and Other Study 
Assessments ................................................................................................................83 
10.4.1 
Pharmacokinetic and Pharmacodynamic Assessments ...........................................83 
10.4.1.1 
Sampling 
Times 
and 
Assays 
for 
Pharmacokinetics 
and 
Pharmacodynamics (Flow Cytometry) ................................................................84 
10.4.1.2 
Sample Collection, Preparation, Labeling, and Storage ......................................88 
10.4.2 
Immunogenicity Assessments .................................................................................88 
10.4.3 
Other Potential Study Assessments ........................................................................88 
10.5 
Medical/Surgical History, Medication History, and Demographics ..........................89 
10.6 
Safety Assessments ....................................................................................................89 
10.6.1 
Clinical Laboratory Evaluation ...............................................................................90 
10.6.2 
Vital Signs ...............................................................................................................93 
10.6.3 
Electrocardiograms .................................................................................................93 
10.6.3.1 
Investigative Site Responsibilities .......................................................................93 
10.6.3.2 
ECG Core Laboratory Responsibilities ...............................................................93 
10.6.4 
Physical Examination .............................................................................................94 


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10.6.5 
Adverse Events .......................................................................................................94 
10.6.5.1 
Definitions ...........................................................................................................94 
10.6.5.2 
Assessment of Intensity .......................................................................................95 
10.6.5.3 
Assessment of Relationship .................................................................................95 
10.6.5.4 
Classifying Infusion Reactions ............................................................................96 
10.6.6 
Serious Adverse Events ..........................................................................................96 
10.6.6.1 
Notification of Institutional Review Board or Independent Ethics 
Committee of Serious Adverse Events ................................................................97 
10.6.6.2 
Adverse Event Contacts ......................................................................................97 
10.6.6.3 
Urgent Safety Measures ......................................................................................97 
10.6.7 
Adverse Event and Serious Adverse Event Reporting ...........................................98 
10.6.7.1 
Reporting of Infusion Reactions ..........................................................................99 
10.6.8 
Other Significant Adverse Events ...........................................................................99 
10.6.9 
Pregnancy Reporting .............................................................................................100 
10.6.10 
Safety Management during the Study ...................................................................100 
10.7 
Appropriateness of Measurements ...........................................................................101 
11 
DATA HANDLING AND QUALITY ASSURANCE ............................................101 
11.1 
Electronic Case Report Forms and Source Documentation .....................................101 
11.2 
Clinical Data Management .......................................................................................101 
11.3 
Archiving ..................................................................................................................102 
12 
STATISTICAL METHODS AND PLANNED ANALYSIS ..................................102 
12.1 
General Statistical Considerations ............................................................................102 
12.2 
Populations to be Analyzed ......................................................................................102 
12.2.1 
Subject Disposition ...............................................................................................103 
12.2.2 
Demographic and Baseline Disease Characteristics .............................................103 
12.2.3 
Prior and Concomitant Medications .....................................................................103 
12.2.4 
Investigational Product Exposure and Compliance ..............................................103 
12.3 
Efficacy Analysis......................................................................................................104 
12.3.1 
Primary Efficacy Analysis ....................................................................................104 
12.3.2 
Secondary Efficacy Analyses ...............................................................................104 
12.3.3 
Exploratory Efficacy Analysis ..............................................................................105 
12.3.4 
Sample Size Determination ..................................................................................106 


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12.3.5 
Significance Level ................................................................................................106 
12.4 
Pharmacokinetic, Pharmacodynamic, and Immunogenicity Analyses .....................106 
12.4.1 
Pharmacokinetic Analyses ....................................................................................106 
12.4.2 
Pharmacodynamic Analyses .................................................................................107 
12.4.3 
Immunogenicity Analyses ....................................................................................107 
12.5 
Analyses of Safety Data ...........................................................................................108 
12.6 
Procedures for Missing, Unused, and Spurious Data ...............................................108 
12.7 
Rules for Excluding Subjects from Analysis............................................................108 
12.8 
Procedures for Reporting Deviations from Original Statistical Plan .......................109 
13 
SPECIAL REQUIREMENTS AND PROCEDURES ............................................109 
13.1 
Institutional Review..................................................................................................109 
13.2 
Ethical Considerations ..............................................................................................109 
13.3 
Investigator’s Responsibilities ..................................................................................110 
13.3.1 
Overall Responsibilities ........................................................................................110 
13.3.2 
Subject Informed Consent ....................................................................................110 
13.3.3 
Confidentiality Regarding Study Subjects ............................................................110 
13.4 
Study Monitoring......................................................................................................111 
13.4.1 
Direct Access to Source Data/Documents ............................................................111 
13.5 
Audit and Inspection.................................................................................................111 
13.5.1 
Record Retention ..................................................................................................111 
13.5.2 
Investigator Information .......................................................................................111 
13.5.3 
Compliance with Law, Audit, and Debarment .....................................................112 
13.5.4 
Administrative ......................................................................................................113 
13.6 
Financial Disclosure .................................................................................................113 
13.7 
Insurance...................................................................................................................114 
13.8 
Publication Policy .....................................................................................................114 
14 
REFERENCES...........................................................................................................115 
15 
APPENDICES/ATTACHMENTS ...........................................................................119 
 


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List of In-text Tables 
Table 8.1.3-1 
Simulated Pharmacokinetic Parameters for the KHK4083 Once 
Every 2 Weeks Dosing Regimen................................................... 57 
Table 8.1.3-2 
Safety Margins for the Planned KHK4083 Doses......................... 58 
Table 9-1 
Study Schedule of Events - Screening, Induction Therapy, and 
Follow-up Period ........................................................................... 67 
Table 9-2 
Study Schedule of Events - Open-label/Long-term Extension 
Maintenance Therapy and Follow-up Period ................................ 72 
Table 10.4.1-1 
Cohorts 1 - 3:  Sample Collection Schedule During Induction 
Therapy (Part A), Long-term Extension, and Open-label 
Extension Therapy for Pharmacokinetics and Pharmacodynamics 
(Flow Cytometry) .......................................................................... 85 
Table 10.4.1-2 
Cohort 4:  Sample Collection Schedule During Induction 
Therapy (Part B) and Long-term Extension Therapy and Open 
Label Extension Therapy for Pharmacokinetics and 
Pharmacodynamics (Flow Cytometry) .......................................... 87 
Table 10.6.1-1 
Clinical Laboratory Assessments .................................................. 91 
 
List of In-text Figures 
Figure 6.1-1 
Study Design Diagram .................................................................. 39 
Figure 8.1-1 
Simulated Pharmacokinetic Profiles Following Multiple-dose 
Administration of KHK4083 for Study 4083-002 ........................ 57 
 
List of Appendices 
Appendix 1 
Primary and Secondary Efficacy Definitions .............................. 120 
Appendix 2 
Mayo Clinic Scoring System for Assessment of Ulcerative 
Colitis Activity (Score 0 to 12) with Modified Mayo Endoscopy 
Subscore ...................................................................................... 121 
Appendix 3 
Modified Baron Endoscopic Scoring System (5-point Scale) ..... 122 
Appendix 4 
Ulcerative Colitis Endoscopic Index of Severity ........................ 123 
Appendix 5 
Clinical Criteria for the Diagnosis of Anaphylaxis ..................... 124 
Appendix 6 
Follow-up and End-of-Study for Subjects who Discontinued 
During the Study ......................................................................... 126 
 


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3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
APC 
antigen-presenting cell 
ASA 
aminosalicylic acid 
AST 
aspartate aminotransferase 
BCG 
bacille Calmette-Guérin 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulations 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HEENT 
head, eyes, ears, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRQL 
health-related quality of life 
IBD 
inflammatory bowel disease 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IGRA 
interferon gamma release assay 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IV 
intravenous 
KKD 
Kyowa Kirin Pharmaceutical Development, Inc.  
LTE 
long-term extension 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
mMES 
modified Mayo endoscopy subscore 
NOAEL 
no-observed-adverse-effect level 
OECD 
Organisation for Economic Co-operation and Development 
OLE 
open-label extension 
PBMC 
peripheral blood mononuclear cell 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PPD 
purified protein derivative 


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Abbreviations (continued) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
TNF 
tumor necrosis factor 
TNF-α 
tumor necrosis factor-alpha 
TNFR 
tumor necrosis factor receptor 
UC 
ulcerative colitis 
UCEIS 
Ulcerative Colitis Endoscopic Index of Severity 
ULN 
upper limit of normal 
US 
United States 
WOCBP 
women of childbearing potential 
wr-CRP 
wide-range C-reactive protein 
Definitions (Refer to Appendix 1 for Primary and Secondary Efficacy Definitions) 
AUC 
area under the concentration-time curve 
AUC0-t 
area under the serum drug concentration-time curve from 0 to the last measurable 
concentration 
AUC2wk 
area under the serum drug concentration-time curve at 2 weeks post-dose 
AUC0-τ 
area under the serum drug concentration-time curve within a dosing interval 
AUC0-∞ 
area under the serum drug concentration-time curve from 0 to infinity 
CLs 
systemic serum clearance 
Cmax 
maximum observed serum concentration 
Cmin 
trough concentration at the end of the dosing interval 
%CV 
percent coefficient of variation 
Rac 
accumulation ratio 
SD 
standard deviation 
t1/2 
terminal elimination half-life 
tmax 
time of maximum observed serum concentration 
Vss 
volume of distribution at steady state 
Vz 
volume of distribution at terminal phase 


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4 
BACKGROUND INFORMATION 
4.1 
Ulcerative Colitis 
Inflammatory bowel diseases (IBDs) comprise ulcerative colitis (UC) and Crohn's disease, 
which are considered to be common gastrointestinal autoimmune diseases, and are referred to 
as immune-mediated inflammatory diseases. (Mahmood, 2012; Khor, 2011) A peak 
incidence of UC occurs early in adult life (15 to 30 years) with a greater prevalence in males, 
nonsmokers or ex-smokers, and in developed countries. (Loftus, 2004; Hanauer, 2006) The 
global incidence rate of UC varies greatly from 0.5 to 24.5 per 100,000 persons. 
(Lakatos, 2006) 
Urbanization and variances in exposure to sunlight, pollution, and industrial chemicals are 
considered potential contributing factors to IBD. (Hanauer, 2006) Other factors such as diet, 
oral contraceptives, perinatal and childhood infections, or atypical mycobacterial infections 
have been suggested but not proven to play a role. (Loftus, 2004) 
Ulcerative colitis symptoms include abdominal pain/cramps, diarrhea that is usually bloody, 
and severe urgency to have a bowel movement. The symptoms can be intermittent with fairly 
long periods between flare-ups and remission. Fatigue and loss of appetite with subsequent 
weight loss are common. Complications can include severe abdominal bloating, bleeding 
from deep ulcerations, anemia, fulminant colitis, and toxic megacolon potentially leading to 
perforation of the colon. In addition, there may be skin lesions, joint pain, eye inflammation, 
and liver disorders. Patients with UC are at increased risk of colon cancer. (Centers for 
Disease Control and Prevention, IBD, 2015) 
Ulcerative colitis is characterized by inflammation limited to the colon that begins in the 
rectum and affects the superficial layers of the colon in an even and continuous distribution. 
The inflammatory changes are limited to the mucosa and submucosa with cryptitis and crypt 
abscesses. Ulcerative colitis is considered to result from an improper mechanism and 
continuing inflammatory response to commensal microbes and environmental conditions in 
patients with genetic risk factors. (Khor, 2011) The intestinal mucosa exists in a functional 
equilibrium with the complex luminal environment dominated by a spectrum of microbial 
species and their products. A functional balance is essential to maintaining normal mucosal 
physiology. In addition to nutrient absorption, intestinal epithelial cells perform both barrier 
and signal-transduction functions. Patients often have a compromised mucosa and an increase 
in presence of mucolytic bacteria. (Khor, 2011)  


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Genome-wide association studies have identified 99 non-overlapping genetic risk loci in IBD 
including 47 risk loci specific to UC of which approximately 30% (28) of IBD-related genetic 
loci are shared between UC and Crohn’s disease. (Franke, 2010; Anderson, 2011) Analyses 
of the genes and genetic loci that contribute to IBD susceptibility show a multitude of 
pathways that are critical for intestinal homeostasis, including barrier function, epithelial 
restitution, microbial defense, innate immune regulation, reactive oxygen species generation, 
autophagy, regulation of adaptive immunity, endoplasmic reticulum stress, and metabolic 
pathways associated with cellular homeostasis. Homeostasis in the gut involves a balance 
between anti-inflammatory and pro-inflammatory signals, whereas an inadequate T-reg-cell 
response occurs with a heightened response mainly involving Th2 cells in UC. (Khor, 2011)  
A recent study showed significantly enhanced apoptosis of circulating lymphocytes in IBD 
patients during flare-ups compared to remission and is considered to be possibly a 
consequence of the systemic disease process. (El-Hodhod, 2013) Increased circulating 
lymphocytes apoptosis may also be attributed to a deficiency in nutrients, which is common 
in IBD patients. (Bager, 2011; El-Hodhod, 2013; Nakajima, 2011; Levin, 2011; 
O’Malley, 2011; Yakut, 2010) 
Cells with high synthetic capacity and secretory activity (e.g., Paneth and goblet) have high 
baseline levels of endoplasmic reticulum stress, leading to activation of the unfolded protein 
response, which controls cellular programs that allow proper protein processing. This 
response is mainly cytoprotective, although it can signal apoptosis after sustained 
endoplasmic reticulum stress. (Khor, 2011) The role of apoptosis in intestinal lymphocytes in 
IBD shows that the inflamed gut T-cells have a resistance to apoptosis, a prolonged survival, 
and an increased cytokine production that may significantly aggravate the inflammation, 
whereas noninflamed gut T-cells have an increased susceptibility towards apoptosis that 
limits expansion of T-cells and down regulates mucosal immune responses. (Sturm, 2008)  
In addition to its effects on cell viability and disruption of normal intestinal homeostasis, due 
to an imbalance of production and apoptosis, sustained endoplasmic reticulum stress also 
activates autophagy and IL-23 release, and may engage inflammatory circuits that are 
subsequently propagated by T cells. (Goodall, 2010; Kaser, 2008; Khor, 2011) 
Apoptotic cells have been shown to actively suppress inflammatory responses by reducing 
the lifespan of activated lymphocytes. (Bodar, 2007; El-Hodhod, 2013; Fadok, 2001) Thus, 
apoptosis plays a critical role in lymphocyte development and homeostasis. Enhanced 
lymphocyte apoptosis can cause immunodeficiency through cell loss. Conversely, inhibition 
of apoptosis can lead to the development of autoimmunity or lymphoma. Two major 


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pathways contribute to the regulation of lymphocyte cell death, death by neglect and death by 
instruction. (El-Hodhod, 2013; Rathmell, 2002) Increased circulating lymphocyte apoptosis 
could also be considered as a protective mechanism against organ injury as increased 
lymphocyte apoptosis was found to be linked to anti-inflammatory cytokine secretion and 
thereby may contribute to preventing unwanted immune response and organ injury. 
(El-Hodhod, 2013; Neuman, 2007) 
The event that initiates the immune response in IBD has not been identified, but possible 
factors include a pathogenic and nonpathogenic organism, an immune response to an 
intraluminal antigen (e.g., protein from cow milk), or an autoimmune process. (Abraham, 
2011; El-Hodhod, 2013; Nell, 2010) During an immune response, homeostasis is disturbed as 
antigen-presenting cells (APCs) become activated and promote the clonal expansion of 
antigen-specific lymphocytes. Shortly after the peak of the response, controlled induction of 
apoptosis, of both APCs and lymphocytes, restores homeostasis. This process is critical to 
ensure protective immunity and avoid lymphoid neoplasia and autoimmunity. (El-Hodhod, 
2013; Hildeman, 2007) The influence of tumor necrosis factor (TNF) on the function of 
APCs varies as TNF can either activate APCs, augment antigen presentation capability, or 
upregulate the expression of costimulatory molecules, or TNF can inhibit the function of 
mature lymphocytes and possibly induce their apoptosis and impair antigen presentation to 
prevent the organ damage. It has been demonstrated that the addition of apoptotic 
lymphocytes to endotoxin-stimulated peripheral blood mononuclear cells (PBMCs) causes a 
shift from secretion of proinflammatory cytokines (TNF-α, IL-1β, and IL-12) to 
anti-inflammatory cytokines (IL-10). (Voll, 1997)  
4.2 
Current Treatment of Ulcerative Colitis and Associated Benefit/Risks 
Topical or oral 5-aminosalicylic acid (5-ASA) is the first line of treatment for mild to 
moderately active UC. Patients with persistently active disease are then typically given oral 
glucocorticoids to induce remission. Once remission is achieved, maintenance therapy, 
typically with 5-ASA, is recommended for those with left-sided colitis, pancolitis or 
extensive disease. 
Patients with severe UC are usually treated with oral glucocorticoids, high dose oral 5-ASA 
and topical therapy, and often receive antibiotic treatment as well as nutritional support. 
Patients with severe or corticosteroid-dependent disease receive additional treatment, such as 
azathioprine or 6-mercaptopurine, or a biologic agent. Tumor necrosis factor-alpha (TNF-α) 
blockers are used to treat autoimmune diseases, including Crohn's disease and UC, either 


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after first-line immunosuppressors (e.g., azathioprine or 6-mercaptopurine) or in association 
with these treatments. (Silva, 2010) 
The following are approved TNF-α blockers: 
• 
Chimeric IgG monoclonal antibody (mAb) infliximab (Remicade; Inflectra and Remsima 
- in the European Union [EU] only) - UC/Crohn’s disease 
• 
Human IgG mAb adalimumab (Humira) - UC/Crohn’s disease 
• 
Fully human mAb golimumab (Simponi) - UC 
• 
Pegylated humanized Fab’ fragment certolizumab pegol (Cimzia) - Crohn’s disease in the 
United States (US) only 
A humanized IgG1 mAb, vedolizumab (Entyvio®), which is an integrin receptor antagonist 
(i.e., binds to the human α4β7 integrin) is approved for both UC and Crohn’s disease in the 
US and EU.  
Serious and sometimes fatal adverse effects have been reported with TNF-α blockers 
(Silva, 2010), including infections due to bacterial, mycobacterial (e.g., tuberculosis [TB]), 
invasive fungal infections (e.g., histoplasmosis, aspergillosis, candidiasis, coccidiomycosis, 
blastomycosis, and pneumocystosis), viral (e.g., hepatitis B), or other opportunistic pathogens 
(e.g., Listeria and Legionella). (US Food and Drug Administration, Drug Safety 
Communications, 2011 and 2013) Lymphoma, including a rare and fatal type called 
hepatosplenic T-cell lymphoma, and other malignancies, can occur in adults and children. 
Other serious risks include melanoma and Merkel cell carcinoma, heart failure, 
demyelinating disorders, hypersensitivity reactions, and hepatitis B reactivation. 
(Marion, 2013) 
A review of the subject’s prior medical history of neoplasias and infections, and evaluation 
for active TB and demyelinating diseases, testing for hepatitis B viral infection and latent 
infection should be conducted. (Silva, 2010) 
4.3 
KHK4083 - Investigational Product 
4.3.1 
KHK4083 Development 
KHK4083 is a fully human, non-fucosylated IgG1 mAb specific for the costimulatory 
molecule OX40 (cluster of differentiation [CD]134, tumor necrosis factor receptor 
[TNFR]SF4), a TNFR family member. KHK4083 binds with high affinity and specificity to 
an extracellular domain epitope of OX40, which plays a key role in maintaining late T-cell 
proliferation and survival by suppressing apoptosis, and in inducing T-cell memory 
formation. OX40 has a unique pattern of expression, being restricted to antigen-activated, 


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effector T-cells (mostly CD4+), transient, and present in diseased areas in human autoimmune 
diseases.  
OX40 has been shown to be highly expressed in the gastrointestinal tissue of patients with 
autoimmune diseases of the gastrointestinal tract (e.g., celiac, UC, Crohn’s disease). In a 
study on the expression of OX40, all UC and Crohn's disease and most celiac disease biopsy 
tissue samples (formalin-fixed, paraffin-embedded tissue stained with anti-OX40 antibody 
and alkaline phosphatase-anti alkaline phosphatase method [APAAP]) were positive, 
indicating the potential role of OX40 in pathogenesis of these diseases. (Stüber, 2000) 
Expression of lymphocyte-endothelial receptor-ligand pairs, α4β7/MAdCAM-1 and 
OX40/OX40 ligand in the colon and jejunum of patients with IBD also have been assessed by 
using endoscopic and per oral jejunal biopsy specimens that were immunostained (i.e., by 
indirect alkaline phosphatase using antibodies against CD3, ICAM-1, α4β7, MAdCAM-1, 
and OX40). The expression of MAdCAM-1 and OX40 ligand on gut endothelial and OX40+ 
cells was increased in sites of mucosal inflammation in patients with IBD. There was no 
evidence of increased lamina propria T-cells or increased vascular adhesion molecule 
expression in the proximal intestine of patients with distal IBD. (Souza, 1999) 
4.3.2 
Nonclinical Development 
The generation of the KHK4083 mAb and its in vitro characterization as well as the 
non-clinical pharmacology, pharmacokinetics (PK), and toxicology study reports are 
thoroughly described in the Investigator’s Brochure. All nonclinical safety studies were 
conducted in Japan, a member country of the Organisation for Economic Co-operation and 
Development (OECD) and compliant with the Mutual Acceptance of Data program. The 
studies conducted in accordance with the OECD Test Guidelines and Principles of Good 
Laboratory Practice (GLP) are identified in the Investigator’s Brochure. The 
nonclinical/toxicological program includes a pivotal 4-week intravenous (IV) GLP study 
(SBL303-081) and a pivotal 26-week subcutaneous (SC) and IV GLP study (SBL303-104) in 
cynomolgus monkeys. In these studies, the no-observed-adverse-effect levels (NOAELs) 
were ≥ 100 mg/kg (IV) and ≥ 30 mg/kg (both SC and IV), in 4-week IV and 26-week SC and 
IV study, respectively. The mean AUC0-∞ (area under the serum drug concentration-time 
curve from 0 to infinity) and mean Cmax for male and female monkeys in the 100 mg/kg dose 
group were 607000 µghr/mL and 5345 µg/mL, respectively, after the first dose. The mean 
AUC0-2wk (area under the serum drug concentration-time curve from 0 to 2 weeks post-dose) 
and mean Cmax for male and female monkeys in the 30 mg/kg IV group were 
301500 µghr/mL and 1510 µg/mL, respectively, after the 13th dose (i.e., steady state). The 


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AUCs were used to calculate the safety margins for the dose levels planned for this Phase 2 
study. Refer to Section 8.1.3.1 for additional details on safety margins and selection of doses. 
4.3.3 
Clinical Program 
The clinical program comprises a Phase 1a/1b study (4083-001, completed in December 
2014) in subjects with mild to moderate plaque-type psoriasis at 4 clinical sites in Canada. 
KHK4083 was well-tolerated and no dose-limiting toxicity was identified in the Phase 1a/1b, 
single-ascending dose study of up to 10 mg/kg, the highest dose studied.  
The implementation of this study is based on the premise that KHK4083 may have the 
potential to reduce OX40-bearing lymphocytes, which have been reported in colonic biopsies 
of patients with UC. (Stüber, 2000) In sites of mucosal inflammation, the expression of OX40 
ligand on gut endothelial and OX40+ cells was increased in the colon and jejunum of patients 
with IBD. (Souza, 1999) Thus, further study of KHK4083 is planned for IBD, in particular in 
subjects with UC. 
5 
OBJECTIVES 
The primary, secondary (including PK and immunogenicity), and exploratory objectives of 
the study (refer to Appendix 1 for primary and secondary efficacy definitions) are as follows: 
Primary: 
• 
Induction Therapy - Part A:  To determine the safety and tolerability of administration 
of multiple ascending doses of KHK4083 and to select the highest dose tolerated by 
subjects with moderately active UC to recommend for use in Part B; 
• 
Induction Therapy - Part B:  To determine if the recommended dose of KHK4083 
identified in Part A improves the mucosa in subjects with moderately active UC at 
Week 12 as measured by the modified Mayo endoscopy subscore (mMES).  
The assessment is based on a mean change in the mMES (subscores from 0 to 3 with 
modified endoscopy finding scoring, i.e., excluding mild friability from a subscore of 1) 
from Baseline (Week 0) to Week 12. Refer to Mayo Clinic Scoring System for 
Assessment of Ulcerative Colitis Activity (Score 0 to 12) with Modified Mayo 
Endoscopy Subscore Appendix 2 for the mMES Scoring System. 
Secondary: 
• 
To determine if KHK4083 at dose levels different than the recommended dose improve 
the mucosa based on the mMES;  
• 
To determine if any dose level of KHK4083 administered as Induction Therapy will meet 
the following objectives at Week 12 (or as noted): 


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– Improve the mucosa based on the modified Baron endoscopic score;  
Refer to Appendix 3 for the modified Baron scoring system. 
– Improve the mucosa based on the Ulcerative Colitis Endoscopic Index of Severity 
(UCEIS); 
The assessment is based on a mean change in the UCEIS (scores from 0 to 8, based on 
findings of vascular pattern, bleeding, and erosions/ulcers) from Baseline (Week 0) to 
Week 12. Refer to Appendix 4 for the UCEIS Scoring System. 
– Induce mucosal healing based on the mMES; 
– Improve clinical signs and symptoms based on total Mayo Clinic score;  
– Improve clinical signs and symptoms based on partial Mayo Clinic scores 
(Week 2 through Week 12, excludes endoscopy subscores); 
– Induce a clinical response based on a reduction in the total Mayo Clinic score 
(i.e., reduction of at least 3 points and a decrease of at least 30% from Baseline 
[Week 0] to Week 12) and rectal bleeding subscale (i.e., reduction of at least 1 point 
from Baseline [Week 0] to Week 12) (or a defined absolute rectal bleeding score of 
0 or 1 at Week 12); 
– Induce clinical remission based on a total Mayo Clinic score (i.e., score of ≤ 2) and 
subscores (i.e., no subscores > 1). 
• 
To characterize the PK of KHK4083 in subjects with moderately active UC following 
multiple dose administration; 
• 
To evaluate the development of antibodies against KHK4083 (immunogenicity). 
Refer to Section 10.2 for additional details on all secondary endpoints. 
Exploratory: 
• 
To determine if multiple doses of KHK4083 administered during the Open-label 
Extension (OLE) / Long-term Extension (LTE) Therapy phase will meet the following 
objectives at Week 52 (or as noted) when compared with Baseline (Week 0) scores (or 
subscores) or assessments: 
– Improve clinical signs and symptoms based on total Mayo Clinic score; 
– Improve clinical signs and symptoms based on partial Mayo Clinic scores (excludes 
endoscopy subscores) at Week 16 through Week 52, and the LTE Therapy Follow-up 
Period (Week 56 through Week 64); 
– Induce a clinical response based on a reduction in the total Mayo Clinic score and 
rectal bleeding subscale (or a defined absolute rectal bleeding score); 
– Induce clinical remission based on a total Mayo Clinic score and subscores; 
– Induce durable clinical responses and durable clinical remissions (present at both 
Weeks 12 and 52), and glucocorticoid-free clinical remission; 
– Induce mucosal healing based on the mMES; 
– Improve the mucosa based on the mMES, UCEIS, and/or modified Baron endoscopic 
score; 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
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– Induce remission (Week 12; Week 52) based on modified Mayo endoscopy, stool 
frequency, and rectal bleeding subscores (defined as an mMES of 0 or 1, stool 
frequency subscore of 0 or 1, and rectal bleeding subscore of 0); 
• 
To evaluate the activity of KHK4083 on health-related quality of life (HRQL), which will 
be based on the subject’s completed Inflammatory Bowel Disease Questionnaires 
(IBDQs) in comparison to Baseline assessments; 
• 
To measure changes from Baseline in corticosteroid (glucocorticoid) dosages; 
• 
To determine the percentage of subjects who are glucocorticoid-free from Week 16 
through Week 52, and through the OLE/LTE Therapy Follow-up Period (Week 56 
through Week 64); 
• 
To evaluate the pharmacodynamic (PD) profile of KHK4083; 
• 
To explore the PK-PD relationships. 
Refer to Section 10.3 for additional details on exploratory endpoints. 
6 
STUDY DESIGN 
6.1 
Overall Study Design and Plan 
This Phase 2, double-blind clinical study of multiple ascending doses of KHK4083 
(or placebo) with an OLE Therapy phase will be conducted in approximately 60 randomized 
adult subjects with moderately active UC who have a documented unsuccessful previous 
treatment. The study design was revised to convert the post induction phase of the study from 
a LTE to an OLE. 
Male and female subjects  18 years of age with moderately active UC, defined as a total 
Mayo Clinic score of 4 to 9 (range:  0 - 12, with higher scores indicating more active disease) 
with an mMES of at least 2 as determined by a central reader, and disease that extends 
≥ 15 cm from the anal verge are eligible to participate in this study.  
This multicenter study will be conducted at approximately 40 investigative sites in the US, 
Russia, Hungary, Poland, Romania, Serbia, and Czech Republic; other countries may be 
included as needed. The study will include a 4-week Screening Period, followed by a total of 
up to 64 weeks (treatment and follow-up) on study from the time of randomization to study 
completion.  
The Treatment Period includes double-blind Induction Therapy (12 weeks) and OLE Therapy 
(40 weeks) for eligible subjects at Week 12. Subjects already enrolled in the double-blind, 
LTE under preceding versions of the protocol who worsen may be eligible to transition to the 
OLE up to Week 28.  Selected Kyowa Kirin Pharmaceutical Development, Inc. (hereinafter 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
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38 
 
referred to as the Sponsor) personnel will be unblinded after the last subject completes 
Induction Therapy (refer to Section 8.4 for details). 
Post-treatment assessments will continue for 16 weeks after the last infusion associated with 
the subject’s treatment period. The on-site follow-up visits will be at Weeks 16, 20, and 26 
for subjects who only receive Induction Therapy or at Weeks 56, 60, and 64 for subjects who 
receive both Induction and OLE/LTE Therapies. The date of the subject’s last post-treatment 
study visit will be considered the End-of-Study date.  
The Study design is displayed in Figure 6.1-1. 


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39 
 
Figure 6.1-1 
Study Design Diagram 
 
Non-completer (NC) - Subject did not complete Induction Therapy 
a: For those subjects who enrolled under Amendment #1- Subjects will be in the study for a total of up to 64 weeks. The 
double blind treatment period includes Induction Therapy (12 weeks) and LTE therapy (40 weeks).  A post treatment 
follow-up period will be conducted at either Weeks 16, 20 and 26 for subjects who only receive Induction Therapy or at 
weeks 56, 60 and 64 for subjects who receive both induction and LTE Therapies 
b: Cohort 4 will receive the recommended dose (1.0, 3.0, or 10 mg/kg) determined from safety assessments of Cohorts 1 - 3 
in Part A. 
c: Endoscopic Responders (ER) include subjects who met the criteria for clinical response at Week 12 and non-responders 
(NR) includes subjects who did not meet the criteria of a clinical response at Week 12. 
d: For those subjects who enroll under Amendment #2-All subjects who complete the induction period, i.e., (received at 
least of 5 of the 6 doses of double-blind therapy and have Week 12 sigmoidoscopy results from the central reader) and are 
eligible to continue on in the study have the option to enter the OLE therapy part of the trial and receive 10 additional 
treatments of KHK4083 once every 4 weeks from week 12 through week 48 at the same dose used in the cohort that they 
were enrolled in. 
C=cohort; IV=intravenous; LTE=long-term extension; OLE=Open-label Extension; MAD=multiple ascending dose; 
R=randomization. 
 
Treatment Period  
(up to 52 weeks)
C1: 1.0 mg/kg or placebo
C2: 3.0 mg/kg or placebo
C3: 10.0 mg/kg or placebo
Part B
C4: Recommended b Dose or 
placebo
Week 52 
Endpoint 
Assessment
Screening 
Period 
(Days -28 to -1)
Double Blind Induction Therapy
Post-treatment
Follow-up 
Period 
LTE Therapya (blinded)
KHK4083 or placebo
OLE Therapyd (unblinded)
KHK4083 only
NC 
Weeks 16, 20 & 26
Weeks 56, 60 & 64
12 weeks
40 weeks
No OLE/LTE therapy
Week 12 
Endpoint 
Assessment
All 
ERc or 
NRc
10 Treatments 
(1 every 4 
weeks)
IV infusion
Once every  2 weeks
KHK4083
1.0 mg/kg
3.0 mg/kg
10.0 mg/kg
Part A (MAD)


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6.1.1 
Induction Therapy:  Week 0 to Week 12 (Last Dose at Week 10) 
Double-blind Induction Therapy is separated into Part A for administration of multiple 
ascending IV doses of KHK4083 (or placebo) to subjects in Cohorts 1 - 3 and Part B for 
administration of the recommended IV dose (one of three dose levels identified in Part A) of 
KHK4083 (or placebo) to subjects in Cohort 4. Subjects in Part A are prohibited from 
participating in Part B. 
Subjects in each cohort will be randomly assigned in a 3:1 ratio to receive KHK4083 or 
placebo by IV infusion over 60 minutes (± 10 minutes). Each subject will receive a total of 
6 treatments (one IV infusion per treatment) every 2 weeks from Week 0 (Day 1) to Week 10 
of Induction Therapy. Safety assessments (e.g., after 2 treatments for 1.0 mg/kg and 3 
treatments for 3.0 and 10 mg/kg are administered and 14-day safety data from the last 
treatment are available) will determine whether dosing will continue for subjects within a 
cohort and if the investigational product will be administered at the next higher dose level for 
subjects in the next cohort in Part A or for Cohort 4 in Part B (refer to Section 6.3 for details 
on the Safety Monitoring Plan).  
For subjects in all cohorts, a sigmoidoscopy with biopsy is scheduled at Week 12 to assess 
improvement in the mucosa from Baseline (Week 0) to Week 12. It is highly recommended 
that the sigmoidoscopy with biopsy be performed within 7 to 13 days prior to the Week 12 
visit. The sigmoidoscopy results from the central reader are required before a subject receives 
treatment in the OLE/LTE Therapy phase. 
6.1.2 
Long-term Extension Therapy:  Week 12 (First Dose) to Week 52 
The LTE is only active for subjects who entered it prior to approval of Amendment 2. 
Subjects who sign an ICF under Amendment 2 are eligible for the OLE (see Section 6.1.3). 
Subjects who completed double-blind Induction Therapy (i.e., at least five of six treatments) 
and had a clinical response or mucosal healing were eligible to continue in double-blind 
LTE Therapy. A clinical response is defined as a reduction in the total Mayo Clinic score of 
at least 3 points and a decrease of at least 30% from Baseline (Week 0) to Week 12, and a 
reduction in the rectal bleeding subscale of at least 1 point from Baseline (Week 0) to Week 
12 or an absolute rectal bleeding score of 0 or 1 at Week 12. Mucosal healing is defined as a 
mMES of 0 or 1. 


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All subjects who qualified were to have been given two options: 
1) To receive no further treatment and proceed directly to the Induction Therapy 
Follow-up Period (Week 16 through Week 26); or  
2) To continue in double-blind LTE Therapy and receive 10 additional treatments of 
KHK4083 (at the same dose administered to that subject during Induction 
Therapy) or placebo as maintenance therapy. Each subject will receive one IV 
infusion every 4 weeks from Week 12 to Week 48 followed by an End-of-LTE 
Therapy visit at Week 52, and then proceed to the LTE Therapy Follow-up Period 
(Week 56 through Week 64). Refer to Section 8.1.4.2 for additional dosing details 
in LTE Therapy. 
Note:  Subjects who already started treatment in the double-blind LTE Therapy 
will continue to receive KHK4083 or placebo during LTE Therapy.  If their UC 
worsens or flares up to Week 28, they may transition to OLE therapy. 
Subjects who did not qualify were to have received no further treatment and entered the 
Induction Therapy Follow-up Period. 
6.1.3 
Open-label Extension Therapy:  Week 12 (First Dose) to Week 52 
Subjects who complete double-blind Induction Therapy (i.e., at least five of six treatments) 
are eligible to enter OLE Therapy (refer to Section 7.4 for specific eligibility criteria).  
All subjects who qualify will be given two options: 
1) To receive no further treatment and proceed directly to the Induction Therapy 
Follow-up Period (Week 16 through Week 26); or  
2) To receive 10 treatments of open-label KHK4083 (at the same dose administered 
to that subject during Induction Therapy) as maintenance therapy. Each subject 
will receive one IV infusion every 4 weeks from Week 12 to Week 48 followed 
by an End-of-OLE Therapy visit at Week 52, and then proceed to the OLE 
Therapy Follow-up Period (Week 56 through Week 64). Refer to Section 8.1.4.2 
for additional dosing details in OLE Therapy. 
6.1.4 
Transitioning from the Long-term Extension to the Open-label 
Extension 
Subjects participating in the double-blind LTE who experience a clinical worsening or a flare 
of disease up to Week 28, as defined by the Investigator, may transition to the OLE. Subjects 
will maintain the same visit schedule, e.g., a subject who completed a Week 20 visit in the 
LTE and transitions to the OLE at Week 24 will have an OLE Week 24 visit. However, for 
the first two open-label doses in the OLE, additional safety monitoring will include ECGs 
and post-infusion monitoring as performed for the OLE Week 12 and Week 16 visits, 
respectively. 


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6.2 
Study Rationale 
In a Phase 1a/1b study (4083-001) in 68 subjects with mild to moderate plaque-type psoriasis, 
no dose-limiting adverse effects were observed following a single SC injection (1.0 mg/kg) or 
IV infusion (≤ 10 mg/kg). The current study of KHK4083 in subjects with UC is based on the 
observation that OX40-bearing lymphocytes have been reported in colonic biopsies of 
patients with UC. (Stüber, 2000) In sites of mucosal inflammation, the expression of OX40 
ligand on gut endothelial and OX40+ cells was increased in the colon and jejunum of patients 
with IBD. (Souza, 1999) 
The 12-week efficacy evaluation for improvement in the mucosa is based on mMES and is 
the primary efficacy endpoint of this study. The continuation of subjects (i.e., who have 
evaluable total Mayo Clinic scores and have a clinical response or mucosal healing) in the 
40-week OLE/LTE Therapy phase allows for extending the period of treatment and 
completing assessments for delayed responses, durable clinical response, and durable clinical 
remission. 
6.3 
Study Safety Monitoring Plan 
All subjects will be assessed regularly for potential occurrence of adverse events (AEs) from 
the time of signing the informed consent form (ICF) until 16 weeks after the last dose. If 
consistent mild and/or moderate infusion reactions are observed, the Sponsor may 
recommend pretreatment of subjects. In the event that any subject experiences an acute 
infusion reaction considered to be a serious adverse event (SAE), a slower infusion rate for 
administration of the investigational product and/or a mandatory pre-medication regimen 
(e.g., anti-emetics, H1 or H2 blockers, and/or corticosteroids) may be introduced. Each 
investigative site must have trained staff and immediate access to emergency supplies and 
equipment including, but not limited to, drugs needed to treat a subject in case of a 
life-threatening emergency.  
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. 
Medical Monitoring meetings will be held on a regular basis to monitor the safety of the 
subjects and adherence to the protocol (e.g., inclusion and exclusion criteria, concomitant 
medications, and visits) in addition to the Safety Monitoring Committee meetings described 
below.  


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The Safety Monitoring Committee, which recommends dose-escalation and continuation of 
the study will meet prior to starting each cohort (based upon projected enrollment rate is 
anticipated to be approximately every 3 months) and as needed during the study. A separate 
Safety Monitoring Committee Charter will identify the membership and define the specific 
procedures of the committee. 
The Safety Monitoring Committee will evaluate the cumulative safety data available after the 
first 8 subjects (1.0 mg/kg dose cohort) at Week 4. For subsequent dose escalation, the Safety 
Monitoring Committee will evaluate the cumulative safety data available after the first 
8 subjects at Week 4 with the first 4 subjects at Week 6 for the 3.0 and 10 mg/kg dose 
cohorts. At each of the timepoints, the committee will assess whether dosing will continue for 
all subjects and if the investigational product will be administered at the next higher dose 
level for subjects in the next cohort in Part A or for Cohort 4 in Part B. The Safety 
Monitoring Committee and Sponsor may dose-reduce cohorts or not escalate to the planned 
doses based upon review of safety data. The OLE dose will be the same as the dose for that 
cohort during the induction therapy, unless dose reduction is recommended by the Safety 
Monitoring Committee and Sponsor. 
The safety monitoring plan is as follows:  
Induction Therapy - Part A (Cohort 1): 
• 
Prior to randomization of the first subject - review rules and reach a consensus; 
• 
When safety data are available on the first 8 of 12 randomized subjects who complete or 
would have completed Week 4 (~Day 29). 
Induction Therapy - Part A (Cohorts 2 and 3): 
• 
When safety data are available on the first 8 randomized subjects in a cohort who 
complete or would have completed Week 4 (~Day 29) with the first 4 subjects in a cohort 
who complete or would have completed Week 6 (~Day 43). 
Induction Therapy - Part B (Cohort 4): 
• 
When safety data are available on the first 8 randomized subjects who complete or would 
have completed Week 6 (~Day 43); 
• 
When safety data are available on all randomized subjects who complete or would have 
completed Week 12. 
Open-label/Long-term Extension Therapy: 
• 
When safety data are available on all subjects who complete or would have completed 
Week 24; 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
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44 
 
• 
When safety data are available on all subjects who complete or would have completed 
Week 36. 
If unblinding of a cohort is necessary, the Sponsor’s physician, clinical pharmacologist, a 
biostatistician, and a representative from Drug Safety Surveillance, all not associated with the 
conduct of the study, will make recommendations for study continuation and design, 
including dose selection for each cohort.  
This study’s safety monitoring plan is justifiable and adequate from a safety standpoint in 
view of the following: 
• 
The design of the safety plan permits a comparison of the safety response to KHK4083 
under baseline and post-KHK4083 administration conditions in the same subject. 
• 
The design of the safety plan allows a comparison of this study’s safety data set with the 
Phase 1a/1b study (4083-001). 
• 
The safety monitoring follow-ups permit the evaluation of late appearing adverse effects 
that may emerge or progress after the administration of KHK4083. 
• 
The measures used to assess safety are well-defined and reliable, and the proposed safety 
analyses are adequate to assess the effects of the administration of KHK4083. 
6.4 
Study Timeframe 
Subsequent to the 4-week Screening Period, the total study participation time is up to 
64 weeks from the time of randomization to study completion. The 52-week Treatment 
Period includes a 12-week Induction Therapy phase and a 40-week OLE/LTE Maintenance 
Therapy phase. A post-treatment Follow-up Period will be conducted either at Week 16 
through Week 26 for subjects who only receive Induction Therapy or at Week 56 through 
Week 64 for subjects who receive both Induction and OLE/LTE therapies. The date of the 
subject’s last post-treatment study visit will be considered the End-of-Study date. 
6.5 
Risks and Benefits to Subjects 
6.5.1 
Risks 
Subjects receiving investigational product should be monitored carefully for hematologic 
abnormalities and any applicable dose modification/stopping rules should be followed. In a 
recently completed clinical study (4083-001) in subjects with psoriasis, no dose-limiting AEs 
were observed during the 56-day safety assessment periods following single SC (1.0 mg/kg) 
or IV (≤ 3.0 mg/kg) doses or during a 70-day safety assessment period following an IV dose 
of 10 mg/kg.  


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6.5.2 
Benefits 
The potential benefits of KHK4083 treatment are to improve the mucosa, induce mucosal 
healing, improve the clinical signs and symptoms of UC, induce a clinical response and 
remission, and maintain a durable clinical response and durable clinical remission by 
continuation of therapy. 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Male and female subjects (age:  ≥ 18 years) with moderately active UC who meet all the 
Inclusion Criteria and none of the Exclusion Criteria will be eligible for entry into this study.  
7.1 
Procedures for Enrollment 
This multicenter study will be conducted in approximately 60 adult subjects with moderately 
active UC at approximately 40 investigative sites in the US, Russia, Hungary, Poland, 
Romania, Serbia and Czech Republic; other countries may be included as needed.  
At the Screening visit, the Investigator will review the written ICF with each subject to 
ensure that the subject understands the study and the study procedures. The subject will read, 
sign, and date the ICF and other locally applicable documents. A photocopy of the signed 
ICF must be provided to the subject and the original document retained in the subject’s 
source or study file. No study-related procedures may be performed until the ICF is signed 
and dated.  
The Interactive Response Technology (IRT) system will be used by the Investigator (or 
designee) for assigning a Subject Identification Number after the ICF is signed and dated.  
A subject who was considered a Screen failure and not dosed with investigational product is 
permitted to be re-screened once due to failure to meet the Inclusion/Exclusion Criteria, 
whereas subjects with other reasons for lack of randomization may be re-screened twice. This 
allows for re-screening in the event a subject fails screening because all assessments were not 
completed within the 28-day screening window. An assigned Subject Identification Number 
will only be used once; thus, numbers for any Screen failures or non-treated, non-evaluable, 
or discontinued subjects will not be re-used. 


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7.2 
Inclusion Criteria 
Subjects may be included in the study if they meet all of the following Inclusion Criteria: 
1) Subject is able and willing to comply with study procedures, and to adhere to 
dosing and visit schedules and follow-up procedures as described in the protocol 
and ICF; 
2) Subject voluntarily signs/dates an Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC)-approved ICF in accordance with regulatory and 
institutional guidelines; 
Note:  Written informed consent must be obtained prior to performing any study-
related procedure. 
3) Male and female subjects  18 years of age at the time of enrollment; 
4) Subject has UC that was diagnosed at least 6 months prior to the Screening visit; 
5) Subject has moderately active UC, defined as: 
a) Total Mayo Clinic score of 4 to 9 (range:  0 to 12, with higher scores 
indicating more disease activity); 
b) Endoscopy subscore (mMES determined by a central reader) of at least 2; and 
c) Disease that extends ≥ 15 cm from the anal verge. 
6) Subject has had previous treatment (within 5 years prior to Screening) with one or 
more of the following:  corticosteroids, immunosuppressive medications or 
TNF antagonist therapy that was unsuccessful because of a lack of efficacy 
response or AEs, as defined below:   
a) corticosteroids for induction therapy of at least prednisolone-equivalent of 20 
mg (or oral budesonide 9 mg) oral daily for 2 weeks or injectable for 1 week, 
or for maintenance therapy at least two failed attempts to reduce to less than 
prednisolone-equivalent 10 mg (or oral budesonide 3 mg) oral daily, or a 
history of intolerance to corticosteroids (including but not limited to 
hypertension, insomnia, osteopenia, osteoporosis, hyperglycemia, infection or 
Cushing’s syndrome); 
b) Azathioprine or 6-mercaptopurine of at least 1.5 mg/kg/day or 0.75 
mg/kg/day, respectively, for 8 weeks, or a history of intolerance to either agent 
(including but not limited to nausea, vomiting, abdominal pain, aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) elevations, 
thiopurine methyltransferase genetic mutation, or infection); 
c) tumor necrosis factor-alpha antagonists for induction therapy with approved 
anti-TNF products including, but not limited to, infliximab 5 mg/kg IV for 2 
doses at least 2 weeks apart, adalimumab 160 mg SC followed by at least 80 
mg SC at least 2 weeks apart, and golimumab 200 mg SC followed by at least 
100 mg at least 2 weeks apart and anti-TNF biosimilar products with approved 
dosages for 2 doses at least 2 weeks apart; or as maintenance therapy for 
recurrence of symptoms despite continued dosing, or history of intolerance 


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(including but not limited to infusion or injection reactions, demyelination or 
infection). 
7) Female subjects who are considered to be women of childbearing potential 
(WOCBP) must have a negative pregnancy test at Screening and Baseline. 
WOCBP must agree to use effective contraception, defined as oral contraceptives 
with one barrier method, or tubal ligation with one barrier method or double 
barrier method (condom plus spermicide or diaphragm plus spermicide) during the 
study and for at least 6 months after the last dose of investigational product. 
Subjects are considered to not be of childbearing potential if they are ≥ 50 years of 
age and without menses for 24 consecutive months and have a follicle-stimulating 
hormone (FSH) level > 25 mIU/mL (or in postmenopausal range per local 
laboratory standards); or have undergone a hysterectomy and/or a bilateral 
salpingo-oophorectomy.  
Egg donation is not permitted while on study medication and for at least 6 months 
after the last dose of study medication. 
8) Male subjects (including those who have had a vasectomy) must use adequate 
contraception (e.g., latex condom, non-latex condom not made of natural animal 
membrane such as polyurethane condom) during the study and for at least 
6 months after the last dose of investigational product.  
Sperm donation is not permitted while on study medication and for at least 6 
months after the last dose of study medication. 
7.3 
Exclusion Criteria 
Subjects must be excluded from participating in this study if they meet any of the following 
Exclusion Criteria: 
1) Subject, who, for any reason, is judged by the Investigator to be inappropriate for 
this study, including a subject who is unable to communicate or cooperate with the 
Investigator, who has/had a psychiatric illness, disability or social situation that 
may compromise the safety of the subject during the study or affect the ability of 
the subject to adhere to study procedures; 
2) Subject has a medical history of clinically significant (as determined by the 
Investigator or the Sponsor) cardiac, renal, hepatic/biliary (e.g., sclerosing 
cholangitis), pulmonary, or other medical conditions or is not generally in good 
health. 
Subjects with the history of immunologic, autoimmune or chronic inflammatory 
disorders (e.g., uveitis, rheumatoid arthritis, ankylosing spondylitis or 
spondyloarthritis, psoriasis) other than UC or autoimmune connective tissue 
diseases (e.g., systemic lupus erythematosus, systemic sclerosis) and are well 
controlled may be included into the trial after consultancy with medical monitor. 
Subjects with thyroid disorders, vitiligo, and alopecia are eligible for inclusion.  


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3) Subject’s UC had failed to respond to: 
a) Two or more biologic treatments with different mechanisms of action 
(e.g., infliximab, vedolizumab and golimumab), or  
b) Three or more anti-TNF biologics, e.g., infliximab, adalimumab; 
4) Subject requires prescription treatment for UC, except for the stable, oral 
treatment of UC as follows: 
a) Aminosalicylates (5-ASA acid or mesalamine ≤ 4.8 g/day; sulfasalazine 
≤ 3 g/day) for at least 14 days prior to the Screening visit; and/or 
b) Glucocorticoids (≤ 20 mg/day prednisolone or the equivalent, or budenoside 
≤ 9 mg/day) for at least 14 days prior to the Screening visit (or for 4 weeks if a 
course of corticosteroids had started at less than 8 weeks prior to Screening 
visit); and/or 
c) Azathioprine up to 3 mg/kg/day or 6-mercaptopurine up to 1.5 mg/kg/day for 
a total treatment period of at least 12 weeks, including 4 weeks of stable 
treatment, prior to the Screening visit. 
5) Subject has received any of the following prior treatments or treatments within the 
specified time: 
a) Natalizumab, efalizumab or rituximab or other lymphocyte-depleting 
treatments, including but not limited, to alkylating agents (such as 
cyclophosphamide or chlorambucil) and total lymphoid irradiation at any time 
prior to randomization (Baseline visit);  
b) TNF antagonists within 8 weeks, or 5 half-lives (based on maximum duration 
but not exceeding 12 weeks), prior to randomization (Baseline visit); 
c) Vedolizumab within 16 weeks prior to randomization (Baseline visit); 
d) Methotrexate, cyclosporine, mycophenolate, tacrolimus, thalidomide, or other 
immune altering drugs within 4 weeks prior to randomization (Baseline visit) 
(ophthalmologic preparations are permitted); 
e) 5-ASA enema, or steroid enema or suppository use within 2 weeks prior to 
randomization (Baseline visit); and/or 
f) Investigational agents within 8 weeks or 5 half-lives (if pharmacology 
information is available) prior to randomization (Baseline visit) whichever is 
longer. 
6) Subject with recent (within 1 year prior to Screening), suspected or confirmed 
symptomatic stenosis of the colon, abdominal abscess, or ischemic colitis based 
on clinical or radiographic data; or who has suspected, confirmed or a history of 
toxic megacolon; or with any colonic resection, subtotal or total colectomy, 
ileostomy, or colostomy; or who had any previous surgery for UC or an 
anticipated requirement for surgery for UC; 
7) Subject with known colonic dysplasia, adenomas or polyposis; 
8) Subject had major surgery within 4 weeks prior to Screening or an anticipated 
requirement for major surgery; 


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9) Subject with enteric pathogens (including Clostridium difficile) detected on stool 
analysis; or Clostridium difficile infection within 8 weeks prior to Screening; or 
intestinal pathogen infection detected within 4 weeks prior to Screening; 
10) Subject with any of the following hematological and chemistry laboratory values: 
a) Platelet count < 100,000/mm3; 
b) Neutrophils < 1500/mm3; 
c) Serum creatinine ≥ 1.6 mg/dL (≥ 144.4 μmol/L); 
d) Alkaline phosphatase > 3 times the upper limit of normal (ULN); 
e) AST or ALT > 2 times ULN; 
f) Total bilirubin > 2 mg/dL, unless due to Gilbert’s Syndrome;  
g) Serum albumin < 3 g/dL; 
h) Hemoglobin < 9 g/dL; 
i) Glycated serum hemoglobin A1c ≥ 9%. 
11) Subject has clinically significant cardiac disease (class II, III, or IV of the New 
York Heart Association [NYHA] classification) (The Criteria Committee of the 
NYHA Nomenclature and Criteria for Diagnosis of Diseases of the Heart and 
Great Vessels, 1994); unstable angina pectoris; myocardial infarction within 6 
months or is post angioplasty or stenting within 6 months; uncontrolled 
hypertension; or clinically significant abnormality, such as cardiac arrhythmia, on 
a 12-lead electrocardiogram (ECG) at Screening; 
12) Subject is pregnant or breastfeeding; 
13) Subject has had major immunologic reaction (e.g., serum sickness, anaphylaxis, or 
anaphylactoid reaction); 
14) Subject is Hepatitis B core antibody or surface antigen positive at Screening 
and/or Hepatitis C antibody positive with detectable RNA at Screening; 
15) Subject has a history of human immunodeficiency virus (HIV) positivity, tests 
positive for HIV at Screening, or has congenital or acquired immunodeficiency; 
16) Subject has or has had active TB, suspected extra-pulmonary TB, a history of 
incompletely treated TB, or latent TB or other latent infection. Subjects with latent 
TB (purified protein derivative [PPD] or interferon gamma release assay [IGRA]) 
may be included in the study if prophylactic therapy for latent TB is started at 
least 4 weeks prior to Screening. Subjects with a potentially untreated other 
infection (clinical findings) are to be excluded.  
Note:  Performing of both IGRA and PPD tests in the same subject should be 
avoided as screening procedures. Positivity of one of the tests cannot be voided by 
negativity of the other, i.e., subjects with positive PPD and negative IGRA test 
performed as a part of Screening will be considered TB positive and will be 
required to start prophylactic anti-TB therapy prior to infusion of investigational 
product according to local treatment standards. All safety laboratory tests may be 
repeated. Screening procedures may be extended by 2 weeks. 


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17) Subject has bacterial infections requiring treatment with oral or parenteral 
antibiotics (topical antibiotics are allowed), within 2 and 4 weeks, respectively, of 
the Screening period;  
18) Subject has a history of systemic opportunistic infection or recurrent infections; 
19) Subject has malignancy or history of malignancy, except for adequately treated 
basal cell skin cancer or adequately treated carcinoma in-situ of the cervix without 
recurrence, and treatment must have been completed at least 5 years before the 
Screening period; 
20) Subject who received a bacille Calmette-Guérin (BCG) vaccine within 6 months 
of randomization or live vaccination (e.g., measles, mumps, rubella [MMR]; 
herpes zoster; varicella, intranasal influenza; and oral poliomyelitis) within 4 
weeks of randomization is to be excluded. Subject is allowed vaccinations of 
inactivated vaccines (e.g., hepatitis, pneumococcal, meningococcal, tetanus, 
diphtheria toxoid, acellular pertussis, inactivated polio, human papilloma and 
influenza – except intranasal influenza); 
21) Subject with a history of substance abuse within 1 year of Screening; or active 
marijuana (medicinal or recreational) use or active substance abuse; 
22) Subject has other severe acute or chronic medical or psychiatric condition or 
laboratory abnormality that may increase the risk associated with study 
participation or investigational product administration, or may interfere with the 
interpretation of study results, as determined by the Investigator; 
23) Subject who previously participated in a study of KHK4083. 
Note:  A subject who was considered a Screen failure and not dosed with 
investigational product in the current study (4083-002) is permitted to be re-
screened once due to failure to meet the Inclusion/Exclusion Criteria, whereas 
subjects with other reasons for lack of randomization may be re-screened twice.  
7.4 
Additional Criteria to Enroll in Open-label Extension Therapy 
Prior to receiving investigational product (one infusion every 4 weeks) in the OLE, subjects 
must meet the following criteria: 
1) Subjects must have completed double-blind Induction Therapy, i.e., at least five of 
six double-blind treatments, or the subject is already in the double-blind LTE and 
not beyond Week 28 with a clinical worsening or a flare of disease as defined by 
the Investigator; 
2) Subjects must have evaluable total Mayo Clinic scores at Baseline and Week 12;  
3) Subjects must have been compliant with the protocol (including concomitant 
medication restrictions); and 
4) Subjects may have no clinically significant additional risks, as determined by the 
Investigator or the Sponsor, of treatment with KHK4083. 


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7.5 
Withdrawal and Termination Criteria 
In accordance with the Declaration of Helsinki, each subject is free to withdraw from the 
study at any time. Investigator(s) also have the right to withdraw subjects from the study in 
the event of illness, AEs, or other reasons concerning the health or well-being of the subject, 
or in the case of lack of compliance with the protocol. 
7.5.1 
Subject Withdrawal 
During the conduct of the study, the Sponsor will review the safety data for trends and signals 
that would indicate the need for withdrawal of a subject. The Investigator may withdraw a 
subject from the study for any of the following reasons: 
• 
For any of the specific criteria listed in Section 7.5.3; 
• 
Pregnancy; 
• 
For any reason judged by the Investigator to be inappropriate to continue in the study, 
including a subject who is unable to communicate or cooperate with the Investigator, who 
has/had a psychiatric illness, disability or social situation that may compromise the safety 
of the subject during the study or affect the ability of the subject to adhere to study 
procedures; 
• 
The study is terminated by the Sponsor; 
• 
Any therapy-related event that is deemed life-threatening, regardless of intensity; 
• 
Protocol noncompliance; 
• 
Withdrawal of consent. 
Should a subject decide to withdraw after administration of the investigational product 
(KHK4083 or placebo), or should the Investigator(s) decide to withdraw the subject, all 
efforts will be made to complete and report the observations up to the time of withdrawal as 
thoroughly as possible. A complete final evaluation at the time of the subject’s withdrawal 
should be completed and an explanation given as to why the subject is withdrawing or being 
withdrawn from the study. 
The reason for withdrawal must be collected. If the reason for withdrawal is a clinical AE, 
whether considered to be related to investigational product or not, 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). The clinical course of the AE will be followed according to 
accepted standards of care or medical practice, even after the end of the period of observation 
until a satisfactory explanation is found or the Investigator considers it medically justifiable 
to terminate follow up (e.g., event returned to subject’s baseline, Grade 1, or stable).  


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7.5.2 
Study or Investigative Site Termination 
The Sponsor reserves the right to terminate the study at any time. Investigators have the 
responsibility to comply with International Conference on Harmonisation (ICH) E6-Good 
Clinical Practice (GCP) guidance. The Safety Monitoring Committee (refer to Section 6.3) 
may recommend termination of the study if the overall risk to subject safety is deemed to be 
unacceptable, including but not limited to serious or severe infection rates ≥ 40% in the first 
cohort of 12 treated subjects (5/12) and similarly in subsequent cohorts. In addition, 
2 subjects with two or more Suspected Unexpected Serious Adverse Reactions (SUSARs) of 
the same System Organ Class (SOC) may result in a recommendation to terminate the study. 
In the event the study will be terminated, the Sponsor must promptly inform the hospital or 
clinic director of all participating institutions, Investigators, and regulatory authorities in 
writing. The Investigator is responsible for notifying subjects, stopping subject screening and 
dosing immediately, and providing appropriate medical care. Subjects dosed will be followed 
for safety for 16 weeks post-treatment and AE resolution. The Sponsor or the IRB/IEC may 
terminate the study for the following (but not limited to) reasons: 
• 
Important safety findings, such as SAEs, which may influence subjects’ well-being; or 
• 
Other newly obtained information or reason(s) that may affect continuation of study. 
The Sponsor or the IRB/IEC may terminate an investigative site for the following (but not 
limited to) reasons: 
• 
Failure of the Investigator to comply with pertinent ICH E6-GCP guidelines and 
regulations; 
• 
If serious protocol violations occur; 
• 
Submission of knowingly false information from the research facility to the Sponsor, 
Medical Monitor, or other party involved in the study; 
• 
Failure of the Investigator to enroll subjects into the study at an acceptable rate as agreed 
to with the Sponsor; or 
• 
Repeated failure to have eCRF data completed and ready for submission to the Sponsor in 
the agreed-upon time. 
7.5.3 
Criteria for Subject Removal from Treatment and the Study 
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 subject to discontinue administration of the 
investigational product, including subjects who have not benefited from treatment or should 


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the subject decide to discontinue study treatment, all efforts will be made to complete and 
report the observations as thoroughly as possible.  
Investigational product administration will be stopped if any of the following events occur:  
• 
Subject experiences a second SUSAR of the same SOC; 
• 
Subject experiences a severe AE that is related to the investigational product; 
Investigational product administration may be withheld for up to 2 weeks if the subject 
experiences a severe event in which it is unclear if the event is related to the 
investigational product. This will allow the Investigator to determine if the event is 
related to the investigational product prior to removing the subject permanently from the 
study. 
• 
Subject experiences a severe, acute infusion reaction despite administration of a 
prophylactic pre-medication regimen or if the subject experiences anaphylaxis regardless 
of having received a pre-medication regimen or not. Anaphylaxis has symptomatic 
bronchospasm and/or allergy-related edema/angioedema as the principal clinical 
manifestation(s); refer to the clinical diagnostic criteria of anaphylaxis defined in 
Appendix 5); 
• 
Subject has two consecutive visits during Induction Therapy with a worsening from 
Baseline in partial Mayo Clinic score of ≥ 3 points (e.g., partial Mayo Clinic score of 3 at 
baseline, 6 at Week 2, and 6 at Week 4) or two consecutive visits during maintenance 
therapy with a worsening from Week 12 in partial Mayo Clinic score of ≥ 3 points at a 
visit and ≥ 5 points at the next visit unless the Investigator, with agreement from the 
Sponsor, determines that there has not been clinically significant worsening, in which 
case the subject may continue to receive study medication at that visit (agreement from 
the Sponsor is to be obtained for each visit); 
• 
Surgery and/or use of prohibited medications are needed to treat the worsening of UC; 
• 
Subject requires a concomitant medication that is prohibited in the study; 
• 
Subject has any clinical AEs, laboratory abnormality, intercurrent illness, or other 
medical condition that indicates to the Investigator that continued participation is not in 
the best interest of the subject. The Investigator should make a distinction between AEs 
that may require only interruption of treatment and those that require discontinuation; 
• 
Subject decides to withdraw consent from the study in the absence of a medical need to 
withdraw as determined by the Investigator;  
• 
Subject is noncompliant in the opinion of the Investigator; 
• 
Administrative reasons; or 
• 
If pregnancy is suspected while the subject is receiving investigational product, the 
treatment must immediately be withheld until the result of pregnancy testing is known. If 
pregnancy is confirmed, the investigational product will be permanently discontinued and 
the subject withdrawn from the study. 
In the case of pregnancy, the Investigator must immediately notify the Sponsor of this event 
and record the pregnancy on the Pregnancy Surveillance Form. The Sponsor must also be 


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notified if a partner of a study subject becomes pregnant while the subject was receiving the 
investigational product. Reasonable attempts will be made to follow the pregnancy to 
conclusion in order to obtain information regarding the outcome.  
7.5.4 
End-of-Treatment Visit 
An End-of-Treatment visit must be conducted for all subjects who discontinue from 
treatment. This visit must occur within 2 weeks or 4 weeks after the last dose of 
investigational product of Induction Therapy or OLE/LTE Therapy, respectively. 
If the subject discontinues during Induction Therapy, the assessments listed in Table 9.1 for 
End-of-Treatment/Week 12 should be performed at the End-of-Treatment visit. A 
sigmoidoscopy will be performed at End-of-Treatment/Week 12 if the subject discontinues 
more than 8 weeks after Baseline visit; the sigmoidoscopy may be performed up to 4 weeks 
after the last dose of study medication. Post-treatment follow-up visits should subsequently 
occur 4, 8 and 14 weeks after the End-of-Treatment/Week 12 visit. 
If the subject discontinues during OLE/LTE therapy, the assessments listed in Table 9.2 for 
End-of-Treatment/Week 52 should be performed at the End-of-Treatment visit. A 
sigmoidoscopy will be performed at End-of-Treatment/Week 52 if the subject discontinues 
more than 8 weeks after the Week 12 visit; the sigmoidoscopy may be performed up to 8 
weeks after the last dose of study medication. Post-treatment follow-up visits should 
subsequently occur 4, 8 and 12 weeks after the End-of-Treatment/Week 52 visit. 
The Investigator must complete all applicable End-of-Treatment visit procedures (e.g., 
sigmoidoscopy, safety laboratory parameters, ECG, physical examination, vital signs) and 
applicable eCRF pages for subjects who discontinue treatment and include the reason for 
discontinuation of treatment.  
7.5.5 
End-of-Study Visit 
If the subject is withdrawn from the study, and thus no subsequent visits are planned, then the 
Investigator must complete all applicable final visit procedures (e.g., safety laboratory 
procedures, ECG, physical examination, vital signs) and applicable eCRF pages for subjects 
who discontinue treatment and include the reason for discontinuation of treatment. If the 
subject discontinues during the Induction Therapy, the assessment listed in Table 9.1 for 
Follow-up 3 should be performed at the End-of-Study visit. If the subject discontinues during 
OLE/LTE Therapy, the assessments listed in Table 9-2 for Follow-up 3 should be performed 
at the End-of -Study visit. 


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If the End-of-Study visit is the same as the End-of-Treatment visit then the End-of-Treatment 
visit assessments should be performed and the End-of-Treatment visit will also be the 
End-of-Study (end-of-trial) visit.  
Once subjects discontinue participation from the study, they will revert to the care of their 
usual physician for treatment/management of their condition/disease as appropriate. 
7.6 
Replacement of Subjects 
A subject who withdraws after randomization will not be replaced and may not re-enter the 
study.  
8 
TREATMENT OF SUBJECTS 
8.1 
Investigational Product(s) 
KHK4083 investigational product, 100 mg/vial (100 mg/mL, 1-mL label fill), is supplied as a 
single-use, preservative-free solution for IV infusion. The KHK4083 investigational product 
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 (USP) Type I glass vials that are stoppered with rubber stoppers and sealed 
with aluminum seals. A volume of 1.3 mL of KHK4083 investigational product is filled per 
vial. A 0.3-mL over-fill is included in each vial to account for vial, needle, and syringe 
holdup. 
Placebo for KHK4083 is supplied in the same container closure system and contains the same 
deliverable volume and excipients as KHK4083 investigational product without the active 
ingredient. 
8.1.1 
Recommended Storage and Use Conditions 
The investigational products (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 on the dilution procedure and recommended storage conditions for diluted 
solutions of KHK4083 investigational product and placebo can be found in the Pharmacy 
Manual. 


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8.1.2 
Investigational Product Destruction 
Upon completion or termination of the study, all vials (used and unopened) of KHK4083 and 
placebo must be destroyed upon authorization by the Sponsor and according to the 
investigative site’s biohazardous waste procedures and local regulations.  
It will be the Investigator’s responsibility to arrange for disposal of all investigational 
products 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 investigational 
product. 
8.1.3 
Dosage and Administration 
8.1.3.1 
Selection of Doses 
The first human study (Study 4083-001, A Single-Ascending-Dose Phase 1a Study and 
Placebo-Controlled, Double-blind, Single-Ascending-Dose Phase 1b Study of an Anti-OX40 
Monoclonal Antibody [KHK4083] in Subjects with Mild-Moderate Plaque-Type Psoriasis) 
was conducted in 68 subjects. Dose escalation of KHK4083 was started at 0.003 mg/kg 
(Cohort 1), followed by single ascending dose cohorts of 0.01, 0.03, 0.1, 0.3, 1.0, and 
3.0 mg/kg (Cohorts 2 - 7) administered as 60-minute IV infusions. A single SC dose of 
1.0 mg/kg (Cohort 8) also was administered. This study was amended to include an additional 
single ascending dose cohort of 10 mg/kg (Cohort 9) administered as a 120-minute IV 
infusion. The doses selected for the current study (4083-002) are based on the Phase 1a/1b 
study, which showed that KHK4083 was well tolerated and there were no dose-limiting 
adverse effects at doses ≤ 10 mg/kg. 
The PK data from IV dose Cohorts 1 to 7 and Cohort 9 were analyzed using a non-linear-
mixed-effect modeling technique. Significant departure from dose proportionality was 
observed as the terminal elimination rate decreased with increasing dose. This is possibly 
related to target-mediated drug disposition. Simultaneous modeling of all PK data was 
performed. A two-compartmental PK disposition model described PK profiles well with 
apparent effect of dose on clearance. Hence, trial simulations were performed for the present 
Phase 2 multiple ascending dose study of KHK4083 for administration every 2 weeks or 
every 4 weeks at 1.0, 3.0, and 10 mg/kg as a 60-minute (± 10 minutes) IV infusion. Simulated 
PK profiles are shown in Figure 8.1-1.  


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Figure 8.1-1 Simulated Pharmacokinetic Profiles Following Multiple-dose 
Administration of KHK4083 for Study 4083-002 
 
The following PK parameters were estimated based on the simulation outputs:  trough 
simulated concentration at the end of steady-state dosing interval (Cmin-ss), maximum 
simulated concentration at steady-state dosing interval Cmax-ss), area under the curve at steady 
state during a dosing interval (AUC2wk), accumulation ratio calculated as AUC2wk for the last 
interval divided by AUC2wk for the first interval (Rac). The results are shown in Table 8.1.3-1.  
Table 8.1.3-1 Simulated Pharmacokinetic Parameters for the KHK4083 Once Every 2 Weeks 
Dosing Regimen 
KHK4083 
Dose (mg/kg) 
AUC2wk 
(μghr/mL) 
Rac 
Cmin-ss (μg/mL) 
Cmax-ss (μg/mL) 
t1/2 (days) 
1.0 
6230 
1.62 
10.9 
36.9 
10.5 
3.0 
29200 
2.17 
62.1 
140.0 
16.3 
10 
159000 
3.14 
385.0 
645.0 
26.2 
AUC2wk=area under the concentration-time curve at 2 weeks post-dose; Cmax-ss=maximum simulated serum concentration at 
steady state; Cmin-ss=trough simulated concentration at the end of the dosing interval at steady state; Rac=accumulation ratio; 
t1/2=terminal elimination half-life. 
In the 26-week GLP toxicology study in male and female cynomolgus monkeys 
(SBL303-104) at the NOAEL of 30 mg/kg, the mean AUC0-2wk and Cmax were 
301500 μghr/mL and 1510 μg/mL, respectively, after the 13th dose (i.e., steady state). The 
safety margins (AUC0-2wk  from the monkey NOAEL/AUC2wk simulated in humans) were 
48.4, 10.3, and 1.9 at 1.0, 3.0, and 10 mg/kg, respectively (Table 8.1.3-2).  
In the 4-week GLP toxicology study in male and female cynomolgus monkeys (SBL303-081) 
at the NOAEL of 100 mg/kg, the mean AUC0-∞ and Cmax were 607000 µghr/mL and 
5345 µg/mL, respectively, after the first dose. The safety margins (AUC0-∞ from the monkey 
NOAEL/AUC2wk simulated in humans) were 97.4, 20.8, and 3.8 at 1.0, 3.0, and 10 mg/kg, 
respectively (Table 8.1.3-2). 


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Table 8.1.3-2 Safety Margins for the Planned KHK4083 Doses 
KHK4083 
Dose (mg/kg) 
26-week GLP Toxicology Studya 
4-week GLP Toxicology Studyb 
Safety Margin 
for AUC2wk 
Safety Margin 
for Cmax-ss 
Safety Margin for 
AUC2wk 
Safety Margin 
for Cmax-ss  
1.0 
48.4 
40.9 
97.4 
144.9 
3.0 
10.3 
10.8 
20.8 
38.2 
10 
1.9 
2.3 
3.8 
8.3 
a: In the 26-week GLP toxicology study in male and female cynomolgus monkeys (SBL303-104), at the NOAEL of 
30 mg/kg, the mean AUC0-2wks and Cmax were 301500 μghr/mL and 1510 μg/mL, respectively, after the 13th dose. Safety 
Margin=AUC0-2wk from monkey NOAEL/AUC2wk simulated in humans. Safety Margin=Cmax from monkey NOAEL/Cmax 
simulated in humans.  
b: In the 4-week GLP toxicology study in male and female cynomolgus monkeys (SBL303-081), at the NOAEL of 
100 mg/kg, the mean AUC0-∞ and Cmax were 607000 µghr/mL and 5345 µg/mL, respectively, after the first dose. 
Safety Margin=AUC0-∞ from monkey NOAEL/AUC2wk simulated in humans; Safety Margin=Cmax from monkey 
NOAEL/Cmax-ss simulated in humans. 
AUC2wk=area under the concentration-time curve at 2 weeks post-dose; AUC0-∞= area under the serum drug 
concentration-time curve from 0 to infinity; Cmax-ss=maximum observed serum concentration at steady state; GLP=Good 
Laboratory Practice; NOAEL=no-observed-adverse-effect level. 
 
The safety margins calculated based on Cmax are comparable to the safety margins calculated 
based on AUC2wk. As the Phase 2 study is to reach the PK exposure at the NOAEL dose level, 
and the 1.0, 3.0, and 10 mg/kg doses given every 2 weeks or every 4 weeks are expected to 
have overall PK exposure lower than the NOAEL, the selected doses are expected to be a 
safe dose for this clinical study. 
8.1.3.2 
Administration 
Treatment will be administered on an outpatient basis. The minimum IV infusion time will be 
60 minutes (± 10 minutes).  
8.1.3.3 
Infusion Reactions 
This study must only be performed in medical facilities with the necessary equipment and 
medications, and staff trained in their use, readily available to manage potential acute 
infusion reactions, including anaphylactic reactions.  
No pre-medication (e.g., anti-emetic; 5HT3 blocker; histamine H1 and/or H2 blocker(s); 
corticosteroid) is planned to be routinely/prophylactically administered prior to KHK4083 
infusion in this study. However, the administration of therapeutic mAbs, even those that are 
humanized or fully human, may be associated with acute infusion reactions, especially with 
the first infusion. Therefore, each subject must be carefully monitored at the investigative site 
for signs of acute, potential dose-limiting infusion reactions during and for at least 3 hours 


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following the completion of the first and second IV infusions of investigational product in 
both phases, and for at least 1 hour following all other IV infusions. In addition, a phone call 
to each subject will be conducted at approximately 48 to 72 hours following the completion 
of the first and second infusions for any subject who does not return for a visit at the 
investigative site. 
Acute infusion 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 diagnostic criteria for anaphylaxis in Appendix 5). Signs and 
symptoms of acute infusion reactions usually develop during or shortly after drug infusion 
and generally resolve completely within 24 hours of completion of the infusion. Acute 
infusion reactions should be classified by intensity (i.e., mild, moderate, or severe) of the AE. 
Refer to Section 10.6.7.1 for reporting an infusion reaction including descriptions of specific 
symptoms observed or reported by the subject. 
Although mild infusion reactions require no intervention and no interruption of the infusion, 
investigators are permitted to interrupt the infusion for mild reactions, observe the subject for 
resolution of any signs/symptoms, and restart the infusion at one-half the infusion rate 
originally prescribed if the reaction substantially resolves. The rate of the remaining infusion 
may be gradually escalated to the originally prescribed rate based on the subject’s subsequent 
tolerance and Investigator judgment. For subjects who continue treatment, subsequent 
infusion(s) may be recommended to be administered at a slower infusion rate. 
If a moderate infusion reaction occurs, stop the infusion for at least 15 to 30 minutes. 
Paracetamol orally and diphenhydramine 50 mg IV or an equivalent anti-histamine may be 
administered. If symptoms abate, re-start the infusion at one–half the previous rate; if 
symptoms recur, permanently discontinue the infusion. For reactions that do not abate after 
30 minutes, worsen or recur, the Investigator should use their medical judgment to consider 
additional medical measures. 
For any subject experiencing an acute infusion reaction of severe intensity, the infusion must 
be immediately discontinued and the subject must receive immediate medical/nursing 
assessment and indicated supportive management per the institutional standard of care and 
local Investigator judgment until the signs/symptoms of the reaction have resolved.  
If consistent mild and/or moderate infusion reactions are observed, the Sponsor (i.e., Medical 
Monitor and/or a representative from Drug Safety Surveillance) and the Investigator 
(or designee) may recommend the pretreatment of subjects or a slower infusion rate. In the 
event that any subject experiences an acute infusion reaction considered to be an SAE, there 


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may be a decision to introduce, for all subjects, a slower infusion rate for administration of 
the investigational product, and/or a mandatory pre-medication regimen (e.g., anti-emetics; 
H1 or H2 blockers; and/or corticosteroids), and/or dose-reduction in a cohort. 
8.1.3.4 
Dose Modifications 
Management of severe or intolerable adverse reactions due to study treatment may require 
concurrent therapy, dose omission, prolonged infusion time, or temporary withholding or 
permanent discontinuation of treatment. No dose reduction should be planned for subsequent 
doses for an individual subject.   
Doses chosen for each cohort, as determined by the Safety Monitoring Committee and 
Sponsor, may result in dose reduction for all subjects enrolled in a cohort. 
8.1.4 
Treatment Period (Weeks 0 to 52) 
The 52-week Treatment Period (last dose Week 48) includes double-blind Induction Therapy 
over 12 weeks followed by OLE/double-blind LTE Therapy over 40 weeks. Subjects will 
continue in the study for 16 weeks after the last infusion associated with the subject’s 
treatment period for on-site post-treatment assessments (refer to Figure 6.1-1 for overall 
study design). No other investigational or commercial agents or therapies other than 
KHK4083 and placebo and those described in Section 8.5 may be administered with the 
intent to treat the subject’s UC. 
8.1.4.1 
Induction Therapy: Weeks 0 to 12 (Last Dose:  Week 10) 
Double-blind Induction Therapy (12 weeks) comprises Part A (Cohorts 1 - 3) for IV 
administration of multiple ascending doses of KHK4083 or placebo; and Part B (Cohort 4) 
for IV administration of the recommended dose of KHK4083 or placebo. Subjects in Part A 
are not allowed to participate in Part B of Induction Therapy. Select Sponsor personnel will 
be unblinded after the last subject completes Induction Therapy (refer to Section 8.4 for 
details). 
Subjects in each cohort will be randomized in a 3:1 ratio to receive KHK4083 or placebo. 
Each subject in each cohort (Cohorts 1 - 4) will be administered one IV infusion of KHK4083 
or placebo once every 2 weeks for a total of 6 treatments, i.e., Day 1 (Week 0), Day 15 
(Week 2), Day 29 (Week 4), Day 43 (Week 6), Day 57 (Week 8), and Day 71 (Week 10).  
• 
Induction Therapy Part A (Cohorts 1 - 3):  36 subjects (12 subjects/cohort) will be 
administered investigational product, i.e., 27 subjects (9 subjects/cohort) will receive 
KHK4083 and 9 subjects (3 subjects/cohort) will receive placebo once every 2 weeks 
(Weeks 0 to 10) as follows:  


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Cohort 1:  1.0 mg/kg or placebo  
Cohort 2:  3.0 mg/kg or placebo  
Cohort 3:  10 mg/kg or placebo  
The cumulative safety data available after the first 8 of 12 subjects randomized in 
Cohort 1 will be evaluated by the Safety Monitoring Committee at Week 4 (~Day 29) to 
assess whether dosing will continue for subjects within Cohort 1 and if investigational 
product will be administered at the next higher dose level for subjects in Cohort 2. For 
Cohorts 2 and 3, the cumulative safety data available after the first 8 subjects in each 
cohort at Week 4 (~Day 29) and the first 4 subjects in each cohort at Week 6 (~Day 43) 
will be evaluated for continuation of all of the subjects and for dose escalation in the next 
cohort, i.e., Cohort 3 in Part A and Cohort 4 in Part B, respectively. The Safety 
Monitoring Committee and Sponsor may dose-reduce cohorts or not escalate to the 
planned doses based upon review of safety data (refer to Section 6.3). 
• 
Induction Therapy Part B (Cohort 4):  The recommended KHK4083 dose (one of three 
dose levels in Cohorts 1 - 3) is selected based on the safety data from Part A. At least 
24 subjects will be administered the recommended dose of KHK4083 (18 subjects) or 
placebo (6 subjects) once every 2 weeks (Weeks 0 to 10) in Cohort 4.  
For subjects in all cohorts, a sigmoidoscopy with biopsy will be performed at Week 12 to 
assess improvement in the mucosa based on a mean change in the mMES from Baseline 
(Week 0) to Week 12. It is highly recommended that the sigmoidoscopy with biopsy be 
performed within 7 to 13 days prior to the Week 12 visit. 
8.1.4.2 
Open-label/Long-term Extension Maintenance Therapy:  Week 12 
(First Dose) to Week 52 
All subjects who qualify and continue double-blind LTE or start open-label maintenance 
therapy will be administered one KHK4083 or placebo (LTE) or one KHK4083 (OLE) IV 
infusion at Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 for a total of 10 additional 
treatments followed by an End-of-OLE/LTE Therapy visit at Week 52, and then proceed to 
the OLE/LTE Therapy Follow-up Period (Week 56 through Week 64). The treatment at 
Week 12 will be administered at the scheduled visit or within 7 days after Week 12. The OLE 
dose will be the same as the dose for that cohort during the induction therapy, unless 
dose-reduction is recommended by the Safety Monitoring Committee and Sponsor (see 
Section 6.3). 
During OLE/LTE Therapy, corticosteroid (glucocorticoid) dosages of prednisolone or its 
equivalent will be permitted to be tapered (decreasing by up to 2.5 mg/day per week) and 
other concomitant medications for UC may be tapered. Bolus or “rescue” treatment with 
systemic corticosteroids or topical corticosteroid enemas or suppositories (in addition to the 
dose of oral corticosteroids at Screening) is permitted only after Week 12 evaluations are 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
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complete. A sigmoidoscopy with biopsy will be performed at the End-of-OLE/LTE Therapy 
visit at Week 52 or within 21 days prior to Week 52. 
8.1.5 
Post-treatment Follow-up Period 
Post-treatment Follow-up assessments will continue for 16 weeks after the last infusion 
associated with the subject’s treatment period. For subjects who only receive Induction 
Therapy (i.e., last dose at Week 10 and do not continue in OLE/LTE Therapy), the Post-
treatment Follow-up visits will be at Weeks 16, 20, and 26. For all subjects who receive both 
Induction Therapy and OLE/LTE Therapy (last dose at Week 48), the Post-treatment Follow-
up visits will be at Weeks 56, 60, and 64. Subjects removed from the study for AEs will be 
followed until there is a return to the subject’s baseline condition, or until a clinically 
satisfactory resolution is achieved. The date of the subject’s last post-treatment study visit 
will be considered the End-of-Study date.  
8.2 
Method of Numbering Subjects and Assigning Subjects to Treatment 
Cohorts or Randomization 
After a subject meets all study eligibility requirements at Screening (refer to Section 7.1 for 
enrollment procedures), the IRT system will be used by the Investigator (or designee) to 
randomize the subject to double-blind Induction Therapy on Day 1 (Week 0). Subjects 
randomly assigned in Cohorts 1 - 3 will receive either KHK4083 (one of three dose levels) or 
placebo in a 3:1 ratio during Part A of Induction Therapy. Additional subjects (Cohort 4) in a 
3:1 ratio will receive the recommended KHK4083 dose or placebo during Part B of Induction 
Therapy. Subjects who received study medication in Part A are not allowed to participate in 
Part B.  
At the end of Induction Therapy, subjects who meet all study eligibility requirements 
described in Section 7.4 will start receiving open-label KHK4083 at the same dose for that 
subject’s cohort.  Subjects who previously met all study eligibility requirements and entered 
the LTE will continue to receive KHK4083 or placebo during LTE Therapy phase; subject in 
the LTE may be eligible for the OLE up to Week 28 as described in Section 6.1.4. 
8.3 
Blinding During the Double-blind Treatment Period (Induction Therapy 
and Long-term Extension Therapy) 
The subject and Investigator (or investigative site personnel) will not know the treatment to 
which the subject is randomized during the double-blind Treatment Period. Placebo will be 
administered by IV infusion to each cohort to ensure blinded treatment. The study is being 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
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63 
 
blinded to prevent bias in the safety evaluation, in particular the severity grading and 
causality determinations of AEs. However, at any time during the study, if a medical 
emergency occurs and subject treatment must be known, the blind may be broken according 
to the procedure in Section 8.4. 
An assigned pharmacist (or qualified designee) at each investigative site will be unblinded 
and responsible for preparing the appropriate treatment based on the treatment assignment by 
the IRT system. The unblinded pharmacist (or qualified designee) will ensure that the 
investigational product administered to each subject is labeled such that the treatment identity 
cannot be determined.  
8.4 
Unblinding During the Treatment Period and After Induction Therapy and 
Long-term Extension Therapy 
A subject’s treatment assignment should only be unblinded by the Investigators and/or 
Sponsor’s Medical Monitor 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. Unblinding for any other reason will be considered a protocol violation.  
The Investigators are strongly encouraged to contact the Medical Monitor before unblinding 
any subject’s treatment assignment. However, the Investigator may unblind for safety reasons 
without prior notification, but must contact the Medical Monitor within one business day 
after the event and must document the unblinding in the subject’s source records together 
with a completed SAE form. Any instance of unblinding will be reported in the clinical study 
report. 
The Investigator or the designee who breaks the blind must record the date and the reasons as 
appropriate. In such cases, treatment with the investigational product must be stopped and the 
Sponsor must be contacted immediately to determine whether the subject should be 
withdrawn from the study. Every attempt should be made to contact the Sponsor before the 
blind is broken. 
The study will be unblinded to select personnel from the Sponsor (or consultants acting on 
behalf of KKD) and/or from participating Contract Research Organizations. The individuals 
will be identified in the Blinding Plan and Unblinding Processes for Study 4083-002. The 
study will be blinded to all other study personnel/consultants, investigative site personnel, 
and study subjects. 
After the last subject completes Part B of Induction Therapy, the study will be unblinded to 
additional select Sponsor personnel. The study will be unblinded to all study 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
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64 
 
personnel/consultants following database lock after the last subject completes the last 
follow-up visit. 
8.5 
Prior and Concurrent Therapy 
All medications (including prescription, non-prescription and supplements) for treatment of 
UC taken within 6 months prior to Screening; any other medication taken 1 month prior to 
Screening; and any concomitant medications (including tracking probiotic usage) during the 
study will be collected. For all biologic treatments, the reason for discontinuation should be 
collected at Screening. Combination medications should be recorded by trade name. 
Stable doses of the following concomitant medications are permitted for UC treatment during 
the study as specified below:   
• 
Aminosalicylates (5-ASA or mesalamine ≤ 4.8 g/day; sulfasalazine ≤ 3 g/day) for at least 
14 days prior to the Screening visit; and/or 
• 
Oral glucocorticoids, ≤ 20 mg/day prednisolone or the equivalent, or budenoside 
≤ 9 mg/d for at least 14 days prior to the Screening visit (or for 4 weeks if a course of 
corticosteroids had started at less than 8 weeks prior to Screening visit); and/or 
• 
Azathioprine up to 3 mg/kg/day or 6-mercaptopurine up to 1.5 mg/kg/day for a total 
treatment period of at least 12 weeks, including 4 weeks of stable treatment, prior to the 
Screening visit. 
Supportive therapy to manage symptoms or AEs is acceptable. Daily, chronic antidiarrheals 
should not be taken.  
One bolus or “rescue” treatment for up to 7 days with each of the following:  systemic 
corticosteroids or topical corticosteroid enemas or suppositories (in addition to the dose of 
oral corticosteroids at Screening) is permitted only after Week 12 evaluations are complete. 
Topical anti-inflammatory agents may be permitted only after Week 12 evaluations are 
complete and application must be withheld for at least 2 weeks prior to the sigmoidoscopy at 
Week 52/End-of-Treatment visit. 
Dose reductions of concurrent medications are permitted for AEs from Baseline through the 
end of the study as allowed by the protocol. Other dose adjustments of concurrent 
medications (including corticosteroids and other treatments for UC) are permitted after the 
Week 12 visit (per Investigator’s judgment), i.e., during OLE/LTE Therapy and the Induction 
Therapy and OLE/LTE Therapy Follow-up Periods. After the Week 12 visit, corticosteroid 
(glucocorticoid) dosages of prednisolone or its equivalent may be tapered by approximately 
2.5 mg/day per week, at the Investigator’s discretion. Subjects who have recurrence of 
clinical symptoms may increase their chronic (> 7 days) dose of corticosteroids and other 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
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65 
 
treatments for UC may increase up to 110% of the original dose at the start of Induction 
Therapy. 
8.5.1 
Prohibited Treatment 
During Screening and Induction Therapy, subjects are not permitted to receive rescue therapy 
for UC including increases in corticosteroids or other medications for UC treatment, except 
as specified above (Section 8.5). 
During Screening, Induction Therapy, and OLE/LTE Therapy, subjects are not permitted to 
receive any additional experimental therapy or any other therapy to treat the UC, except as 
specified above. The following is a list of specific prohibited treatments:  
• 
B-cell depleting agents including vedolizumab, natalizumab, efalizumab or rituximab or 
other lymphocyte-depleting treatments, including but not limited to alkylating agents 
(such as cyclophosphamide or chlorambucil) and total lymphoid irradiation;  
• 
Methotrexate, cyclosporine, mycophenolate, tacrolimus, thalidomide, or other immune 
altering drugs; (Note:  ophthalmologic preparations are permitted.) 
• 
TNF antagonists. 
The above prohibited treatments are permitted during the Induction Therapy Follow-up 
Period and OLE/LTE Therapy Follow-up Period of the study.  
Some medications, such as nonsteroidal anti-inflammatory drugs, may need to be 
administered or held prior to a sigmoidoscopy with biopsy. Those will be detailed in a 
sigmoidoscopy manual. 
8.6 
Treatment Compliance 
The Investigator is required to ensure compliance with respect to the KHK4083 (or placebo) 
dosing schedule required by the protocol. At least five of six IV infusions of investigational 
product are required to be administered during Induction Therapy for treatment compliance in 
this study. At least half of the IV infusions of investigational product are required to be 
administered during OLE/LTE Therapy for treatment compliance in this study.  
8.6.1 
Study Visit Outside of Planned Scheduled - Delay in Dosing 
During Induction Therapy, investigational product (KHK4083 or placebo) will be 
administered every 2 weeks, for a total of 6 doses. A visit window, ± 2 days at Week 2, and 
± 4 days for all other doses, has been defined. If the study visit/dosing does not occur during 
the planned visit window, investigational product should not be administered at the visit and 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
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66 
 
the next dose should be administered at the next visit. KHK4083 or placebo should not be 
administered less than 6 days from the previous dosing.  
9 
STUDY PROCEDURES 
It is important to maintain the visit structure as accurately as possible. Whenever an 
adjustment to this structure is necessary, the date of the adjusted visit should occur within the 
number of days (before or after) specified in the planned schedules for Screening, Induction 
Therapy, and Induction Therapy Post-treatment Follow-up Period (refer to Study Schedule of 
Events, Table 9-1) and for OLE/LTE Therapy and OLE/LTE Therapy Post-treatment Follow-
up Period (refer to Study Schedule of Events, Table 9-2). The timing of any subsequent visits 
should be scheduled to maintain the visit structure relative to the first day that investigational 
product was administered. 
Screening evaluations used to determine the subject’s study eligibility must be completed 
within the Screening Period (Day −28 to Day −1) prior to starting treatment on Day 1 
(Week 0) unless otherwise specified. Written informed consent must be obtained prior to any 
study-specific procedures. Results of all Screening evaluations must be reviewed by the 
Investigator or his/her designee to ensure that all eligibility criteria have been satisfied prior 
to randomization. For subjects who complete double-blind Induction Therapy and are eligible 
at Week 12 to receive treatment, additional criteria are required for enrollment in OLE/LTE 
Therapy (refer to Section 7.4 for the list of criteria). 
All efficacy, PK, PD, immunogenicity, and safety measurements obtained during the course 
of the study are summarized in Table 9-1, Table 9-2, Table 10.4.1-1, and Table 10.4.1-2. 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
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Table 9-1 Study Schedule of Events - Screening, Induction Therapy, and Follow-up Period  
Procedure 
Screening 
Treatment Period - Double-blind Induction Therapy:   
Weeks 0 to 12 (Last dose at Week 10)a 
(All Randomized Subjects) 
Induction Therapy  
Post-treatment 
Follow-up Period for 
Subjects Not Enrolling in  
OLE Therapy 
 
Baseline 
 
 
 
 
 
End-of- 
Induction 
Therapy 
Follow-
up 
1 
Follow-
up 
2 
Follow-
up  
3  
Day −28 
to Day −1 
Week 0 
Day 1 
Week 2 
± 2 days 
Week 4 
± 4 days 
Week 6 
± 4 days 
Week 8 
± 4 days 
Week 10 
± 4 days 
End-of-
Treatment 
Week 12 
± 4 days 
Week 16 
± 7 days 
Week 20 
± 7 days 
End-of-
Study 
Week 26  
± 7 days 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Medical, Diet & Surgical 
History/ Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examinationb 
X 
X 
 
 
 
 
 
X 
 
 
 
Brief Physical Examinationc 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
Vital Signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
Xe 
 
 
 
Xe 
Xe 
 
 
 
 
Hematology (CBC with diff 
& platelets) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry Profile 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Profile 
X 
X 
 
 
 
 
 
X 
 
 
 
Multiplex-31 Assayf 
 
X 
X 
 
 
 
 
X 
 
 
 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum FSHg 
X 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancyg 
X 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancyg 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 


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Table 9-1 Study Schedule of Events - Screening, Induction Therapy, and Follow-up Period  
Procedure 
Screening 
Treatment Period - Double-blind Induction Therapy:   
Weeks 0 to 12 (Last dose at Week 10)a 
(All Randomized Subjects) 
Induction Therapy  
Post-treatment 
Follow-up Period for 
Subjects Not Enrolling in  
OLE Therapy 
 
Baseline 
 
 
 
 
 
End-of- 
Induction 
Therapy 
Follow-
up 
1 
Follow-
up 
2 
Follow-
up  
3  
Day −28 
to Day −1 
Week 0 
Day 1 
Week 2 
± 2 days 
Week 4 
± 4 days 
Week 6 
± 4 days 
Week 8 
± 4 days 
Week 10 
± 4 days 
End-of-
Treatment 
Week 12 
± 4 days 
Week 16 
± 7 days 
Week 20 
± 7 days 
End-of-
Study 
Week 26  
± 7 days 
Stool Enteric Pathogens 
(including Clostridium 
difficile) 
X 
 
 
 
 
 
 
X 
 
 
 
Hemoglobin A1c 
X 
 
 
 
 
 
 
 
 
 
 
HIV Test; Hepatitis B (core 
antibody or surface antigen); 
Hepatitis C antibody 
X 
 
 
 
 
 
 
 
 
 
 
PPD (or QuantiFERON)-
TBh 
X 
 
 
 
 
 
 
 
 
 
 
Delayed-type 
Hypersensitivity Skin Testi 
(US and other selected 
countries)  
X 
 
 
 
 
 
 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Diary Training 
X 
 
 
 
 
 
 
 
 
 
 
Partial Mayo Clinic Score 
(without sigmoidoscopy, 
includes review of diary) 
with Physician’s Global 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
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69 
 
Table 9-1 Study Schedule of Events - Screening, Induction Therapy, and Follow-up Period  
Procedure 
Screening 
Treatment Period - Double-blind Induction Therapy:   
Weeks 0 to 12 (Last dose at Week 10)a 
(All Randomized Subjects) 
Induction Therapy  
Post-treatment 
Follow-up Period for 
Subjects Not Enrolling in  
OLE Therapy 
 
Baseline 
 
 
 
 
 
End-of- 
Induction 
Therapy 
Follow-
up 
1 
Follow-
up 
2 
Follow-
up  
3  
Day −28 
to Day −1 
Week 0 
Day 1 
Week 2 
± 2 days 
Week 4 
± 4 days 
Week 6 
± 4 days 
Week 8 
± 4 days 
Week 10 
± 4 days 
End-of-
Treatment 
Week 12 
± 4 days 
Week 16 
± 7 days 
Week 20 
± 7 days 
End-of-
Study 
Week 26  
± 7 days 
Flexible Sigmoidoscopy 
with biopsy for mMES, 
UCEIS, modified Baron 
score & total Mayo Clinic 
score (includes review of 
diary) 
X (within 
7 to 
28 days 
prior to 
first dose) 
 
 
 
 
 
 
Xj 
(recommend 
7 to 13 days 
prior to 
Week 12 
LTE dosing) 
 
 
 
IBDQ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fecal Calprotectink 
 
X 
X 
 
 
 
 
X 
 
 
 
wr-CRP Assay 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Pharmacokinetics 
 
For PK Sample Collection Schedule Refer to Table 10.4.1-1 for Cohorts 1 - 3 during Induction Therapy (Part A) and LTE  
and Table 10.4.1-2 for Cohort 4 during Induction Therapy (Part B) and LTE 
Anti-KHK4083 Antibodiesl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Flow Cytometry  
 
Refer to Table 10.4.1-1 for Cohorts 1 - 3 and Table 10.4.1-2 for Cohort 4  
Future Biomarker Analyses 
(whole blood)m 
 
X 
X 
 
 
 
 
X 
 
 
X 
Adverse Eventsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant 
Medicationso 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigational Product 
Administrationa 
On-site (plus phone call) 
Post-infusion Monitoring 
Requiredp 
 
X 
X 
X 
X 
X 
X 
 
 
 
 


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Table 9-1 Study Schedule of Events - Screening, Induction Therapy, and Follow-up Period  
Procedure 
Screening 
Treatment Period - Double-blind Induction Therapy:   
Weeks 0 to 12 (Last dose at Week 10)a 
(All Randomized Subjects) 
Induction Therapy  
Post-treatment 
Follow-up Period for 
Subjects Not Enrolling in  
OLE Therapy 
 
Baseline 
 
 
 
 
 
End-of- 
Induction 
Therapy 
Follow-
up 
1 
Follow-
up 
2 
Follow-
up  
3  
Day −28 
to Day −1 
Week 0 
Day 1 
Week 2 
± 2 days 
Week 4 
± 4 days 
Week 6 
± 4 days 
Week 8 
± 4 days 
Week 10 
± 4 days 
End-of-
Treatment 
Week 12 
± 4 days 
Week 16 
± 7 days 
Week 20 
± 7 days 
End-of-
Study 
Week 26  
± 7 days 
Determine if Eligible for 
OLE at Week 12 
 
 
 
 
 
 
 
X 
 
 
 
 
Footnotes to Table 9-1. 
a: Induction Therapy Dosing Regimen:  Part A Cohorts 1 - 3 (KHK4083:  1.0, 3.0, and 10 mg/kg or placebo) once every 2 weeks (Weeks 0 to 10); and Part B Cohort 4 
(KHK4083:  recommended dose, i.e., one of three dose levels in Cohorts 1 - 3 based on the safety data from Part A, or placebo) once every 2 weeks (Weeks 0 to 10).  
b: Complete physical examinations include general appearance and examination of the HEENT and body systems (cardiovascular, respiratory, abdominal, musculoskeletal, 
extremities, lymph nodes, and skin). 
c: Brief physical examinations only include the HEENT, cardiovascular, respiratory, and abdominal examinations. 
d: Vital signs include systolic and diastolic blood pressure, radial pulse, respiration rate, and oral body temperature.  
e: Perform ECG pre-dose and at the end of infusion. 
f: If the subject does not continue in OLE Therapy, a sample for the multiplex-31 assay will also be collected at one of the follow-up visits. 
g: Female subjects considered to be women of childbearing potential must have a negative pregnancy test at Screening and Baseline. Subjects are considered to not be of 
childbearing potential if they are ≥ 50 years of age and without menses for 24 consecutive months; have an FSH level > 25 mIU/mL (or in postmenopausal range per local 
laboratory standards); or have undergone a hysterectomy and/or a bilateral salpingo-oophorectomy. 
h: Subjects with a low risk of an infection only need an interferon gamma release assay. 
i: For the delayed-type hypersensitivity test, the skin testing site will be read within 48 to 72 hours following intradermal injection of the Candida albicans antigen. The largest 
diameter of induration will be measured in mm and collected. 
j: If the subject discontinues more than 8 weeks after the Baseline visit, a sigmoidoscopy must be performed at End-of-Treatment. The sigmoidoscopy may be performed up to 4 
weeks after the last dose of study medication. 
k: Fecal calprotectin concentration, which is usually elevated in subjects with moderately active UC, will be measured. Fecal samples will be collected as specified in the stool 
collection instruction section of the laboratory manual. 
l: Samples for anti-KHK4083 antibodies must be taken prior to dosing and taken at the same time as pre-dose PK samples shown in Table 10.4.1-1 and Table 10.4.1-2. 
m: Whole blood will be collected and stored (frozen) for potential exploratory biomarker analyses in the future at:  Baseline (Week 0), Week 2, Week 12 (End-of-Induction 
Therapy), and Induction Therapy Post-treatment Follow-up 3 visit (if the subject does not continue in OLE Therapy). 
n: The collection of adverse event information should commence following the subject’s written consent to participate in the study. 
 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
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Footnotes to Table 9-1.(cont’d) 
o: All medications (including prescription, non-prescription and supplements) for treatment of UC taken within 6 months prior to Screening; any other medication taken 1 month 
prior to Screening; and any concomitant medications (including tracking probiotic usage) during the study must be recorded. For all biologic treatments, the reason for 
discontinuation should be recorded at Screening. 
p: All subjects are required to remain at the investigative site to be carefully monitored after each infusion for potential infusion reactions or other adverse events. Post-infusion 
safety monitoring is as follows:   
 
Week 0 (Day 1 Baseline):  minimum of 3 hours post-infusion at site and a phone call at approximately 48 to 72 hours post-infusion for any subject who does not return for 
the scheduled visit at the investigative site; 
 
Week 2:  minimum of 3 hours post-infusion at site and a phone call at approximately 48 to 72 hours post-infusion for any subject who does not return for a visit at the 
investigative site; 
 
Weeks 4, 6, 8 and 10:  minimum of 1 hour post-infusion at site. 
CBC=complete blood count; ECG=electrocardiogram; eCRF=electronic case report form; FSH=follicle-stimulating hormone; HEENT=head, eyes, ears, nose, and throat; 
HIV=human immunodeficiency virus; IBDQ=Inflammatory Bowel Disease Questionnaire; LTE=long-term extension; mMES=modified Mayo endoscopy subscore; OLE=open-
label extension; PK=pharmacokinetic(s); PPD=purified protein derivative; TB=tuberculosis; UC=ulcerative colitis; UCEIS=Ulcerative Colitis Endoscopic Index of Severity; 
US=United States; wr-CRP=wide-range C-reactive protein. 
 


Clinical Protocol 4083-002, Amendment 2 
 
 
 
 
 
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Table 9-2 Study Schedule of Events - Open-label/Long-term Extension Maintenance Therapy and Follow-up Period 
Procedure 
Treatment Period - OLE/LTE Therapy:  Week 12 (First Dose) to Week 52a 
OLE/LTE Therapy 
Post-treatment 
Follow-up Period 
 
 
 
 
 
 
 
 
 
 
End-of-
OLE/LTE 
Therapy 
Follow-
up  
1 
Follow-
up  
2  
Follow- 
up 
3  
Week 12 
Week 
16 
± 7 
days 
Week 
20 
± 7 
days 
Week  
24 
± 7 
days 
Week  
28 
± 7 
days 
Week  
32 
 ± 7 
days 
Week  
36 
± 7 
days  
Week  
40 
± 7 
days 
Week  
44 
± 7 
days 
Week  
48 
± 7 
days 
End-of-
Treatment 
Week 
52  
± 7 
 days 
Week 
56 
± 7 
days 
Week 
60  
± 7 
days 
End-of-
Study 
Week 
64 
± 7 
days 
Inclusion/Exclusion Criteriab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationc 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Brief Physical Examinationd 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Vital Signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
Xf 
Xf 
 
 
 
 
 
 
 
 
X 
 
 
 
Hematology (CBC with diff & 
platelets) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry Profile 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Profile 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Multiplex-31 Assay 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancyg 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Urine Pregnancyg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stool Enteric Pathogens 
(including Clostridium 
difficile) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Partial Mayo Clinic Score 
(without sigmoidoscopy, 
includes review of diary) with 
Physician’s Global Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 9-2 Study Schedule of Events - Open-label/Long-term Extension Maintenance Therapy and Follow-up Period 
Procedure 
Treatment Period - OLE/LTE Therapy:  Week 12 (First Dose) to Week 52a 
OLE/LTE Therapy 
Post-treatment 
Follow-up Period 
 
 
 
 
 
 
 
 
 
 
End-of-
OLE/LTE 
Therapy 
Follow-
up  
1 
Follow-
up  
2  
Follow- 
up 
3  
Week 12 
Week 
16 
± 7 
days 
Week 
20 
± 7 
days 
Week  
24 
± 7 
days 
Week  
28 
± 7 
days 
Week  
32 
 ± 7 
days 
Week  
36 
± 7 
days  
Week  
40 
± 7 
days 
Week  
44 
± 7 
days 
Week  
48 
± 7 
days 
End-of-
Treatment 
Week 
52  
± 7 
 days 
Week 
56 
± 7 
days 
Week 
60  
± 7 
days 
End-of-
Study 
Week 
64 
± 7 
days 
Flexible Sigmoidoscopy with 
biopsy for mMES, UCEIS, 
modified Baron score & total 
Mayo Clinic score (includes 
review of diary)  
X  
(recommend 
7 to 13 days 
prior to 
Week 12 
 
 
 
 
 
 
 
 
 
Xh (at visit 
or within 
21 days 
prior to 
Week 52) 
 
 
 
IBDQ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fecal Calprotectini 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
wr-CRP Assay 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Pharmacokinetics 
For PK Sample Collection Schedule Refer to Table 10.4.1-1 for Cohorts 1 - 3 during Induction Therapy (Part A) and OLE/LTE  
and Table 10.4.1-2 for Cohort 4 during Induction Therapy (Part B) and OLE/LTE 
Anti-KHK4083 Antibodiesj  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Flow Cytometry  
Refer to Table 10.4.1-1 for Cohorts 1 - 3 and Table 10.4.1-2 for Cohort 4 
 
 
 
Future Biomarker Analyses  
(whole blood)k 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medicationsl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigational Product 
Administrationa 
On-site Post-infusion 
Monitoring Requiredm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 


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Footnotes to Table 9-2 
a: The OLE Therapy Dosing Regimen:  10 KHK4083 treatments to be administered as one IV infusion every 4 weeks (Weeks 12 to 48) at the dose administered to the subjects in the 
cohort (or a lower dose if that cohort is discontinued) during Induction Therapy. LTE Therapy Dosing Regimen:  10 additional KHK4083 or placebo treatments to be administered as 
one IV infusion every 4 weeks (Weeks 12 to 48) at the dose administered to the subjects in the cohort (or a lower dose if that cohort is discontinued) during Induction Therapy. 
Subjects in LTE who transition to the OLE should have visits and assessments as described in Section 6.1.4. 
b: Subjects who complete double-blind Induction Therapy must meet additional eligibility criteria (refer to Section 7.4) to receive OLE Therapy once every 4 weeks (first dose at 
Week 12) with a post-treatment Follow-up Period for 16 weeks after the subject’s last infusion. The treatment at Week 12 will be administered at the scheduled visit or within 7 days 
after Week 12. Subjects participating in the double-blind LTE who experience a clinical worsening or a flare of disease up to Week 28, as defined by the Investigator, may transition 
to the OLE (refer to Section 6.1.4). 
c: Complete physical examinations include general appearance and examination of the HEENT and body systems (cardiovascular, respiratory, abdominal, musculoskeletal, extremities, 
lymph nodes, and skin). 
d: Brief physical examinations only include the HEENT, cardiovascular, respiratory, and abdominal examinations. 
e: Vital signs include systolic and diastolic blood pressure, radial pulse, respiration rate, and oral body temperature.  
f: Perform ECG predose and at the end of infusion. Subjects who transition from LTE to OLE must have ECGs performed predose and at the end of infusion for the first two infusions. 
g: Female subjects considered to be women of childbearing potential must have a negative pregnancy test at Screening and Baseline. Subjects are considered to not be of childbearing 
potential if they are ≥ 50 years of age and without menses for 24 consecutive months; have a follicle-stimulating hormone level > 25 mIU/mL (or in postmenopausal range per local 
laboratory standards); or have undergone a hysterectomy and/or a bilateral salpingo-oophorectomy. 
h: If the subject discontinues more than 8 weeks after the Week 12 visit, a sigmoidoscopy must be performed at End-of-Treatment. The sigmoidoscopy may be performed up to 4 weeks 
after the last dose of study medication. 
i: Fecal calprotectin concentration, which is usually elevated in subjects with moderately active UC, will be measured.  
j: Samples for anti-KHK4083 antibodies must be taken prior to dosing and taken at the same time as pre-dose PK samples shown in the Table 10.4.1-1 and Table 10.4.1-2. 
k: Whole blood will be collected and stored (frozen) for potential exploratory biomarker analyses in the future at Week 52 (End-of-OLE/LTE Therapy) and at the OLE/LTE Therapy 
Post-treatment Follow-up 3 visit. 
l: Record concomitant medications during the study and probiotic usage. 
m: All subjects are required to remain at the investigative site to be carefully monitored after each infusion for potential infusion reactions or other adverse events. Post-infusion safety 
monitoring is as follows:   
 
Week 12 (first dose in OLE Therapy) or first dose in subjects who transition from LTE to OLE:  minimum of 3 hours post-infusion at site and a phone call at approximately 48 to 
72 hours post-infusion for any subject who does not return for a visit at the investigative site; 
 
Week 16 (second dose in OLE Therapy) or second dose in subjects who transition from LTE to OLE :  minimum of 3 hours post-infusion at site and a phone call at approximately 
48 to 72 hours post-infusion for any subject who does not return for a visit at the investigative site; 
 
All other doses in OLE after the first 2 doses:  minimum of 1 hour post-infusion at site. 
CBC=complete blood count; ECG=electrocardiogram; HEENT=head, eyes, ears, nose, and throat; IBDQ=Inflammatory Bowel Disease Questionnaire; IV=intravenous; LTE=long-term 
extension; mMES=modified Mayo endoscopy subscore; OLE-open-label extension; PK=pharmacokinetic(s); UC=ulcerative colitis; UCEIS=Ulcerative Colitis Endoscopic Index of 
Severity; wr-CRP=wide-range C-reactive protein. 
 


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9.1 
Screening Period (Day −28 to Day −1) 
At the Screening visit, the Investigator will review the ICF with each subject to ensure that 
the subject understands the study and the study procedures. The subject will read, sign, and 
date the ICF and other locally applicable documents. Screening evaluations used to determine 
the subject’s study eligibility must be completed within the Screening Period (Day −28 to 
Day −1) prior to starting treatment on Day 1 (Week 0), and include a baseline sigmoidoscopy 
with biopsy being completed within 7 to 28 days prior to Day 1. For subjects who are 
rescreened, the original screening sigmoidoscopy can be used to satisfy the entry criteria if 
obtained within 42 days prior to the first dose. All sigmoidoscopy procedures will be 
performed using a flexible sigmoidoscope. Biopsies will be collected during the 
sigmoidoscopy procedure and tissue samples will be examined at a central laboratory. 
Immunohistochemical staining will be performed on all biopsy samples (refer to Section 
10.4.1). Sigmoidoscopy scores will be determined by a central reader. The sigmoidoscopy 
results from the central reader are required before a subject is randomized in the study. 
Subjects will be instructed on how to appropriately complete a daily diary to document 
symptoms of UC including stool frequency, rectal bleeding, abdominal discomfort, and 
general sense of well-being. Symptoms of UC must be recorded throughout the Screening 
Period. Diary entries will be reviewed by site personnel at all visits.   
All subjects must satisfy all the Inclusion Criteria and none of the Exclusion Criteria listed in 
Sections 7.2 and 7.3, respectively.  
A subject who was considered a Screen failure and not dosed with the investigational product 
is permitted to be re-screened once due to failure to meet the Inclusion/Exclusion Criteria, 
whereas subjects with other reasons for lack of randomization may be re-screened twice.  
The following additional assessments will be performed during the Screening Period 
(Day −28 to Day −1) (refer to Table 9-1 for the schedule of study events at Screening): 
• 
Main diagnosis - moderately active UC, severity of UC, duration of UC (sigmoidoscopy 
scores will be determined by a central reader); 
• 
Demographics - age at Screening, sex, race, and ethnicity identifications; 
• 
Medical and Surgical History - including concurrent illnesses; chest x-ray if needed 
(within previous 3 months) results, vaccinations (within previous 6 months), previous 
surgery for UC or other major or abdominal surgery, and anticipated requirement for 
surgery for UC or other major surgery; 
• 
Childbearing potential; 
• 
Complete physical examination (Section 10.6.4); 


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• 
Vital Signs (systolic and diastolic blood pressure, radial pulse, and respiration rate) and 
body temperature (oral) (Section 10.6.2); 
• 
Body weight and height (Section 10.6.4); 
• 
12-lead ECG (Section 10.6.3); 
• 
Previous treatment with corticosteroids, immunosuppressive medications or TNF 
antagonist therapy, any prior biologic treatment (e.g., infliximab, adalimumab, or 
golimumab), and prior investigational products or therapies (Section 8.5); 
• 
Prior and concurrent prescriptions and non-prescription medications, including any other 
UC treatments such as probiotics and other over-the-counter medications and 
supplements. Stable doses of aminosalicylates, oral glucocorticoids, azathioprine, and 
6-mercaptopurine are permitted as described in Section 8.5 (refer to Section 8.5.1 for 
prohibited medications); 
• 
Tobacco use, alcohol use, active marijuana (medicinal or recreational) use, illicit 
substance use; 
• 
Allergies/hypersensitivities; 
• 
Diet special for UC; 
• 
Pre-treatment AEs (Section 10.6.5); 
• 
Clinical Laboratory Evaluations (Table 9-1; refer to Section 10.6.1 for list of tests):  
Blood samples will be drawn at Screening for serum chemistry, hematology, coagulation 
profile, serum pregnancy, hepatitis B and C, and HIV testing; TB screening will be 
performed using a PPD skin test or IGRA; urine samples will be collected for analysis 
and urine drug screen; and fecal samples will be collected (before the start of the 
preparations required for the sigmoidoscopy or as specified in the stool collection 
instruction section of the laboratory manual) for analysis, i.e., cultures for enteric 
pathogens, ova and parasite evaluation, and Clostridium difficile assay.  
• 
Delayed-type hypersensitivity skin test with the Candida albicans antigen - at all 
investigative sites in the US and in other selected countries (Section 10.4.1). The skin 
testing site will be read within 48 to 72 hours following intradermal injection of the 
antigen. The largest diameter of induration will be measured in mm and recorded. 
Total and partial Mayo scores for inclusion criteria will be determined based upon the Diary 
entries and Physician's Global Assessment at the Baseline Visit. 
9.2 
Baseline Visit (Week 0, Day 1) 
Before administration of KHK4083 or placebo, the subject’s eligibility criteria 
(Inclusion/Exclusion Criteria) and results of Screening assessments must be reviewed by the 
Investigator (his/her designee) to ensure that the subject is qualified to be randomized in the 
study. A partial Mayo Clinic score (without sigmoidoscopy) including the Physician’s Global 
Assessment, which is to be performed after review of all available clinical data, will be 
recorded at Baseline.  A total Mayo clinical score will be evaluated at Baseline, using subject 


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diary entries within the 10 days prior to Baseline, combined with the sigmoidoscopy results 
prior to Baseline and the Physician’s Global Assessment. Diary entries for the three 
qualifying days closest to Baseline will be used for this evaluation but the entries do not have 
to be made on consecutive days. A total Mayo score of 4-10 and endoscopy subscore (mMES 
determined by a central reader) of at least 2 are required as per the Inclusion Criteria (refer to 
Inclusion Criteria #5) 
The sigmoidoscopy results from the central reader are required before a subject is 
randomized in the study (Note:  A sigmoidoscopy with biopsy, for mMES, UCEIS, modified 
Baron score and total Mayo Clinic score, is to be performed before randomization and within 
7 to 28 days prior to the first dose; an mMES of at least 2 is required. For subjects who are 
rescreened, the original screening sigmoidoscopy can be used to satisfy the entry criteria if 
obtained within 42 days prior to the first dose.  
An IBDQ will be administered as a quality-of-life assessment at Baseline.  
The following will be collected at Baseline (Day 1) (refer to Table 9-1 for the schedule of 
study events at Baseline). 
• 
Complete physical examination (Section 10.6.4); 
• 
Vital signs (systolic and diastolic blood pressure, radial pulse, and respiration rate) and 
body temperature (oral) (Section 10.6.2); 
• 
Body weight (Section 10.6.4); 
• 
12-lead ECG (Section 10.6.3); 
• 
Adverse events (pre-treatment and on-site post-infusion monitoring is required for at least 
3 hours after the first dose as well as a phone call at approximately 48 to 72 hours 
post-infusion for any subject who does not return for the scheduled visit at the 
investigative site) (Section 10.6.5); 
• 
Concomitant medications (Section 8.5); 
• 
Clinical laboratory evaluations (refer to Section 10.6.1 for list of tests):  Blood samples 
will be collected at Baseline for serum chemistry, hematology, coagulation profile, and 
the multiplex-31 assay; a urine sample for urinalysis; and fecal sample (collect as 
specified in the stool collection instruction section of the laboratory manual) for PD 
assessment only; 
• 
PK sampling at pre-dose and post-dose timepoints (refer to Table 10.4.1-1 and 
Table 10.4.1-2 for schedule of times for sample collection); 
• 
PD assessments including fecal calprotectin, wide-range C-reactive protein (wr-CRP), 
and flow cytometry (refer to Table 10.4.1-1 and Table 10.4.1-2 for schedule of sample 
times); 
• 
Immunogenicity assessment - serum samples at pre-dose timepoints (Section 10.4.2); 


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• 
Other potential study assessments - whole blood samples for future biomarker analyses 
(Section 10.4.3). 
9.3 
Double-blind Treatment Period (Induction Therapy and Long-term 
Extension Therapy) and Open-label Extension Therapy 
The double-blind Treatment Period comprises a 12-week Induction Therapy phase 
(Part A:  Cohorts 1 - 3, multiple ascending doses; Part B:  Cohort 4, recommended dose) 
followed by a 40-week OLE/LTE Therapy phase. Subjects in Part A are not allowed to 
participate in Part B.  
A sigmoidoscopy with biopsy for mMES, UCEIS, modified Baron score and total Mayo 
Clinic score will be performed at Week 12 (i.e., it is highly recommended to perform the 
procedure 7 to 13 days prior to the Week 12 visit), and at the Week 52 visit or within 21 days 
prior to Week 52. The mMES will be determined by a central reader at Weeks 12 and 52. The 
sigmoidoscopy results from the central reader are required before a subject receives treatment 
in the OLE/LTE Therapy phase at Week 12. A total Mayo Clinic score will also be evaluated 
at Weeks 12 (prior to OLE/LTE dosing) and 52, using subject diary entries within the 7 days 
prior to each visit and sigmoidoscopy results prior to each visit. Since the preparations for the 
sigmoidoscopy can interfere with the assessment of other clinical parameters, the Mayo 
Clinic score should not include diary entries recorded on the day prior to, the day of, or the 
day after the sigmoidoscopy. A partial Mayo Clinic score (without sigmoidoscopy) including 
the Physician’s Global Assessment, which is to be performed after review of all available 
clinical data, and the results from the IBDQ will be recorded at each visit during the 
Treatment Period. Mayo Clinic subscores will be derived from the diaries over the 2 to 3 
qualifying days that are closest to each visit. 
In addition, the following will be collected during the Treatment Period according to the 
schedule of study events in Table 9-1 (Induction Therapy) and Table 9-2 (OLE/LTE 
Maintenance Therapy): 
• 
Brief physical examination (Section 10.6.4); 
• 
Vital signs (systolic and diastolic blood pressure, radial pulse, and respiration rate) and 
body temperature (oral) (Section 10.6.2); 
• 
Body weight (Section 10.6.4); 
• 
12-lead ECG (Section 10.6.3); 
• 
Adverse events -  
– On-site post-infusion monitoring is required for at least 3 hours after the first 2 
double-blind infusions (Weeks 0 and 2) are completed for each subject and for at least 


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1 hour after all other double-blind infusions (Weeks 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 
36, 40, 44, and 48).  
– On-site post-infusion monitoring is required for at least 3 hours after the first 2 open-
label infusions (Weeks 12 and 16) are completed for each subject and for at least 
1 hour after all other open-label infusions (Weeks 20, 24, 28, 32, 36, 40, 44, and 48)  
Note: Some subjects in the LTE may transition to the OLE after Week 12 and up to 
Week 28. Post-infusion monitoring is required for at least 3 hours after the first 2 
open-label infusions. 
– In addition, a phone call to each subject will be conducted at approximately 48 to 
72 hours following the completion of the first and second infusions (double-blind and 
open-label) for any subject who does not return for a visit at the investigative site 
(Section 10.6.5);  
• 
Concomitant medications (Section 8.5); 
• 
Clinical laboratory evaluations (refer to Section 10.6.1 for list of tests):  Blood samples 
will be collected at specified times for serum chemistry, hematology, coagulation profile, 
and the multiplex-31 assay; urine samples for urinalysis; and fecal samples (collect before 
the start of the preparations required for the sigmoidoscopy or as specified in the stool 
collection instruction of the laboratory manual) for PD assessments as described below 
and for cultures for enteric pathogens, ova and parasite evaluations, and Clostridium 
difficile assays at Weeks 12 and 52; 
• 
PK sampling at pre-dose and post-dose timepoints (refer to Table 10.4.1-1 and 
Table 10.4.1-2 for schedule of days/times for sample collection); 
• 
PD assessments including fecal calprotectin, wr-CRP, delayed-type hypersensitivity 
testing, and flow cytometry (refer to Table 10.4.1-1 and Table 10.4.1-2 for schedule of 
sample times). The delayed-type hypersensitivity skin testing site will be read within 
48 to 72 hours following intradermal injection of the Candida albicans antigen at 
Week 10. The largest diameter of induration will be measured in mm and recorded; 
• 
Immunogenicity assessment - serum samples at pre-dose or time of visit timepoints 
(Section 10.4.2); 
• 
Other potential study assessments - whole blood samples will be collected for future 
biomarker analyses (Section 10.4.3).  
9.4 
Post-treatment Follow-up Period  
A safety Post-treatment Follow-up Period will continue for 16 weeks after the last infusion 
associated with the subject’s treatment period and will include 3 Post-treatment Follow-up 
visits. For subjects who only receive Induction Therapy (i.e., do not continue in OLE/LTE 
Therapy), the Post-treatment Follow-up visits will be at Weeks 16, 20, and 26. For all 
subjects who receive both Induction Therapy and OLE/LTE Therapy, the post-treatment 
follow-up visits will be at Weeks 56, 60, and 64. A partial Mayo Clinic score (without 
sigmoidoscopy) including the Physician’s Global Assessment, which is to be performed after 


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review of all available clinical data, and the results from the IBDQ will be recorded at each 
visit during the Treatment Period. Subjects removed from the study for AEs will be followed 
until there is a return to the subject’s baseline condition, or until a clinically satisfactory 
resolution is achieved. Safety measurements will be performed from KHK4083 (or placebo) 
administration until the final safety follow-up assessment. In addition, the following will be 
collected during the Post-treatment Follow-up Period according to the schedule of study 
events in Table 9-1 (Induction Therapy) and Table 9-2 (OLE/LTE Maintenance Therapy): 
• 
Brief physical examination (Section 10.6.4); 
• 
Vital signs (systolic and diastolic blood pressure, radial pulse, and respiration rate) and 
body temperature (oral) (Section 10.6.2); 
• 
Body weight (Section 10.6.4); 
• 
Adverse events (Section 10.6.5);  
• 
Concomitant medications (Section 8.5); 
• 
Clinical laboratory evaluations (refer to Section 10.6.1 for list of tests):  Blood samples 
will be collected at specified times for serum chemistry, hematology, and the 
multiplex-31 assays (i.e., if the subject does not continue in OLE Therapy); urine samples 
will be collected for urinalysis; 
• 
PK sampling at the time of the follow-up visits (refer to Table 10.4.1-1 and 
Table 10.4.1-2 for schedule of days/times for sample collection); 
• 
PD assessment - wr-CRP testing at follow-up visit (Week 26 or Week 64); 
• 
Immunogenicity assessment - serum samples at the time of the follow-up visits 
(Section 10.4.2).  
10 
EFFICACY, PHARMACOKINETIC, PHARMACODYNAMIC, 
IMMUNOGENICITY, SAFETY, AND OTHER VARIABLES 
The efficacy variables include mMES, UCEIS score, modified Baron endoscopic score, total 
Mayo Clinic score, partial Mayo Clinic score (without sigmoidoscopy), and an IBDQ score.  
The PK variables include the maximum observed serum concentration (Cmax); time of 
maximum observed serum concentration (tmax), trough concentration at the end of the dosing 
interval (Cmin), area under the serum concentration-time curve (AUC0-t, AUC0-τ, AUC0-∞), 
terminal elimination half-life (t1/2), systemic serum clearance (CLs), volume of distribution at 
steady state (Vss), volume of distribution at terminal phase (Vz), and accumulation ratio (Rac).  
The PD variables include the measurement of fecal calprotectin, and C-reactive protein 
concentrations (using wr-CRP assay, see Central Laboratory Manual for details). Other PD 
assessments include delayed-type hypersensitivity skin testing with the Candida albicans 
antigen (at all investigative sites in the US and in other selected countries), 


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immunohistochemical staining for OX40 or other immune-related antigens on all endoscopic 
biopsy samples, and flow cytometry analyses on whole blood or PBMCs for the measurement 
of specific immune-related cells. 
For immunogenicity, the development of anti-KHK4083 antibodies will be assessed.  
The safety variables include AEs, SAEs, physical examinations, vital signs, body weight, 
12-lead ECGs, and clinical laboratory evaluations (serum chemistry, hematology, coagulation 
profile, and urinalysis). Details of the safety assessments are provided in Section 10.6. 
10.1 Primary Endpoints 
10.1.1 
Efficacy 
Subjects with moderately active UC will primarily be evaluated for an improvement in the 
mucosa determined by their mMES (subscores from 0 to 3, with modified endoscopy finding 
scoring, i.e., by excluding mild friability from a subscore of 1) at completion of double-blind 
Induction Therapy. The primary efficacy endpoint will be the mean change in the mMES 
from Baseline (Week 0) to Week 12 for all subjects who receive the recommended dose in 
Parts A and B.  
10.1.2 
Safety 
The safety and tolerability of KHK4083 will be determined by physical examination, vital 
signs, body weight, 12-lead ECGs, and clinical laboratory findings; and the number and 
percentage of subjects reporting AEs (frequency, severity, and relationship to investigational 
product), SAEs, and treatment discontinuation due to AEs.  
10.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints for all subjects who receive the recommended dose during 
double-blind Induction Therapy are as follows: 
• 
Improvement in the mucosa at Week 12; 
– Changes in the mucosa will be based on the percentage of subjects with at least a 
1-point improvement in their mMES (0 to 3) from Baseline (Week 0) to Week 12; 
and/or  
– Changes in the mucosa will be based the percentage of subjects with at least a 1-point 
improvement in their modified Baron endoscopic score (5-point scale) from Baseline 
(Week 0) to Week 12; and/or 
– 
Changes in the mucosa will be based on the mean change in UCEIS (0 to 8) and 
subscores from Baseline (Week 0) to Week 12. 


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• 
Mucosal healing at Week 12;  
Mucosal healing is defined as a mMES of 0 or 1. 
• 
Clinical improvement at Week 12; 
Improvement will be based on a reduction (mean change from Baseline [Week 0] at 
Week 12) in the total Mayo Clinic score (0 to 12). 
• 
Clinical improvement at Weeks 2, 4, 6, 8, 10, and 12; 
Improvement will be based on mean changes from Baseline (Week 0) in the partial 
(excludes endoscopy subscores) Mayo Clinic score (0 to 10).  
• 
Clinical response at Week 12;  
A clinical response is defined as a reduction in the total Mayo Clinic score of at least 
3 points and a decrease of at least 30% from Baseline (Week 0) to Week 12, and a 
reduction in the rectal bleeding subscale of at least 1 point from Baseline (Week 0) to 
Week 12 or an absolute rectal bleeding score of 0 or 1 at Week 12. 
• 
Clinical remission at Week 12;  
Clinical remission is defined as a total Mayo Clinic score of ≤ 2 and no subscores > 1. 
For all subjects who receive KHK4083 at dose levels different than the recommended dose 
during double-blind Induction Therapy, improvement in the mucosa at Week 12 based on the 
mean change in the mMES from Baseline (Week 0) to Week 12 is the main secondary 
endpoint. The other secondary efficacy endpoints at Week 12 for all subjects who receive 
KHK4083 at other than the recommended dose are the same as those listed and defined 
above, i.e., improvement in the mucosa based on the modified Baron endoscopic score and 
the UCEIS; mucosal healing; clinical improvement based on total, as well as partial (excludes 
endoscopy subscore at Weeks 2, 4, 6, 8, 10, and 12) Mayo Clinic scores; clinical response; 
and clinical remission. The PK for KHK4083 will be characterized in the UC subject 
population following multiple ascending doses. 
10.3 Exploratory Endpoints 
Efficacy and PD exploratory endpoints will be included in this study for all subjects with 
moderately active UC who receive both Induction Therapy and OLE/LTE Maintenance 
Therapy. The exploratory endpoints for all subjects who receive both Induction Therapy and 
OLE/LTE Maintenance Therapy are as follows: 
• 
Clinical improvement at Week 52; 
Improvement will be based on a reduction (mean change from Baseline [Week 0] to 
Week 52) in the total Mayo Clinic score (0 to 12).  
• 
Clinical improvement at Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 and at 
OLE/LTE Therapy Follow-up Period visits (Weeks 56, 60, and 64); 
Improvement will be based on mean changes from Baseline (Week 0) in the partial 
(excludes endoscopy subscores) Mayo Clinic score (0 to 10).  


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• 
Clinical response at Week 52;  
A clinical response is defined as a reduction in the total Mayo Clinic score of at least 
3 points and a decrease of at least 30% from Baseline (Week 0) to Week 52, and a 
reduction in the rectal bleeding subscale of at least 1 point from Baseline (Week 0) to 
Week 52 or an absolute rectal bleeding score of 0 or 1 at Week 52. 
• 
Clinical remission (i.e., a total Mayo Clinic score of ≤ 2 and no subscores > 1) at 
Week 52; 
• 
Durable clinical responses and durable clinical remissions at Week 52 (i.e., present at 
both Week 12 and Week 52), and glucocorticoid-free clinical remission at Week 52; 
• 
Mucosal healing (i.e., an mMES of 0 or 1) at Week 52;  
• 
Improvement in the mucosa according to the following assessments:  
– At least a 1-point improvement in the mMES from Baseline (Week 0) to Week 52; 
– A mean change in the UCEIS score from Baseline (Week 0) to Week 52; and/or 
– At least a 1-point improvement in the modified Baron endoscopic score from Baseline 
(Week 0) to Week 52. 
• 
Remission (i.e., mMES of 0 or 1, stool frequency subscore of 0 or 1, and rectal bleeding 
subscore of 0) rates at Week 12 and Week 52; 
• 
Improvement in the HRQL, which will be based on the subject’s completed IBDQs; 
• 
Lowered corticosteroid (glucocorticoid) dosages; 
• 
Glucocorticoid-free treatment duration from Week 16 through Week 52, and through the 
OLE/LTE Therapy Follow-up Period (Week 56 through Week 64); 
• 
PD profile of KHK4083; 
• 
PK-PD relationships. 
10.4 Pharmacokinetic, Pharmacodynamic, Immunogenicity and Other Study 
Assessments 
10.4.1 
Pharmacokinetic and Pharmacodynamic Assessments 
Pharmacokinetics: 
Blood samples for the measurement of KHK4083 in serum will be collected from all subjects 
in this study. The serum KHK4083 concentration data will be used to evaluate the PK of 
KHK4083. 
Pharmacodynamic Assessments:  
The PD assessments include fecal calprotectin at Weeks 0 (Baseline), 2, 12 (End-of-Induction 
Therapy visit), and 52 (End-of-OLE/LTE Therapy visit); and wr-CRP assays at Week 0 
(Baseline), all visits during Induction Therapy, at Induction Therapy Follow-up Visit 3 
(Week 26 only for subjects not continuing to OLE/LTE Therapy), during OLE/LTE Therapy 


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at Weeks 24, 36, and 52, and at OLE/LTE Therapy Follow-up Visit 3 (Week 64). Refer to 
Table 9-1 and Table 9-2 assessments at each therapy phase of the Treatment Period.  
Delayed-type hypersensitivity skin testing with the Candida albicans antigen will be 
performed at Screening and Week 10 of Induction Therapy at all investigative sites in the US 
and in other selected countries.  
Immunohistochemical staining will be performed on all biopsy samples obtained through 
sigmoidoscopy (Baseline [Week 0], Week 12, and Week 52).  
Flow cytometry analyses will be performed on whole blood or PBMCs for the measurement 
of specific immune-related cells. The samples will be collected at Week 0 (Days 1, 2, and 8), 
during Induction Therapy (Weeks 2, 4, and 6), Week 12 (End-of-Induction Therapy visit), 
and at Week 52 (End-of-OLE/LTE Therapy visit) (refer to Section 10.4.1.1 for specific 
collection times). Additional whole blood samples may be collected as needed if a subject 
experiences a flare-up during OLE/LTE Therapy. 
10.4.1.1 
Sampling Times and Assays for Pharmacokinetics and 
Pharmacodynamics (Flow Cytometry) 
Serum samples for PK and PD will be collected from subjects in Cohorts 1 - 3 during 
Induction Therapy (Part A) and OLE/LTE Therapy according to the schedule in 
Table 10.4.1-1 and subjects in Cohort 4 during Induction Therapy (Part B) and OLE/LTE 
Therapy according to the schedule in Table 10.4.1-2.  
 


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Table 10.4.1-1 Cohorts 1 - 3:  Sample Collection Schedule During Induction Therapy 
(Part A), Long-term Extension, and Open-label Extension Therapy for 
Pharmacokinetics and Pharmacodynamics (Flow Cytometry) 
Visit (Days within 
Scheduled Visit) 
Day 
Time 
PK 
PD (FCM) 
Double-blind Induction Therapy (Part A) 
Week 0 
1 
Before Administration 
X 
X 
End of Infusion 
X 
 
4 hours ± 15 min from  
Start of Infusion 
X 
 
2 
At the time of visit 
X 
Xa 
8 (± 1 day) 
At the time of visit 
X 
Xa 
Week 2 (± 2 days) 
1b 
Before administration 
X 
X 
Week 4 (± 4 days) 
1 
Before administration 
X 
X 
Week 6 (± 4 days) 
1 
Before administration 
X 
X 
Week 8 (± 4 days) 
1 
Before administration 
X 
 
Week 10 (± 4 days) 
1 
Before administration 
X 
 
End of Infusion 
X 
 
4 hours ± 15 min from  
Start of Infusion 
X 
 
2 
At the time of visit 
X 
 
8 (± 1 day) 
At the time of visit 
X 
 
End-of-Treatment 
Week 12 (± 4 days) 
  1c 
At the End-of-Induction 
Therapy visit 
X 
X 
Week 16 (± 7 days) 
Follow-up 1 
  1d 
At the time of visit 
X 
 
Week 20 (± 7 days) 
Follow-up 2 
  1d 
At the time of visit 
X 
 
Week 26 (± 7 days) 
Follow-up 3 
  1d 
At the time of visit 
X 
 
Double-blind Long-term Extension Therapy  or Open Label Extensione 
Week 12 (± 4 days) 
  1c 
Before administration  
X 
 
Week 16 (± 7 days) 
1 
Before administration 
X 
 
Week 20 (± 7 days) 
1 
Before administration 
X 
 
Week 24 (± 7 days) 
1 
Before administration 
X 
 
Week 28 (± 7 days) 
1 
Before administration 
X 
 
Week 32 (± 7 days) 
1 
Before administration 
X 
 
Week 36 (± 7 days) 
1 
Before administration 
X 
 
Week 40 (± 7 days) 
1 
Before administration 
X 
 
Week 44 (± 7 days) 
1 
Before administration 
X 
 


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Table 10.4.1-1 Cohorts 1 - 3:  Sample Collection Schedule During Induction Therapy 
(Part A), Long-term Extension, and Open-label Extension Therapy for 
Pharmacokinetics and Pharmacodynamics (Flow Cytometry) 
Visit (Days within 
Scheduled Visit) 
Day 
Time 
PK 
PD (FCM) 
Double-blind Long-term Extension Therapy or Open Label Extension(cont’d) 
Week 48 (± 7 days)f 
1 
Before administration 
X 
 
End of Infusionf 
X 
 
4 hours ± 15 min from  
Start of Infusionf 
X 
 
2  
At the time of visitf 
X 
 
8 (± 1 day) 
At the time of visitf 
X 
 
15 (± 1day) 
At the time of visitf 
X 
 
22 (± 1 day) 
At the time of visitf 
X 
 
Week 52 (± 7 days) 
1g 
At the time of visit 
X 
X 
Week 56 (± 7 days) 
Follow-up 1 
1 
At the time of visit 
X 
 
Week 60 (± 7 days) 
Follow-up 2 
1 
At the time of visit 
X 
 
Week 64 (± 7 days) 
Follow-up 3 
End-of-Study 
1 
At the time of visit 
X 
 
a: Hematology parameters will also be assessed. 
b: Sample will be considered a Day 15 post-dose sample for Week 0 and a pre-dose sample for Week 2. 
c: For subjects who do not continue OLE/LTE Therapy, this sample will be Day 15 post-dose sample for Week 10; for 
subjects who continue the OLE/LTE Therapy, this sample will be a pre-dose sample at Week 12. 
d: Sample will be collected only if the subject enters the Induction Therapy Post-treatment Follow-up Period and is not 
continuing to OLE/LTE Therapy. 
e: If a subject experiences a flare-up during OLE/LTE Therapy whole blood samples may be collected. 
f: All post-infusion samples may be collected at Week 44 instead of the Week 48 visit. 
g: Sample will be considered Day 28 post-dose for Week 48. 
FCM=flow cytometry; LTE=long-term extension; OLE=open-label extension; PD=pharmacodynamics; 
PK=pharmacokinetics.  
 
 
 


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Table 10.4.1-2 Cohort 4:  Sample Collection Schedule During Induction Therapy 
(Part B) and Long-term Extension Therapy and Open Label Extension 
Therapy for Pharmacokinetics and Pharmacodynamics (Flow 
Cytometry) 
Visit (Days within 
Scheduled Visit) 
Day 
Time 
PK 
PD (FCM) 
Double-blind Induction Therapy (Part B) 
Week 0 
1 
Before Administration 
X 
X 
End of Infusion 
X 
 
Week 2 (± 2 days) 
  1a 
Before administration 
X 
X 
Week 4 (± 4 days) 
1 
Before administration 
X 
X 
Week 6 (± 4 days) 
1 
Before administration 
X 
X 
Week 8 (± 4 days) 
1 
Before administration 
X 
 
Week 10 (± 4 days) 
1 
Before administration 
X 
 
End of Infusion 
X 
 
End-of-Treatment/ 
Week 12 (± 4 days) 
  1b 
At the End-of-Induction 
Therapy visit 
X 
X 
Week 16 (± 7 days) 
Follow-up 1 
  1c 
At the time of visit 
X 
 
Week 20 (± 7 days) 
Follow-up 2 
  1c 
At the time of visit 
X 
 
Week 26 (± 7 days) 
Follow-up 3 
  1c 
At the time of visit 
X 
 
Double-blind Long-term Extension Therapy or Open Label Extension Therapyd 
Week 12 (± 4 days) 
  1b 
Before administration  
X 
 
Week 16 (± 7 days) 
1 
Before administration 
X 
 
Week 20 (± 7 days) 
1 
Before administration 
X 
 
Week 24 (± 7 days) 
1 
Before administration 
X 
 
Week 28 (± 7 days) 
1 
Before administration 
X 
 
Week 32 (± 7 days) 
1 
Before administration 
X 
 
Week 36 (± 7 days) 
1 
Before administration 
X 
 
Week 40 (± 7 days) 
1 
Before administration 
X 
 
Week 44 (± 7 days) 
1 
Before administration 
X 
 
Week 48 (± 7 days) 
1 
Before administration 
X 
 
End-of-Treatment/ 
Week 52 (± 7 days) 
  1e 
At the time of visit 
X 
X 
Week 56 (± 7 days) 
Follow-up 1 
1 
At the time of visit 
X 
 
Week 60 (± 7 days) 
Follow-up 2 
1 
At the time of visit 
X 
 
Week 64 (± 7 days) 
Follow-up 3 
End-of-Study 
1 
At the time of visit 
X 
 
 
 
 
 


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Footnotes to Table 10.4.1-2. 
a: Sample will be considered a Day 15 post-dose sample for Week 0 and a pre-dose sample for Week 2. 
b: For subjects who do not continue OLE/LTE Therapy, this sample will be Day 15 post-dose sample for Week 10; for 
subjects who continue the OLE/LTE Therapy, this sample will be a pre-dose sample at Week 12. 
c: Sample will be collected only if the subject enters the Induction Therapy Post-treatment Follow-up Period and is not 
continuing to LTE Therapy. 
d: If a subject experiences a flare-up during OLE/LTE Therapy collect whole blood and FCM. 
e: Sample will be considered Day 28 post-dose for Week 48. 
FCM=flow cytometry; LTE=long-term extension; OLE=open-label extension; PD=pharmacodynamics; 
PK=pharmacokinetics 
 
10.4.1.2 
Sample Collection, Preparation, Labeling, and Storage  
All PK samples must be shipped to the designated central laboratory for storage and batches 
of samples will be shipped to the analytical testing laboratory. Details of the collection, 
storage, handling, and shipping of all samples are provided in the Central Laboratory Manual 
sent to investigative sites prior to the study initiation visit.  
10.4.2 
Immunogenicity Assessments 
Immunogenicity assessments for detection of antibodies against KHK4083 will be evaluated 
from samples collected from all subjects during the study. 
Serum samples will be collected before the initial dose of investigational product at specified 
collection time windows at Week 0 (Baseline, Day 1) and at all visit weeks during Induction 
Therapy (pre-dose at Weeks 2, 4, 6, 8, and 10); at the End-of-Induction Therapy visit (only 
for subjects not continuing to OLE/LTE Therapy); during the Induction Therapy Follow-up 
Period (only for subjects not continuing to OLE/LTE Therapy) visits (Weeks 16, 20, and 26); 
during OLE/LTE Therapy (pre-dose at Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48); at 
the End-of-OLE/LTE Therapy visit (Week 52); and during the OLE/LTE Therapy Follow-up 
Period visits (Weeks 56, 60, and 64) as described in the visit schedule for sample collection 
in Table 9-1 and Table 9-2.  
Details of the collection, storage, handling, and shipping of all samples are provided in the 
Central Laboratory Manual that will be sent to investigative sites prior to the study initiation 
visit. 
10.4.3 
Other Potential Study Assessments 
For future exploratory biomarker analyses, whole blood samples will be collected as 
described in the visit schedule for sample collection in Table 9-1 and Table 9-2. All samples 


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will be labeled and maintained in frozen storage conditions according to the instructions 
provided in the Central Laboratory Manual.  
10.5 Medical/Surgical History, Medication History, and Demographics 
Subject demographics (race, ethnicity, sex, and age), medical history including vaccinations 
(within previous 6 months), current medical conditions, diagnosed chronic conditions, and 
conditions resolved within the past year will be recorded in detail at the Screening visit. The 
subject’s surgical history particularly previous surgery for UC or other major or abdominal 
surgery, and anticipated requirement for surgery for UC or other major surgery will also be 
recorded at the Screening visit (refer to Section 9.1).  
Any prior biologic treatment or prior investigational products or therapies including the 
reason for discontinuation of treatment and all medications for treatment of UC taken within 
6 months prior to Screening; and any other previous medication taken 1 month prior to 
Screening will be documented in detail. Refer to products listed in Inclusion Criteria 
(Section 7.2) and Exclusion Criteria (Section 7.3); and to Section 8.5 and Section 8.5.1 
(prohibited medications) for additional medication details during the Screening and 
Treatment Period.  
Additional background information will be recorded at Screening including tobacco, alcohol, 
active marijuana (medicinal or recreational), and illicit substance use; allergies/ 
hypersensitivities; and probiotic use and special diet for UC. 
10.6 Safety Assessments 
All subjects will be assessed regularly for potential occurrence of AEs from the time of 
signing the ICF until 16 weeks after the last dose of investigational product or any time 
thereafter if a causal relationship is suspected. 
The following information will be collected to evaluate the safety profile of the study 
population: 
• 
Clinical laboratory evaluations (serum chemistry, hematology, coagulation profile, and 
urinalysis);  
• 
Vital signs and body weight;  
• 
12-lead ECG; 
• 
Physical examination; and 
• 
Adverse events (including SAEs). 


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10.6.1 
Clinical Laboratory Evaluation 
Clinical laboratory parameters assessed in this study are displayed in Table 10.6.1-1. The 
collection times for blood, urine, and fecal specimens during the study are specified in 
Table 9-1 and Table 9-2. 


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Table 10.6.1-1 
Clinical Laboratory Assessments 
Serum Chemistrya 
 
SGOT (AST) 
SGPT (ALT) 
Creatine kinase 
LDH 
Alkaline phosphatase 
Total bilirubin 
Folate 
Glucose 
Creatinine 
Albumin 
BUN 
Sodium 
Potassium 
Calcium 
Vitamin B12 
Chloride 
Total cholesterol 
Triglycerides  
Uric Acid 
Amylase 
Lipase 
wr-CRP Assay 
To be performed on serum chemistry samples at Week 0 (Baseline), all visits 
during Induction Therapy, Week 26 (only for subjects not continuing to OLE/LTE 
Therapy), and at Weeks 24, 36, 52, and 64. 
Multiplex-31 Assay 
To be performed at Baseline (Week 0), Week 2, Week 12, and Week 52 or at a 
follow-up visit if the subject does not continue in OLE/LTE Therapy. 
Diabetes Screening 
Subjects with glycated serum hemoglobin A1c ≥ 9% will be excluded from the 
study. 
Coagulation Profile 
prothrombin time 
partial thromboplastin time 
Hematologya 
Hemoglobin 
Hematocrit 
RBCs 
WBC count 
Differential and absolute counts 
Platelet count 
Urinalysis  
Color 
Specific Gravity 
pH 
Protein  
Glucose 
Ketones 
Bilirubin 
Urobilinogen 
Occult blood 
Nitrites 
Microscopic examination, if clinically indicated, 
including RBCs, WBCs, casts, bacteria and crystals 
Urine Drug Screening 
Barbiturates, Benzodiazepines, Amphetamines, Cocaine, Cannabinoids, Opiates, 
Methamphetamine, Alcohol, and Cotinine 
Serum FSH Test 
To be performed on all presumed post-menopausal females at Screening. 
Post-menopausal females are defined as females with the complete absence of 
menses for 24 consecutive months; have an FSH level > 25 mIU/mL (or in 
postmenopausal range per local laboratory standards) in the absence of hormone 
replacement therapy.  
Serum and/or Urine 
Pregnancy Test 
(minimum sensitivity 
25 IU/L or equivalent 
units of β-HCG) 
To be performed for all female subjects considered to be women of childbearing 
potential at Screening and at specified timepoints during the Treatment Period.  
Note:  Subjects are considered to not be of childbearing potential if they are 
≥ 50 years of age and without menses for 24 consecutive months and have an FSH 
level > 25 mIU/mL (or in postmenopausal range per local laboratory standards); 
or have undergone a hysterectomy and/or a bilateral salpingo-oophorectomy. 
Hepatitis B and C, and 
HIV testing 
hepatitis B surface antigen or hepatitis B core antibody  
hepatitis C antibody (If positive, do reflex to RNA by RT-PCR testing) 
HIV-1 antibodies, HIV-1 antigen, HIV-2 antibody 


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Table 10.6.1-1 
Clinical Laboratory Assessments 
Tuberculosis Screening 
using PPD Skin Test (by 
investigative site) and/or 
IGRA (clinical laboratory) 
(See details in Section 7.3, 
Exclusion Criterion 16) 
Standard PPD skin test or IGRA (but not both) to be performed at Screening at 
investigative site. If positive (i.e., PPD measures > 5 mm induration), follow up 
after Screening is required. An IGRA is to be performed at Screening if a subject 
has a history of positive PPD.  
Note:  Performing of both IGRA and PPD tests in the same subject should be 
avoided as Screening procedures. Positivity of one of the tests cannot be voided by 
negativity of the other, i.e., subjects with positive PPD and negative IGRA test 
performed as a part of Screening will be considered TB positive and will be 
required to start prophylactic anti-TB therapy prior to infusion of investigational 
product according to local treatment standards. All safety laboratory tests may be 
repeated. Screening procedures may be extended by 2 weeks. 
Delayed-Type 
Hypersensitivity Skin 
Test 
At investigative sites in the US and other identified countries, the skin tests are to 
be performed at Screening and Week 10. The skin testing site will be read within 
48 to 72 hours following intradermal injection of the Candida albicans antigen. 
The largest diameter of induration will be measured in mm and collected. 
Fecal Sample Analysis 
Stool cultures to identify enteric pathogens, ova and parasite evaluations, and 
Clostridium difficile assays are to be performed at Screening, Week 12, and 
Week 52. Refer to PD assessments for fecal calprotectin measurements at Baseline 
(Week 0) and Weeks 2, 12, and 52. 
a: A subject will be excluded from the study if a specific serum chemistry or hematology value at Screening is outside of 
the acceptable range as defined in Section 7.3, Exclusion Criteria. 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; β-HCG=beta human chorionic 
gonadotrophin; ; FSH=follicle-stimulating hormone; HIV=human immunodeficiency virus; IGRA=interferon gamma release 
assay; LDH=lactate dehydrogenase; LTE=long-term extension; OLE-open-label extension; PD=pharmacodynamic(s); 
PPD=purified protein derivative; RBC=red blood cell; RNA=ribonucleic acid; RT-PCR=Real-time reverse transcription-
polymerase chain reaction; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; 
TB=tuberculosis; US=United States; WBC=white blood cell; wr-CRP=wide-range C-reactive protein. 
 
Any clinically important abnormal laboratory values noted at the Screening visit will be 
recorded as medical history. In addition, in order for the Sponsor to collect additional 
information about clinically important laboratory abnormalities, at minimum, the following 
laboratory abnormalities should be captured as appropriate: 
• 
Any laboratory test result that meets the criteria for an SAE; 
• 
Any laboratory abnormality that requires the subject to have study treatment discontinued 
or interrupted; 
• 
Any laboratory abnormality that requires the subject to receive specific corrective 
therapy. 
All clinically important abnormal laboratory tests occurring during the study will be repeated 
at appropriate intervals until (1) the value returns to baseline, (2) the value is judged to be 
clinically acceptable by the Investigator and the Sponsor, or (3) a diagnosis that explains the 


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abnormal laboratory value is made. When possible, the Investigator should report the clinical 
rather than the laboratory term (e.g., anemia versus low hemoglobin). 
10.6.2 
Vital Signs 
Vital signs and body temperature (measured orally) will be measured at Screening, all visits 
during the Treatment Period, and Follow-up Period visits. Vital signs, including systolic and 
diastolic blood pressure, radial pulse and respiration rate, will be measured after the subject 
has rested for at least 5 minutes in a supine or semi-supine position. Vital signs and body 
temperature will be monitored during IV infusion of the investigational product and 
periodically over the observation period after infusion. Additional vital sign measurements 
will be obtained at the discretion of the Investigator or designee if clinically significant signs 
or symptoms occur.  
10.6.3 
Electrocardiograms 
A standard 12-lead ECG will be performed at Screening; during Induction Therapy (pre-dose 
and at the end of infusion) on Day 1 (Baseline, Week 0), Week 8, and Week 10 (refer to 
Table 9-1); during OLE therapy on Week 12 (pre-dose and at the end of infusion), Week 16 
(pre-dose and at the end of infusion) (refer to Table 9-2); and at Week 52 of OLE/LTE 
Therapy (refer to Table 9-2). Subjects who transition from LTE to OLE must have ECGs 
performed pre-dose and at the end of infusion for the first two infusions. The ECGs will be 
recorded after the subject has rested for approximately 5 minutes in a supine position. When 
PK collections and ECG recordings are scheduled at the same time point, the ECG recording 
should be prior to the PK sample collection. 
10.6.3.1 
Investigative Site Responsibilities 
The Investigator is responsible for evaluating the ECG interpretation in relationship to 
clinical signs and symptoms and reaching a medical decision regarding the subject’s medical 
status. The ECG findings should be assessed by the Investigator as normal, abnormal not 
clinically significant, or abnormal clinically significant, as appropriate. All abnormalities, 
whether assessed as clinically significant or not, will be recorded. The ECG tracing should be 
initialed and dated by the Investigator. 
10.6.3.2 
ECG Core Laboratory Responsibilities 
The use of a central ECG laboratory or central reader may be requested on an adhoc basis. 


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10.6.4 
Physical Examination 
The Investigator will perform complete physical examinations including general appearance 
and examination of head, eyes, ears, nose, and throat (HEENT) and body systems 
(cardiovascular, respiratory, abdominal, musculoskeletal, extremities, lymph nodes, and skin) 
at Screening, Baseline (Week 0, Day 1), End-of-Induction Therapy (Week 12), and 
End-of-OLE/LTE Therapy (Week 52). Brief physical examinations (only include HEENT, 
cardiovascular, respiratory, and abdominal examinations) will be performed at all other visits 
during the Treatment Period and Follow-up Periods as specified in Table 9-1 and Table 9-2. 
Body weight (kg) and height (cm) will be obtained while the subject is wearing light clothing 
(without shoes). Body weight will be documented during the Screening visit and at each 
study visit during the Treatment Period and Follow-up Period; height will be recorded at the 
Screening visit only (refer to Table 9-1 and Table 9-2) 
10.6.5 
Adverse Events 
10.6.5.1 
Definitions 
An AE is defined as any untoward medical occurrence in a clinical study subject 
administered an investigational product and does not necessarily have a causal relationship 
with the treatment. An AE can therefore be any unfavorable and/or unintended sign (e.g., an 
abnormal laboratory finding), symptom or disease temporally associated with the use of an 
investigational product 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;  
• 
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. 
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). 
10.6.5.2 
Assessment of Intensity 
All AEs will be classified either as mild, moderate, or severe in intensity as defined below:  
• 
Mild – Event results in mild or transient discomfort, not requiring intervention, or 
treatment; does not limit or interfere with daily activities (e.g., insomnia, mild headache).  
• 
Moderate – Event is sufficiently discomforting so as to limit or interfere with daily 
activities; may require interventional treatment (e.g., fever requiring antipyretic 
medication).  
• 
Severe – Event results in significant symptoms that prevents normal daily activities; 
requires interventional treatment and may require hospitalization or invasive intervention 
(e.g., anemia resulting in blood transfusion). 
Refer to Section 7.5.3 regarding withholding investigational product administration if the 
subject experiences a severe AE not related or of unclear relationship to the 
investigational product; and discontinuing investigational product administration if the 
subject experiences a severe AE related to the investigation product. 
The Investigator will be instructed to closely monitor each subject who experiences an AE 
(whether ascribed to the investigational product 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). 
10.6.5.3 
Assessment of Relationship 
The causal relationship of each AE to the investigational product (KHK4083 or placebo) 
must be determined by a medically qualified individual. The causal relationship should be 
assessed as one of the following: 
Related 
There is a reasonable causal relationship between the investigational product 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 investigational product 
administration and the AE.  


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10.6.5.4 
Classifying Infusion Reactions  
• 
Mild - infusion reaction requires no intervention and no interruption of the infusion; 
however, infusion interruption is permitted to observe the subject for resolution of any 
signs/symptoms before re-starting the infusion. 
• 
Moderate - infusion reaction requires possible intervention (e.g., paracetamol orally and 
diphenhydramine 50 mg IV or an equivalent anti-histamine may be administered) and 
interruption of the infusion for at least 15 to 30 minutes prior to re-starting or 
discontinuing the infusion. 
• 
Severe - infusion reaction requires medical intervention (i.e., immediate medical/nursing 
assessment and indicated supportive management per the institutional standard of care 
and local Investigator judgment until the signs/symptoms of the reaction have resolved) 
and immediate discontinuation of the infusion. 
Refer to Section 8.1.3.3 for additional details on continuing or discontinuing investigational 
product administration following an acute infusion reaction. 
10.6.6 
Serious Adverse Events 
An SAE is defined as any AE that: 
• 
Results in death. 
• 
Is immediately life threatening. The term “life threatening” as part of the definition of 
“serious” refers to an event in which the subject was at imminent risk of death without 
urgent intervention at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability or incapacity or substantial disruption of the 
ability to conduct normal life functions. 
• 
Is a congenital anomaly or birth defect. 
• 
Is another important medical event. Important medical events 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. 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
“serious,” which is based on the outcome or action criteria usually associated with events that 


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pose a threat to life or functioning. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
All AEs, whether non-serious or serious, must be recorded as appropriate. In addition, any 
AE that is initially considered serious or becomes serious must be reported as an SAE.  
10.6.6.1 
Notification of Institutional Review Board or Independent Ethics 
Committee of Serious Adverse Events 
The Investigator must comply with the applicable regulatory requirements related to the 
reporting of SAEs to the IRB or IEC. The IRB/IEC must be informed in a timely manner by 
the Investigator of SAEs occurring at their investigative site during the study. Investigators 
must also submit safety information provided by the Sponsor to the IRB. Investigators (or the 
Sponsor accordingly to specified regulations) also must submit safety information to the IEC. 
10.6.6.2 
Adverse Event Contacts 
All SAE reports and follow-up SAE documentation should be emailed to the Sponsor’s Drug 
Safety Surveillance Department:  SAESource@kyowa-kirin-pharma.com. 
10.6.6.3 
Urgent Safety Measures 
In accordance with the principles of GCP as described in ICH E6, 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 subject(s) without prior IRB/IEC approval/favorable 
opinion. 
The Investigator may take appropriate urgent safety measures in order to protect the subjects 
of a 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. 
All dose-limiting toxicity reports, non-emergency inquiries, and general information 
regarding this study should be directed to the Clinical Trial Manager, or Medical Monitor. 
All urgent safety measures meeting the criteria for an SAE must be reported to the Sponsor 
within 24 hours of taking safety measures. Such reports can be initiated by telephone but 
must be officially documented by the Investigator by email (SAESource@kyowa-kirin-
pharma.com) and must include details of what measures were taken and the circumstances 
giving rise to those measures. 


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10.6.7 
Adverse Event and Serious Adverse Event Reporting 
The description of each AE will identify the subject, date of onset, the date of resolution, the 
severity of the event, the action taken regarding the AE and the investigational product 
(KHK4083 or placebo), the outcome of the event, and the relationship of the event to 
KHK4083 or placebo. A medical condition present at Screening, but that has increased in 
frequency or severity, must be recorded as an AE. For screen failures, SAEs should be 
collected and recorded only until the subject is determined to be a screen failure. Screening or 
withdraws consent to participate in the study, except for SAEs that occur outside of that 
window which are attributed to screening-specific procedures. All AEs with onset after 
signing of the ICF should be collected. Adverse events which occur prior to first 
administration of investigational product should be identified as occurring pretreatment. No 
AE data should be entered on the eCRF for screen failures. 
Standard medical terminology should be used to document AEs. The subject’s exact 
description of the event will be recorded in the source documentation. In the case of signs and 
symptoms, the underlying illness or diagnosis will be recorded as the event when known. For 
SAEs, a single term for the diagnosis or underlying illness should be provided on the SAE 
Report form; if the underlying illness/diagnosis is unknown, the chief sign/symptom making 
the event serious should be recorded. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported according to regulatory guidelines. 
All serious and non-serious AEs must be followed for a final outcome until the end of the 
Post-treatment Follow-up Period. An outcome of “unknown” is not considered to be an 
acceptable final outcome. An outcome of “not resolved” is an acceptable final outcome for 
non-serious AEs at the end of a subject’s participation in a study, and for SAEs at database 
lock. 
All SAEs require expeditious handling to comply with regulatory requirements. Any SAE 
occurring in a clinical study subject 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 
Report form and e-mail it to the Sponsor or designee. All telephone communication regarding 
an SAE must be followed by a written report.  
The Investigator is obligated to immediately report to the Sponsor or designee any SAE 
occurring at any time after the subject signs the ICF and within 16 weeks after the last dose of 
investigational product, independent of the circumstances or suspected cause. In addition, the 
Investigator must promptly report to the Sponsor any SAE occurring at any other time after 


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completion of the study if a causal relationship to KHK4083 is suspected. 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 medical assessment of the case and 
independent determination of causality. Supporting documentation such as hospital discharge 
summaries or appropriate 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. The Investigator will ensure that information reported immediately 
by telephone or other means and information entered on the SAE Report form is accurate and 
consistent. 
10.6.7.1 
Reporting of Infusion Reactions 
The signs and symptoms of an infusion reaction usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of the infusion. 
Infusion reactions should be recorded so that the presenting sign/symptom is part of the 
reported AE term(s) (e.g., chills or infusion reaction, fever). Acute infusion 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 5 
for the clinical criteria for diagnosis of anaphylaxis. 
The start of the infusion reaction with respect to the administration of the investigational 
product as well as the duration of each symptom should be recorded. 
The intensity of the infusion reaction (refer to Section 10.6.5.4 for definitions of mild, 
moderate, or severe infusion reactions) and causal relationship (i.e., related or not related) to 
the investigational product (refer to Section 10.6.5.3 ) should be determined and reported. 
10.6.8 
Other Significant Adverse Events 
Clinical laboratory abnormalities that qualify as AEs (other than those meeting the definition 
for serious) and/or any events that lead to an intervention (including premature 
discontinuation or prolonged infusion time of the investigational product, or significant 
additional concomitant therapy) will be reported and evaluated as AEs. 
Any clinically important changes noted during interim or final physical examinations, ECGs, 
x-rays, or any other potential safety assessments, whether or not these procedures are 
required by the protocol, must also be collected, and if serious recorded on the SAE Report 
form, when possible, in order for the Sponsor to collect additional information about that 


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abnormality, including information regarding relationship to KHK4083 or placebo, any 
action taken, and resolution.  
10.6.9 
Pregnancy Reporting 
This process is aimed at ensuring the appropriate monitoring of the potential risk related to 
investigational product exposure of pregnant women and/or fetuses as well as the risks 
associated with exposure of a father, regarding congenital abnormalities or birth defects in 
their offspring. It also ensures compliance with applicable international and local regulations. 
The requirements are applicable to all subjects following exposure to the investigational 
product (KHK4083 or placebo). 
Female study subjects: The subject must be advised by the Investigator to inform the 
Investigator immediately if she suspects she may be pregnant.  
Male study subjects: The subject must be advised by the Investigator to inform the 
Investigator immediately if they suspect their partner became pregnant after the subject was 
administered investigational product. 
When a study subject reports a pregnancy (post-KHK4083 administration) to the Investigator, 
KHK4083 should be stopped immediately and a pregnancy test should be arranged for the 
subject (or their partner) by the Investigator within 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 investigational product. Every attempt will be made to follow the pregnancy to 
conclusion to obtain information regarding the outcome. 
10.6.10 Safety Management during the Study 
The Sponsor has primary responsibility for the ongoing medical review of safety data 
throughout the study. This includes AEs considered to be medically significant and making 
recommendations with the input of the Medical Monitor regarding further conduct of the 
study. The Safety Monitoring Committee will meet as needed in addition to the scheduled 
times according to the monitoring plan. Refer to Section 6.3 for details on the safety 
monitoring plan. 


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10.7 Appropriateness of Measurements 
All assessments and measurements are appropriate and generally regarded as standard care or 
medical practice.  
11 
DATA HANDLING AND QUALITY ASSURANCE 
11.1 Electronic Case Report Forms and Source Documentation 
Subject data will be entered into study eCRFs, transmitted electronically to the data 
management vendor and the Sponsor, and combined with data provided from other sources. 
Management of clinical data will be performed in accordance with applicable industry 
standards and data cleaning procedures to ensure the integrity of the data. It is the 
responsibility of the investigative site to prepare and maintain the adequate and accurate 
eCRFs that have been designed by the Sponsor to record all observations and other data 
pertinent to the clinical investigation. The eCRFs are used to record information collected in 
the performance of this study and that will be entered into the electronic data capture (EDC) 
system. These eCRFs are organized as an ordered series of electronic data entry modules 
specific for each scheduled and unscheduled study visit. 
The investigative site EDC users will exercise due diligence in ensuring that study data are 
entered accurately and in their entirety from the investigative site’s source documents and 
flow sheets into the appropriate data entry fields. Only staff listed on the “Delegation of 
Authority” page in the study file notebook and who have been appropriately trained to use the 
EDC system will be issued a user identification code allowing them to make entries and edits 
to the EDC system and to respond to queries. Only the Investigator will be issued a user 
identification code allowing the application of an electronic signature to a completed study 
subject record signifying the data has been reviewed and verified as complete and accurate. 
By signing this protocol, the 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 US investigative sites, compliance is required with all applicable 
provisions of the Health Insurance Portability and Accountability Act (HIPAA) and its 
implementing regulations. 
11.2 Clinical Data Management 
Data management will be carried out by the contract research organization selected by the 
Sponsor. The Sponsor will provide oversight and will have the overall responsibility for the 


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processing and quality control of the data. The handling of data, including data quality 
control, will comply with all applicable regulatory guidelines. 
Management of clinical data will be performed in accordance with applicable industry 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removal of 
errors and inconsistencies in the data.  
11.3 Archiving 
Electronic case report forms, including queries and audit trails, will be retained by the 
Sponsor, while the Investigator will receive a copy of the site data in the Portable Document 
Format on a compact disc-read only memory following study completion. 
All study documentation at the investigative site and the Sponsor’s site will be archived in 
accordance with ICH E6-GCP. 
12 
STATISTICAL METHODS AND PLANNED ANALYSIS 
12.1 General Statistical Considerations 
All categorical variables will be summarized by counts and percentages. Descriptive statistics 
(mean, standard deviation [SD], median, minimum, and maximum) for continuous variables 
will be utilized. All summaries and analyses conducted will be by treatment cohort 
(KHK4083 dose levels; combined KHK4083; and placebo) and by visit. The specifics for 
these outputs will be described in detail within the Statistical Analysis Plan (SAP). The last 
pre-administration observation will be used as the Baseline value for calculating post-
administration changes from Baseline. For efficacy assessments, Baseline is defined as 
Week 0. Data obtained and entered into the database will be provided in separate data listings 
showing individual subject values. The planning and reporting of statistical analysis will be 
carried out as described in the Sponsor’s work instructions and standard operating procedures 
(SOPs) governing clinical studies. 
12.2 Populations to be Analyzed 
The following analysis sets will be used in the study: 
• 
Safety Analysis Set: Includes all subjects who received any (even a partial dose) 
investigational product (KHK4083 or placebo); 
• 
Full Analysis Set (FAS): Includes all subjects who receive at least one full dose of 
investigational product and who have Baseline data and at least one post-treatment 
assessment of the primary efficacy variable.  


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Major protocol deviations will be assessed through the study team’s review and the handling 
of these deviations described in the SAP. 
12.2.1 
Subject Disposition 
The number of subjects enrolled and completed/discontinued for each of the periods 
(Screening, Induction Therapy, Induction Therapy Follow-up Period, OLE/LTE Therapy, and 
LTE Therapy Follow-up Period) will be presented. A summary of reasons for discontinuation 
will be provided. The number of subjects in the Safety Analysis Set and FAS will be 
provided as well as the number of subjects who were excluded from each analysis set. The 
reasons why subjects were excluded from any analysis set will be summarized and listed 
individually. 
12.2.2 
Demographic and Baseline Disease Characteristics 
Summaries will include demographics (including age, race, ethnicity, and sex), height, body 
weight, and Baseline values for UC assessment in the Safety Analysis Set. All demographic 
data, including medical/surgical history and physical examination results of note, will be 
listed by subject. 
12.2.3 
Prior and Concomitant Medications 
The World Health Organization Drug Dictionary will be used to classify prior and 
concomitant medications by Therapeutic Class and Preferred Term. Prior medications include 
any previous biologic treatment (for any indication), all treatment for UC taken within 
6 months prior to Screening, and any other previous medication taken within 1 month prior to 
Screening. Concomitant medications include medications that started at any time and were 
taken at any time during the study including the follow-up period. Probiotic usage is to be 
tracked during the study. 
Prior and concomitant medications will be summarized separately in the Safety Analysis Set. 
12.2.4 
Investigational Product Exposure and Compliance 
Extent of exposure for each subject will be calculated as total amount of investigational 
product administered for the entire Treatment Period. Extent of exposure and total number of 
doses administered for each treatment during Induction Therapy and OLE/LTE Therapy will 
be summarized as well as the number of doses administered to subjects by period.  


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12.3 Efficacy Analysis 
All efficacy analyses will be performed in the FAS unless otherwise specified. 
12.3.1 
Primary Efficacy Analysis 
The primary efficacy variable is the change from Baseline (Week 0) in mucosal score 
presented by the mMES at Week 12 for subjects who received the recommended dose during 
Induction Therapy. This includes Part A subjects who received the recommended dose 
identified for Part B as well as the subjects who received the recommended dose during 
Part B of Induction Therapy. (Note: For all other subjects who receive KHK4083 at dose 
levels different than the recommended dose in Parts A and B of Induction Therapy, this 
efficacy variable will be considered the main secondary variable.) The primary variable will 
be used for an exploratory efficacy analysis using a linear model with Baseline values as a 
covariate to estimate the difference between treatment cohorts (each KHK4083 dose level 
versus placebo).  
In order to test for optimal dose levels within this fitted linear model, three types of contrasts 
will be defined to demonstrate which KHK4083 dose level is deemed closest to optimal. The 
first contrast is for the scenario of “10 mg/kg is closest to optimal” and its vector, (P L M H), 
is (-1 -1 -1 3), where P: Placebo; L: 1.0 mg/kg; M: 3.0 mg/kg; and H: 10 kg/mg. The second 
contrast is for the scenario of “3.0 mg/kg is closest to optimal” and its vector is (-1 -1 1 1). 
The third contrast is for the scenario of “1.0 mg/kg is closest to optimal” and its vector is 
(-3 1 1 1). Each contrast will be tested within the fitted model to determine the dose level 
providing optimum benefit over placebo.  
12.3.2 
Secondary Efficacy Analyses 
The secondary efficacy variables for all subjects (i.e., recommended dose or any other dose 
level in Parts A and B of Induction Therapy) are as follows: 
• 
The percentages of subjects with at least a 1-point improvement in their mMES from 
Baseline (Week 0) to Week 12. 
• 
The percentages of subjects with at least a 1-point improvement in their modified Baron 
endoscopic score from Baseline (Week 0) to Week 12. 
• 
The mean change in UCEIS (0 to 8) and subscores from Baseline (Week 0) to Week 12. 
• 
The percentage of subjects with a mucosal healing (the mMES ≤ 1) at Week 12.  
• 
The change from Baseline (Week 0) in total Mayo Clinic score (0 to 12) at Week 12. 
• 
The change from Baseline (Week 0) in partial Mayo Clinic scores (0 to 9; without 
sigmoidoscopy) at Weeks 2, 4, 6, 8, 10, and 12. 


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• 
The percentages of clinical response (the change from Baseline in the total Mayo Clinic 
score ≤ −3 and the percentage change from Baseline in the total Mayo Clinic score 
≤ −30% to Week 12, with an accompanying decrease in the rectal bleeding subscore of at 
least 1 point or an absolute rectal bleeding subscore of ≤ 1).  
• 
The percentages of clinical remission (a total Mayo Clinic score ≤ 2 and no 
subscores > 1) at Week 12. 
Treatment (each KHK4083 dose level versus placebo) comparisons by cohort will be 
performed with the linear model for all secondary efficacy analyses of continuous variables.  
12.3.3 
Exploratory Efficacy Analysis 
Clinical improvement (changes from Baseline [Week 0] to Week 52 in the total Mayo Clinic 
score) at Week 52 will be summarized. In addition, change from Baseline (Week 0) in partial 
Mayo Clinic scores (without sigmoidoscopy) will be summarized by study visit at Weeks 16, 
20, 24, 28, 32, 36, 40, 44, 48, and 52 and at OLE/LTE Therapy Follow-up Period visits 
(Weeks 56, 60, and 64).  
Clinical response at Week 52 will be summarized. Clinical remission will be summarized at 
Week 52.  
At Weeks 12 and 52, durable clinical response and durable clinical remission (present at both 
Weeks 12 and 52), and glucocorticoid-free clinical remission at Week 52 will be 
summarized.  
Remission (mMES of 0 or 1, stool frequency subscore of 0 or 1 and rectal bleeding subscore 
of 0) rates at Weeks 12 and 52 will be summarized. 
The percentage of subjects with mucosal healing at Week 52 will be summarized. The 
percentages of subjects with improvement in the mucosa (change from Baseline of at least a 
1-point improvement in the mMES and/or in the modified Baron endoscopic scores; and/or 
mean change from Baseline in the UCEIS score) at Week 52. 
The change from Baseline in HRQL based on IBDQ will be analyzed for total score and 
4 subscale scores at all study visits (Weeks 2 to 52, including Induction Therapy Follow-up 
Period visits (Weeks 16, 20, and 26) and LTE Therapy Follow-up Period visits (Weeks 56, 
60, and 64). 
At Weeks 16 through 52 and through the OLE/LTE Therapy Follow-up Period (Week 56 
through Week 64), the change from Baseline in corticosteroid (glucocorticoid) dosages and 
the duration of glucocorticoid-free treatment will be summarized.  


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Treatment (each KHK4083 dose level versus placebo) comparisons by cohort and OLE/LTE 
will be performed with the linear model for all exploratory efficacy analyses of continuous 
variables.  
Exploratory analyses are described in detail in the SAP. 
12.3.4 
Sample Size Determination 
Assuming a 15% dropout rate, it is anticipated that approximately 60 subjects will be 
required to be randomized in order to achieve 51 evaluable subjects in the FAS. In Part A 
(Cohorts 1 - 3), the sample size is based on the feasibility of the safety and tolerability 
assessment to recommend starting the treatment of the next cohort of 12 subjects/cohort 
(9 subjects to receive KHK4083 and 3 subjects to receive placebo).In Part B (Cohort 4) for 
the treatment of 24 subjects (18 subjects to receive KHK4083 at the recommended dose 
based on the safety and tolerability in Part A and 6 subjects to receive placebo), the sample 
size is based on the feasibility of exploratory assessments in efficacy and safety at the 
recommended dose level. Based on the UCEIS and Mayo Clinic scores and from combining 
Part A and Part B, it is planned to have approximately a total of 27 randomized subjects 
receive the recommended dose of KHK4083 and 15 subjects receive placebo. 
12.3.5 
Significance Level 
All statistical analyses in this Phase 2 study will be descriptive or exploratory, and no 
adjustment to control Type I error will be performed. 
12.4 Pharmacokinetic, Pharmacodynamic, and Immunogenicity Analyses 
12.4.1 
Pharmacokinetic Analyses 
All subjects with sufficient quantifiable data will be included in the PK analysis. Serum 
concentration data will be summarized with descriptive statistics at each scheduled time 
point. Individual serum concentrations at each sampling time point for KHK4083 will be 
presented by listings. Descriptive summary statistics of serum concentrations including 
means, ranges, SD, and percent coefficient of variation (%CV) will be presented. Individual 
and mean concentrations versus time will be plotted on linear and semi-logarithmic scales.  
Concentration-time data for Cohorts 1 - 3 (Induction Therapy - Part A and LTE Therapy) will 
be analyzed individually by non-compartmental analysis methods using actual elapsed times 
relative to the last dosing. The following PK parameters will be summarized: Cmax, tmax, Cmin, 
AUC0-t, AUC0-τ, AUC0-∞, t1/2, CLs, Vss, Vz, and Rac. The PK parameters for KHK4083 will be 


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summarized by dose level and Treatment Period (i.e., Induction Therapy and LTE Therapy). 
All PK parameters will be summarized using descriptive statistics (mean, SD, maximum, 
median, minimum, and %CV).  
A sparse PK sampling strategy was planned for Cohort 4 (Induction Therapy - Part B and 
LTE Therapy), therefore population PK analysis using mixed-effect modeling will be applied 
to the data from both Cohorts 1 - 3 (Part A) and Cohort 4 (Part B). The PK exposure 
parameters will be calculated using a final population PK model.  
The dose proportionality of KHK4083 PK exposure parameters will be assessed using the 
Power Model for Cohorts 1 - 3 (Induction Therapy - Part A and OLE/LTE Therapy). The 
PK exposure parameters include Cmax, AUC0-t, and AUC0-∞, as appropriate. The PK-PD 
relationships will be explored using graphic tools or modeling as needed.  
Additional details of the PK and PK-PD analyses will be addressed in a separate PK-PD 
Analysis Plan. 
12.4.2 
Pharmacodynamic Analyses 
The PD parameters will be determined in subjects with moderately active UC and 
summarized by dose level and Treatment Period (i.e., Induction Therapy - Part A and Part B, 
and OLE/LTE Therapy). For the delayed-type hypersensitivity assay, values will be 
summarized at Screening and Week 10 for selected investigative sites. For fecal calprotectin, 
mean change and mean percentage change from Baseline (Week 0) at Week 12 and median 
values at Weeks 2, 12, and 52 will be analyzed for subjects who received the recommended 
dose. For the wr-CRP assays, mean change and mean percentage change from Baseline 
(Week 0) at Week 12 and median values at Weeks 2 through 12 and at Weeks 24, 36, 52, and 
64 will be analyzed for the subjects who received the recommended dose. The details will be 
described in the PK-PD Analysis Plan. 
12.4.3 
Immunogenicity Analyses 
The immunogenicity of KHK4083 will be determined in subjects with moderately active UC. 
The percentage of subjects with confirmed anti-KHK4083 antibodies will be summarized by 
dose level and Treatment Period (i.e., Induction Therapy - Part A and Part B, and OLE/LTE 
Therapy), visit (week), and overall. The effect of positive anti-KHK4083 antibodies on the 
PK, and possibly efficacy and safety, will be explored. 


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12.5 Analyses of Safety Data 
The overall safety and tolerability of KHK4083 compared to placebo administered in 
multiple IV doses will be determined for reported AEs (including SAEs), physical 
examinations, vital signs, body weight, 12-lead ECGs, and clinical laboratory tests. All 
summaries will be prepared for the Safety Analysis Set.  
All subjects will be assessed from the signing of the ICF until 16 weeks after the last dose for 
potential AEs. Treatment-emergent adverse events (TEAEs) will be grouped and tabulated by 
MedDRA Preferred Terms (PT) and SOC. All TEAEs will be summarized showing the 
number and percentage of subjects for each event with a start time within the Treatment 
Period (i.e., Induction Therapy and OLE or LTE Therapy) and by cohort (KHK4083 versus 
placebo) during Induction Therapy or KHK4083 dose level versus placebo during OLE/LTE 
Therapy. 
Secondary safety variables in each cohort (Induction Therapy) or KHK4083 dose level 
(LTE Therapy) will be: 
• 
Serum chemistry, hematology, coagulation profile, and urinalysis parameters; 
• 
Vital signs (systolic and diastolic blood pressure, radial pulse rate, and respiration rate);  
• 
Incidence of abnormal 12-lead ECG findings.  
Subject listings, summary tables, and figures including the change over time and shift tables 
will be generated for vital signs (including body temperature, systolic and diastolic blood 
pressure, radial pulse rate, and respiratory rate), 12-lead ECGs, body weight, and clinical 
laboratory assessments (serum chemistry, hematology, coagulation profile, and urinalysis). 
The results from physical examination will be presented in the subject data listings.  
12.6 Procedures for Missing, Unused, and Spurious Data 
Missing values will not be substituted by estimated values, but treated as missing in the 
statistical evaluation. All data from all subjects dosed in the study will be included in all 
listings, plots, summary tables, and statistical analyses when appropriate. 
12.7 Rules for Excluding Subjects from Analysis 
All dosed subjects will be included in the analyses unless otherwise specified. The Sponsor 
will decide whether any subject or any individual values belonging to a subject will be 
excluded from the evaluations when the protocol violation is considered to have a negative 
impact on the scientific aspects and interpretation of the study results. If the subject has 


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received any investigational product (KHK4083 or placebo), all available safety data will be 
used. The reason(s) for any exclusion will be described in the final Clinical Study Report. 
12.8 Procedures for Reporting Deviations from Original Statistical Plan 
Any deviations from the statistical analysis outlined in this protocol will be described, and 
reasons for the deviations listed, in the final Clinical Study Report. 
13 
SPECIAL REQUIREMENTS AND PROCEDURES 
13.1 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) 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. 
No changes from the final approved (authorized) protocol will be initiated without the 
IRB’s/IEC’s prior written approval or favorable opinion of a written amendment, except 
when necessary to eliminate immediate hazards to the subjects or when the change(s) 
involves only logistics or administration. The Sponsor will authorize and the Principal 
Investigator(s) will sign the protocol amendment prior to submission to the IRB/IEC. 
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. 
13.2 Ethical Considerations 
The Investigator is responsible for conducting the study in full accordance with the protocol, 
US Food and Drug Administration (FDA), Code of Federal Regulations (CFR), Title 21, 
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. 
Inability to comply with these standards by any participating investigative site will be 
documented. 
The Investigator will be responsible for preparing documents for submission to the relevant 
IRB/IEC and obtaining written approval for this study. Approval will be obtained prior to the 
initiation of the study. 


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13.3 Investigator’s Responsibilities 
13.3.1 
Overall Responsibilities 
The Investigator(s) is/are responsible for conducting the study in full accordance with the 
protocol and the 2013 revision of the Declaration of Helsinki, the GCP: Consolidated 
Guideline, approved by the ICH, and any applicable national and local laws and regulations. 
Information regarding any investigative site participating in this study that cannot comply 
with these standards will be documented. 
13.3.2 
Subject Informed Consent 
Written and oral information about the study in a language understandable by the subject will 
be given to all subjects. Each subject’s willingness to participate in the study will be 
documented in a signed and dated ICF before any procedures or assessments are initiated and 
after the aims, methods, anticipated benefits, potential hazards, and insurance 
arrangement/policy are explained. It will also be explained to the subjects that they are free to 
refuse entry into the study and free to withdraw from the study at any time without prejudice 
to future treatment. The informed consent process will be documented in the subject's 
medical record and the Investigator will sign, date and time the ICF after the subject has 
signed, dated and recorded the time. The Investigator(s) will keep the original ICFs and 
copies will be given to the subjects. 
13.3.3 
Confidentiality Regarding Study Subjects 
Particular attention is required to the regulations provided by the US FDA under the Freedom 
of Information Act providing, in part, that information furnished to Investigators and IRBs 
will be kept confidential by the FDA (i.e., only for information maintained in confidence by 
the Investigator and IRB). 
The Investigator(s) must assure that the privacy of the subjects, including their personal 
identity and all other personal medical information, will be maintained at all times. In eCRFs 
and other documents or image material (including materials from all examinations including 
colonoscopies) submitted to the Sponsor, subjects will not be identified by their names, but 
by subject identification numbers. 
Personal medical information may be scrutinized for the purpose of verifying data recorded 
in the eCRF. This may be done by the monitor(s), properly authorized persons on behalf of 
the Sponsor, the quality assurance unit, or regulatory authorities. Personal medical 
information will always be treated as confidential. 


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13.4 Study Monitoring 
Study monitoring will be performed in accordance with ICH E6-GCP, the protocol, and 
applicable local regulations.  
13.4.1 
Direct Access to Source Data/Documents 
By signing this protocol, the 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 HIPAA and its implementing regulations. 
The monitor(s), auditor(s), authorized personnel of the Sponsor, health authority inspector(s) 
or their agents, and authorized members of IECs/IRBs will be given direct access to source 
data and documentation (e.g., medical charts/records, laboratory results, printouts, 
videotapes, etc.) for source data verification, provided that subject confidentiality is 
maintained in accordance with regulatory/local requirements. 
13.5 Audit and Inspection 
According to ICH E6-GCP, the Sponsor or regulatory authorities may audit the investigative 
site. The Quality Assurance Unit of KKD, independent of the Clinical Research and 
Development Department, is responsible for auditing the study. 
The Investigator(s) must accept that regulatory authorities may conduct an inspection to 
verify compliance of the study with GCP. 
13.5.1 
Record Retention 
Study data and other essential documents should be retained for a minimum of 2 years after 
the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product. 
However, these documents should be retained for a longer period if required by the 
applicable legal requirements. The Sponsor (or its designee) will inform the Investigator, in 
writing, as to when these documents no longer need to be maintained. 
13.5.2 
Investigator Information 
By signing this protocol, the Investigator recognizes that certain personal identifying 
information with respect to the Investigator, and all sub-Investigators and study investigative 


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112 
 
site personnel, may be used and disclosed for study management purposes, as part of a 
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 your country and other countries, including 
countries that do not have laws protecting such information. Additionally, the Investigator’s 
name and business contact information may be included when reporting certain SAEs to 
regulatory agencies or to other Investigators. By signing this protocol, the Investigator 
expressly consents to these uses and disclosures. 
In order to facilitate contact between Investigators, the Sponsor may share an Investigator’s 
name and contact information with other participating Investigators upon request. 
13.5.3 
Compliance with Law, Audit, and Debarment 
By signing this protocol, the 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. 
24) Complete, and/or update the FDA Form 1572 in a timely manner, and conduct the 
study in accordance with the specifications on Page 2 of FDA Form 1572. 
25) Allow monitoring, audits, IRB/IEC review, and regulatory agency inspection of 
study-related documents and procedures; and provide for direct access to all 
study-related source data and documents. 
a) 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.  
b) Promptly inform the Sponsor of any regulatory agency inspection conducted 
for this study. 
c) 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.  
26) Provide all data, and upon completion or termination of the clinical study submit 
any other reports to the Sponsor as required by this protocol or as otherwise 
required pursuant to any agreement with the Sponsor. 
27) 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, 


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113 
 
to the best of the 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. 
28) 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 Investigator further agrees to provide this information on a 
Financial 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 13.6 for 
additional details. 
The ICH E6-GCP guidelines recommend that the 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, KKD will 
promptly notify that investigative site’s IRB/IEC. 
13.5.4 
Administrative 
All references to the Sponsor/KKD in this section include all designees, e.g., Contract 
Research Organizations or Consultants acting on behalf of the Sponsor. 
13.6 Financial Disclosure 
Financial disclosures by the Investigator(s) (or investigating institution) and the Sponsor will 
comply with local regulations.  
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 investigating institution) who is not a full-time or part-time employee to the FDA. 
Therefore, the Investigator(s) (or investigating institution) must provide the Sponsor with 
sufficient, accurate financial certification that none of the following financial arrangements 
(further defined 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.  


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114 
 
13.7 Insurance 
This study is covered under the Sponsor’s Liability Insurance Policy. A Certificate of 
Insurance and/or an information leaflet containing essential information about the insurance 
coverage can be provided upon request. 
13.8 Publication Policy 
The study is part of a multicenter study; accordingly, the Institution and Principal Investigator 
of the study 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 Investigators and the Institutions from all appropriate sites contributing data, analyses and 
comments. However, if such a multicenter publication is not submitted within 
twelve (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 
Institution and/or such Principal Investigator may publish the results from the institution site 
individually in accordance with the following requirements. Prior to submission of any 
materials for publication or presentation, the Institution will provide such materials or 
manuscript to the Sponsor for review. Details of the Sponsor’s publication policy can be 
found in the Clinical Trial Agreement.  


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115 
 
14 
REFERENCES  
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microbes in inflammatory bowel disease. Gastroenterol. 2011;140(6):1729–37. 
2. Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, Taylor KD, et al. 
Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of 
confirmed associations to 47. Nature Genet. 2011;43:246–52.  
3. Bager P, Befrits R, Wikman O, Lindgren S, Moum B, Hjortswang H, et al. The 
prevalence of anemia and iron deficiency in IBD outpatients in Scandinavia. Scand J 
Gastroenterol. 2011;46(3):304–09. 
4. Bodar EJ, van der Hilst JCH, van Heerde W, van der Meer JWM, Drenth JPH, Simon A. 
Defective apoptosis of peripheral-blood lymphocytes in hyper-IgD and periodic fever 
syndrome. Blood. 2007;109(6):2416–18. 
5. Centers for Disease Control and Prevention. Inflammatory Bowel Disease (IBD) 
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6. The Criteria Committee of the New York Heart Association Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, MA: Little, 
Brown & Co; 1994:253-256. 
7. El-Hodhod MA, Aly RH, Youssef SR, Mohamed SI. Enhanced blood lymphocytes 
apoptosis in children with inflammatory bowel disease. ISRN Gastroenterol. 
2013;(ID415417):1-7. 
8. Fadok VA, Bratton DL, Guthrie L, Henson PM. Differential effects of apoptotic versus 
lysed cells on macrophage production of cytokines: role of proteases. J Immunol. 
2001;166(11):6847–54. 
9. Franke A, McGovern DP, Barrett JC, Wang, K, Radford-Smith GL, Ahmad T, et al. 
Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease 
susceptibility loci. Nature Genet. 2010;42:1118–25.  
10. Goodall JC, Wu C, Zhang Y, McNeill L, Ellis L. Saudek V, et al. Endoplasmic reticulum 
stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression. 
Proc Natl Acad Sci USA. 2010;107:17698–703.  
11. Hanauer S. Inflammatory bowel disease: epidemiology, pathogenesis and therapeutic 
opportunities. Inflamm Bowel Dis. 2006;12:S3-9(Suppl 1). 


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12. Hildeman D, Jorgensen T, Kappler J, Marrack P. Apoptosis and the homeostatic control 
of immune responses. Curr Opin Immunol. 2007;19(5):516–21. 
13. Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, et al. XBP1 links ER stress 
to intestinal inflammation and confers genetic risk for human inflammatory bowel 
disease. Cell. 2008;134(5):743–56.  
14. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. 
Nature. 2011;474(7351):307–17. 
15. Lakatos PL. Recent trends in the epidemiology of inflammatory bowel diseases: up or 
down? World J Gastroenterol. 2006;12(38):6102–08. 
16. Lee JK, Vadas P.  Anaphylaxis: mechanisms and management. Clin Exp Allergy. 
2011;41(7):923-38. 
17. Levin AD, Wadhera V, Leach ST, Woodhead HJ, Lemberg DA, Mendoza-Cruz AC, et al. 
Vitamin D deficiency in children with inflammatory bowel disease. Dig Dis Sci. 
2011;56(3):830–36. 
18. Loftus EV. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, 
and environmental influences. Gastroenterol. 2004;126(6):1504–17. 
19. Mahmood T, Yang PC. OX40L-OX40 interactions: a possible target for gastrointestinal 
autoimmune diseases. N Am J Med Sci. 2012;4(11):533-36. 
20. Marion JF. The PURSUIT trial: clinical implications in the treatment of moderately to 
severely active ulcerative colitis. Janssen Biotech, Inc; 2013 Dec. Available from: 
https://a68bb2c2708045fd2620-
fd7cac6ddbe3ceb34ed04891f318081a.ssl.cf3.rackcdn.com/ 
units/links_downloads/61753326e250d37e05fe9d5f2e4dd4d1_007838-
131220_Dr.Marionlabelupdate_PIattached.pdf 
21. Nakajima S, Iijima H, Egawa S, Shinzaki S, Kondo J, Inoue T, et al. Association of 
vitamin K deficiency with bone metabolism and clinical disease activity in inflammatory 
bowel disease. Nutrition. 2011;27(10):1023–28. 
22. Nell S, Suerbaum S, Josenhans C. The impact of the microbiota on the pathogenesis of 
IBD: lessons from mouse infection models. Nat Rev Microbio. 2010;8(8):564–77. 
23. Neuman MG. Immune dysfunction in inflammatory bowel disease. Transl Res. 
2007;149(4):173–86. 


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24. O’Malley T, Heuberger R. Vitamin D status and supplementation in pediatric 
gastrointestinal disease. J Spec Pediatr Nurs. 2011;16(2):140–50. 
25. Rathmell JC, Thompson CB. Pathways of apoptosis in lymphocyte development, 
homeostasis, and disease. Cell. 2002;109(2):S97–S107. 
26. Sampson HA, Munoz-Furlong 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):391-97. 
27. Silva LCR, Ortigosa LC, Benard G. Anti-TNF-α agents in the treatment of immune-
mediated inflammatory diseases: mechanisms of action and pitfalls. Immunotherapy. 
2010;2(6):817–33. 
28. Souza HS, Elia CCS, Spencer J, MacDonald TT. Expression of lymphocyte-endothelial 
receptor-ligand pairs, α4β7/MAdCAM-1 and OX40/OX40 ligand in the colon and 
jejunum of patients with inflammatory bowel disease. Gut. 1999;45(6):856-63. 
29. Simons KJ, Simons FER. Epinephrine and its use in anaphylaxis: current issues 
[abstract]. Current opinion in allergy & clinical immunology. 2010;10(4):354-361. 
30. 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):594-99. 
31. Sturm A. What is the role of apoptosis in the normal and inflamed intestine? Inflamm 
Bowel Dis. 2008;14(Suppl 2):S113–14. 
32. Travis SP, Schnell D, Krzeski P, Abreu MT, Altman DG, Colombel JF, et al. Developing 
an instrument to assess the endoscopic severity of ulcerative colitis: the Ulcerative Colitis 
Endoscopic Index of Severity (UCEIS). Gut. 2012;61(4):535-42. 
33. US Food and Drug Administration, Drug Safety Communication:  Safety review update 
on reports of hepatosplenic T-cell lymphoma in adolescents and young adults receiving 
tumor necrosis factor (TNF) blockers, azathioprine and/or mercaptopurine. 2011. 
http://www.fda.gov/drugs/drugsafety/ucm250913.htm. Accessed: 26 June 2015 
34. US Food and Drug Administration, Drug Safety Communication:  Boxed warning and 
new recommendations to decrease risk of hepatitis B reactivation with the immune-
suppressing and anti-cancer drugs Arzerra (ofatumumab) and Rituxan (rituximab). 2013. 
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35. US Food and Drug Administration, Guidance for Industry Immunogenicity Assessment 
for Therapeutic Protein Products. 2014. 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm338856.pdf. Accessed 12 October 2015. 
36. Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I. Immunosuppressive 
effects of apoptotic cells. Nature. 1997;390(6658):350–51. 
37. Yakut M, Üstün Y, Kabaçam G, Soykan I. Serum vitamin B12 and folate status in patients 
with inflammatory bowel diseases. Eur J Intern Med. 2010;21(4):320–23. 
 


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15 
APPENDICES/ATTACHMENTS 


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Appendix 1 Primary and Secondary Efficacy Definitions 
 
Term 
Definition 
Clinical Improvement 
(Week 12) 
A reduction, i.e., mean change from Baseline (Week 0) at Week 12, in the total 
Mayo Clinic score (0 to 12). 
Clinical Improvement 
(Weeks 2, 4, 6, 8, 10, and 12) 
Mean changes from Baseline (Week 0) in the partial (excludes endoscopy 
subscores) Mayo Clinic score (0 to 9). 
Clinical Response  
(Week 12) 
A reduction in the total Mayo Clinic score of at least 3 points and a decrease of 
at least 30% from Baseline (Week 0) to Week 12, and a reduction in the rectal 
bleeding subscale of at least 1 point from Baseline (Week 0) to Week 12 or an 
absolute rectal bleeding score of 0 or 1 at Week 12. 
Clinical Remission  
(Week 12) 
A total Mayo Clinic score of ≤ 2 and no subscores > 1. 
Improvement in the Mucosa 
(Measured by modified Mayo  
endoscopy subscore 
[mMES]) (Week 12) 
Percentage of subjects with at least a 1-point improvement in their mMES 
(0 to 3) from Baseline (Week 0) to Week 12. 
Improvement in the Mucosa 
(Measured by Ulcerative 
Colitis Endoscopic Index of 
Severity [UCEIS]) 
(Week 12) 
A mean change in the UCEIS (scores from 0 to 8, based on findings of vascular 
pattern, bleeding, and erosions/ulcers) from Baseline (Week 0) to Week 12. 
Improvement in the Mucosa 
(Measured by modified 
Baron scoring system) 
(Week 12) 
Percentage of subjects with at least a 1-point improvement in their modified 
Baron endoscopic score (5-point scale) from Baseline (Week 0) to Week 12. 
Mucosal Healing 
(Week 12) 
An mMES of 0 or 1. 
 


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Appendix 2 
Mayo Clinic Scoring System for Assessment of Ulcerative Colitis 
Activity (Score 0 to 12) with Modified Mayo Endoscopy Subscore 
Score Range:  0 to 12 a, b 
Stool Frequency (subject to establish his/her ‘normal’ frequency)c (Subscore 0 to 3): 
0 = Normal number of stools for this subject 
1 = 1 to 2 stools more than normal 
2 = 3 to 4 stools more than normal 
3 = 5 or more stools more than normal 
Rectal Bleeding (most severe bleeding of day to be recorded)c (Subscore 0 to 3): 
0 = No blood seen 
1 = Streaks of blood with stool less than half the time 
2 = Obvious blood with stool most of the time 
3 = Blood alone passes 
Endoscopy Findingsb (Subscore 0 to 3): 
0 = Normal or inactive disease 
1 = Mild disease (erythema, decreased vascular pattern) 
2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions) 
3 = Severe disease (spontaneous bleeding, ulceration) 
Physician’s Global Assessmentc, d (Subscore 0 to 3): 
0 = Normal 
1 = Mild disease 
2 = Moderate disease 
 
3 = Severe disease 
a: Higher scores indicate more severe disease. The total Mayo Clinic score (0 to 12) is a sum of the four subscores. 
b: Partial Mayo Clinic scores (0 to 9) exclude the Endoscopy Findings subscore because no endoscopy is performed. 
Endoscopy Findings subscore is amended by removing mild friability from a subscore of 1; thus any friability, even if 
mild, results in an endoscopic subscore of at least 2. 
c: Based on a review of the subject’s diary. Mayo Clinic subscores will be derived from the diaries over 2 to 3 qualifying 
days that are closest to each visit. 
d: Based on subject’s daily recollection of abdominal discomfort and general sense of well-being, and other observations 
(e.g., physical findings and the subject’s performance status). 


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Appendix 3 
Modified Baron Endoscopic Scoring System (5-point Scale) 
5-point Scale: 
0 = normal mucosa, not friable 
1 = granular mucosa with abnormal vascular pattern, not friable 
2 = friable mucosa, no spontaneous bleeding 
3 = micro-ulcerations with spontaneous bleeding 
4 = gross ulceration 


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Appendix 4 
Ulcerative Colitis Endoscopic Index of Severity 
 
 
 
(Modified scoring based on scale provided in Travis, 2012) 
Descriptor (score 
most severe lesions) 
Likert Scale Anchor 
Points 
Definition 
Vascular pattern 
Normal (0) 
Normal vascular pattern with arborization of capillaries 
clearly defined, or with blurring or patchy loss of capillary 
margins 
Patchy obliteration (1) 
Patchy obliteration of vascular pattern 
Obliterated (2) 
Complete obliteration of vascular pattern 
Bleeding 
None (0) 
No visible blood 
Mucosal (1) 
Some spots or streaks of coagulated blood on the surface of 
the mucosa ahead of the scope, which can be washed away 
Luminal mild (2) 
Some free liquid blood in the lumen 
Luminal moderate or 
severe (3) 
Frank blood in the lumen ahead of endoscope or visible 
oozing from mucosa after washing intraluminal blood, or 
visible oozing from a hemorrhagic mucosa 
Erosions and ulcers 
None (0) 
Normal mucosa, no visible erosions or ulcers 
Erosions (1) 
Tiny (≤ 5 mm) defects in the mucosa, of a white or yellow 
color with a flat edge 
Superficial ulcer (2) 
Larger (> 5 mm) defects in the mucosa, which are discrete 
fibrin-covered ulcers in comparison with erosions, but 
remain superficial 
Deep ulcer (3) 
Deeper excavated defects in the mucosa, with a slightly 
raised edge 
. 


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Appendix 5 
Clinical Criteria for the Diagnosis of Anaphylaxis 
(US Food and Drug Administration, Guidance for Industry 
Immunogenicity Assessment for Therapeutic Protein Products - 
Appendix A) 


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125 
 
APPENDIX A 
1) 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, 
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, 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 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.  


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Appendix 6 Follow-up and End-of-Study for Subjects who Discontinued During the 
Study 
 
 
 
Induction (12 w)
Maintenance-OLE/LTE (40w) 
EOT-w12, FU1-w16, FU2-w20, FU3-w26/EOS 
(4 visits)
DC from study 
before w12
EOS-FU3/ EOT
(1 visit)a
DC from treatment 
before w12
DC from study
DC from treatment
EOS-FU3/ EOT
(1 visit)b
DC=discontinuation;  EOT=end-of-treatment; FU=follow-up; LTE=long-term extension; OLE=open-
label-extension; w=week
a: EOT visit within 2 weeks after the last dose of IP. Endoscopy will be performed if the subject 
discontinues more than 8 weeks after Baseline visit.
b: EOT visit within 4 weeks after the last dose of IP. Endoscopy will be performed if the subject 
discontinues more than 8 weeks after Week 12 visit.
EOT-w52,FU1-w56, FU2-w60, FU3-w64/EOS 
(4 visits)

SAP_001.pdf: 
 
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STATISTICAL ANALYSIS PLAN 
 
Protocol No. 4083-002 
 
 
A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Multiple 
Ascending Dose Study (Induction Therapy and Long-term Extension Therapy) of an 
Anti-OX40 Monoclonal Antibody (KHK4083) in Subjects with Moderately Active 
Ulcerative Colitis 
 
 
 
 


 
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STATISTICAL ANALYSIS PLAN 
 
Document Information  
Protocol Number: 
4083-002 
Version: 
Final 2.0 
Document Date: 
06 Oct 2017 
Prepared for: 
Kyowa Kirin Pharmaceutical Development, Inc. 
Prepared by: 
Hongsuk Song 
Senior Biostatistician, CROS NT 


 
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Document Date: 
06 Oct 2017 
 
 
APPROVAL PAGE 
 
The Statistical Analysis Plan has been completed and reviewed and the contents are approved for 
use for the analysis. 
 
Lead Statistician details: 
Name: 
Hongsuk Song 
Job Role: 
Lead Statistician 
Company: 
CROS NT 
Signature: 
 
Date of signature: 
(DD Mmm YYYY) 
 
Sponsor Approver details: 
Name: 
Agron Collaku, Ph.D. 
Job Role: 
Senior Manager, Biostatistics 
Company: 
Kyowa Kirin Pharmaceutical Development, Inc. 
Signature: 
 
Date of signature: 
(DD Mmm YYYY) 
 
Sponsor Approver details: 
Name: 
June (Junfang) Li, Ph.D. 
Job Role: 
Vice President, Biometrics 
Company: 
Kyowa Kirin Pharmaceutical Development, Inc. 
Signature: 
 
Date of signature: 
(DD Mmm YYYY) 
 


 
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Protocol Number: 
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Final Version 2.0 
Document Date: 
06 Oct 2017 
 
 
Contents 
Abbreviations ...................................................................................................................................... 6 
1. 
Introduction ................................................................................................................................. 8 
2. 
Study Objectives .......................................................................................................................... 8 
2.1 
Primary objectives ..................................................................................................................... 8 
2.2 
Secondary objectives ................................................................................................................. 9 
2.3 
Exploratory objectives ............................................................................................................... 9 
3. 
Study Design ............................................................................................................................. 10 
3.1 
General design and plan ........................................................................................................... 10 
3.2 
Sample size justification .......................................................................................................... 16 
3.3 
Randomization and blinding .................................................................................................... 16 
3.4 
Efficacy endpoints ................................................................................................................... 16 
3.4.1 
Primary endpoint .............................................................................................................. 16 
3.4.2 
Secondary efficacy endpoints ........................................................................................... 17 
3.4.3 
Exploratory efficacy endpoints ......................................................................................... 17 
3.5 
Safety endpoints ....................................................................................................................... 18 
3.6 
Other endpoints ........................................................................................................................ 18 
4. 
Statistical Analysis .................................................................................................................... 19 
4.1 
General ..................................................................................................................................... 19 
4.2 
Analysis sets ............................................................................................................................ 22 
4.3 
Covariates ................................................................................................................................ 23 
4.4 
Handling of missing and incomplete data ................................................................................ 23 
4.5 
Changes in the planned analysis .............................................................................................. 23 
4.6 
Data Review Meeting .............................................................................................................. 24 
4.7 
Software ................................................................................................................................... 24 
5. 
Evaluation of Demographic and Baseline Characteristics ........................................................ 24 
5.1 
Subject enrollment and disposition .......................................................................................... 24 
5.2 
Protocol deviations .................................................................................................................. 25 
5.3 
Demographics and baseline characteristics ............................................................................. 25 
5.4 
Medical, diet and surgical history ............................................................................................ 25 
5.5 
Prior and concomitant medications .......................................................................................... 26 
6. 
Evaluation of Treatment Exposure ............................................................................................ 26 
6.1 
Exposure to investigational product ........................................................................................ 26 
6.2 
Evaluation of pharmacokinetics ............................................................................................... 27 
6.3 
Evaluation of immunogenicity ................................................................................................. 27 
7. 
Evaluation of Efficacy ............................................................................................................... 27 
7.1 
Analysis of primary endpoint .................................................................................................. 28 
7.2 
Analysis of secondary efficacy endpoints................................................................................ 30 


 
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7.3 
Analysis of exploratory efficacy endpoints ............................................................................. 31 
7.4 
Evaluation of pharmacodynamics ............................................................................................ 34 
8. 
Evaluation of Safety .................................................................................................................. 34 
8.1 
Adverse events ......................................................................................................................... 34 
8.2 
Clinical laboratory evaluation .................................................................................................. 35 
8.3 
Vital signs and body weight ..................................................................................................... 35 
8.4 
ECGs ........................................................................................................................................ 35 
8.5 
Physical examination except body weight ............................................................................... 36 
9. 
Tables and Listings .................................................................................................................... 37 
9.1 
Programs and tables quality control ......................................................................................... 37 
9.2 
Programming conventions ....................................................................................................... 37 
9.3 
Glucocorticoid ......................................................................................................................... 39 
9.4 
Tables ....................................................................................................................................... 40 
9.5 
Figures ..................................................................................................................................... 47 
9.6 
Listings ..................................................................................................................................... 51 
9.7 
Table, Figure, and Listing shells .............................................................................................. 53 
10. 
Literature and references ........................................................................................................ 53 
 


 
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Abbreviations 
AEs 
adverse events  
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CBC 
complete blood count 
CI 
confidence interval 
CRF 
case report form 
ECGs 
electrocardiograms 
eCRF 
electronic case report form 
FAS 
full analysis set 
FSH 
follicle-stimulating hormone 
HRQL 
health-related quality of life 
IBDQs 
inflammatory bowel disease questionnaires 
ICF 
informed consent form 
IRT  
interactive response technology 
IV 
intravenous 
KKD 
Kyowa Kirin Pharmaceutical Development, Inc. 
LTE 
long-term extension 
MedDRA  
Medical Dictionary for Regulatory Activities 
mMES 
modified mayo endoscopy subscore 
MMRM 
mixed model for repeated measures 
OLE 
open-label extension  
PD 
pharmacodynamic 
PGX 
pharmacogenomics 
PK 
pharmacokinetics 
SAE(s)  
serious adverse event(s)  
SAP 
statistical analysis plan 
SAS 
statistical analysis software 
SBP 
systolic blood pressure 
SOC  
system organ class 
TEAE 
treatment-emergent adverse event 
TNFR 
tumor necrosis factor receptor 
UC 
ulcerative colitis 
UCEIS 
ulcerative colitis endoscopic index of severity 
US 
United States 
wr-CRP 
wide-range C-reactive protein 


 
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Revision History 
Document Version Changes Made 
Document Date 
Version Draft 1.0 
First draft based on Protocol draft 4083-002, dated 07 
July 2015 and Final CRF, dated 23 Nov 2015. 
31 Mar 2016 
Version Draft 2.0 
Second draft based on Protocol 4083-002 
Amendment 1, dated 15 Oct 2015 and Final CRF, 
dated 23 Nov 2015. 
08 Apr 2016 
Version Draft 3.0 
Third draft based on Sponsor revision of draft version 
2.0 
12 May 2016 
Version Draft 4.0 
Third draft based on Sponsor revision of draft version 
3.0 
25 Oct 2016 
Version 1 
 
09 Dec 2016 
Version 2 
Amended for denominator changes, TLF list changes, 
and unblinding at Week 12. 
06 Oct 2017 


 
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1.  Introduction 
Ulcerative colitis (UC) is considered as one of the common gastrointestinal autoimmune diseases, 
and is referred to as immune-mediated inflammatory disease. KHK4083 is a fully human, non-
fucosylated IgG1 monoclonal antibody (mAb) specific for the costimulatory molecule OX40, a 
tumor necrosis factor receptor (TNFR) family member. KHK4083 binds with high affinity and 
specificity to an extracellular domain epitope of OX40, which plays a key role in maintaining late 
T-cell proliferation and survival by suppressing apoptosis, and in inducing T-cell memory 
formation. 
 
This study will determine the safety and tolerability of administration of multiple ascending doses 
of KHK4083, and determine if the recommended dose of KHK4083 improves the mucosa in 
subjects with moderately active UC. 
 
This statistical analysis plan (SAP) describes the statistical analysis and summary to be performed 
for the study described in Protocol 4083-002 Amendment 2, dated 04 Oct 2016 and titled: 
 
“A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Multiple Ascending Dose 
Study (Induction Therapy and Long-term Extension Therapy) of an Anti-OX40 Monoclonal 
Antibody (KHK4083) in Subjects with Moderately Active Ulcerative Colitis” 
 
The purpose of this SAP is to outline the planned analyses of clinical efficacy and safety data to be 
performed to support the completion of the Clinical Study Report (CSR) for Protocol 4083-002.  
The planned analyses identified in this SAP will be included in regulatory submissions and/or 
future manuscripts.  The analyses of pharmacokinetic (PK) and immunogenicity data are not 
detailed in this SAP, and will come under separate cover. Also, exploratory analyses not identified 
in this SAP may be performed to support the clinical development program. 
 
The reader of this SAP is encouraged to also read the clinical protocol and annotated case report 
forms (eCRFs) for details on the planned conduct of this study. Operational aspects related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless relevant 
to the planned analyses. 
2.  Study Objectives 
The primary, secondary, and exploratory objectives of the study are as follows: 
2.1 
Primary objectives 
 Induction Therapy - Part A: To determine the safety and tolerability of administration of 
multiple ascending doses of KHK4083 and to select the highest dose tolerated by subjects with 
moderately active UC to recommend for use in Part B; 


 
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 Induction Therapy - Part B: To determine if the recommended dose of KHK4083 identified 
in Part A improves the mucosa in subjects with moderately active UC at Week 12 as measured 
by the modified Mayo endoscopy subscore (mMES). 
2.2 
Secondary objectives 
 To determine if KHK4083 at dose levels different than the recommended dose improve the 
mucosa based on the mMES; 
 To determine if any dose level of KHK4083 administered as Induction Therapy will meet the 
following objectives at Week 12: 
 
- 
Improve the mucosa based on the modified Baron endoscopic score; 
- 
Improve the mucosa based on the Ulcerative Colitis Endoscopic Index of Severity (UCEIS); 
- 
Induce mucosal healing based on the mMES; 
- 
Improve clinical signs and symptoms based on total Mayo Clinic score; 
- 
Improve clinical signs and symptoms based on partial Mayo Clinic scores (Week 2 through 
Week 12, excludes endoscopy subscores); 
- 
Induce a clinical response based on a reduction in the total Mayo Clinic score (i.e., 
reduction of at least 3 points and a decrease of at least 30% from Baseline [Week 0] to 
Week 12) and rectal bleeding subscale (i.e., reduction of at least 1 point from Baseline 
[Week 0] to Week 12) (or a defined absolute rectal bleeding score of 0 or 1 at Week 12); 
- 
Induce clinical remission based on a total Mayo Clinic score (i.e., score of ≤ 2) and 
subscores (i.e., no subscores > 1). 
 
 To characterize the PK of KHK4083 in subjects with moderately active UC following multiple 
dose administration; 
 To evaluate the development of antibodies against KHK4083 (immunogenicity). 
2.3 
Exploratory objectives 
 To determine if multiple doses of KHK4083 administered during Open-label Extension (OLE) 
or Long-term Extension (LTE) Therapy will meet the following objectives at Week 52 (or as 
noted) when compared with Baseline (Week 0) scores (or subscores) or assessments: 
 
- 
Improve clinical signs and symptoms based on total Mayo Clinic score; 
- 
Improve clinical signs and symptoms based on partial Mayo Clinic scores (excludes 
endoscopy subscores) at Week 16 through Week 52, and the OLE/LTE Therapy Follow-up 
Period (Week 56 through Week 64); 
- 
Induce a clinical response based on a reduction in the total Mayo Clinic score and rectal 
bleeding subscale (or a defined absolute rectal bleeding score); 
- 
Induce clinical remission based on a total Mayo Clinic score and subscores; 
- 
Induce durable clinical responses and durable clinical remissions (present at both Weeks 12 
and 52), and glucocorticoid-free clinical remission; 
- 
Induce mucosal healing based on the mMES; 


 
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- 
Improve the mucosa based on the mMES, UCEIS, and/or modified Baron endoscopic score; 
- 
Induce a remission (Week 12; Week 52) based on modified Mayo endoscopy, stool 
frequency, and rectal bleeding subscores (defined as an mMES of 0 or 1, stool frequency 
subscore of 0 or 1, and rectal bleeding subscore of 0). 
 
 To evaluate the activity of KHK4083 on health-related quality of life (HRQL), which will be 
based on the subject’s completed Inflammatory Bowel Disease Questionnaires (IBDQs) in 
comparison to Baseline assessments; 
 To measure changes from Baseline in corticosteroid (glucocorticoid) dosages; 
 To determine the percentage of subjects who are glucocorticoid-free from Week 16 through 
Week 52, and through the OLE/LTE Therapy Follow-up Period (Week 56 through Week 64); 
 To evaluate the pharmacodynamic (PD) profile of KHK4083; 
 To explore the PK-PD relationships. 
3.  Study Design 
3.1 
General design and plan  
To show the changes in the study design among protocols, the Study design is described in Table 1, 
and the Study design diagrams are displayed in Figure 1 and Figure 2. However, as the subject 
enrollment started after Protocol Amendment 1, Protocol version 1 is not included.   
 
 


 
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Table 1 Study Design 
 
Protocol Amendment 1 
Protocol Amendment 2 
Overall 
Study 
Design and 
Plan 
This Phase 2, double-blind clinical study of multiple ascending doses 
of KHK4083 (or placebo) with an LTE Therapy phase will be 
conducted in approximately 60 randomized adult subjects with 
moderately active UC who have a documented unsuccessful previous 
treatment. 
 
The study will include a 4-week Screening Period, followed by a total 
of up to 64 weeks (treatment and follow-up) on study from the time of 
randomization to study completion.  
 
The Treatment Period includes double-blind Induction Therapy (12 
weeks) and double-blind LTE Therapy (40 weeks) for eligible subjects 
at Week 12. 
 
Post-treatment assessments will continue for 16 weeks after the last 
infusion associated with the subject’s treatment period. The on-site 
follow-up visits will be at Weeks 16, 20, and 26 for subjects who only 
receive Induction Therapy or at Weeks 56, 60, and 64 for subjects who 
receive both Induction and LTE Therapies. The date of the subject’s 
last post-treatment study visit will be considered the End of Study date. 
This Phase 2, double-blind clinical study of multiple ascending doses 
of KHK4083 (or placebo) with an OLE Therapy phase will be 
conducted in approximately 60 randomized adult subjects with 
moderately active UC who have a documented unsuccessful previous 
treatment. 
 
The study will include a 4-week Screening Period, followed by a total 
of up to 64 weeks (treatment and follow-up) on study from the time of 
randomization to study completion. 
 
The Treatment Period includes double-blind Induction Therapy (12 
weeks) and OLE Therapy (40 weeks) for eligible subjects at Week 12. 
Subjects already enrolled in the double-blind, LTE under preceding 
versions of the protocol who worsen may be eligible to transition to the 
OLE up to Week 28.  
 
Post-treatment assessments will continue for 16 weeks after the last 
infusion associated with the subject’s treatment period. The on-site 
follow-up visits will be at Weeks 16, 20, and 26 for subjects who only 
receive Induction Therapy or at Weeks 56, 60, and 64 for subjects who 
receive both Induction and OLE/LTE Therapies. The date of the 
subject’s last post-treatment study visit will be considered the End-of-
Study date. 
Induction 
Therapy: 
Week 0 to 
Week 12 
(Last Dose 
at Week 10) 
Double-blind Induction Therapy is separated into Part A for 
administration of multiple ascending IV doses of KHK4083 (or 
placebo) to subjects in Cohorts 1 - 3 and Part B for administration of 
the recommended IV dose (one of three dose levels identified in Part 
A) of KHK4083 (or placebo) to subjects in Cohort 4. Subjects in Part 
A are prohibited from participating in Part B. 
Double-blind Induction Therapy is separated into Part A for 
administration of multiple ascending IV doses of KHK4083 (or 
placebo) to subjects in Cohorts 1 - 3 and Part B for administration of 
the recommended IV dose (one of three dose levels identified in Part 
A) of KHK4083 (or placebo) to subjects in Cohort 4. Subjects in Part 
A are prohibited from participating in Part B. 


 
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Protocol Amendment 1 
Protocol Amendment 2 
Long-term 
Extension 
Therapy: 
Week 12 
(First Dose) 
to Week 52 
Subjects who complete double-blind Induction Therapy (i.e., at least 
five of six treatments) and have a clinical response or mucosal healing 
are eligible to continue in double-blind LTE Therapy 
 
All subjects who qualify will be given two options: 
1) To receive no further treatment and proceed directly to the Induction 
Therapy Follow-up Period (Week 16 through Week 26); or 
2) To continue in double-blind LTE Therapy and receive 10 additional 
treatments of KHK4083 (at the same dose administered to that subject 
during Induction Therapy) or placebo as maintenance therapy. Each 
subject will receive one IV infusion every 4 weeks from Week 12 to 
Week 48 followed by an End-of-LTE Therapy visit at 
Week 52, and then proceed to the LTE Therapy Follow-up Period 
(Week 56 through Week 64). Refer to Section 8.1.4.2 for additional 
dosing details in LTE Therapy.  
 
All other subjects, including those who do not complete double-blind 
Induction Therapy (non-completers), do not meet the criteria for a 
clinical response, or do not have mucosal healing at Week 12 will 
receive no further treatment, and thus enter the Induction Therapy 
Follow-up Period. 
The LTE is only active for subjects who entered it prior to approval of 
Amendment 2. Subjects who sign an ICF under Amendment 2 are 
eligible for the OLE. Subjects who completed double-blind Induction 
Therapy (i.e., at least five of six treatments) and had a clinical response 
or mucosal healing were eligible to continue in double-blind LTE 
Therapy. 
 
All subjects who qualified were to have been given two options: 
1) To receive no further treatment and proceed directly to the Induction 
Therapy Follow-up Period (Week 16 through Week 26); or  
2) To continue in double-blind LTE Therapy and receive 10 additional 
treatments of KHK4083 (at the same dose administered to that subject 
during Induction Therapy) or placebo as maintenance therapy. Each 
subject will receive one IV infusion every 4 weeks from Week 12 to 
Week 48 followed by an End-of-LTE Therapy visit at Week 52, and 
then proceed to the LTE Therapy Follow-up Period (Week 56 through 
Week 64).  
Note: Subjects who already started treatment in the double-blind LTE 
Therapy will continue to receive KHK4083 or placebo during LTE 
Therapy. If their UC worsens or flares up to Week 28, they may 
transition to OLE therapy. 
 
Subjects who did not qualify were to have received no further 
treatment and entered the Induction Therapy Follow-up Period. 


 
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Protocol Amendment 1 
Protocol Amendment 2 
Open-label 
Extension 
Therapy: 
Week 12 
(First Dose) 
to Week 52 
 
Subjects who complete double-blind Induction Therapy (i.e., at least 
five of six treatments) are eligible to enter OLE Therapy (refer to 
Section 7.4 for specific eligibility criteria). All subjects who qualify 
will be given two options: 
1) To receive no further treatment and proceed directly to the Induction 
Therapy 
Follow-up Period (Week 16 through Week 26); or  
2) To receive 10 treatments of open-label KHK4083 (at the same dose 
administered to that subject during Induction Therapy) as maintenance 
therapy. Each subject will receive one IV infusion every 4 weeks from 
Week 12 to Week 48 followed by an End-of-OLE Therapy visit at 
Week 52, and then proceed to the OLE 
Therapy Follow-up Period (Week 56 through Week 64).  
 
Subjects participating in the double-blind LTE who experience a 
clinical worsening or a flare of disease up to Week 28, as defined by 
the Investigator, may transition to the OLE.  
 
Subjects will maintain the same visit schedule, e.g., a subject who 
completed a Week 20 visit in the LTE and transitions to the OLE at 
Week 24 will have an OLE Week 24 visit. However, for the first two 
open-label doses in the OLE, additional safety monitoring will include 
ECGs and post-infusion monitoring as performed for the OLE Week 
12 and Week 16 visits, respectively. 
 


 
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Figure 1 Study Design Diagram in Protocol Amendment 1 
 
 


 
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Figure 2 Study Design Diagram in Protocol Amendment 2 


 
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3.2 
Sample size justification 
Assuming a 15% dropout rate, it is anticipated that approximately 60 subjects will be required to be 
randomized in order to achieve 51 evaluable subjects in the full analysis set (FAS). In Part A (Cohorts 
1 - 3), the sample size is based on the feasibility of the safety and tolerability assessment to 
recommend starting the treatment of the next cohort of 12 subjects/cohort (9 subjects to receive 
KHK4083 and 3 subjects to receive placebo). In Part B (Cohort 4) for the treatment of 24 subjects (18 
subjects to receive KHK4083 at the recommended dose based on the safety and tolerability in Part A 
and 6 subjects to receive placebo), the sample size is based on the feasibility of exploratory 
assessments in efficacy and safety at the recommended dose level. Based on the UCEIS and Mayo 
Clinic scores and from combining Part A and Part B, it is planned to have approximately a total of 27 
randomized subjects receive the recommended dose of KHK4083 and 15 subjects receive placebo. 
3.3 
Randomization and blinding 
After a subject meets all study eligibility requirements at Screening, the Interactive Response 
Technology (IRT) system will be used by the Investigator (or designee) to randomize the subject to 
double-blind Induction Therapy on Day 1 (Week 0). Subjects randomly assigned in Cohorts 1 - 3 will 
receive either KHK4083 (one of three dose levels) or placebo in a 3:1 ratio during Part A of Induction 
Therapy. Additional subjects (Cohort 4) in a 3:1 ratio will receive the recommended KHK4083 dose or 
placebo during Part B of Induction Therapy.  
 
The subject, Investigator (or investigative site personnel) and KHK4083 study team at KKD will not 
know the treatment to which the subject is randomized during the double-blind Treatment Period. 
Placebo will be administered by IV infusion to each cohort to ensure blinded treatment. The study is 
being blinded to prevent bias in the safety evaluation, in particular the severity grading and causality 
determinations of AEs. However, at any time during the study, if a medical emergency occurs and 
subject treatment must be known, the blind may be broken according to the procedure described in 
protocol. 
3.4 
Efficacy endpoints 
3.4.1 Primary endpoint  
Subjects with moderately active UC will primarily be evaluated for an improvement in the mucosa 
determined by their mMES (subscores from 0 to 3, with modified endoscopy finding scoring, i.e., by 
excluding mild friability from a subscore of 1) at completion of double-blind Induction Therapy. The 
primary efficacy endpoint will be the mean change in the mMES from Baseline (Week 0) to Week 12 
for all subjects who receive the recommended dose in Parts A and B. 


 
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3.4.2 Secondary efficacy endpoints 
The secondary efficacy endpoints for all subjects who receive the recommended dose during double-
blind Induction Therapy are as follows: 
 
 Improvement in the mucosa at Week 12; 
– Changes in the mucosa will be based on the percentage of subjects with at least a 1-point 
improvement in their mMES (0 to 3) from Baseline (Week 0) to Week 12; and/or 
– Changes in the mucosa will be based on the percentage of subjects with at least a 1-point 
improvement in their modified Baron endoscopic score (5-point scale) from Baseline (Week 0) to 
Week 12; and/or 
– Changes in the mucosa will be based on the mean change in UCEIS (0 to 8) and subscores from 
Baseline (Week 0) to Week 12. 
  
 Mucosal healing at Week 12;  
Mucosal healing is defined as a mMES of 0 or 1. 
 Clinical improvement at Week 12; 
Improvement will be based on a reduction (mean change from Baseline [Week 0] at Week 12) in 
the total Mayo Clinic score (0 to 12). 
  Clinical improvement at Weeks 2, 4, 6, 8, 10, and 12; 
Improvement will be based on mean changes from Baseline (Week 0) in the partial (excludes 
endoscopy subscores) Mayo Clinic score (0 to 10). 
 Clinical response at Week 12; 
A clinical response is defined as a reduction in the total Mayo Clinic score of at least 3 points and a 
decrease of at least 30% from Baseline (Week 0) to Week 12, and a reduction in the rectal bleeding 
subscale of at least 1 point from Baseline (Week 0) to Week 12 or an absolute rectal bleeding score 
of 0 or 1 at Week 12. 
 Clinical remission at Week 12; 
Clinical remission is defined as a total Mayo Clinic score of ≤ 2 and no subscores > 1. 
 
For all subjects who receive KHK4083 at dose levels different than the recommended dose during 
double-blind Induction Therapy, improvement in the mucosa at Week 12 based on the mean change in 
the mMES from Baseline (Week 0) to Week 12 is the main secondary endpoint. The other secondary 
efficacy endpoints at Week 12 for all subjects who receive KHK4083 at other than the recommended 
dose are the same as those listed and defined above, i.e., improvement in the mucosa based on the 
modified Baron endoscopic score and the UCEIS; mucosal healing; clinical improvement based on 
total, as well as partial (excludes endoscopy subscore at Weeks 2, 4, 6, 8, 10, and 12) Mayo Clinic 
scores; clinical response; and clinical remission.  
3.4.3 Exploratory efficacy endpoints 


 
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Efficacy exploratory endpoints will be included in this study for all subjects with moderately active 
UC who receive both Induction Therapy and OLE/LTE Therapy. The exploratory endpoints for all 
subjects who receive both Induction Therapy and OLE/LTE Therapy are as follows: 
 
 Clinical improvement at Week 52; 
Improvement will be based on a reduction (mean change from Baseline [Week 0] to Week 52) in 
the total Mayo Clinic score (0 to 12). 
 Clinical improvement at Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 and at OLE/LTE Therapy 
Follow-up Period visits (Weeks 56, 60, and 64); 
Improvement will be based on mean changes from Baseline (Week 0) in the partial (excludes 
endoscopy subscores) Mayo Clinic score (0 to 10). 
  Clinical response at Week 52; 
A clinical response is defined as a reduction in the total Mayo Clinic score of at least 
3 points and a decrease of at least 30% from Baseline (Week 0) to Week 52, and a reduction in the 
rectal bleeding subscale of at least 1 point from Baseline (Week 0) to Week 52 or an absolute rectal 
bleeding score of 0 or 1 at Week 52. 
  Clinical remission (i.e., a total Mayo Clinic score of ≤ 2 and no subscores > 1) at Week 52; 
 Durable clinical responses and durable clinical remissions at Week 52 (i.e., present at both Week 
12 and Week 52), and glucocorticoid-free clinical remission at Week 52; 
  Mucosal healing (i.e., an mMES of 0 or 1) at Week 52; 
  Improvement in the mucosa according to the following assessments: 
– At least a 1-point improvement in the mMES from Baseline (Week 0) to Week 52; 
– A mean change in the UCEIS score from Baseline (Week 0) to Week 52; and/or 
– At least a 1-point improvement in the modified Baron endoscopic score from Baseline 
(Week 0) to Week 52. 
 Remission (i.e., mMES of 0 or 1, stool frequency subscore of 0 or 1, and rectal bleeding subscore 
of 0) rates at Week 12 and Week 52; 
 Improvement in the HRQL, which will be based on the subject’s completed IBDQs; 
 Lowered corticosteroid (glucocorticoid) dosages; 
 Glucocorticoid-free treatment duration from Week 16 through Week 52, and through the OLE/LTE 
Therapy Follow-up Period (Week 56 through Week 64); 
3.5 
Safety endpoints 
The safety and tolerability of KHK4083 will be determined by physical examination, vital signs, body 
weight, 12-lead ECGs, and clinical laboratory findings; and the number and percentage of subjects 
reporting AEs (frequency, severity, and relationship to investigational product), SAEs, and treatment 
discontinuation due to AEs. 
3.6 
Other endpoints 


 
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 PD profile of KHK4083 
 PK-PD relationships 
 
The analysis of PK, PD and immunogenicity data and parameters corresponding to those data are 
beyond the scope of this SAP.  Separate analysis plans may be developed for these analyses. 
4.  Statistical Analysis 
4.1 
General 
General descriptive statistics for continuous variables include the n (number of observed values), the 
mean, standard deviation, median, minimum, and maximum values.  For categorical variables, the 
number and percentage of subjects with a specific level of the variable will be presented.  The 
percentage will be calculated using the subjects with a reported value. Counts of missing subjects will 
be identified for variables that had one or more subjects with a missing result.  Descriptive statistics 
will be presented by treatment Cohort (KHK4083 dose levels; combined KHK4083; and placebo) and 
by visit.  
 
Unless there are any notes, the following rules will be applied for all tables and figures; 
 Data from placebo subjects in each Cohort will be combined, not depending on treatment 
period (Double-Blind Induction Therapy, Long-Term Extension Therapy, Open-Label 
Extension Therapy, or Follow-up).  
 In the case that Screening or Baseline is necessary in the tables and figures related to LTE 
Therapy Period, OLE Therapy Period, or Follow-up Period, the data at Screening or Baseline 
will be used or displayed.  
 Double-Blind Therapy Period will be defined as the period including both Double-Blind 
Induction Therapy Period and LTE Therapy Period. 
 When “Week xx” (xx: number) is necessary, “Week xx” displayed on CRF will be used or 
displayed.  
 
To explain how data are summarized, the figure showing the relationship between period and dose of 
Investigational Product is displayed in Figure 3 and the table defining the category is displayed in 
Table 2. 


 
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Figure 3 Relationship between Period and Dose of Investigational Product 
Double-Blind Induction Therapy
LTE Therapy (blinded)
Follow-up
Double-Blind Induction Therapy
OLE Therapy (unblinded)
Follow-up
Double-Blind Induction Therapy
LTE Therapy 
(blinded)
OLE Therapy 
(unblinded)
Follow-up
Placebo Randomized (0 mg/kg)
4083 Randomized (1, 3, or 10 mg/kg)
Same Placebo dose (0 mg/kg)
Same 4083 dose (1, 3 or 10 mg/kg)
No administration
No administration
Placebo Randomized (0 mg/kg)
4083 Randomized (1, 3 or 10 mg/kg)
Same Placebo 
dose (0 mg/kg)
No administration
No administration
Same 4083 dose
(1, 3 or 10 mg/kg)
Same 4083 dose
(1, 3 or 10 mg/kg)
Same 4083 dose
(1, 3 or 10 mg/kg)
Placebo Randomized (0 mg/kg)
4083 Randomized (1, 3, or 10 mg/kg)
Same 4083 dose (1, 3 or 10 mg/kg)
Same 4083 dose (1, 3 or 10 mg/kg)
No administration
No administration
Enrollment at Protocol
Amendment 1
Enrollment at Protocol 
Amendment 2
Subjects who do not move to OLE/LTE Therapy
Double-Blind Induction Therapy
Follow-up
Placebo Randomized (0 mg/kg)
4083 Randomized (1, 3, or 10 mg/kg)
No administration
No administration
Subjects who move to OLE/LTE Therapy
 
Table 2 Category in Tables and Figures 
 
4083 Randomized 
Placebo Randomized 
 
Cohort 
1 
Cohort 
2 
Cohort 
3 
Cohort 
4 
Cohort 
1 
Cohort 
2 
Cohort 
3 
Cohort 
4 
Summary Pattern 
Category In Tables and Figures 
Double-Blind Induction Therapy Period 
1.0 
mg/kg 
3.0 
mg/kg 
10 
mg/kg 
1.0, 3.0 
or 10 
mg/kg 
Placebo 
Double-Blind Therapy Period 1) 
Double-Blind Therapy Period and Double-Blind Therapy Follow-up 
Period 2) 
LTE Therapy Period 
LTE Therapy Period and Double-Blind Therapy Follow-up Period 
OLE Therapy Period 
1.0 
mg/kg 
3.0 
mg/kg 
10 
mg/kg 
1.0, 3.0 
or 10 
mg/kg 
Placebo 3) 
OLE Therapy Period and OLE Therapy Follow-up Period 
1) Double-Blind Therapy Period includes both Double-Blind Induction Therapy Period and LTE Therapy Period.  
2) Double-Blind Therapy Follow-up Period includes both Follow-up Periods after Double-Blind Therapy Period and LTE Therapy Period. 
3) For subjects randomized to Placebo, they receive 4083 administration during the duration but they are summarized as one category as “Placebo”.  
 
Image which shows the relationship between summary pattern and data will be displayed in Figure 4. 
Figure 4 Summary Patterns 


 
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1) Double-Blind Induction Therapy Period 
2) Double-Blind Therapy Period 
3) Double-Blind Therapy Period and Double-Blind Therapy 
Follow-up Period 
4) LTE Therapy Period 
5) LTE Therapy Period and Double-Blind Therapy Follow-
up Period 
6) OLE Therapy Period 
7) OLE Therapy Period and OLE Therapy Follow-up Period  
 
General reporting conventions will include the following:  
 The baseline value for any measurement is the last value obtained prior to receiving 
administration of KHK4083 or placebo on Day 1 at Week 0.  All nominal time points will be 
used for analysis; actual assessment times will not be used to reclassify the time point at which 
a measure was taken. 


 
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 Study day: Study day will be calculated relative to the date of KHK4083 or placebo 
administration (Day 1) as:  
o (If  Date of event > Date of first investigational product administration) Date of event – 
Date of first investigational product administration + 1 and   
o (If  Date of event < Date of first investigational product administration) Date of event – 
Date of first investigational product administration 
This formula will be used when calculating days to a specific event (i.e., concomitant 
medication and/or AE start date).  A negative study day indicates an event prior to 
investigational product administration. 
 Unless otherwise noted, all percentages will be presented to one decimal place. 
 Individual data listings of all data represented on the eCRF will be provided as an appendix to 
facilitate investigation of the tabulated values and to allow for the clinical review of all 
variables. All data listings will be sorted by dose Cohort, site-subject number, visit, and time 
points where appropriate.  
 Post-dose data from unscheduled visits will be excluded from the summary tables but included 
in the data listings. 
 
Statistical hypothetical testing will not be carried in this study. However, in the case that p-value is 
derived, it will be rounded to three decimal places. 
 
All statistical analyses will be performed using Statistical Analysis System (SAS) statistical software 
(Version 9.2 or higher). AEs will be coded for summarization using Medical Dictionary for Regulatory 
Activities (MedDRA® Version 18.1).  Concomitant medications will be coded using WHO Drug 
Dictionary (enhanced) 1st Q2015 B-format. 
4.2 
Analysis sets 
Subjects will be screened to determine if they meet all inclusion and no exclusion criteria. Subjects 
will be analyzed according to the treatment they actually received. The following analysis sets will be 
used in the study: 
 Safety Analysis Set: Includes all subjects who received any (even a partial dose) 
investigational product (KHK4083 or placebo); The Safety Analysis Set will be used to 
perform all safety analyses as the basis for all summaries proposed in this SAP.   
 Full Analysis Set (FAS): Includes all subjects who receive at least one full dose of 
investigational product and who have Baseline data and at least one post-treatment assessment 
of the primary efficacy variable.  Summaries of efficacy will be presented for the FAS. 


 
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4.3 
Covariates 
All analysis of covariance (ANCOVA) models and linear Mixed Model will include the baseline value 
of the variable as a covariate and treatment as class type fixed effects. 
4.4 
Handling of missing and incomplete data 
Available data at each time point will be presented. The denominator for percentages will be based on 
the number of subjects in the appropriate treatment or cohort group for summary purposes. 
4.5 
Changes in the planned analysis 
The primary endpoint and main secondary endpoints of the study are based on 12 week Induction 
Therapy data. After the last subject completes Part B of Induction Therapy, the study will be unblinded.  
A cut with 12 week data will be applied. Baseline characteristics, prior/concomitant medication, 12-
week efficacy data, 12-week AE data and 12-week exposure data will be cleaned before unblinding. 
The list of efficacy and safety tables that will be produced with results of 12 week Induction Therapy 
data is provided in Section 9.4.1. Results of these analysis will be used to make a determination on 
whether or not KHK4083 meets the criteria for proof of concept of efficacy.  Subjects that were 
enrolled per Protocol Amendment 1 and continued to be blinded in the Long Term Extension period 
will remain blinded. Also investigators will remain blinded for these subjects. 
 


 
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4.6 
Data Review Meeting 
One data review meeting is planned before final database soft lock. 
4.7 
Software 
Version 9.2 (or higher) of the SAS® statistical software package will be used to provide all summaries 
and data listings.  
5.  Evaluation of Demographic and Baseline Characteristics 
5.1 
Subject enrollment and disposition 
The number of Subjects screened and in each visit week will be presented by treatment Cohort.  
Subject disposition will be summarized including the number and percentage of subjects enrolled and 
completed each of the study periods (Double-Blind Induction Therapy Period, Doubld-Blind Induction 
Therapy Follow-up Period, OLE/LTE Therapy Period, and OLE/LTE Therapy Follow-up Period), 
discontinued from the treatment, discontinued the study and completed the study. The number of 
subjects who moved from LTE to OLE Therapy Period. The definitions for completions and 
discontinuations are shown below;  
 Subjects who have the CRF page of “Week 12” will be defined as those who completed 
Induction Therapy.  
 Subjects who have the CRF page of “Follow-up 3 - Subjects not enrolling in LTE Therapy 
Period” or “Follow-up 3 - Subjects not enrolling in OLE Therapy Period” will be defined as 
those who completed Double-Blind Induction Therapy Follow-up Period. 
 Subjects who have the CRF page of “Week 52” will be defined as those who completed 
OLE/LTE Therapy Period. 
 Subjects who have the CRF page of “Follow-Up 3 - Post Long Term Extension Therapy” will 
be defined as those who completed OLE/LTE Therapy Follow-up Period. 
 Subjects who have the CRF page of “End of treatment” will be defined as those who 
discontinued the treatment. 
 Subjects who have “No” for the question of “Did the subject complete the study?” on the CRF 
page of “End of study” will be defined as those who discontinued the study. 
 Subjects who have “Yes” for the question of “Did the subject complete the study?” on the CRF 
page of “End of study” will be defined as those who completed the study. 
 
The number of subjects in the Safety Analysis Set and FAS will be provided. Disposition information 
will be provided overall and separately for each treatment Cohort. 


 
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The reasons why subjects were excluded from any analysis set will be listed individually. 
In addition table summaries of the primary reason for discontinuation/withdrawal from the study will 
be presented by means of number and percentage of subjects by treatment cohort, period and overall.  
5.2 
Protocol deviations 
Before unblinding, investigator and KKD will address all protocol deviations highlighted during the 
study a list will be presented in addition to a summary of the major and minor deviations from the 
protocol. 
5.3 
Demographics and baseline characteristics 
Demographic characteristics (including age, race, ethnicity, and sex), height, weight, BMI (where 
BMI = Body weight (kg)/Height (m)²), duration of  UC diagnosis, and Baseline values for UC 
assessment will be summarized by treatment Cohort using descriptive statistics in the Safety Analysis 
Set.  
 
The following UC assessments scores will be provided: 
1. Each subscore (for Mayo Clinic Score (0 to 3 for each subscore) 
a. Stool frequency 
b. Rectal bleeding 
c. Modified Mayo endoscopy subscore (mMES) 
d. Physician’s global assessment 
2. Ulcerative Colitis Endoscopic Index of Severity (UCEIS) Score (0 to 8) 
3. Modified Baron Endoscopic Score ( 0 to 4) 
4. Total Mayo Clinic Score (0 to 12) is the sum of stool frequency (subscore 0 to 3), rectal 
bleeding (subscore 0 to 3), mMES (subscore 0 to 3) and physician’s global assessment 
(subscore 0 to 3). 
5. Partial Mayo Clinic Scores (0 to 9) is the Complete Mayo Clinic Score without the mMES. 
6. Total Inflammatory Bowel Disease Questionnaire (IBDQ) score is a quality-of-life assessment 
at Baseline. It is the sum of IBDQ Sub Scores. 
7. Four IBDQ Sub Scores include bowel-related symptoms, systemic function, social function, 
and emotional status. 
 
No statistical comparisons of differences in demographics/baseline data will be performed. 
Data listings will also be provided for all demographic information and baseline characteristics.  
5.4 
Medical, diet and surgical history 
Medical history and concomitant diseases will be coded using MedDRA (version 18.1) and frequency 
distributions and percentages will be summarised by sequence for the Safety Analysis Set by System 


 
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Organ Class (SOC) and Preferred Term. Medical history will be defined as the event that the answer 
for the question of “Ongoing at time of Informed Consent” on the CRF page of “Medical/Surgical 
History” is “No”. Concomitant disease will be defined as the event that the answer for that question is 
“Yes”. 
 
Medical/surgical history and physical examination results of note, will also be listed by subject. 
5.5 
Prior and concomitant medications 
Start and stop dates of medication or non-drug therapy will be compared to the start date of 
investigational product dosing to allow medications/treatments to be classified as either prior or 
concomitant.  
Prior medications include any previous biologic treatment (for any indication), all treatment for UC 
taken within 6 months prior to Screening, and any other previous medication taken within 1 month 
prior to Screening. Concomitant medications include medications that started at any time and were 
taken at any time during the study including the follow-up period. Probiotic usage is to be tracked 
during the study.  
If a start or stop date of medication or non-drug therapy is partial, the date will be compared as far as 
possible with the investigational product dosing start date. The medication or non-drug therapy will be 
assumed to be concomitant, unless there is clear evidence (through comparison of partial dates) to 
suggest that the medication stopped prior to the investigational product dosing start date. If the stop 
dates are missing, medications will be assumed to be concomitant.  
The World Health Organization Drug Dictionary will be used to classify prior and concomitant 
medications by Therapeutic Class and Preferred Term. Prior medications will be summarized in the 
Safety Analysis Set. Concomitant medications will be summarized by each period (Double-Blind 
Induction Therapy Period, OLE Therapy Period, LTE Therapy Period, or Follow-up Period) in the 
Safety Analysis Set. 
6.  Evaluation of Treatment Exposure 
6.1 
Exposure to investigational product 
Subjects who received investigational product are those who have the infusion initiation time recorded, 
and subjects who completed investigational product are those who have the completion time recorded. 
The definition of treatment duration in weeks will be derived from the recorded date and time of the IV 
infusion of investigational product as follow: 
- 
Induction therapy: IV infusion of KHK4083 or placebo once every 2 weeks for a total of 6 
treatments. For eligible subjects the first dose date for the Induction therapy is recorded at Day 
1 (Week 0) after screening period; the last recorded dose date for the Induction therapy should 
be recorded at Day 71 (Week 10). Under this condition the treatment duration for the Induction 


 
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therapy is derived as [(last dose date of the Induction therapy - first dose date of the induction 
therapy)+1]/7, and the results will be expressed in weeks and rounded to the nearest integer. 
- 
Long-term Extension Therapy (LTE): all the subjects who qualify and agreed to continue the 
treatment will receive 10 additional IV infusions of KHK4083 or placebo once every 4 weeks 
starting from Week 12 (+/- 7 days). Under this condition the treatment duration for the LTE 
therapy is derived as [(last dose date - first dose date of the LTE therapy)+1]/7, and the results 
will be express in weeks and rounded to the nearest integer.   
- 
Open-label Extension Therapy (OLE): all the subjects who qualify and agreed to continue the 
treatment will receive up to10 additional IV infusions of KHK4083 once every 4 weeks starting 
from the first dose of the OLE therapy [“Week” of the first dose of the OLE therapy is different 
among subjects: Week 12 (+/- 7 days), Week 16 (+/- 7 days), Week 20 (+/- 7 days), Week 24 
(+/- 7 days), or Week 28 (+/- 7 days)]. Under this condition the treatment duration for the OLE 
therapy is derived as [(last dose date - first dose date of the OLE therapy)+1]/7 results will be 
expressed in weeks and rounded to the nearest integer. 
- 
Overall: for subjects who had completed the Induction therapy and continued to the OLE or 
LTE therapy, the overall treatment duration under each investigational product administered 
will be derived as [(last dose date - first dose date)+1]/7, and the results will be expressed in 
weeks and rounded to the nearest integer. 
The total dose administration is the sum of investigational product administered. The cumulative 
administered volume is the sum of dose of investigational product administered. Both the total 
administration and the cumulative administered volume will be derived by each treatment period 
(Double-Blind Induction Therapy Period, LTE Therapy Period, OLE Therapy Period, and Overall) as 
well as the duration of treatment. 
 
Total dose administered, duration of treatment, and cumulative administered volume will be 
summarized by each treatment period (Double-Blind Induction Therapy Period, LTE Therapy Period, 
OLE Therapy Period, and Overall). 
6.2 
Evaluation of pharmacokinetics  
The analysis and reporting of PK data and parameters are beyond the scope of this SAP. A separate 
analysis plan is planned to be developed for this analysis and a final report will be provided under 
separate cover.  
 
 
6.3 
Evaluation of immunogenicity   
The analysis and report of Anti-drug antibody will be provided under separate cover as well as PK.  
7.  Evaluation of Efficacy 


 
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The efficacy endpoints will be evaluated in FAS population and results will be presented in listings 
and tables. Continuous variables will be tabulated with descriptive statistics. Categorical measures will 
be summarized as number and percentage of subjects. 
7.1 
Analysis of primary endpoint 
The primary efficacy endpoint is the mean change in mucosal score presented by mMES (subscores 
from 0 to 3 with modified endoscopy finding scoring, i.e., excluding mild friability from a subscore of 
1) from Baseline (Week 0) to Week 12 for all subjects who received the recommended dose during 
Induction Therapy. This includes Part A subjects who received the recommended dose identified for 
Part B as well as the subjects who received the recommended dose during Part B of Induction Therapy. 
Change from Baseline in mMES as well as Baseline and Week 12 will be summarized by treatments 
(each KHK4083 dose level and placebo) by means of descriptive statistics (number of subject n, mean, 
standard deviation, median, min and max); the 95% confidence Interval (CI) for the change from 
baseline will be derived as follow: 
Upper 95%CI = µx + t(α,df)SE(µx) 
Lower 95%CI = µx - t(α,df)SE(µx) 
where: 
- 
µx is the arithmetic mean estimate of the change from baseline 
- 
t is the value from a t table distribution with α = 0.05 and df degree of freedom 
SE is the Standard error of the mean estimate. 
A comparison between treatments (each KHK4083 dose level versus placebo) will be performed using 
an ANCOVA model with change from Baseline in mMES as dependent variable and treatment as 
fixed effect and baseline value as covariate. The number of subjects and the number of subjects 
considered in the model will be provided by treatment. The adjusted means for treatments (least 
squares means) and the relative 95% CIs will be presented. The difference between the adjusted means 
for each treatment groups from placebo (Difference in Least Squares Mean from Placebo) will be 
calculated with the relative 95% CI and p-value. Least squares means with 95% CIs and differences in 
least squares mean from placebo with 95% CIs will be graphically presented.  
 
In order to test for optimal dose levels within this fitted linear model, three types of contrasts will be 
defined to demonstrate which KHK4083 dose level is deemed closest to optimal. The first contrast is 
for the scenario of “10 mg/kg is closest to optimal” and its vector, (P L M H), is (-1 -1 -1 3), where P: 
Placebo; L: 1.0 mg/kg; M: 3.0 mg/kg; and H: 10 kg/mg. The second contrast is for the scenario of “3.0 
mg/kg is closest to optimal” and its vector is (-1 -1 1 1). The third contrast is for the scenario of “1.0 
mg/kg is closest to optimal” and its vector is (-3 1 1 1). Each contrast will be tested within the fitted 
model to determine the dose level providing optimum benefit over placebo. 
 
SAS® code 
Proc GLM data=dataset; 
Class tmt; 
Model change=tmt baseline / solution clparm; 


 
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Lsmeans tmt/cl stderr; 
Estimate “1.0 mg Vs Placebo” tmt  -1 1 0 0; 
Estimate “3.0 mg Vs Placebo” tmt  -1 0 1 0; 
Estimate “10 mg Vs Placebo”  tmt  -1 0 0 1; 
Contrast “1.0 mg is closest to optimal” tmt   -3  1  1  1; 
Contrast “3.0 mg is closest to optimal” tmt   -1 -1  1  1; 
Contrast “10 mg is closest to optimal”  tmt   -1 -1 -1  3; 
Run; 


 
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7.2 
Analysis of secondary efficacy endpoints 
The secondary efficacy variables for all subjects (i.e., recommended dose or any other dose level in 
Parts A and B of Induction Therapy) are listed in the following table.  
 
Efficacy Variables 
Definition 
Improvement in the Mucosa 
(Measured by modified Mayo 
endoscopy subscore 
[mMES]) (Week 12) 
Percentage of subjects with at least a 1-point improvement in 
their mMES (0 to 3) from Baseline (Week 0) to Week 12. 
Improvement in the Mucosa 
(Measured by modified Baron 
scoring system)  
(Week 12) 
Percentage of subjects with at least a 1-point improvement in 
their modified Baron endoscopic score (5-point scale) from 
Baseline (Week 0) to Week 12. 
Improvement in the Mucosa 
(Measured by Ulcerative Colitis 
Endoscopic Index of Severity 
[UCEIS]) (Week 12) 
A mean change in the UCEIS (scores from 0 to 8, based on 
findings of vascular pattern, bleeding, and erosions/ulcers) from 
Baseline (Week 0) to Week 12. 
Mucosal Healing (Week 12) 
The percentage of subjects with mMES of 0 or 1 at Week 12. 
Clinical Improvement 
 (Week 12) 
Mean change from Baseline (Week 0) at Week 12, in the total 
Mayo Clinic score (0 to 12). 
Clinical Improvement  
(Weeks 2, 4, 6, 8, 10, and 12) 
Mean changes from Baseline (Week 0) in the partial (excludes 
endoscopy subscores) Mayo Clinic score (0 to 10). 
Clinical Response  (Week 12) 
A reduction in the total Mayo Clinic score of at least 3 points 
and a decrease of at least 30% from Baseline (Week 0) to Week 
12, and a reduction in the rectal bleeding subscale of at least 1 
point from Baseline (Week 0) to Week 12 or an absolute rectal 
bleeding score of 0 or 1 at Week 12. 
Clinical Remission (Week 12) 
A total Mayo Clinic score of ≤ 2 and no subscores > 1. 
 
All secondary efficacy variables will be summarized by treatments (each KHK4083 dose level and 
placebo). Change from Baseline in UCEIS, total Mayo Clinic score as well as Baseline and Week 
12 will be summarized by treatments. Partial Mayo Clinic scores and changes from Baseline will 
be summarized from Baseline to Week 12 by treatments. Summaries statistics and 95% CI will be 
presented and estimated as described in section 7.1 of this SAP.  
 
A comparison between treatments (each KHK4083 dose level versus placebo) will be performed 
using an ANCOVA model with changes from Baseline in UCEIS, total Mayo Clinic score and 
partial Mayo Clinic score at Week 12 as dependent variables, treatment as fixed effect and baseline 
value as covariate. The number of subjects and the number of subjects considered in the model will 
be provided by treatment. The adjusted means for treatments (least squares means) and the relative 
95% CIs will be presented. The difference between the adjusted means for each treatment groups 
from placebo (Difference in Least Squares Mean from Placebo) will be calculated with the relative 
95% CI and p-value. Least squares means with 95% CIs and differences in least squares mean from 
placebo with 95% CIs will be graphically presented. 


 
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7.3 
Analysis of exploratory efficacy endpoints 
All exploratory efficacy variables will be summarized by treatments. The changes from Baseline in 
mMES, UCEIS and total Mayo Clinic score as well as Baseline and Week 52 will be summarized 
by treatments. In addition, the partial Mayo Clinic scores (without sigmoidoscopy) and changes 
from Baseline will be summarized by study visit at Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 
and at OLE/LTE Therapy Follow-up Period visits (Weeks 56, 60, and 64). 
 
The change from Baseline in HRQL based on IBDQ will be analyzed for total score and 
4 subscale scores at all study visits (Weeks 2 to 52, including Induction Therapy Follow-up 
Period visits (Weeks 16, 20, and 26) and OLE/LTE Therapy Follow-up Period visits (Weeks 56, 
60, and 64). 
 
Remission (mMES of 0 or 1, stool frequency subscore of 0 or 1 and rectal bleeding subscore of 0) 
rates at Week 12 will be summarized. Remission rates at Week 52 will be summarized by Double-
Blind Period and OLE Therapy Period as well. 
 
Clinical response and clinical remission will be summarized at Week 52. The percentage of 
subjects with mucosal healing, and the percentages of subjects with improvement in the mucosa 
(change from Baseline of at least a 1-point improvement in the mMES and/or in the modified 
Baron endoscopic scores) at Week 52 will be summarized by Double-Blind Period and OLE 
Therapy Period. 
 
Durable clinical response and durable clinical remission at Week 52 will be summarized by 
Double-Blind Period and OLE Therapy Period. Durable clinical response and durable clinical 
remission at Week 52 will be defined as follows: 
 Duration clinical response at Week 52 will be defined in the case that clinical response is 
present at both Weeks 12 and 52. 
 Duration clinical remission at Week 52 will be defined in the case that clinical remission is 
present at both Weeks 12 and 52. 
 
Glucocorticoid-free clinical remission at Week 52 will be summarized by Double-Blind Period and 
OLE Therapy Period. At Weeks 16 through 52 and through the OLE/LTE Therapy Follow-up 
Period (Week 56 through Week 64), the change from baseline in corticosteroid (glucocorticoid) 
dosages and the duration of glucocorticoid-free treatment will be summarized. Those parameters 
definitions are shown below. 
 Glucocorticoid-free clinical remission at Week 52 
o Glucocorticoid-free clinical remission at Week 52 will be defined in the case that 
clinical remission is present at Week 52 and no glucocorticoid listed in Section 9.3 
is used from Week 16 through Week 52.  
 Glucocorticoid dosages:  
o Baseline glucocorticoid dosages (times) will be defined as the total number of 
administrations of glucocorticoid listed in Section 9.3 that is used during Double-
Blind Induction Period (from Day 1 to a day before Week 16). For the subject who 
receives no glucocorticoid, the dosages will be 0. 


 
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o Glucocorticoid dosages (times) at Week 16 through Week 52 will be defined as the 
total number of administrations of glucocorticoid listed in Section 9.3 that is used 
during OLE/LTE Therapy Period (from Week 16 to Week 52). For the subject who 
receive no glucocorticoid, the dosages will be 0.  
o Glucocorticoid dosages (times) at Week 16 through LTE Therapy Follow-up Period 
will be defined as the total number of administrations of glucocorticoid listed in 
Section 9.3 that is used during LTE Therapy Period and LTE Therapy Follow-up 
Period (from Week 16 to Follow-up 3). For the subject who receives no 
glucocorticoid, the dosages will be 0. 
o Glucocorticoid dosages (times) at Week 16 through OLE Therapy Follow-up Period 
will be defined as the total number of administrations of glucocorticoid listed in 
Section 9.3 that is used during OLE Therapy Period and OLE Therapy Follow-up 
Period (from Week 16 to Follow-up 3). For the subject who receives no 
glucocorticoid, the dosages will be 0. 
o If there is glucocorticoid that the number of administrations is unknown, it will be 
assumed that the glucocorticoid was used at a frequency of an administration per 
day.   
o For the subjects who do not move to OLE/LTE Therapy Period, “Glucocorticoid 
dosages (times) at Week 16 through Week 52” and “Glucocorticoid dosages (times) 
at Week 16 through OLE/LTE Therapy Follow-up Period” will not be defined. 
 Change from baseline in corticosteroid (glucocorticoid) dosages will be defined as follows: 
o Change from baseline in corticosteroid (glucocorticoid) dosages at Week 16 through 
Week 52 =  Glucocorticoid dosages at Week 16 through Week 52 - Baseline 
glucocorticoid dosages 
o Change from baseline in corticosteroid (glucocorticoid) dosages at Week 16 through 
LTE Therapy Follow-up Period = Glucocorticoid dosages at Week 16 through LTE 
Therapy Follow-up Period - Baseline glucocorticoid dosages 
o Change from baseline in corticosteroid (glucocorticoid) dosages at Week 16 through 
OLE Therapy Follow-up Period = Glucocorticoid dosages at Week 16 through OLE 
Therapy Follow-up Period - Baseline glucocorticoid dosages  
 Duration of glucocorticoid-free treatment will be defined as the duration that no 
glucocorticoid listed in Section 9.3 is used from Week 16 through Follow-up 3. 
o Duration of glucocorticoid-free treatment (days) = Date of first glucocorticoid after 
Week 16 visit - Date of Week 16 visit 
o If the subject received glucocorticoid on the date of Week 16 visit, the duration of 
glucocorticoid-free treatment for the subject is 0. 
 
A comparison between treatments (each KHK4083 dose level versus placebo) will be performed 
using an ANCOVA model with changes from Baseline in UCEIS, total Mayo Clinic score and 
partial Mayo Clinic score at Week 52 during Double-Blind Therapy Period as dependent variables, 
treatment as fixed effect and baseline value as covariate. The number of subjects and the number of 
subjects considered in the model will be provided by treatment. The adjusted means for treatments 
(least squares means) and the relative 95% CIs will be presented. The difference between the 
adjusted means for each treatment groups from placebo (Difference in Least Squares Mean from 
Placebo) will be calculated with the relative 95% CI and p-value. If ANCOVA cannot be applied 


 
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due to the issue that the parameters cannot be estimated appropriately, these analyses using 
ANCOVA for Week 52 will not be applied.    
 
Means with SDs for the efficacy variables (mMES, UCEIS, total Mayo score and partial Mayo 
score) at all visits will be performed graphically by each treatment (e.g. Placebo, 1.0 mg/kg, 3.0 
mg/kg, or 10 mg/kg) and by Double-Blind Therapy Period and OLE Therapy Period. For partial 
Mayo score, Means with SDs as all visits will be performed graphically by “Double-Blind Therapy 
Period and Double-Blind Therapy Follow-up Period” and “OLE Therapy Period and OLE Therapy 
Follow-up Period”. Mean changes from Baseline will also be performed in the same manner. 
 
To take into consideration about the repeat measurements in partial Mayo Clinic score, an analysis 
using a Mixed Model for Repeated Measures (MMRM) will be performed. A comparison between 
treatments (each KHK4083 dose level versus placebo) will be performed using a MMRM with the 
change from baseline in partial Mayo Clinic scores during Double-Blind Therapy Period and 
Double-Blind Therapy Follow-up Period as dependent variable, treatment as fixed effect and 
baseline value as covariate, and visit as random effects. The interaction between treatment and visit 
also will be included. An unstructured covariance matrix will be considered and the Kenward-
Roger adjustment will be used for the degrees of freedom. In the case that the unstructured 
covariance matrix cannot be used, a compound symmetry will be used as the covariance matrix 
instead of the unstructured one. The number of subjects, the number of subjects considered in the 
model and the number of observations considered in the model will be provided by treatments. The 
adjusted means for treatments (least squares means) at each visit and the relative 95% CIs will be 
presented. The differences between the adjusted means for treatments from placebo (Difference in 
Least Squares Mean from Placebo) at each visit will be calculated with the relative 95% CIs and p-
values. If MMRM cannot be applied due to the issue that the parameters cannot be estimated 
appropriately, the structure of covariance matrix will be changed to compound symmetry. If 
MMRM cannot be applied by using the covariance matrix of compound symmetry, this analysis 
using MMRM will not be applied.   
 
SAS® code 
proc mixed data=dat001 ORDER=DATA; 
  class visit tmt; 
  model chg=tmt visit baseline tmt*visit /solution ddfm=kr; 
  repeated visit / type=un subject= subjectj; 
  lsmeans tmt*visit / slice=tmt pdiff diff alpha=0.05 cl; 
  lsmeans tmt / pdiff diff alpha=0.05 cl; 
run; 
 
For the following scores, to show changes in score during the study, those scores will be 
summarized by treatments. 
 Subscores of Mayo Clinic Score other than mMES: “Stool Frequency”, “Rectal Bleeding”, 
and “Physician’s Global Assessment” 
 Modified Baron Endoscopic Score 
 Subscores of UCEIS: “Vascular pattern”, ”Bleeding”, and “Erosions and ulcers” 
 


 
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To show the differences between Investigational products in each cohorts, the efficacy variables 
(mMES, UCEIS, total Mayo score and partial Mayo score) at all visits will be summarized by 
treatments and cohorts. 
7.4 
Evaluation of pharmacodynamics 
The analysis of PD data and parameters are beyond the scope of this SAP.  Separate analysis plans 
may be developed for these analyses. In this SAP only listing of the following PD parameters is 
planned: 
 - Fecal calprotein. 
- wr-CRP 
- delayed type hypersensitivity skin testing 
8.  Evaluation of Safety 
All analysis of safety will be performed using the Safety Analysis Set. 
 
Results of all safety assessments, including physical examinations, body weight, vital sign 
determinations, AE monitoring, ECGs, and clinical laboratory evaluations, will be summarized 
with descriptive statistics by dose Cohort and overall, and/or presented in data listings.  
8.1 
Adverse events 
The onset date of an adverse event will be compared to the date of investigational product dosing to 
determine if the adverse event is treatment-emergent or not. Adverse events with an onset date on 
or after the first date of investigational product dosing will be classified as treatment emergent 
adverse events (TEAEs). If the adverse event onset date is missing or partial, the date will be 
compared as far as possible with the date of investigational product dosing. Adverse events will be 
assumed to be TEAEs unless there is clear evidence (through comparison of partial dates) to 
suggest that the adverse event started prior to receiving the dose of investigational product. 
TEAE will be summarized in a table that presents the number and percentage of subjects with any 
TEAE, with any serious TEAE, with any drug-related TEAE, with any TEAE leading to 
discontinuation and death overall and within each treatment period (Double-Blind Induction 
Therapy Period, LTE Therapy Period, and OLE Therapy Period) by treatments (each KHK4083 
dose level versus placebo).  It will also include the total number of adverse events in each of these 
categories. All TEAEs will be summarized showing the number and percentage of subjects for each 
event with a start time within the treatment period (i.e., Double-Blind Induction Therapy Period, 
LTE Therapy Period, and OLE Therapy Period) and by treatments (each KHK4083 dose level 
versus placebo) during Induction Therapy or KHK4083 dose level versus placebo during OLE 
/LTE Therapy Period. All TEAEs will be summarized by SOC and Preferred Term as well as by 
Preferred Term in decreasing frequency. Two additional summary tables are presented for serious 
TEAEs and Related TEAEs. 
 


 
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Listings of all adverse events (including non-treatment-emergent events) will be provided.  This 
listing will be presented by dose cohort and will include site-subject identifier, adverse event (SOC, 
Preferred Term, reported term), start date, stop date, study day, severity grade, seriousness, 
relationship to drug, action taken with study treatment, and outcome.  Also SAEs will be listed in a 
similar format as described above. Deaths which are adverse events leading to death, adverse 
events leading to discontinuation and adverse events with withdrawal of investigational product 
also will be listed in the same manner.   
8.2 
Clinical laboratory evaluation 
Laboratory values (chemistry, hematology, coagulation profile, and urinalyses) will be numerically 
described by visit for observed values and change from baseline by treatments (each KHK4083 
dose level versus placebo). The numbers and percentages of subjects with high, normal and low 
laboratory results will be also summarized for each visit by treatments (Placebo, 1.0 mg/kg, 3.0 
mg/kg, and 10 mg/kg) and treatment periods (“Double-Blind Therapy Period and Double-Blind 
Therapy Follow-up Period” and “OLE Therapy Period and OLE Therapy Follow-up Period”). For 
the laboratory values which have the normal (e.g., below/within above the normal range) or 
categorical result (e.g., −/±/+), shift tables will display the cross tabulation of the baseline versus 
the results of the post-baseline by treatments (Placebo, 1.0 mg/kg, 3.0 mg/kg, and 10 mg/kg) and 
treatment periods (“Double-Blind Therapy Period and Double-Blind Therapy Follow-up Period” 
and “OLE Therapy Period and OLE Therapy Follow-up Period”).  
 
Means with SDs for numeric parameters among lab values at all visits will be performed 
graphically by treatments. Mean changes from Baseline will also be performed in the same manner. 
 
Data listings will be generated of all safety lab values that are outside of the normal range. Listing 
will also be prepared for multiplex-31 assay data. 
8.3 
Vital signs and body weight 
Vital signs, including systolic and diastolic blood pressures (mm Hg), radial pulse rate (beats/min), 
and respiration rate (breaths/min), oral body temperature (degrees Celsius), and body weight (kg) 
will be summarized descriptively by time point of collection for the data as observed.  Change from 
baseline results will be summarized in the same manner as the laboratory values. 
8.4 
ECGs 
Electrocardiogram measurements include heart rate (beats/min), RR interval (msec), PR interval 
(msec), QRS duration (msec), QT interval (msec), QTc interval (msec) and ECG interpretation. A 
standard 12-lead ECG will be performed at Screening; during Induction Therapy (predose and at 
the end of infusion) on Day 1 (Baseline, Week 0), Week 8, and Week 10 and at Week 52 of 
OLE/LTE Therapy Period. The ECGs will be recorded after the subject has rested for 
approximately 5 minutes in a supine position. 


 
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Summary statistics for the actual ECG parameter values and change from baseline will be provided 
for each visit. The number and percentage of subjects with elevated QTcF values (> 450 msec, 
> 480 msec, and > 500 msec) at each scheduled visit (time point) and overall for all post-baseline 
visits will be presented by treatments (each KHK4083 dose level versus placebo). In addition, the 
number and percentage of subjects with QTcF values that increase by > 30 msec and > 60 msec 
from baseline will be presented by treatments at each scheduled visit (time point) and overall for all 
post-baseline visits. QTcF will be calculated by the Fridericia formula that 
“(QTcF = QT/(RR)1/3)”. 
 
A shift table from baseline to the worst post-baseline values during the treatment period will be 
provided for QTcF interval. Both scheduled and unscheduled visits during the treatment period will 
be considered. The following categories will be used: ≤ 450 msec, > 450 and ≤ 480 msec, > 480 
and ≤ 500 msec, and > 500 msec. 
 
The numbers and percentages of subjects with reported ‘Abnormal, Clinically Significant Change’ 
ECG results will be also summarized for each visit by treatments (Placebo, 1.0 mg/kg, 3.0 mg/kg, 
and 10 mg/kg) and treatment periods (“Double-Blind Therapy Period and Double-Blind Therapy 
Follow-up Period” and “OLE Therapy Period and OLE Therapy Follow-up Period”).  
 
All ECG parameters will be presented in data listings. 
8.5 
Physical examination except body weight 
The complete physical examination will include examination of all pertinent body systems while 
the subsequent physical examinations will include specific assessments of any changes from 
previous status and review of those organ systems as deemed appropriate for that subject. Physical 
examination results will be included in individual subject listings.   


 
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9.  Tables and Listings 
9.1 
Programs and tables quality control 
The statistical programmer of the tables and listings will carefully review the programs and will 
verify that no error message is highlighted in the ‘LOG’ file. Moreover, a second statistical 
programmer will verify the internal consistency of each table by checking the results using 
different SAS programs.  
 
The following level of validation will be implemented:  
 
Validation of statistical datasets: independent programming, with a comparison of the results 
against the initial datasets. 
 
Validation of statistical output:  independent programming, with a comparison of the results against 
the initial output. 
9.2 
Programming conventions 
All tables/listings will be presented in landscape format.  
The standard font size is 9 points Courier New for all tables. Listings will be presented with an 8 or 
7 points Courier New.  
 
Titles will be center-aligned; footnotes will be left-aligned.  
Each table/figure/listing will have 2 titles: 
 
The 1st title will be the table/figure/listing number with the description of the table/figure 
/listing;  
 
The 2nd title will be a description of the study population presented in the table/figure/listing. 
Some tables will have another title (before 2nd title) with a description of the statistical method 
used in those tables. 
 
Any footnote added to explain the table/listing/figure contents will be presented in the following 
format: 
Note 1: Percentages are calculated on the number of subjects (N). 
Note 2: A serious adverse event is an.... 
Note 3: ………. 
 
The last two footnotes of each table/figure will be footers indicating: 
 
the reference listing of the data; 
 
the program name, the date and time of generation and the SAS® version used. 
The last footnote of each listing will be a footer indicating the program name, the date and time of 
generation and the SAS® version used. 
 


 
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In the tables and listing the treatment under comparison will be labeled as “Cohort 1 1.0 mg/kg”, 
‘Cohort 2 3.0 mg/kg’ “Cohort 3 10 mg/kg”, ‘Cohort 4 XX mg/kg’ (XX is the recommended dose) 
and “Placebo”. 
 
In tables and figures, unless otherwise stated, the number of subjects corresponding to analysis set 
will be shown at the part of “N=XX” together with the labels of treatment group.  
 For example, in Table 14.3.1-1.1 “Overall summary of treatment-emergent adverse events 
during study / safety analysis set”, the part of “N=XX” will display the number of subjects in 
safety analysis set corresponding to the labels of the treatment group (e.g. 1.0 mg/kg, 
3.0 mg/kg, 10 mg/kg, Placebo) and All.  
 
Unless otherwise stated, listings will be presented by randomized treatment, and sorted by cohort 
and the site-subject identifier.  
 
Except for the listings 16.2.1-1.2 (based on screening failure subjects) and 16.2.1-1 (based on all 
subjects), all the listings will be based on the randomized subjects. 
 
In all the listings on safety variables, a column with a flag (§) for treatment misallocation will 
identify the treatment misallocations. 
The derived variables will be identified in the listings with a flag (*). 
 
Tabular display of data for prior / concomitant medications, and all tabular displays of adverse 
event data should be presented by the body system, drug class, or SOC with the highest occurrence 
in the active treatment group (KHK4083 combined group) in decreasing order. Within the body 
system, drug class and SOC, medical history (by Preferred Term), drugs (by ATC1 code), and 
adverse events (by Preferred Term) should be displayed in decreasing order. If incidence for more 
than 1 term is identical, they should then be sorted alphabetically. 
 
In general, dates will be presented on listings in the format ddmmmyyyy (date9.) and time in the 
format hh:mm (time5.). In case of partial dates or times, missing information will be replaced by 
dashes. Numeric variables will be listed generally with the same number of decimal places as in the 
actual data. 
 
The following rules on decimal places will be considered in the listings for the derived variables (in 
the analyses approximations will not be performed): 
 
Age (years), duration of treatment (days): 0 decimal place; 
 
Change from baseline: same as the variable considered. 
 
The following rules on decimal places will be considered for the results of the analyses (if the 
analyses are performed on derived variables, the level of precision of the actual data is derived 
from the previous list): 
 
Min, max: same as actual data; 
 
Mean and its confidence limits (unadjusted and adjusted), adjusted difference between means 
and its confidence limits, SD, median: actual data + 1 decimal; 
 
Percentage: 1 decimal place. 
 


 
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9.3 
Glucocorticoid 
Among concomitant medications which started to be administered from Day 1, those 
corresponding to the list below will be defined as glucocorticoid and considered in Tables and 
Listings relative to glucocorticoid. 
 Medications that ATC code is “H02AB” (that is assigned to “Glucocorticoids”).


 
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9.4 
Tables 
Number 
Title 
Table 14.1-1 
Disposition of Subjects / Summary of All Subjects 
Table 14.1-2.1  
Demographic Characteristics / Safety Analysis Set 
Table 14.1-2.2  
Baseline Assessment of Ulcerative Colitis / Safety Analysis Set 
Table 14.1-2.3  
Demographic Characteristics / Full Analysis Set 
Table 14.1-2.4  
Baseline Assessment of Ulcerative Colitis / Full Analysis Set 
Table 14.1-3.1  
Prior Medications / Safety Analysis Set 
Table 14.1-3.2  
Concomitant Medications During Induction Period / Safety Analysis Set 
Table 14.1-3.3  
Concomitant Medications During Double-Blind Long Term Extension and Follow-Up Therapy / Safety Analysis Set 
Table 14.1-3.4  
Concomitant Medications During Open-Label Extension Therapy Period and Follow-Up Therapy / Safety Analysis Set 
Table 14.1-4.1  
Medical and Surgical History / Safety Analysis Set 
Table 14.1-4.2  
Concomitant Diseases / Safety Analysis Set 
Table 14.1-5  
Exposure to Investigational Product During Induction Therapy Period / Safety Analysis Set 
Table 14.1-6  
Exposure to Investigational Product During Long-Term Extension Therapy Period / Safety Analysis Set 
Table 14.1-7  
Exposure to Investigational Product During Open-Label Extension Therapy Period / Safety Analysis Set 
Table 14.1-8 
Exposure to Investigational Product During Study / Safety Analysis Set 
Table 14.2-1.1  
Summary of Baseline and Change from Baseline of Modified Mayo Endoscopy (MMES) / Full Analysis Set 
Table 14.2-1.2  
Change from Baseline in MMES at Week 12 / Full Analysis Set 
Table 14.2-2.1  
UCEIS During Induction Therapy Period / Full Analysis Set 
Table 14.2-2.2  
Total Mayo Clinic Score at During Induction Therapy Period / Full Analysis Set 
Table 14.2-2.3  
Partial Mayo Clinic Score at During Induction Therapy Period / Full Analysis Set 
Table 14.2-2.4  
Clinical Improvement at Week 12 / Full Analysis Set 
Table 14.2-2.5.1  
Change from Baseline in UCEIS at Week 12 / Full Analysis Set 
Table 14.2-2.5.2  
Change from Baseline in Total Mayo Clinic Score at Week 12 / Full Analysis Set 
Table 14.2-2.5.3  
Change from Baseline in Partial Mayo Clinic Score at Week 12 / Full Analysis Set 


 
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Number 
Title 
Table 14.2-3.1.1  
Summary of Score and Change from Baseline in MMES During Long-Term Extension Therapy Period / Full Analysis Set 
Table 14.2-3.1.2  
Summary of Score and Change from Baseline in MMES During Open-Label Extension Therapy Period / Full Analysis Set 
Table 14.2-3.2.1  
Summary of Score and Change from Baseline in UCEIS During Long-Term Extension Therapy Period / Full Analysis Set 
Table 14.2-3.2.2  
Summary of Score and Change from Baseline in UCEIS During Open-Label Extension Therapy Period / Full Analysis Set 
Table 14.2-3.3.1  
Summary of Score and Change from Baseline in Total Mayo Score During Long-Term Extension Period / Full Analysis 
Set 
Table 14.2-3.3.2  
Summary of Score and Change from Baseline in Total Mayo Score During Open-Label Extension Period / Full Analysis 
Set 
Table 14.2-3.3.3  
Summary of Score and Change from Baseline in Partial Mayo Clinic Scores During Long-Term Extension Therapy Period 
and Double-Blind Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.3.4  
Summary of Score and Change from Baseline in Partial Mayo Clinic Scores During Open-Label Extension Therapy Period 
and Open-Label Extension Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.4.1  
Summary Score and Change from Baseline in IBDQ Total Score During Long-Term Extension Therapy Period and 
Double-Blind Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.4.2  
Summary Score and Change from Baseline in IBDQ Total Score During Open-Label Extension Therapy Period and Open-
Label Extension Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.4.3  
Summary Score and Change from Baseline in IBDQ - Bowel-Related Symptoms Score During Long-Term Extension 
Therapy Period and Double-Blind Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.4.4  
Summary Score and Change from Baseline in IBDQ - Bowel-Related Symptoms Score During Open-Label Extension 
Therapy Period and Open-Label Extension Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.4.5  
Summary Score and Change from Baseline in IBDQ - Systemic Function Score During Long-Term Extension Therapy 
Period and Double-Blind Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.4.6  
Summary Score and Change from Baseline in IBDQ - Systemic Function Score During Open-Label Extension Therapy 
Period and Open-Label Extension Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.4.7  
Summary Score and Change from Baseline in IBDQ - Social Function Score During Long-Term Extension Therapy 
Period and Double-Blind Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.4.8  
Summary Score and Change from Baseline in IBDQ - Social Function Score During Open-Label Extension Therapy 
Period and Open-Label Extension Therapy Follow-Up Period / Full Analysis Set 


 
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Number 
Title 
Table 14.2-3.4.9  
Summary Score and Change from Baseline in IBDQ - Emotional Status Score During Long-Term Extension Therapy 
Period and Double-Blind Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.4.10 
Summary Score and Change from Baseline in IBDQ - Emotional Status Score During Open-Label Extension Therapy 
Period and Open-Label Extension Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.5.1  
Summary Score and Change from Baseline in Corticosteroid (Glucocorticoid) Dosages During Long-Term Extension 
Therapy Period and Double-Blind Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.5.2  
Summary Score and Change from Baseline in Corticosteroid (Glucocorticoid) Dosages During Open-Label Extension 
Therapy Period and Open-Label Extension Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.5.3  
Summary Score and Change from Baseline in Duration of Corticosteroid-Free Treatment During Long-Term Extension 
Therapy Period and Double-Blind Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.5.4  
Summary Score and Change from Baseline in Duration of Corticosteroid-Free Treatment During Open-Label Extension 
Therapy Period and Open-Label Extension Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.6  
Percentage of Clinical Response at Week 52 During Double-Blind Therapy Period / Full Analysis Set 
Table 14.2-3.7  
Percentage of Clinical Response at Week 52 During Open-Label Extension Therapy Period / Full Analysis Set 
Table 14.2-3.8.1  
Change from Baseline in UCEIS at Week 52 During Double-Blind Therapy Period / Full Analysis Set 
Table 14.2-3.8.2  
Change from Baseline in Total Mayo Clinic Score at Week 52 During Double-Blind Therapy Period / Full Analysis Set 
Table 14.2-3.8.3  
Change from Baseline in Total Partial Clinic Score at Week 52 During Double-Blind Therapy Period / Full Analysis Set 
Table 14.2-3.8.4  
Mean Change from Baseline in Partial Mayo Clinic Scores During Double-Blind Therapy Period and Double-Blind 
Therapy Follow-Up Period / Mixed Model for Repeated Measures / Full Analysis Set 
Table 14.2-3.9.1  
Summary of Score and Change from Baseline in Mayo Clinic Score - Stool Frequency During Double-Blind Therapy 
Period and Double-Blind Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.9.2  
Summary of Score and Change from Baseline in Mayo Clinic Score - Stool Frequency During Open-Label Extension 
Therapy Period and Open-Label Extension Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.9.3  
Summary of Score and Change from Baseline in Mayo Clinic Score - Rectal Bleeding During Double-Blind Therapy 
Period and Double-Blind Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.9.4  
Summary of Score and Change from Baseline in Mayo Clinic Score - Rectal Bleeding During Open-Label Extension 
Therapy Period and Open-Label Extension Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.9.5  
Summary of Score and Change from Baseline in Mayo Clinic Score - Physician’s Global Assessment During Double-


 
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Number 
Title 
Blind Therapy Period and Double-Blind Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.9.6  
Summary of Score and Change from Baseline in Mayo Clinic Score - Physician’s Global Assessment During Open-Label 
Extension Therapy Period and Open-Label Extension Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-3.9.7  
Summary of Score and Change from Baseline in Modified Baron Endoscopic Score During Double-Blind Therapy Period 
/ Full Analysis Set 
Table 14.2-3.9.8  
Summary of Score and Change from Baseline in Modified Baron Endoscopic Score During Open-Label Extension 
Therapy Period / Full Analysis Set 
Table 14.2-3.9.9  
Summary of Score and Change from Baseline in UCEIS Subscore - Vascular Pattern During Double-Blind Therapy Period 
/ Full Analysis Set 
Table 14.2-3.9.10  
Summary of Score and Change from Baseline in UCEIS Subscore - Vascular Pattern During Open-Label Extension 
Therapy Period / Full Analysis Set 
Table 14.2-3.9.11  
Summary of Score and Change from Baseline in UCEIS Subscore - Bleeding During Double-Blind Therapy Period / Full 
Analysis Set 
Table 14.2-3.9.12  
Summary of Score and Change from Baseline in UCEIS Subscore - Bleeding During Open-Label Extension Therapy 
Period / Full Analysis Set 
Table 14.2-3.9.13  
Summary of Score and Change from Baseline in UCEIS Subscore - Erosions and Ulcers During Double-Blind Therapy 
Period / Full Analysis Set 
Table 14.2-3.9.14 
Summary of Score and Change from Baseline in UCEIS Subscore - Erosions and Ulcers During Open-Label Extension 
Therapy Period / Full Analysis Set 
Table 14.2-8.1  
Summary of Score and Change from Baseline in MMES During Double-Blind Therapy / Full Analysis Set 
Table 14.2-8.2 
Summary of Score and Change from Baseline in MMES During Open-Label Extension Therapy / Full Analysis Set 
Table 14.2-8.3 
Summary of Score and Change from Baseline in UCEIS During Double-Blind Therapy / Full Analysis Set 
Table 14.2-8.4 
Summary of Score and Change from Baseline in UCEIS During Open-Label Extension Therapy Period / Full Analysis Set 
Table 14.2-8.5 
Summary of Score and Change from Baseline in Total Mayo Score During Double-Blind Therapy Period / Full Analysis 
Set 
Table 14.2-8.6 
Summary of Score and Change from Baseline in Total Mayo Score During Open-Label Extension Period / Full Analysis 
Set 
Table 14.2-8.7 
Summary of Score and Change from Baseline in Partial Mayo Score During Double-Blind Therapy Period and Double-


 
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Number 
Title 
Blind Therapy Follow-Up Period / Full Analysis Set 
Table 14.2-8.8 
Summary of Score and Change from Baseline in Partial Mayo Score During Open-Label Extension Therapy Period and 
Open-Label Extension Therapy Follow-Up Period / Full Analysis Set 
Table 14.3.1-1.1  
Overall Summary of Treatment-Emergent Adverse Events During Study / Safety Analysis Set 
Table 14.3.1-1.2  
Summary of Treatment-Emergent Adverse Events During Double-Blind Therapy Period and Double-Blind Therapy 
Follow-Up Period / Safety Analysis Set 
Table 14.3.1-1.3  
Summary of Treatment-Emergent Adverse Events During Double-Blind Induction Therapy Period / Safety Analysis Set 
Table 14.3.1-1.4  
Summary of Treatment-Emergent Adverse Events During Open-Label Extension Therapy Period and Open-Label 
Extension Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.1-2.1  
Treatment-Emergent Adverse Events By System Organ Class and Preferred Term During Double-Blind Therapy Period 
and Double-Blind Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.1-2.2  
Treatment-Emergent Adverse Events By System Organ Class and Preferred Term Double-Blind Induction Therapy Period 
/ Safety Analysis Set 
Table 14.3.1-2.3  
Treatment-Emergent Adverse Events By System Organ Class and Preferred Term During Open-Label Extension Therapy 
Period and Open-Label Extension Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.1-2.4  
Treatment-Emergent Adverse Events By System Organ Class, Preferred Term and Relationship to Investigational Product 
During Double-Blind Therapy Period and Double-Blind Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.1-2.5  
Treatment-Emergent Adverse Events By System Organ Class, Preferred Term and Relationship to Investigational Product 
During Double-Blind Induction Therapy Period / Safety Analysis Set 
Table 14.3.1-2.6  
Treatment-Emergent Adverse Events By System Organ Class, Preferred Term and Relationship to Investigational Product 
During Open-Label Extension Therapy Period and Open-Label Extension Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.1-3.1  
Treatment-Emergent Adverse Events By Maximum Severity, System Organ Class and Preferred Term During Double-
Blind Therapy Period and Double-Blind Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.1-3.2  
Treatment-Emergent Adverse Events By Maximum Severity, System Organ Class and Preferred Term During Double-
Blind Induction Therapy Period / Safety Analysis Set 
Table 14.3.1-3.3  
Treatment-Emergent Adverse Events By Maximum Severity, System Organ Class and Preferred Term During Open-Label 
Extension Therapy Period and Open-Label Extension Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.1-4.1  
Serious Treatment-Emergent Adverse Events By System Organ Class and Preferred Term During Double-Blind Therapy 


 
Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
FRM_ST03_032 
01 
23 Apr 2015 
45 of 53 
 
Protocol Number: 
4083-002 
Final Version 2.0 
Document Date: 
06 Oct 2017 
 
 
Number 
Title 
Period and Double-Blind Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.1-4.2  
Serious Treatment-Emergent Adverse Events By System Organ Class and Preferred Term During Double-Blind Induction 
Therapy Period / Safety Analysis Set 
Table 14.3.1-4.3  
Serious Treatment-Emergent Adverse Events By System Organ Class and Preferred Term During Open-Label Extension 
Therapy Period and Open-Label Extension Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.1-5.1  
Treatment-Emergent Adverse Events Leading to Discontinuation from The Study By System Organ Class and Preferred 
Term During Double-Blind Therapy Period and Double-Blind Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.1-5.2  
Treatment-Emergent Adverse Events Leading to Discontinuation from The Study By System Organ Class and Preferred 
Term During Double-Blind Induction Therapy Period / Safety Analysis Set 
Table 14.3.1-5.3  
Treatment-Emergent Adverse Events Leading to Discontinuation from The Study By System Organ Class and Preferred 
Term During Open-Label Extension Therapy Period and Open-Label Extension Therapy Follow-Up Period / Safety 
Analysis Set 
Table 14.3.4-1.1  
Vital Signs and Body Weight and Change from Baseline During Double-Blind Therapy Period and Double-Blind Therapy 
Follow-Up Period / Safety Analysis Set 
Table 14.3.4-1.2  
Vital Signs and Body Weight and Change from Baseline During Open-Label Extension Therapy Period and Open-Label 
Extension Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.4-2.1  
Summary of Clinical Laboratory Values-Hematology During Double-Blind Therapy Period and Double-Blind Therapy 
Follow-Up Period / Safety Analysis Set 
Table 14.3.4-2.2  
Summary of Clinical Laboratory Values-Hematology During Open-Label Extension Therapy Period and Open-Label 
Extension Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.4-2.3  
Summary of Clinical Laboratory Values- Serum Chemistry During Double-Blind Therapy Period and Double-Blind 
Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.4-2.4  
Summary of Clinical Laboratory Values- Serum Chemistry During Open-Label Extension Therapy Period and Open-Label 
Extension Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.4-2.5  
Summary of Clinical Laboratory Values- Coagulation Profile During Double-Blind Therapy Period and Double-Blind 
Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.4-2.6  
Summary of Clinical Laboratory Values- Coagulation Profile During Open-Label Extension Therapy Period and Open-
Label Extension Therapy Follow-Up Period / Safety Analysis Set 


 
Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
FRM_ST03_032 
01 
23 Apr 2015 
46 of 53 
 
Protocol Number: 
4083-002 
Final Version 2.0 
Document Date: 
06 Oct 2017 
 
 
Number 
Title 
Table 14.3.4-2.7  
Summary of Clinical Laboratory Values- Urinalyses During Double-Blind Therapy Period and Double-Blind Therapy 
Follow-Up Period / Safety Analysis Set 
Table 14.3.4-2.8  
Summary of Clinical Laboratory Values- Urinalyses During Open-Label Extension Therapy Period and Open-Label 
Extension Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.4-2.9  
Shift Table of Clinical Laboratory Values -Hematology During Double-Blind Therapy Period and Double-Blind Therapy 
Follow-Up Period / Safety Analysis Set 
Table 14.3.4-2.10  
Shift Table of Clinical Laboratory Values -Hematology During Open-Label Extension Therapy Period and Open-Label 
Extension Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.4-2.11  
Shift Table of Clinical Laboratory Values - Serum Chemistry During Double-Blind Therapy Period and Double-Blind 
Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.4-2.12  
Shift Table of Clinical Laboratory Values - Serum Chemistry During Open-Label Extension Therapy Period and Open-
Label Extension Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.4-2.13  
Shift Table of Clinical Laboratory Values -Coagulation Profile During Double-Blind Therapy Period and Double-Blind 
Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.4-2.14  
Shift Table of Clinical Laboratory Values -Coagulation Profile During Open-Label Extension Therapy Period and Open-
Label Extension Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.4-2.15  
Shift Table of Clinical Laboratory Values - Urinalyses During Double-Blind Therapy Period and Double-Blind Therapy 
Follow-Up Period / Safety Analysis Set 
Table 14.3.4-2.16  
Shift Table of Clinical Laboratory Values - Urinalyses During Open-Label Extension Therapy Period and Open-Label 
Extension Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.4-3.1  
12-Lead Electrocardiogram Parameters During Double-Blind Therapy Period and Double-Blind Therapy Follow-Up 
Period / Safety Analysis Set 
Table 14.3.4-3.2  
12-Lead Electrocardiogram Parameters During Open-Label Extension Therapy Period and Open-Label Extension Therapy 
Follow-Up Period / Safety Analysis Set 
Table 14.3.4-3.3  
12-Lead Electrocardiogram: Summary of Elevated QTCF Values During Double-Blind Therapy Period and Double-Blind 
Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.4-3.4  
12-Lead Electrocardiogram: Summary of Elevated QTCF Values During Open-Label Extension Therapy Period and 
Open-Label Extension Therapy Follow-Up Period / Safety Analysis Set 


 
Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
FRM_ST03_032 
01 
23 Apr 2015 
47 of 53 
 
Protocol Number: 
4083-002 
Final Version 2.0 
Document Date: 
06 Oct 2017 
 
 
Number 
Title 
Table 14.3.4-3.5  
12-Lead Electrocardiogram: QTCF Change from Baseline - Categorical Analysis During Double-Blind Therapy Period 
and Double-Blind Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.4-3.6  
12-Lead Electrocardiogram: QTCF Change from Baseline - Categorical Analysis During Open-Label Extension Therapy 
Period and Open-Label Extension Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.4-3.7  
12-Lead Electrocardiogram: QTCF Categorical Analysis During Double-Blind Therapy Period and Double-Blind Therapy 
Follow-Up Period / Safety Analysis Set 
Table 14.3.4-3.8  
12-Lead Electrocardiogram: QTCF Categorical Analysis During Open-Label Extension Therapy Period and Open-Label 
Extension Therapy Follow-Up Period / Safety Analysis Set 
Table 14.3.4-3.9  
12-Lead Electrocardiogram: Shift Table of QTCF Values During Double-Blind Therapy Period and Double-Blind Therapy 
Follow-Up Period / Safety Analysis Set 
Table 14.3.4-3.10 
12-Lead Electrocardiogram: Shift Table of QTCF Values Open-Label Extension Therapy Period and Open-Label 
Extension Therapy Follow-Up Period / Safety Analysis Set 
9.4.1 
Tables for Un-Blinded 12 Week Induction Therapy Data 
Number 
Title 
Table 14.1.1  
Disposition of Subjects for Induction Therapy Period 
Table 14.1.4.1  
Demographics (Safety Analysis Set) 
Table 14.2.1.1  
Baseline and Change from Baseline of Modified Mayo Endoscopic Score (MMES) at Week 12 (induction Therapy) 
Table 14.2.1.2  
Analysis of Change from Baseline in MMES at Week 12 
Table 14.2.2.1  
Baseline and Change from Baseline in UCEIS at Week 12 
Table 14.2.2.2  
Baseline and Change from Baseline in Total Mayo Clinic Score at Week 12 
Table 14.2.2.3  
Partial Mayo Clinic Score during Induction Therapy 
Table 14.2.2.4  
Clinical Improvement (%) at Week 12 in MMES, Modified Baron Endoscopic Score, Mucosal Healing, Clinical Response 
and Clinical Remission   
Table 14.2.2.5.1  
Analysis of Change from Baseline in UCEIS at Week 12 
Table 14.2.2.5.2  
Analysis of Change from Baseline in Total Mayo Clinic Score at Week 12 
Table 14.2.2.5.3  
Analysis of Change from Baseline in Partial Mayo Clinic Score at Week 12 


 
Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
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01 
23 Apr 2015 
48 of 53 
 
Protocol Number: 
4083-002 
Final Version 2.0 
Document Date: 
06 Oct 2017 
 
 
Number 
Title 
Table 14.2.3.9.1  
Baseline and Change from Baseline in Mayo Clinic Score - Stool Frequency during 12 Week Induction Therapy 
Table 14.2.3.9.3  
Baseline and Change from Baseline in Mayo Clinic Score - Rectal Bleeding during 12 Week Induction Therapy 
Table 14.2.3.9.7  
Baseline and Change from Baseline in Modified Baron Endoscopic Score at 12 Week Induction Therapy 
Table 14.2.3.9.9  
Baseline and Change from Baseline in UCEIS Subscore - Vascular Pattern at 12 Week Induction Therapy 
Table 14.2.3.9.11  
Baseline and Change from Baseline in UCEIS Subscore - Bleeding at 12 Week Induction Therapy 
Table 14.2.3.9.13  
Baseline and Change from Baseline in UCEIS Subscore - Erosions and Ulcers at 12 Week Induction Therapy 
Table 14.3.1.1.3  
Overall Summary of Treatment Emergent Adverse Events during Induction Therapy 
Table 14.3.1-2.2  
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term during Double-Blind Induction Therapy 
Period 
Table 14.3.1.2.5  
Treatment-Related Treatment-Emergent Adverse Events by System Organ Class, Preferred Term during Double Blind 
Induction Therapy. 
Table 14.3.1.4.2  
Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term during Double-Blind Induction 
Therapy Period 
9.5 
Figures 
Number 
Title 
Figure 15.1.1  
Least Squares Means Adjusted for Baseline of MMES at Week 12 / Full Analysis Set 
Figure 15.1.2  
Difference in Least Squares Means from Placebo Adjusted for Baseline of MMES at Week 12 / Full Analysis Set 
Figure 15.2.1  
Least Squares Means of UCEIS at Week 12 / Full Analysis Set 
Figure 15.2.2  
Difference in Least Squares Means from Placebo of UCEIS at Week 12 / Full Analysis Set 
Figure 15.2.3  
Least Squares Means of Total Mayo Clinic Scores at Week 12 / Full Analysis Set 
Figure 15.2.4  
Difference in Least Squares Means from Placebo of Total Mayo Clinic Scores at Week 12 / Full Analysis Set 
Figure 15.2.5  
Least Squares Means of Partial Mayo Clinic Scores at Week 12 / Full Analysis Set 
Figure 15.2.6  
Difference in Least Squares Means from Placebo of Partial Mayo Clinic Scores at Week 12 / Full Analysis Set 
Figure 15.3.1  
MMES During Double-Blind Therapy Period / Full Analysis Set 
Figure 15.3.2  
MMES During Open-Label Extension Therapy Period / Full Analysis Set 


 
Forms  
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Statistical Analysis Plan Template 
Code 
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06 Oct 2017 
 
 
Number 
Title 
Figure 15.3.3  
UCEIS During Double-Blind Therapy Period / Full Analysis Set 
Figure 15.3.4  
UCEIS During Open-Label Extension Therapy Period / Full Analysis Set 
Figure 15.3.5  
Total Mayo Clinic Scores During Double-Blind Therapy Period / Full Analysis Set 
Figure 15.3.6  
Total Mayo Clinic Scores During Open-Label Extension Therapy Period / Full Analysis Set 
Figure 15.3.7  
Partial Mayo Clinic Scores During Double-Blind Therapy Period and Double-Blind Therapy Follow-Up Period / Full 
Analysis Set 
Figure 15.3.8  
Partial Mayo Clinic Scores During Open-Label Extension Therapy Period and Open-Label Extension Therapy Follow-Up 
Period / Full Analysis Set 
Figure 15.3.9  
Change from Baseline of MMES During Double-Blind Therapy Period / Full Analysis Set 
Figure 15.3.10  
Change from Baseline of MMES During Open-Label Extension Therapy Period / Full Analysis Set 
Figure 15.3.11  
Change from Baseline of UCEIS During Double-Blind Therapy Period / Full Analysis Set 
Figure 15.3.12  
Change from Baseline of UCEIS During Open-Label Extension Therapy Period / Full Analysis Set 
Figure 15.3.13  
Change from Baseline of Total Mayo Clinic Scores During Double-Blind Therapy Period / Full Analysis Set 
Figure 15.3.14  
Change from Baseline of Total Mayo Clinic During Open-Label Extension Therapy Period / Full Analysis Set 
Figure 15.3.15  
Change from Baseline of Partial Mayo Clinic Scores During Double-Blind Therapy Period and Double-Blind Therapy 
Follow-Up Period / Full Analysis Set 
Figure 15.3.16  
Change from Baseline of Partial Mayo Clinic Scores During Open-Label Extension Therapy Period and Open-Label 
Extension Therapy Follow-Up Period / Full Analysis Set 
Figure 15.4.1  
Laboratory-Hematology During Double-Blind Therapy Period and Double-Blind Therapy Follow-Up Period / Safety 
Analysis Set 
Figure 15.4.2  
Laboratory-Hematology During Open-Label Extension Therapy Period and Open-Label Extension Therapy Follow-Up 
Period / Safety Analysis Set 
Figure 15.4.3  
Laboratory-Clinical Chemistry During Double-Blind Therapy Period and Double-Blind Therapy Follow-Up Period / Safety 
Analysis Set 
Figure 15.4.4  
Laboratory-Clinical Chemistry During Open-Label Extension Therapy Period and Open-Label Extension Therapy Follow-
Up Period / Safety Analysis Set 
Figure 15.4.5  
Laboratory- Coagulation Profile During Double-Blind Therapy Period and Double-Blind Therapy Follow-Up Period / 
Safety Analysis Set 


 
Forms  
Title 
Statistical Analysis Plan Template 
Code 
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Protocol Number: 
4083-002 
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Document Date: 
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Number 
Title 
Figure 15.4.6  
Laboratory- Coagulation Profile During Open-Label Extension Therapy Period and Open-Label Extension Therapy Follow-
Up Period / Safety Analysis Set 
Figure 15.4.9  
12-Lead Electrocardiogram Parameters During Double-Blind Therapy Period and Double-Blind Therapy Follow-Up Period 
/ Safety Analysis Set 
Figure 15.4.10 
12-Lead Electrocardiogram Parameters During Open-Label Extension Therapy Period and Open-Label Extension Therapy 
Follow-Up Period / Safety Analysis Set 
Figure 15.5.1  
Change from Baseline of Laboratory-Hematology During Double-Blind Therapy Period and Double-Blind Therapy Follow-
Up Period / Safety Analysis Set 
Figure 15.5.2  
Change from Baseline of Laboratory-Hematology During Open-Label Extension Therapy Period and Open-Label Extension 
Therapy Follow-Up Period / Safety Analysis Set 
Figure 15.5.3  
Change from Baseline of Laboratory-Clinical Chemistry During Double-Blind Therapy Period and Double-Blind Therapy 
Follow-Up Period / Safety Analysis Set 
Figure 15.5.4  
Change from Baseline of Laboratory-Clinical Chemistry During Open-Label Extension Therapy Period and Open-Label 
Extension Therapy Follow-Up Period / Safety Analysis Set 
Figure 15.5.5  
Change from Baseline of Laboratory- Coagulation Profile During Double-Blind Therapy Period and Double-Blind Therapy 
Follow-Up Period / Safety Analysis Set 
Figure 15.5.6  
Change from Baseline of Laboratory- Coagulation Profile During Open-Label Extension Therapy Period and Open-Label 
Extension Therapy Follow-Up Period / Safety Analysis Set 
Figure 15.5.7  
Change from Baseline of 12-Lead Electrocardiogram Parameters Profile During Double-Blind Therapy Period and Double-
Blind Therapy Follow-Up Period / Safety Analysis Set 
Figure 15.5.8  
Change from Baseline of 12-Lead Electrocardiogram Parameters During Open-Label Extension Therapy Period and Open-
Label Extension Therapy Follow-Up Period / Safety Analysis Set 
 
 


 
Forms  
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Code 
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Document Date: 
06 Oct 2017 
 
 
9.6 
Listings 
Number 
Title 
Listing 16.2.1-1.1  Disposition of Subjects - / All Subjects 
Listing 16.2.1-1.2  Screening Failures / Screening Failure Subjects 
Listing 16.2.2-1  
Protocol Deviations / Randomized Subjects 
Listing 16.2.2-2  
Violations of Inclusion / Exclusion Criteria / Randomized Subjects 
Listing 16.2.3-1  
Populations for Analysis / Randomized Subjects 
Listing 16.2.4-1  
Demographics and Baseline Characteristic / Randomized Subjects 
Listing 16.2.4-2  
Baseline UC Assessment and UC Diagnosis / Randomized Subjects 
Listing 16.2.4-3  
Pregnancy Test / Randomized Subjects 
Listing 16.2.4-4  
Medical / Surgical History / Randomized Subjects 
Listing 16.2.4-5  
Physical Examinations / Randomized Subjects 
Listing 16.2.5-1  
Prior and Concomitant Medications / Randomized Subjects 
Listing 16.2.5-2  
Study Medication Administration / Randomized Subjects 
Listing 16.2.5-3  
Study Medication Duration and Number of Dose / Randomized Subjects 
Listing 16.2.6-1  
MMES at All Study Visits / Randomized Subjects 
Listing 16.2.6-2.1  UCEIS and Baron Endoscopic Score at All Study Visits / Randomized Subjects 
Listing 16.2.6-2.2  Total and Partial Mayo Clinic Scores at All Study Visits / Randomized Subjects 
Listing 16.2.6-2.3  Clinical Response at Week 12 and Week 52 / Randomized Subjects 
Listing 16.2.6-3.1  Total and 4 Subscale IBDQ Scores at All Study Visits / Randomized Subjects 
Listing 16.2.6-3.2  Corticosteroid Dosages and The Duration of Glucocorticoid-Free Treatment / Randomized Subjects 
Listing 16.2.7-1  
Pre-Treatment Adverse Events / Summary of All Subjects / Randomized Subjects 
Listing 16.2.7-2.1  Treatment-Emergent Adverse Events / Randomized Subjects 
Listing 16.2.7-2.2  Serious Treatment-Emergent Adverse Events / Randomized Subjects 
Listing 16.2.7-2.3  Treatment-Emergent Adverse Events Leading to Deaths / Randomized Subjects 
Listing 16.2.7-2.4  Treatment-Emergent Adverse Events Leading to Discontinuation / Randomized Subjects 
Listing 16.2.7-2.5  Treatment-Emergent Adverse Events with Withdrawal of Investigational Product / Randomized Subjects 


 
Forms  
Title 
Statistical Analysis Plan Template 
Code 
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Document Date: 
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Number 
Title 
Listing 16.2.8-1  
Vital Signs / Randomized Subjects 
Listing 16.2.8-2  
Clinical Laboratory Values-Hematology / Randomized Subjects 
Listing 16.2.8-3  
Clinical Laboratory Values-Clinical Chemistry / Randomized Subjects 
Listing 16.2.8-4  
Clinical Laboratory Values- Coagulation Profile / Randomized Subjects 
Listing 16.2.8-5  
Clinical Laboratory Values-Urinalysis / Randomized Subjects 
Listing 16.2.8-6  
Clinical Abnormal Laboratory Values / Randomized Subjects 
Listing 16.2.8-7  
12-Lead Ecg - Quantitative Data / Randomized Subjects 


 
Forms  
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Statistical Analysis Plan Template 
Code 
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Document Date: 
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9.7 
Table, Figure, and Listing shells 
Table, figure, and listing shells are provided in a separate document. 
10.  
Literature and references  
 CROS NT Standard Operating Procedure ST/03_V01 “Statistical Analysis Plan”;  
 European Medicines Agency (EMA), International Conference on Harmonisation (ICH) E3 
Harmonised Guideline (1996) “Structure and Content of Clinical Study Reports”; 
 EMA, ICH E9 Harmonised Guideline (1998) “Statistical Principles for Clinical Trials”.