A Prospective Multicenter Study to Observe the Effectiveness on Ulcerative Colitis and Predictive Factors of Clinical Response in Korean Patients Treated With Adalimumab (EUREKA Study)
Conditions: Ulcerative Colitis
Sponsor: AbbVie

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
1
7LWOH3DJH
7LWOH
A Prospective Multi-Center study to observe the (ffectiveness on 
8lcerative Colitis and predictive factors of clinical 5(sponse in 
.orean Patients treated with $dalimumab (EUREKA study) 
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Amendment 1 
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26 SEP, 2016 
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AbbVie Korea 
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To evaluate the real world effectiveness of adalimumab in Korean 
patients with Ulcerative Colitis (UC) and to explorepotential predictive 
factors of clinical response.
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South Korea 
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NCT02499263

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
2
0DUNHWLQJ$XWKRULVDWLRQ+ROGHUV
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AbbVie Korea 
6th Fl., Samtan Bldg. 421 YoungDong-Daero, KangNam-Gu, 
Seoul, Korea 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
3
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7.1
Introduction ................................................................................................ 9
7.2
Rationale .................................................................................................. 10
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9.1
Study Design ............................................................................................ 11
9.2
Setting ...................................................................................................... 13
9.2.1
Selection of Study Population .................................................................. 13
9.2.2
Drop-Out Subjects ................................................................................... 14
9.2.3
Investigator Selection Criteria ................................................................. 14
9.3
Methodology ............................................................................................ 14
9.4
Data Sources ............................................................................................ 18
9.5
Study Size ................................................................................................ 18
9.6
Data Management .................................................................................... 19
9.7
Data Analysis ........................................................................................... 19
9.7.1
Safety Analysis ........................................................................................ 21
9.7.2
Exploratory Analysis ............................................................................... 21
9.8
Quality Control ........................................................................................ 22
9.9
Limitations of the Research Methods ...................................................... 22
9.10
Other Aspects ........................................................................................... 22
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11.1
Medical Complaints ................................................................................. 24
11.1.1
Adverse Event Definition and Serious Adverse Event Categories .......... 24
11.1.2
Severity .................................................................................................... 25

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
4
11.1.3
Relationship to Pharmaceutical Product .................................................. 26
11.1.4
Serious Adverse Event Collection Period ................................................ 26
11.1.5
Serious Adverse Event Reporting ............................................................ 26
11.1.6
Pregnancy Reporting ................................................................................ 27
11.2
Product Complaint ................................................................................... 27
11.2.1
Definition ................................................................................................. 27
11.2.2
Reporting .................................................................................................. 28
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Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
5

$EEUHYLDWLRQV
AAA 
Antibodies Against Adalimumab 
AE
Adverse Event  
ADR
Adverse Drug Reaction
CRA
Clinical Research Associate
CRF
Case Report Form
IBD 
Inflammatory Bowel Disease
MedDRA 
Medical Dictionary for Regulatory Activities 
NSAID 
Non-steroidal Anti-inflammatory drug 
SAE 
Serious Adverse Event 
TNF 
Tumor Necrosis Factor 
UC 
Ulcerative Colitis
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SDP :  
 
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DreamCIS 
Rm. 1010 130, Sajik-ro, Jongno-gu, Seoul, 110-756, Korea  
Phone: +82-2-2010-4500 
Fax: +82-2-720-5385  

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
6

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A Prospective Multi-Center study to observe the Effectiveness on Ulcerative Colitis and predictive 
factors of clinical REsponse in Korean Patients treated with Adalimumab (EUREKA study)
5DWLRQDOHDQG%DFNJURXQG
Ulcerative colitis (UC) is a chronic inflammatory bowel disorder characterized by a relapsing and 
remitting course. In Korea, the incidence and prevalence of CD and UC are low compared to that in 
Europe and the USA, but are increasing rapidly. According to a recent epidemiological survey of IBD in 
Korea that extrapolated the national incidence from the actual measured incidence in a sample from an 
urban district in Seoul, the mean annual incidence of UC in Korea increased from 0.34 per 100,000 
inhabitants in 1986-1990 to 3.08 per 100,000 inhabitants in 2001-2005 (1). The adjusted prevalence rate 
of UC per 100,000 inhabitants was 30.87 (95% CI, 27.47-34.27). Genotypic features and clinical 
characteristics of Korean IBD are somewhat different from those seen in Western countries. For example 
the HLA-DRB1*1502 allele was shown to be positively associated with UC in Korea, whereas in 
Western populations this association is absent (2). The clinical features of UC at diagnosis are reported 
to be similar in Koreans and Westerners (3), however, the clinical course of UC in Korean patients 
seems milder than that in Western countries, as indicated by the lower rates of colectomy and better 
responses to pharmacological management (4). In terms of drug toxicity, Korean patients with IBD who 
are treated with AZA/6-MP experience myelotoxicity more frequently than similarly treated Europeans. 
Among 133 IBD patients treated with azathioprine in Korea, leucopenia occurred in 75 cases (56.4%), 
which more frequent than the rates reported in Western studies (5). In a retrospective study of infliximab 
in 134 Korean UC patients, the rates of clinical response and remission were 87% and 45% at week 8 
(6). Long-term clinical response and remission rates were 71% and 52%, respectively, and mucosal 
healing was the only factor influencing long-term response. Recently (2013), adalimumab, already used 
in the treatment of CD, was approved treating moderately to severely active UC in adults with an 
inadequate response to conventional therapy or who are intolerant to or have medical contraindications 
for such therapies. To our best knowledge, there is no published data about the effectiveness and safety 
of adalimumab for the treatment of UC in Korean patients. In addition, gut bacteria play an important 
role in the onset and perpetuation of intestinal inflammation in IBD. Some dysbiosis have been found in 
UC as well as Crohn’s disease, and also their relationship to the clinical course of IBD has been 
suggested. Composition of Fecal microbiota (16S rRNA gene sequencing) will be regarded as predictive 
factors of clinical response in this study (7-9). This will be the first prospective study to evaluate the 
effectiveness of adalimumab in Korean patients with UC in the real-life clinical setting and tto explore 
predictive factors of clinical response. 
5HVHDUFK4XHVWLRQDQG2EMHFWLYHV
To evaluate the real world effectiveness of adalimumab in Korean patients with Ulcerative Colitis (UC) 
and to explore potential predictive factors of clinical response to adalimumab treatment in patients with 
UC.
6WXG\'HVLJQ

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
7
This is a prospective, single country, multi-center study in UC patients treated with adalimumab. 147 
subjects will be enrolled at approximately 20 sites. The baseline assessment should be performed prior to 
the first dose of adalimimab (Visit1). Study visits will be conducted at weeks 8, 16, 24, 32, 40, 48 and 56 
in accordance with clinical practice. All subjects will have one Follow-up approximately 70 days after 
the last dose of adalimumab. 
The prescription of adalimumab is at the discretion of the physician in accordance with clinical practice 
and label, and is made independently from this study and precedes the decision to offer the patient the 
opportunity to participate in this study.
Primary Endpoint: 
•
Clinical response at week 8 
•
Clinical response at week 56 in week 8 responders 
Secondary Endpoints:  
•
Clinical remission at week 8 and 56 
•
Steroid free remission at week 8 and 56 
•
Mucosal healing at week 8 and  56 
•
Change of partial Mayo score from baseline overtime 
•
The change of the composition of Fecal micro biota from baseline at week 56 
•
The mean change of Fecal calprotectin level from baseline at week 56  
3RSXODWLRQ
Subject will be adults with UC who meet the eligibility criteria. 
Inclusion Criteria 
•
Subject must be an adult Ӌ19 years 
•
Subject with active moderate-to-severe ulcerative colitis patients with Mayo score of Ӌ6 points 
and endoscopic sub-score of Ӌ2 points despite treatment with corticosteroids and/or 
immunosuppressants 
•
Subjects must have tuberculosis (TB) Screening Assessment in accordance Korean 
reimbursement guideline 
•
Subjects who are started on adalimumab treatment in normal clinical practice setting 
•
Subject must provide written authorization form to use personal and/or health data prior to the 
entry into the study 
Exclusion Criteria 
•
Female subjects who are pregnant or breast feeding 
•
Subject applies with any contraindication to adalimumab 
•
Subject is  participating in other clinical trials
9DULDEOHV
•
Demographics: Age, Gender,  Co-morbidity, disease duration and extent 
•
UC-related medication  
•
Full and partial Mayo score  
•
Endoscopic sub-score for mucosal healing 
•
General lab test including CRP, albumin and hemoglobin 
•
Adalimumab related test: trough level and  antibody level 
•
Stool examination: Fecal calprotectin level and Fecal microbiota (16S rRNA gene sequencing) 
•
Adalimumab administration

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
8
'DWD6RXUFH   
The investigator should maintain source documents for each subject in the study, consisting of medical 
records containing demographic data, and other information to be collected.  
6WXG\6L]H
With reference to adalimumab real life data in UC, clinical response rate to adalimumab at week 12 was 
75%(10). Assuming 95% confidence interval, 15% confidence interval width and an estimated drop-out 
rate of 5%, we aim to recruit up to 147 subjects in this study. 
'DWD$QDO\VLV   
The study population will be classified by ITT (Intend-To-Treat) set and PP (Per-Protocol) set. 
-ITT set: The ITT set will include all subjets intended to treat with adalimumab. At week 8,  all subjects 
who have received adalimumab treatment at least once will be includd and at week 56, all subjects who 
have clinical response at week 8 wiil be included. 
-PP set: The PP set will include all subjects who meet the eligibility criteria for this study and complete 
the evaluation without any major protocol deviation among the ITT set. At week 8, all subjects who 
meet the eiligibility criteria and complete the evaluation at week 8 will be included and at week 56, all 
subjects who complete the evaluation and the study follow-up without any major protocol deviation. 
General Considerations 
As an observational study, the study variables will be analysed and described using descriptive statistics. 
Continuous variables will be described, using the mean and 95% confidence intervals For categorical 
variables, the frequency and proportion will be presented. The values such as arithmetic mean, standard 
deviation, and proportion will be rounded to two decimal places. If the observation value is missing 
value, it will be treated as a missing value in the analysis. 
Baseline Characteristics including demographics 
Descriptive statistics will be used to present variables regarding demographics and disease/medication 
related data. Continuous variables will be described with the number of patients, arithmetic mean, 
standard deviation, median, minimum and maximum. For categorical variables, the frequency and 
proportion will be presented. The values such as arithmetic mean, standard deviation, and proportion 
will be rounded to two decimal places. 
If the observation value is missing value, it will be treated as a missing value in the analysis. Statistical 
analyses will be performed using SAS V9.2 or higher. 
0LOHVWRQHV  Start of Data Collection: 1Q 2015 
End of Data Collection: 2Q 2017  
Final Report of Study Results: 4Q 2017 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
9
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1 
08Mar2015 
Change 
the 
collection 
period for SAE  
Pregnancy and malignancy 
text to be added 
Product complaints text 
added 
Update 
Rivese reporting date for drop out 
subjects and collection period for 
SAE 
Add definition of product complaint,  
justification for not including all AEs,  
collection period for pregnancy and  
definition of product complaint 
2 
26Sep2016 
Sample size 
Reference 
Amendment 
Change of sample size and reference 

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Major study milestones and their planned dates are as follows: 
Start of Data Collection: 
1Q 2015
End of Data Collection: 
2Q 2017
Final Report of Study Results: 
4Q 2017

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,QWURGXFWLRQ
 Ulcerative colitis (UC) is a chronic inflammatory bowel disorder characterized by a 
relapsing and remitting course. In Korea, the incidence and prevalence of CD and UC are 
low compared to that in Europe and the USA, but are increasing rapidly. According to a 
recent epidemiological survey of IBD in Korea that extrapolated the national incidence 
from the actual measured incidence in a sample from an urban district in Seoul, the mean 
annual incidence of UC in Korea increased from 0.34 per 100,000 inhabitants in 1986-
1990 to 3.08 per 100,000 inhabitants in 2001-2005(1). The adjusted prevalence rate of UC 
per 100,000 inhabitants was 30.87 (95% CI, 27.47-34.27). Genotypic features and clinical 
characteristics of Korean IBD are somewhat different from those seen in Western 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
10 
countries. For example the HLA-DRB1*1502 allele was shown to be positively associated 
with UC in Korea, whereas in Western populations this association is absent(2). The 
clinical features of UC at diagnosis are reported to be similar in Koreans and Westerners(3),
however, the clinical course of UC in Korean patients seems milder than that in Western 
countries, as indicated by the lower rates of colectomy and better responses to 
pharmacological management(4). In terms of drug toxicity, Korean patients with IBD who 
are treated with AZA/6-MP experience myelotoxicity more frequently than similarly 
treated Europeans. Among 133 IBD patients treated with azathioprine in Korea, 
leucopenia occurred in 75 cases (56.4%), which more frequent than the rates reported in 
Western studies(5). In a retrospective study of infliximab in 134 Korean UC patients, the 
rates of clinical response and remission were 87% and 45% at week 8(6). Long-term 
clinical response and remission rates were 71% and 52%, respectively, and mucosal 
healing was the only factor influencing long-term response. Recently (2013), adalimumab 
was already used in the treatment of CD, was approved treating moderately to severely 
active UC in adults with an inadequate response to conventional therapy or who are 
intolerant to or have medical contraindications for such therapies. To our best knowledge, 
there is no published data about the effectiveness and safety of adalimumab for the 
treatment of UC in Korean patients. In addition, gut bacteria play an important role in the 
onset and perpetuation of intestinal inflammation in IBD. Some dysbiosis have been 
found in UC as well as Crohn’s disease, and also their relationship to the clinical course of 
IBD has been suggested. Composition of Fecal microbiota (16S rRNA gene sequencing) 
will be regarded as predictive factors of clinical response in this study(7-9).

5DWLRQDOH
 This will be the first prospective study to evaluate the effectiveness of adalimumab in 
Korean patients with UC in the real-life clinical setting and to explore clinical predictive 
factors of response. 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
11 

5HVHDUFK4XHVWLRQDQG2EMHFWLYHV
To evaluate the real world effectiveness of adalimumab in Korean patients with 
Ulcerative Colitis (UC) through a prospective study and to explore potential predictive 
factors of clinical response to adalimumab treatment. 

5HVHDUFK0HWKRGV

6WXG\'HVLJQ
This is a prospective, single-country, multi-center study in UC patients treated with 
adalimumab. The prescription of adalimumab is at the discretion of the physician in 
accordance with clinical practice and label, is made independently from this study and 
precedes the decision to offer the patient the opportunity to participate in this study. 
Up to 147 subjects will be enrolled at approximately 20 sites.  
The baseline assessment should be performed prior to the first dose of adalimumab 
(Visit1). Patients will be given adalimumab 160 mg at week 0, 80 mg at week 2, and then 
40 mg every other week on label. Study visits will be conducted at weeks 8, 16, 24, 32, 40, 
48 and 56 after baseline in accordance with clinical practice (window period for each 
follow up visit will be ±1 week). All subjects will have one Follow-up for safety 
approximately 70 days after the last dose of adalimumab. 
Clinical response will be assessed at week 8, and patients with clinical response at week 
8 will be allowed to continue on adalimumab treatment as per Korean reimbursement 
guidelines and will be followed up in the study.  Clinical response is defined as a decrease 
from baseline in the total Mayo score by at least 3 points and at least 30% with an 
accompanying decrease in rectal bleeding subscore of at least 1 point or absolute rectal 
bleeding sub-score of 0 or 1. 
3ULPDU\(QGSRLQW
•
The percentage of patients with clinical response at week 8  

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
12 
•
The percentage of patients with clinical response at week 56 in week 8 responders 
Clinical response is defined as reduction in complete Mayo score of  3 points and 
30% from Baseline (Week 0) with an accompanying decrease in rectal bleeding 
subscore of  1 point or absolute rectal bleeding subscore of  1 point at week 8.  
Durable clinical response is defined as reduction in complete Mayo score of  3 
points and  30% from Baseline (Week 0) with an accompanying decrease in rectal 
bleeding subscore of  1 point or absolute rectal bleeding subscore of  1 point at 
both week 8 and 56. 
6HFRQGDU\(QGSRLQW
•
The percentage of patients with clinical remission at week 8 and 56 (in week 8 
sesponders) 
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VXEVFRUHH[FHHGLQJSRLQW
•
The percentage of patients with steroid-free remission at week 8 and 56 (in week 
8 responders). 
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RIV\VWHPLFVWHURLGVZLWKLQWKHSDVWZHHNVSULRUWRDVVHVVPHQW
•
The percentage of patients with mucosal healing at week 8 and 56 (in  week 8 
responders). 
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•
The change of partial Mayo score from baseline overtime 
•
The change of the composition of Fecal micro biota from baseline at week 56 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
13 
•
The mean change of Fecal calprotectin level from baseline at week 56  
([SORUDWRU\GDWDDQDO\VLV
In addition to the above secondary end-points, exploratory analysis will be conducted to 
identify potential predictive factors of clinical effectiveness of adalimumab. These would 
include age, disease duration, disease extent, ESR and CRP concentrations, level of 
hemoglobin, albumin level, Fecal calprotectin level, the composition of Fecal microbiota 
at baseline, and week 8, trough levels of adalimumab at week 8 and TNF antagonist 
naivety will be considered.

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Subject will be adults with UC who meet the eligibility criteria.  
,QFOXVLRQ&ULWHULD
z
Subject must be an adult 19 years 
z
Subject with active moderate-to-severe ulcerative colitis patients with Mayo score 
of  6 points and endoscopic sub-score of  2 points despite treatment with 
corticosteroids and/or immunosuppressants.  
z
Subject who must have tuberculosis (TB) Screening Assessment in accordance 
with Korean reimbursement guideline 
z
Subjects who are started on adalimumab treatment in normal clinical practice 
setting by their physician. 
z
Subject must provide written authorization form to use personal and/or health 
data prior to the entry into the study 
([FOXVLRQ&ULWHULD
z
Female subjects who are pregnant or breast feeding 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
14 
z
Subjects with any contraindication to adalimumab 
z
Subjects that is participating in other clinical trials 

'URS2XW6XEMHFWV
Once a subject is dropped out from the study, no further information for that subject will 
be collected. However, the reason for drop-out will be reported and serious adverse events 
will be reported to AbbVie until 70 days following the intake of the last dose of 
adalimumab. 
Subjects will be dropped out from the study: 
1)
If the subjects choose to withdraw from the study 
2) Where ethical or practical conflicts hinder the procedure of the study, and such 
cases will be determined based on the investigator’s judgment 
3)
In case of Adalimumab discontinuation at any point during study period 

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The gastroenterologist will be selected based on the following criteria: 
z
Those who work in hospitals that have sufficient numbers of eligible patients. 
z
Those who agree to devote adequate time to conduct the study in accordance with 
the protocol. 
z
Those who are trained in Good clinical practice and commit to reporting any 
serious adverse events in patients using an AbbVie product to AbbVie in 
accordance with the protocol. 

0HWKRGRORJ\
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Participating subjects will be followed up at week 8, 16, 24, 32, 40, 48 and 56 in 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
15 
accordance with clinical practice after baseline (window period for each follow up visit 
will be ±1 week).  Demographics, disease and medication related data will be collected at 
baseline. Also, general laboratory tests will be conducted and Mayo score will be 
calculated.
Subjects will be administered adalimumab 160 mg at week 0, 80 mg at week 2, and then 
40 mg every other week per the Korean label. Clinical response will be assessed at week 8, 
and subjects showing clinical response at week 8 will be allowed to continue on 
Adalimumab treatment as per Korean reimbursement guidelines and will be followed up 
in the study. 
Clinical response is defined as a decrease from baseline in the total Mayo score at least 3 
points and at least 30% with an accompanying decrease in rectal bleeding sub-score of at 
least 1 point or an absolute rectal bleeding sub-score of 0 or 1.
On every follow-up visit, partial Mayo score will be measured to observe the 
effectiveness of adalimumab and general lab test will be carried out as per Korean clinical 
practice. Endoscopy will be performed and full Mayo score will be calculated at baseline, 
week 8, week 56 and inadequate response in accordance with Korean clinical practice.  
/DERUDWRU\YDULDEOHV
)HFDOVDPSOHV
Fecal calprotectin and the composition of Fecal microbiota (16S rRNA gene sequencing) 
will be measured at baseline, week 8 and 56. In addition to 16S rRNA gene sequencing 
for microbiome analysis, stool samples will be frozen and stored in order to facilitate 
additional testing including metagenomic sequencing for microbiome analysis in the 
future.   
%ORRGVDPSOHV
Trough levels of adalimumab will be measured at week 8 and at the time of inadequate 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
16 
response despite dose escalation. Antibodies against adalimumab (AAA) will be measured 
at inadequate response despite dose escalation. Inadequate response is defined as: (1) 
partial Mayo score equal to or above baseline score on 2 consecutive visits at least 14 
days apart (for patients with a partial Mayo score of 4-7 at baseline); (2) partial Mayo 
score 7 on 2 consecutive visits at least 14 days apart (for patients with a partial Mayo 
score of 8 or 9 at baseline). In case of inadequate response, subjects will move to 40 mg 
every week. Unresponsive subjects to dose escalation will discontinue on their physician’s 
judgement.  
In the event of adalimumab discontinuation, the reason for discontinuation will be 
collected.   
In the analyses of each individual predictive factors, subjects of various ages, disease 
duration, disease extent, ESR and CRP concentrations, level of hemoglobin, albumin level, 
Fecal calprotectin level and the composition of Fecal microbiota at baseline and week 8, 
trough levels of adalimumab at week 8 TNF antagonist naivety will be considered.
The following variables will be collected at baseline and every follow-up visit thereafter 
during the study period. 
:LQGRZSHULRGIRUHDFKIROORZXSYLVLWZLOOEHZHHN
%DVHOLQH
1) Demographics: Age, Gender, Weight,  Co-morbidity, Date of  UC diagnosis, 
Disease duration and extent 
2) UC-related medication and history of other anti -TNF experience 
3) Full Mayo score including endoscopic sub-score 

Adalimumab 
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4) General lab test: hemoglobin, albumin , ESR and CRP 
5) Stool examination: calprotectin level and the composition of Fecal microbiota 
6) Adalimumab administration 
:HHNDIWHUEDVHOLQH
1) Full Mayo score including endoscopic sub-score 
2) General lab test: hemoglobin, albumin , ESR and CRP 
3) Adalimumab related lab test: adalimumab trough level 
4) Stool examination: calprotectin level and the composition of Fecal microbiota 
5) Adalimumab administration schedule 
:HHNDQGDIWHUEDVHOLQH
1) Partial Mayo score 
:HHNDIWHUEDVHOLQH
1) Full Mayo score including endoscopic sub-score 
2) General lab test: hemoglobin, albumin, ESR and  CRP 
3) Stool examination: calprotectin level and the composition of Fecal microbiota 
$GGLWLRQDOGDWDFROOHFWHG
In the event of inadequate response even if dose escalation, as part of the evaluation of 
patients in accordance with local clinical practice, the following data may be collected: 
1) Endoscopy findings 

Adalimumab 
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Amendment 1 (26 September 2016) 
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2) Trough level of adalimumab and Antibodies against adalimumab 
3) The composition of fecal microbiota 

'DWD6RXUFHV
The investigator should maintain source documents for each subject in the study, 
consisting of medical records containing demographic data, and other information to be 
collected.  
Case Report Forms will be supplied by AbbVie, and used to transmit the collected 
information during this study to AbbVie.  
Case report forms will include patient demographic information, e.g., gender, age, 
weight, unique patient study number, family history of UC, co-morbidity and the 
information to be evaluated according to the study protocol. Case report forms will 
maintain patient confidentiality, e.g., patient names must not be collected and full date of 
birth must not be collected (age is acceptable). The investigator or staff under his/her 
supervision must complete the case report forms, and neither AbbVie nor any agents 
acting on behalf of AbbVie may complete the case report forms. 

6WXG\6L]H
The primary endpoint of this study is to investigate the effectiveness of adalimumab in 
Korean patients with Ulcerative Colitis (UC) in real life settings. 
With reference to adalimumab real life data in UC, clinical response rate to adalimumab 
at week 12 was about 75%(10). Assuming 95% confidence interval, 15% confidence 
interval width and an estimated drop-out rate of 5%, we aim to recruit up to 147 subjects 
in this study. 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
19 

'DWD0DQDJHPHQW
Investigator should complete, sign and date the CRFs accurately. All CRFs must be 
legible and completed in indelible ballpoint ink. Corrections to the CRFs should be made 
with a single line, be initialed and dated, with the reason for changes given. Data are not 
to be obliterated by blacking out, correction fluid, or by erasing the original entry. 
At the completion of the study, the completed signed and dated case report forms of all 
enrolled subjects should be provided to AbbVie by the investigator. ONLY data specified 
in the protocol should be collected and submitted to AbbVie. 
CRAs or their designees will be responsible to review the collected case report forms for 
completeness and conclusiveness. 

'DWD$QDO\VLV
The study population will be classified by ITT (Intend-To-Treat) set and PP (Per-
Protocol) set. 
-ITT set: The ITT set will include all subjets intended to treat with adalimumab. At week 
8,  all subjects who have received adalimumab treatment at least once will be includd and , 
at week 56, all subjects who have clinical response at week 8 wiil be included. 
-PP set: The PP set will include all subjects who meet the eligibility criteria for this study 
and complete the evaluation without any major protocol deviation among the ITT set. At 
week 8, all subjects who meet the eiligibility criteria and complete the evaluation at week 
8 will be included and at week 56, all subjects who complete the evaluation and the study 
follow-up without any major protocol deviation. 
*HQHUDO&RQVLGHUDWLRQV
Continuous variables will be described with the number of subjects, arithmetic mean and 
standard deviation. For categorical variables, the frequency and proportion will be 
presented. The values such as arithmetic mean, standard deviation, and proportion will be 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
20 
rounded to two decimal places. If the observation value is missing value, it will be treated 
as a missing value in the analysis. 
%DVHOLQH&KDUDFWHULVWLFVLQFOXGLQJGHPRJUDSKLFV
Descriptive statistics will be used to present variables regarding demographics and 
disease/medication related data. Continuous variables will be described with the number 
of subjects, arithmetic mean and standard deviation. For categorical variables, the 
frequency and proportion will be presented. The values such as arithmetic mean, standard 
deviation, and proportion will be rounded to two decimal places. 
If the observation value is missing value, NRI and LOCF will be used for a missing 
value. Statistical analyses will be performed using SAS V9.2 or higher. 
3ULPDU\(QGSRLQW
•
The percentage of subjects with clinical response at week 8  
•
The percentage of subjects with clinical response at week 56 in in week 8 
responders 
; The frequency and proportion of subjects with clinical response at week 8 and 56 
will be presented. 
6HFRQGDU\(QGSRLQWV
•
The percentage of subjects with clinical remission at week 8 and 56 (in week 8 
responders) 
; The frequency and proportion of subjects with clinical remission at week 8 and 56 
will be presented. 
•
The percentage of subjects with steroid-free remission at week 8 and 56 (in  week 
8 responders) 

Adalimumab 
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Amendment 1 (26 September 2016) 
21 
; The frequency and proportion of subjects with steroid-free remission at week 8 and 
56 will be presented. 
•
The percentage of subjects with mucosal healing at week 8 and 56 (in week 8 
responders) 
; The frequency and proportion of subjects with mucosal healing at week 8 and 56 
will be presented. 
•
The change of partial Mayo score from baseline overtime 
; The descriptive statistics (the number of patients, mean, standard deviation, min, 
max) for partial Mayo score according to study visit and the change from baseline 
overtime will be presented.  
•
The change of the composition of Fecal micro biota from baseline at week 56 
•
The mean change of Fecal calprotectin level from baseline at week 56  

6DIHW\$QDO\VLV
The serious adverse event · adverse drug reaction will be coded by MedDRA latest 
version. 
The cumulative total number and percentage of subjects reporting serious adverse event · 
adverse drug reaction will be tabulated. Also, AEs leading to discontinuation of 
adalimumab will be collected and tabulated. 

([SORUDWRU\$QDO\VLV
In addition to the above secondary end-points, exploratory analysis will focus on 
identifying potential predictive factors of clinical effectiveness of adalimiumab. These 
would include age, disease duration, disease extent, ESR and CRP concentrations, level of 
hemoglobin, albumin level, Fecal calprotectin level and the composition of Fecal 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
22 
microbiota at baseline and week 8 trough levels of adalimumab at week 8, TNF antagonist 
naivety will be considered. 

4XDOLW\&RQWURO
Prior to the initiation of the study, an investigator’s meeting or initiation visit will be 
held with AbbVie personnel or his/her designee, the investigators and their study 
coordinators. This meeting will include a review of the protocol and CRF completion 
guideline. 
Investigator must assure that the study is conducted in accordance with the protocol and 
all relevant regulations and CRF is completed accurately. 
In general, monitoring for any site is not required, but, for quality assurance, internal 
consistency check for completeness and consistency of data will be done to ensure the 
integrity of the information reported. 
CRF will be reviewed by CRAs at AbbVie or their designees for completeness and 
conclusiveness and when necessary, query will be generated and will be resolved by the 
site staffs.  
All data hand-entered in the database will be verified by a double-key entry procedure. 
Any discrepancies will be reviewed against the hard copy CRF and corrected. After 
completion of the entry process, computer logic checks will be run. Any necessary 
corrections will be made to the database and documented. 

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NA 

2WKHU$VSHFWV
NA 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
23 

3URWHFWLRQRI+XPDQ6XEMHFWV
The study should receive approval from the Institutional Review Board (IRB) of the each 
institution, and then a written study agreement should be made with institutions before the 
initiation of the study in each institution. 
Patient written authorization form to use and/or disclose personal and/or health data from 
subjects must be obtained prior to enrolling the subject and the investigator is required to 
document this authorization.  
Subject confidentiality must be maintained at all times; therefore demographics that 
could identify the patients will not be collected.  
Monitoring for any sites is not required. However internal consistency check for 
completeness and consistency of data will be done to ensure integrity of the information 
reported. 

0DQDJHPHQWDQG5HSRUWLQJRI&RPSODLQWV
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution. 
The investigational product in this trial contains both:  
x
Biologic compound(s) and 
x
Device component(s) (pre-filled syringe, pen). 
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 11.2.2). For adverse events, please refer to 
Sections 11.1.1 through 11.1.6. For product complaints, please refer to Section 11.2. 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
24 

0HGLFDO&RPSODLQWV

$GYHUVH (YHQW 'HILQLWLRQ DQG 6HULRXV $GYHUVH (YHQW
&DWHJRULHV
An adverse event (AE) is defined as any untoward medical occurrence in a patient, 
which does not necessarily have a causal relationship with their treatment. An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not the event is considered causally related to the use of the 
product. 
Such an event can result from use of the drug as stipulated in the labeling, as well as 
from accidental or intentional overdose, drug abuse, or drug withdrawal. Any worsening 
of a pre-existing condition or illness is considered an adverse event. 
If an adverse event meets any of the following criteria, it is considered a serious adverse 
event (SAE): 
'HDWKRI3DWLHQW
An event that results in the death of a patient. 
/LIH7KUHDWHQLQJ
An event that, in the opinion of the investigator, 
would have resulted in immediate fatality if medical 
intervention had not been taken. This does not include 
an event that would have been fatal if it had occurred 
in a more severe form. 
+RVSLWDOL]DWLRQ
An event that results in an admission to the hospital 
for any length of time. This does not include an 
emergency room visit or admission to an outpatient 
facility. 
3URORQJDWLRQRI
+RVSLWDOL]DWLRQ
An event that occurs while the study patient is 
hospitalized and prolongs the patient's hospital stay. 
&RQJHQLWDO$QRPDO\
An anomaly detected at or after birth, or any anomaly 
that results in fetal loss. 
3HUVLVWHQWRU6LJQLILFDQW
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
25 
'LVDELOLW\,QFDSDFLW\
patient. Disability is not intended to include 
experiences of relatively minor medical significance 
such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained 
ankle). 
,PSRUWDQW0HGLFDO(YHQW
5HTXLULQJ0HGLFDORU
6XUJLFDO,QWHUYHQWLRQWR
3UHYHQW6HULRXV2XWFRPH
An important medical event that may not be 
immediately life-threatening or result in death or 
hospitalization, but based on medical judgment may 
jeopardize the patient and may require medical or 
surgical intervention to prevent any of the outcomes 
listed above (i.e., death of patient, life threatening, 
hospitalization, 
prolongation 
of 
hospitalization, 
congenital anomaly, or persistent or significant 
disability/incapacity). Additionally, any elective or 
spontaneous abortion or stillbirth is considered an 
important medical event. Examples of such events 
include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug 
dependency or drug abuse. 

6HYHULW\
The following definitions will be used to rate the severity for any adverse event being 
collected as an endpoint/data point in the study and for all serious adverse events. 
0LOG
The adverse event is transient and easily tolerated by the patient. 
0RGHUDWH
The adverse event causes the patient discomfort and interrupts the 
patient's usual activities. 
6HYHUH
The adverse event causes considerable interference with the 
patient's usual activities and may be incapacitating or life 
threatening. 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
26 

5HODWLRQVKLSWR3KDUPDFHXWLFDO3URGXFW
The following definitions will be used to assess the relationship of the adverse event to 
the use of product: 
5HDVRQDEOH3RVVLELOLW\
An adverse event where there is evidence to suggest a 
causal relationship between the product and the adverse 
event. 
1R5HDVRQDEOH3RVVLELOLW\
An adverse event where there is no evidence to suggest a 
causal relationship between the product and the adverse 
event. 
If no reasonable possibility of being related to product is given, an alternate etiology 
must be provided for the adverse event. 

6HULRXV$GYHUVH(YHQW&ROOHFWLRQ3HULRG
Serious adverse events will be reported to AbbVie from the time the physician obtains 
the patient's authorization to use and disclose information (or the patient's informed 
consent) until 70 days following the intake of the last dose of adalimumab taken during 
the study. 

6HULRXV$GYHUVH(YHQW5HSRUWLQJ
This protocol requires all SAEs as outlined in protocol section 11.1.1 to be actively 
solicited. The safety profile of adalimumab which has over 3.5 million PYs of post-
marketing exposure is stable and well established; non-serious events will not be actively 
solicited as these events are not likely to contribute to the further understanding of the 
safety profile of the product. Any non-serious AEs will be collected as spontaneous 
reports if AbbVie is notified. 
In the event of a serious adverse event, and additionally, any non-serious event of 
malignancy in patients 30 years of age and younger, whether related to study drug or not, 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
27 
the physician will notify the AbbVie contact person identified below within 24 hours of 
the physician becoming aware of the event.  
$EE9LH6DIHW\.RUHD

3UHJQDQF\5HSRUWLQJ
Pregnancies in patients will be collected from the date of the first dose through 150 days 
following the last dose of adalimumab taken during the study. In the event of a pregnancy 
occurrence in the patient, the physician will notify AbbVie contact person identified in 
Section 11.1.5 within 24 hours of the physician becoming aware of the pregnancy. 

3URGXFW &RPSODLQW

'HILQLWLRQ
A Product Complaint is any Complaint (see Section 11.0 for the definition) related to the 
biologic or drug component of the product or to the medical device component(s). 
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example: printing illegible), 
missing components/product, device not working properly, or packaging issues. 
For medical devices, a product complaint also includes all deaths of a patient using the 
device, any illness, injury, or adverse event in the proximity of the device, an adverse 
event that could be a result of using the device, any event needing medical or surgical 
intervention including hospitalization while using the device and use errors. 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
28 
Any information available to help in the determination of causality by the device to the 
events outlined directly above should be captured. 

5HSRUWLQJ
Product Complaints concerning the investigational product and/or device must be 
reported to the Sponsor within 24 hours of the study site's knowledge of the event via 
local Product Complaint reporting practices. Product Complaints occurring during the 
study will be followed-up to a satisfactory conclusion. All follow-up information is to be 
reported to the Sponsor (or an authorized representative) and documented in source as 
required by the Sponsor. Product Complaints associated with adverse events will be 
reported in the study summary. All other complaints will be monitored on an ongoing 
basis. 
Product complaints involving a non-Sponsor investigational product and/or device 
should be reported to the identified contact or manufacturer, as necessary per local 
regulations. 
Product Complaints may require return of the product with the alleged complaint 
condition (syringe, pen, etc.). In instances where a return is requested, every effort should 
be made by the investigator to return the product within 30 days. If returns cannot be 
accommodated within 30 days, the site will need to provide justification and an estimated 
date of return. 
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required. 

3ODQVIRU'LVVHPLQDWLQJDQG&RPPXQLFDWLQJ6WXG\
5HVXOWV
At the end of the study, a study report will be written by AbbVie in collaboration with 
the principal investigator. This report will contain a description of the objectives of the 

Adalimumab 
P15-346 Protocol 
Amendment 1 (26 September 2016) 
29 
study, the methodology of the study and its results and conclusions. The completed case 
report forms and the study report must be treated as the confidential property of AbbVie 
and may not be released to unauthorized people in any form (publications or 
presentations) without express written approval from AbbVie. The results of this study 
may be published by AbbVie or by any one of the participating investigators after 
agreement with AbbVie. 

Adalimumab 
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Amendment 1 (26 September 2016) 
30 

5HIHUHQFHV
1. Yang SK, Yun S, Kim JH, et al. Epidemiology of inflammatory bowel disease in 
the Songpa-Kangdong district, Seoul, Korea, 1986-2005: a KASID study. 
Inflamm Bowel Dis 2008;14:542-549. 
2. Myung SJ, Yang SK, Jung HY, et al. HLA-DRB1*1502 confers susceptibility to 
ulcerative colitis, but is negatively associated with its intractability: a Korean 
study. Int J Colorectal Dis 2002;17:233-237. 
3. Park SH, Kim YM, Yang SK, et al. Clinical features and natural history of 
ulcerative colitis in Korea. Inflamm Bowel Dis 2007;13:278-283. 
4. Eun Soo Kim and Won Ho Kim. Inflammatory Bowel Disease in Korea: 
Epidemiological, Genomic, Clinical, and Therapeutic Characteristics. Gut and 
Liver, Vol. 4, No. 1, March 2010, pp. 1-14. 
5. Kim JH, Cheon JH, Kim WH. The frequency and the course of the adverse effects 
of azathioprine/6-mercaptopurine treatment in patients with inflammatory bowel 
disease. Korean J Gastroenterol 2008;51:291-297. 
6. Lee KM et al. Efficacy, safety, and predictors of response to infliximab therapy 
for ulcerative colitis: a Korean multicenter retrospective study. J Gastroentero 
Hepatol 2013 Dec;28(12):1829-33Prideaux L, Kang S, Wagner J, et al. Impact of 
ethnicity, geography, and disease on the microbiota in health and inflammatory 
bowel disease. Inflamm Bowel Dis. 201319:2906-18. 
7. Prideaux L, Kang S, Wagner J, et al. Impact of ethnicity, geography, and disease 
on the microbiota in health and inflammatory bowel disease. Inflamm Bowel Dis. 
201319:2906-18. 
8. Machiels K, Joossens M, Sabino J, et al. A decrease of the butyrate-producing 
species Roseburia hominis and Faecali bacterium prausnitzii defines dysbiosis in 
patients with ulcerative colitis. Gut. 2014 Aug;63(8):1275-83.

Adalimumab 
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31 
9. Wills ES, Jonkers DM, Savelkoul PH, Masclee AA, Pierik MJ, Penders J. Fecal 
microbial composition of ulcerative colitis and Crohn's disease patients in 
remission and subsequent exacerbation.. PLoS One. 2014 Mar 7;9(3):e90981.  
10.  F. Beart, N. Vande Casteele, S.Tops, et al. Prior response to infliximab and early 
serum drug concentrations predict effects of adalimumab in ulcerative colitis. 
Aliment Pharmacol Ther. 2014;40:1324-32.