Clinical Effectiveness and Safety of Vedolizumab Intravenous in Real World Clinical Practice in Ulcerative Colitis Korean Patients: a Multicenter Post-marketing Observational Study
Conditions: Colitis, Ulcerative
Sponsor: Takeda




Title: Clinical effectiveness and safety of vedolizumab intravenous in real world clinical practice 
in ulcerative colitis Korean patients: a multicenter postmarketing observational study
NCT Number: NCT03535649
Protocol Approve Date: 24 September 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.

Vedolizumab-5045
Study Protocol Final Ver. 4.1, 24-SEP-2018 
Page 1 of 47 
Non-Interventional Study Protocol 
Title: 
Clinical effectiveness and safety of vedolizumab intravenous in real world 
clinical practice in ulcerative colitis Korean patients: a multicenter post-
marketing observational study 
Short title: 
Vedolizumab in ulcerative colitis Korean patients 
Study ID: 
Vedolizumab-5045 
Sponsor: 
Takeda Pharmaceuticals Korea Co., Ltd. 
(Daechi-dong, 12F) 8, Teheran-ro 98-gil, 
Gangnam-gu, Seoul 06181, Korea 
Phone: +82 2 3484 0800 
Fax: 
+82 2 3484 0808 
Study phase:  Medical Affairs, Post-Approval Company Sponsored (Observational) 
Date of final version 4.1 of protocol: 24 September 2018 (Amendment 4) 
Proper
f Takeda: For non-commercial use only and subject to the applicable Terms of Use

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Vedolizumab-5045 
 
 
Study Protocol Final Ver. 4.1, 24-SEP-2018 
Page 4 of 47 
INVESTIGATOR SIGNATURE PAGE 
I confirm that I have read and that I understand this protocol and any other product 
information provided by the sponsor. I agree to conduct this study in accordance with the 
requirements of this protocol and also to protect the rights, safety, privacy, and well-being of 
study patients in accordance with the following: 
 The ethical principles that have their origin in the Declaration of Helsinki.  
 International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline. 
 All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
 Regulatory requirements for reporting serious adverse events as defined in this protocol. 
 
 
 
 
Signature of Investigator 
Date 
 
 
<Investigator Name (print or type)> 
 
<Investigator’s Title> 
 
<Location of Facility (City, State/Provence)> 
 
<Location of Facility (Country)> 
 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Vedolizumab-5045
Study Protocol Final Ver. 4.1, 24-SEP-2018 
Page 5 of 47 
STUDY SUMMARY 
Name of Sponsor(s): 
Takeda Korea 
Compound/Product [if applicable]: 
Vedolizumab 
Title of Protocol: Clinical effectiveness and safety of vedolizumab intravenous in real world clinical 
practice in ulcerative colitis Korean patients: a multicenter post-marketing observational study 
Study Number: Vedolizumab-5045  
Phase: 4 (observational) 
Study Design: 
This is an observational, multicenter, post-marketing study that will analyze real world data on the 
effectiveness and safety of vedolizumab intravenous (IV) in South Korean patients presenting 
ulcerative colitis (UC) and having failed tumor necrosis factor (TNF)-α antagonist therapy (as per the 
approved label).  
Patients will be identified from the medical records and enrolled in the study if they meet the 
inclusion and exclusion criteria. Screening logs of potential patients will be maintained at each of the 
sites, to record reasons why the patient failed eligibility screening. Both retrospective and prospective 
patient data will be collected, with prospective data collected for treatment baseline visit (i.e. first date 
of vedolizumab treatment) and follow up visits. Prospective data will be collected according to each 
site’s IRB definition (i.e. whether treatment baseline and follow up visits happens post initial IRB 
submission date, or post initial IRB approval date, etc). 
The study will collect information on demographics, risk factors, clinical data, laboratory and 
endoscopic data, previous UC medications and surgeries, UC medications and concomitant treatments 
at baseline (start of vedolizumab treatment) and follow-up. The safety outcome measures will include: 
adverse events of special interest (AESIs) (serious infections, opportunistic infections, hepatitis viral 
infection, gastrointestinal infections, respiratory infections, other clinically significant infections, 
malignancies, infusion-related reactions, and hepatic injury), serious adverse events (SAEs), and 
pregnancy outcomes. The data will be abstracted, if available, from the medical charts. 
Data on pregnancy and pregnancy outcomes will be collected subject to a written informed consent 
from the patient or the patient’s partner. 
Primary Objectives: 

To assess the clinical effectiveness of vedolizumab IV in UC Korean patients by the clinical
response at 6 weeks.

To assess the safety of vedolizumab IV in UC Korean patients.
Secondary Objectives: 

To assess the clinical effectiveness of vedolizumab IV in UC Korean patients by the clinical
response at 14 weeks and clinical remission at 6 and 14 weeks.

To assess the clinical effectiveness of vedolizumab IV in UC Korean patients on mucosal healing
at 6 and 14 weeks.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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Vedolizumab-5045 
 
 
Study Protocol Final Ver. 4.1, 24-SEP-2018 
Page 8 of 47 
Sample Size Justification: 
 
The sample size for the study is not based on statistical considerations because it does not consider 
hypothesis testing/power calculation or precision around an estimate. The sample size of 
approximately 100 patients was selected because of potential availability of patients treated with 
vedolizumab IV in South Korea during the study period. 
 
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Vedolizumab-5045 
 
 
Study Protocol Final Ver. 4.1, 24-SEP-2018 
Page 9 of 47 
Table of Contents 
1 
Administrative Information .............................................................................................................. 2 
1.1 
Contacts .................................................................................................................................. 2 
1.2 
Approval ................................................................................................................................. 3 
2 
Introduction ..................................................................................................................................... 14 
2.1 
Ulcerative Colitis .................................................................................................................. 14 
2.2 
Vedolizumab ........................................................................................................................ 15 
2.3 
Study Rationale .................................................................................................................... 16 
3 
Study Objectives and Outcomes ..................................................................................................... 17 
3.1 
Objectives ............................................................................................................................. 17 
3.1.1 
Primary Objectives ................................................................................................ 17 
3.1.2 
Secondary Objectives ............................................................................................ 17 
3.1.3 
Exploratory Objectives ......................................................................................... 17 
3.2 
Outcomes .............................................................................................................................. 17 
3.2.1 
Primary Outcomes ................................................................................................. 18 
3.2.2 
Secondary Outcomes ............................................................................................. 18 
3.2.3 
Exploratory Outcomes .......................................................................................... 18 
4 
Study Administrative Structure ...................................................................................................... 19 
4.1 
National Coordinating Principal Investigator ....................................................................... 19 
4.2 
Study Institutions and Investigators ..................................................................................... 19 
4.3 
Sponsor Personnel ................................................................................................................ 20 
4.4 
Contract Research Organization ........................................................................................... 20 
5 
Ethics .............................................................................................................................................. 21 
5.1 
Ethical Conduct of the Study ................................................................................................ 21 
5.2 
Independent Ethics Committee / Institutional Review Board and Authorities ..................... 21 
5.3 
Authorities ............................................................................................................................ 22 
5.4 
Patient Information and Informed Consent .......................................................................... 22 
6 
Study Design and Plan .................................................................................................................... 24 
6.1 
Study Schedule ..................................................................................................................... 24 
6.2 
Discussion of Study Design .................................................................................................. 25 
6.3 
Study Population .................................................................................................................. 26 
6.4 
Selection of Study Population .............................................................................................. 26 
6.4.1 
Inclusion Criteria ................................................................................................... 26 
6.4.2 
Exclusion Criteria ................................................................................................. 26 
6.5 
Study Variables .................................................................................................................... 26 
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Study Protocol Final Ver. 4.1, 24-SEP-2018 
Page 10 of 47 
6.5.1 
Demographics and Risk Factors Data ................................................................... 27 
6.5.2 
Clinical Data ......................................................................................................... 28 
6.5.3 
Laboratory and Endoscopic Data .......................................................................... 28 
6.5.4 
Treatment Data ...................................................................................................... 28 
6.5.5 
Adverse Events Data ............................................................................................. 29 
6.6 
Study Plan ............................................................................................................................. 32 
7 
Safety Reporting ............................................................................................................................. 34 
7.1 
Definitions ............................................................................................................................ 34 
7.1.1 
Adverse Event ....................................................................................................... 34 
7.1.2 
Adverse Drug Reaction ......................................................................................... 34 
7.1.3 
Special Situation Reports and Product Quality Issues .......................................... 34 
7.1.4 
Serious Adverse Event .......................................................................................... 35 
7.2 
Collection and Notification of Adverse Events, Special Situation Reports and Product 
Quality Issues to Takeda Pharmacovigilance ....................................................................... 37 
7.3 
Reporting of Adverse Drug Reactions and Special Situation Reports to Regulatory 
Agencies ............................................................................................................................... 37 
8 
Data Quality Control and Assurance .............................................................................................. 38 
8.1 
Quality Control ..................................................................................................................... 38 
8.2 
Audit from Quality Assurance Unit ...................................................................................... 38 
8.3 
Inspection by Institutional Review Board / Institutional Ethics Committee or Competent 
Authority .............................................................................................................................. 38 
8.4 
Data Management ................................................................................................................. 38 
8.4.1 
Data Collection Tools ........................................................................................... 39 
9 
Statistical Methods and Determination of Sample Size .................................................................. 40 
9.1 
Description of Analysis Set .................................................................................................. 40 
9.2 Method of Statistical Analysis .................................................................................................. 40 
9.3 Analysis of Study Outcomes ..................................................................................................... 40 
9.1.1 
Analysis of Primary Outcomes ............................................................................. 41 
9.1.2 
Analysis of Secondary Outcomes ......................................................................... 41 
9.1.3 
Analysis of Exploratory Outcomes ....................................................................... 41 
9.2 
Interim Analyses ................................................................................................................... 42 
9.3 
Determination of Sample Size .............................................................................................. 42 
10 Reports ............................................................................................................................................ 43 
11 Plans for Disseminating and Communicating Study Results ......................................................... 43 
12 Archiving of Study Documentation ................................................................................................ 43 
13 References ....................................................................................................................................... 45 
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Vedolizumab-5045 
 
 
Study Protocol Final Ver. 4.1, 24-SEP-2018 
Page 11 of 47 
14 Appendices ..................................................................................................................................... 47 
14.1 Annex 1. Mayo Score. .......................................................................................................... 47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study Protocol Final Ver. 4.1, 24-SEP-2018 
Page 12 of 47 
List of Abbreviations and Definition of Terms 
5-ASA: 
5-Aminosalicylic Acid 
ADR:  
Adverse Drug Reaction 
AE: 
 
Adverse Event 
AESI:  
Adverse Event of Special Interest 
CA: 
 
Competent Authority 
CD:   
Crohn’s Disease 
CI:  
 
Confidence Interval 
CMV:  
Cytomegalovirus 
CRO:  
Contract Research Organization 
EMA:   
European Medicines Agency 
GCP:  
Good Clinical Practice 
GI: 
 
Gastrointestinal 
GPP:  
Good Pharmacoepidemiology Practices 
GVP:   
Good Pharmacovigilance Practices 
HLT:  
High-Level Term 
HR: 
 
Hazard Ratio 
ICF:   
Informed Consent Form 
ICH:  
International Conference on Harmonisation 
IEC: 
 
Independent Ethics Committee 
IRB:  
Institutional Review Board 
ISPE:   
International Society for Pharmacoepidemiology 
IV:  
 
Intravenous 
JCV:   
John Cunningham Virus 
mAb:   
Monoclonal Antibodies 
MAdCAM-1: Mucosal Addressin Cell Adhesion Molecule-1 
MedDRA:  
Medical Dictionary for Regulatory Activities 
PML:  
Progressive Multifocal Leukoencephalopathy  
PY: 
 
Person-Year 
SADR: 
Serious Adverse Drug Reaction 
SAE:  
Serious Adverse Event 
SAP:  
Statistical Analysis Plan 
SD:  
 
Standard Deviation 
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SIS:   
Subject Information Sheet 
SMQ:   
Sub-standardized MedDRA query 
SOC:  
System Organ Class 
SSR:  
Special Situation Report 
TB:  
 
Tuberculosis 
TNF-α:  
Tumor Necrosis Factor alpha 
UC:   
Ulcerative Colitis 
 
 
 
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Study Protocol Final Ver. 4.1, 24-SEP-2018 
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2 
Introduction 
 
2.1 
Ulcerative Colitis 
Ulcerative Colitis (UC) is a chronic, relapsing, remitting inflammatory disease of the colonic 
mucosa and submucosa. The incidence and prevalence of UC in South Korea (Korea) is low 
compared to other regions, but has showed a 10-fold increase in the last 20 years [Kim 2010, 
Ng 2016]. Globally, the highest incidences have been found in northern Europe and North 
America: 11.4 and 12.9 per 100,000 persons, respectively [Burisch 2013, Loftus 2016, 
Rocchi 2012]. While the mean annual incidence rates of UC in Korea are lower, they have 
increased from 1.3 to 5.0 per 100,000 inhabitants between 2001 and 2006 [Kim 2010, Kim 
2015]. 
 
UC is a lifelong disease that causes considerable morbidity in a relatively young patient 
population. The etiology is not fully understood. The risk factors include: a history of a 
recent bacterial infection (e.g., Salmonella, Campylobacter), immune system malfunction, 
family history of the disease, young age (usually UC begins before 30), Caucasians’ and 
Jews’ ethnicities (compared to Asian), and smoking [Ananthakrishnan 2017, Adams 2013, 
Choi 2017]. Many patients require frequent hospitalizations, enteral nutrition, and surgical 
procedures (e.g., colectomies). The majority will have flares alternating with periods of 
remission, with a small proportion of patients having progressive or persistent symptoms 
[Ananthakrishnan 2017]. UC patients are often unable to function normally in society by 
virtue of having uncontrolled disease.  
 
Current UC treatments have been effective for many patients but have numerous limitations 
for those with moderate to severe disease. Pharmacologic treatments for UC include 5-
aminosalicylic acids (5-ASAs), corticosteroids, and immunomodulators (thiopurines such as 
azathioprine and 6-mercaptopurine, along with methotrexate). Monoclonal antibodies (mAb) 
directed against tumor necrosis factor alpha (TNF-α) are recommended when adequate 
dosage and duration of treatment with corticosteroid or combination of corticosteroid and 
thiopurine do not improve symptoms, or if the treatment is not tolerable to the patient [Choi 
2017]. In Korea, infliximab, adalimumab, and golimumab are used as anti-TNF therapies, all 
of which showed therapeutic effects in terms of remission induction and maintenance in 
patients with moderate to severe active UC [Choi 2017]. Although TNF-α antagonists 
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Study Protocol Final Ver. 4.1, 24-SEP-2018 
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represent an important addition to the pharmacologic armamentarium, they are effective in 
only a subset of patients, with approximately two-thirds of patients in controlled trials failing 
treatment at the end of the first year of therapy [Hanauer 2002, Rutgeerts 2005, Colombel 
2007].  
 
2.2 
Vedolizumab 
Vedolizumab is a humanized immunoglobulin G1 mAb directed against the human 
lymphocyte integrin α4β7. The α4β7 integrin mediates lymphocyte trafficking to GI mucosa 
and gut-associated lymphoid tissue through adhesive interactions with mucosal addressin cell 
adhesion molecule-1 (MAdCAM-1), which is expressed on the endothelium of mesenteric 
lymph nodes and GI mucosa. Vedolizumab exclusively targets the α4β7 integrin, 
antagonizing its adherence to MAdCAM-1 and thus impairing the migration of leukocytes 
into GI mucosa. By virtue of its gut-selective mechanism of action, vedolizumab is expected 
to have anti-inflammatory activity without the generalized immunosuppression found with 
current treatments for UC. 
 
The efficacy of vedolizumab in UC patients was demonstrated in a phase III randomized, 
double-blind, placebo-controlled, multicenter study that assessed the effect of vedolizumab 
induction and maintenance treatment on UC clinical response in 374 and 521 (open-label) 
patients with active moderate to severe disease. Vedolizumab patients had a statistically 
significant improvement in clinical response (i.e., reduction in the Mayo score of ≥ 3 points 
and ≥ 30% from baseline, and decrease of at least 1 point on the rectal bleeding subscale or 
an absolute rectal bleeding score of 0 or 1) and remission (i.e., Mayo score ≤ 2 and no sub-
score > 1) at 6 weeks, mucosal healing (i.e., endoscopic sub-score of 0 or 1), durable clinical 
response (i.e., remission at both weeks 6 and 52) and remission at 52 weeks, and 
corticosteroid-free remission at week 52 in patients receiving glucocorticoids at baseline 
compared to placebo. Response rates at week 6 were 47.1% and 25.5% among patients in the 
vedolizumab and placebo groups, respectively (difference with adjustment for stratification 
factors, 21.7 percentage points; 95% confidence interval [CI]: 11.6 to 31.7; P<0.001). At 
week 52, 41.8% of patients who continued to receive vedolizumab every 8 weeks and 44.8% 
of patients who continued to receive vedolizumab every 4 weeks were in clinical remission, 
as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 
percentage points for vedolizumab every 8 weeks vs. placebo [95% CI: 14.9 to 37.2; 
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Study Protocol Final Ver. 4.1, 24-SEP-2018 
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P<0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI: 
17.9 to 40.4; P<0.001]) [Feagan 2013]. 
 
Vedolizumab has also shown a favorable safety profile with low incidence rates of serious 
infections, infusion-related reactions and malignancies over an extended treatment period in 
another phase III, open-label, multicenter study which enrolled 2830 UC and Crohn’s 
Disease (CD) patients treated with vedolizumab. In this study, safety data from 6 trials were 
integrated and adverse events (AEs) were evaluated in patients who received ≥ 1 dose of 
vedolizumab or placebo. In total, these patients accumulated 4811 person-years (PYs) of 
vedolizumab exposure (median exposure range: 1-1977 days). No increased risk of any 
infection or serious infection was associated with this exposure. Serious clostridial 
infections, sepsis and tuberculosis (TB) were reported infrequently (≤ 0.6% of patients). No 
cases of progressive multifocal leukoencephalopathy (PML) were observed. Independent risk 
factors for serious infection in UC were prior failure of a TNF-α antagonist (Hazard Ratio 
(HR): 1.99; 95% CI: 1.16 to 3.42; p=0.0122) and narcotic analgesic use (HR: 2.68; 95% CI: 
1.57 to 4.58; p=0.0003). Investigator-defined infusion-related reactions were reported for ≤ 
5% of patients in each study. Eighteen vedolizumab-exposed patients (< 1%) were diagnosed 
with a malignancy [Colombel 2017]. 
 
Vedolizumab was approved in Korea on June 19th, 2015 for use in both UC and CD patients 
with inadequate response, lost response, or who were intolerant to TNF-α antagonist [Choi 
2017]. 
 
2.3 
Study Rationale 
Despite that there are several observational studies assessing the clinical effectiveness of 
vedolizumab, including a consecutive cohort of 115 UC German patients reporting 23.5% of 
clinical remission at 14 weeks [Baumgart 2016], there is currently no observational study 
assessing the effectiveness and safety of vedolizumab intravenous (IV) in a real world 
clinical setting in Korea. This post-marketing observational study aims to show that real 
world effectiveness and safety outcomes from daily clinical practice in Korean patients 
diagnosed with UC and having failed TNF-α antagonist therapy are consistent with those 
reported in randomized controlled trials. 
 
 
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Study Protocol Final Ver. 4.1, 24-SEP-2018 
Page 21 of 47 
5 
Ethics 
This is an observational chart review study, where the existence of the study poses no 
medical risk for the patient. 
 
5.1 
Ethical Conduct of the Study 
This study will be conducted in accordance with the protocol, the current version of the 
Declaration of Helsinki [WMA 2008], International Conference on Harmonisation (ICH) E6 
Good Clinical Practice (GCP) consolidated guideline, European Medicines Agency (EMA) 
Good 
Pharmacovigilance 
Practices 
[EMA 
2014], 
International 
Society 
for 
Pharmacoepidemiology (ISPE) Good Pharmacoepidemiology Practices (GPP) guideline 
[ISPE 2016] and any local regulations. Special attention will be paid to data protection.  
 
The Sponsor and the CRO will ensure that the protocol and any amendments are submitted to 
the relevant Independent Ethics Committees (IECs) / Institutional Review Boards (IRBs) 
according to local requirements. 
 
The Sponsor is responsible for meeting the ICH requirement for yearly updates to the IECs / 
IRBs, if applicable. 
 
 
5.2 
Independent Ethics Committee / Institutional Review Board and Authorities 
The CRO or the Site Study Responsible will coordinate the submissions to the IECs (or IRB 
or Research Ethics Board [REB]) and any other necessary authorities, as per international and 
local requirements. The study protocol will be submitted by the CRO to the central/local 
board for its review. Subject enrolment will not start at any site before the Sponsor has 
obtained waiver of requirement to obtain informed consent from the IECs to collect 
retrospective data, where the retrospective data collection cut-off is defined according to each 
site’s IRB policy (i.e. until one day prior initial IRB submission date, or until one day prior 
initial IRB approval date, etc). 
For patients whose treatment baseline (i.e. first date of vedolizumab treatment) and follow up 
visits occur prospectively (as defined by each site’s IRB policy, as above), a signed informed 
consent must be obtained from each subject prior to any prospective data collection. 
Collection of pregnancy and pregnancy outcomes data is also subjected to a signed informed 
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Study Protocol Final Ver. 4.1, 24-SEP-2018 
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consent from the patient or the patient’s partner. Otherwise, only retrospective data will be 
collected for the study. For details on both the rationale for the waiver of requirement to 
obtain informed consent and the informed consent for collection of  treatment baseline and 
follow up visits data, see Section 5.4 on Patient Information and Informed Consent. 
 
According to applicable regulations, the appointed CRO or the Site Study Responsible will 
notify or obtain approval from the relevant IEC / IRB of the protocol and any amendments. 
The CRO or the Site Study Responsible will submit required documents to the IEC / IRB, 
such as: 
 Periodic updates on the progress of the study. 
 Notification of the end-of-study. 
 A summary of the study results. 
 
The Sponsor or the CRO will keep an updated list of all submission and approval dates of all 
documents submitted to the IEC / IRB and will provide the Site Study Responsible with a 
copy of this list. Copies of the documents will be distributed upon request. 
 
5.3 
Authorities 
The Sponsor or the CRO may send study documents to the competent authority (CA) and / or 
other national or regional authorities, if required per the local regulation. The Sponsor or the 
CRO will keep an updated list of submission and approval dates and a copy of all documents 
submitted.   
 
5.4 
Patient Information and Informed Consent 
The rights, safety, and well-being of the trial patients are the most important considerations 
and should prevail over interests of science and society. This study will comply with ethical 
and regulatory requirements for each participating country. 
 
No informed consent will be obtained to collect retrospective data (where the retrospective 
data collection cut-off is defined according to each site’s IRB policy i.e. until one day prior 
initial IRB submission date, or until one day prior initial IRB approval date, etc), as only 
retrospective observational chart-abstracted data is included, and no patient identifier data 
(e.g. name, initials, national identity number, resident registration number, date and month of 
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Study Protocol Final Ver. 4.1, 24-SEP-2018 
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birth, etc) will be collected. A waiver of requirement to obtain informed consent will be 
sought, allowing for inclusion of patients treated with vedolizumab intravenous (IV) during a 
specific period in a participating center. In particular, a waiver of requirement to obtain 
informed consent allows for inclusion of data from deceased patients, and from patients who 
have completed UC therapy and are not actively followed-up. All data collected will be 
encrypted to ensure confidentiality and data protection. 
 
Detailed explanation of data protection, data encryption, and patient confidentiality measures 
will be included in each application for local ethics approval. Where necessary, these will 
include country-specific measures. Patient data will be entered only where a locally-
applicable informed consent waiver is granted. 
 
For patients whose treatment baseline (i.e. first date of vedolizumab treatment) and follow up 
visits occur prospectively (as defined by each site’s IRB policy, as above), it is the 
responsibility of the investigator to obtain written informed consent from each subject 
participating in this study, after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study (with written assent for underage subjects). 
Additionally, collection of pregnancy and pregnancy outcomes data is also subjected to a 
written informed consent from the patient or the patient’s partner. 
 
For subjects not qualified or incapable of giving legal consent, written consent must be 
obtained from the legally acceptable representative. In the case where both the subject and 
his/her legally acceptable representative are unable to read, an impartial witness should be 
present during the entire informed consent discussion. After the subject and representative 
have orally consented to participation in the trial, the witness’ signature on the form will 
attest that the information in the consent form was accurately explained and understood. The 
investigator or designee must also explain that the subjects are completely free to refuse to 
enter the study or to withdraw from it at any time, for any reason.  
 
 
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6 
Study Design and Plan 
This is an observational, multicenter, post-marketing study that will analyze real world data 
on the effectiveness and safety of vedolizumab IV in Korean patients presenting UC and 
having failed TNF-α antagonist therapy (as per the approved vedolizumab label in Korea).  
 
It is anticipated that at least 100 patients in a total of about 15 sites will be treated with 
vedolizumab IV from August 2017, when vedolizumab IV became available in Korea, to the 
end of the eligibility period. Patients will be identified from the medical records and enrolled 
in the study if they meet the inclusion and exclusion criteria. Screening logs of potential 
patients will be maintained at each of the sites, to record reasons why the patient failed 
eligibility screening. If available, basic demographic information will be recorded in the 
screening log to allow comparisons between patients who are enrolled and not enrolled. Only 
available patient data will be collected, which includes data until the day of enrollment to the 
study or until the earliest occurrence of any of the following: end of treatment, lost to follow-
up, or death. 
 
An interim analysis will be performed after approx. 50 patients are included. Primary and 
secondary outcomes will be considered for such analysis. 
 
This is a non-interventional chart review study. All decisions on clinical management and 
treatment have been made by the investigator as part of routine of standard of care, and 
independently of participation in the study. Data are collected if available per clinical 
routine. 
 
6.1 
Study Schedule  
Planned eligibility period: 
From August 2017, up until a 100 patients 
(at least) are enrolled 
Planned collection of the first data point: 
 
August 2018 
Planned collection of the last data point: 
100 patients (at least) are enrolled  
Planned analysis completion: 
 
 
January 2019 
Planned completion of study report: 
March 2019 
 
Note: the study schedule may be changed based on the protocol approval date and progress. 
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Study Protocol Final Ver. 4.1, 24-SEP-2018 
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6.2 
Discussion of Study Design   
The study has several limitations, among them:  
 
Selection bias  
Selection bias is the selection of individuals, groups or sites in such a way that the sample 
obtained is not representative of the population intended to be analyzed. As there is no 
probabilistic selection of sites or randomization of patients (i.e., if not all eligible patients will 
be approached for study participation), a selection bias cannot be ruled out. 
 
Information bias 
In observational study designs the investigator has restricted control over the data that is 
collected in the medical record. Furthermore, since the medical charts used were not designed 
for the study, the available data may be of insufficient quality. These data may be incomplete, 
inaccurate, or inconsistently measured between patients, especially in the case of safety 
assessments. 
 
Channeling bias 
Channeling bias is a form of allocation bias, where drugs with similar therapeutic indications 
are prescribed to groups of patients with prognostic differences. As vedolizumab is a new and 
first-in-class treatment for UC, it is possible that patients receiving vedolizumab in the early 
months of commercialization will have more severe disease or will be in greater need of a 
new therapy than those seen in subsequent years. This channeling of such patients into 
vedolizumab therapy may yield a safety and effectiveness profile different to that observed in 
later years.  
 
Limited use of vedolizumab 
It is anticipated that approximately 100 patients will be treated with vedolizumab in Korea 
during the study period and enrolled in the study. Because of this small study population, the 
clinical effectiveness assessments and the safety incidence rates may be based on low 
numbers / few events and thus have wide 95% CIs. In addition, for outcomes with few events 
it may not be possible to undertake stratified analyses. 
 
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Study Protocol Final Ver. 4.1, 24-SEP-2018 
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6.3 
Study Population 
The study population will be adult patients (≥ 19 years of age) diagnosed with moderately to 
severely active UC, having failed TNF-α antagonist therapy and who have been prescribed 
vedolizumab IV (and received at least one dose) in a routine clinical practical setting. Patients 
who are eligible (i.e., fulfill all inclusion criteria and none of the exclusion criteria) will be 
enrolled into the study.  
 
6.4 
 Selection of Study Population 
 
6.4.1 Inclusion Criteria 
Patient eligibility is determined according to the following criteria prior to entry into the 
study: 
 Female or male patient with moderately to severely active UC and having failed TNF-α 
antagonist therapy. 
 Patient was > 19 years of age at time of initiating vedolizumab IV. 
 
6.4.2 Exclusion Criteria 
Any patient who meets any of the following criteria will not qualify for entry into the study: 
 
Patient was treated with vedolizumab IV outside of the locally approved label in Korea. 
 
Patient was enrolled in an interventional Intestinal Bowel Disease clinical trial at time of 
using vedolizumab IV. 
 
6.5 
Study Variables 
The study will collect information on demographics, risk factors, clinical data, laboratory and 
endoscopic data, previous UC medications and surgeries, UC medications and concomitant 
treatments at baseline (i.e., start of vedolizumab treatment) and follow-up. 
• Index date: the index date is defined as the date of the first treatment with vedolizumab, 
between August 1, 2017 and the date when at least 100 cases are collected. 
• Index period: the index period is defined from August 1, 2017 up until 100 cases (at 
least) are collected; when eligible patient medical records (defined by index treatment 
date) should be identified. 
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Study Protocol Final Ver. 4.1, 24-SEP-2018 
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• Follow-up period: the follow-up period is defined as the time between the index date and 
when all relevant data for outcomes will be collected until the occurrence of any of 
following: end of treatment, lost to follow up, or death. 
 
The safety outcome measures will include: AESIs (i.e., serious infections, opportunistic 
infections, hepatitis viral infection, GI infections, respiratory infections, other clinically 
significant infections, malignancies, infusion-related reactions, and hepatic injury), SAEs, 
and pregnancy outcomes. 
 
The data will be abstracted, if available, from the medical charts. 
 
6.5.1 Demographics and Risk Factors Data 
 Year of birth. 
 Sex. 
 Body mass index, or height and weight, at baseline (i.e., start of vedolizumab treatment). 
 Previous and current (at baseline) smoking status. 
 UC/Inflammatory Bowel Disease family history. 
 Selected comorbidities: 
o Multiple sclerosis. 
o Rheumatoid arthritis.  
o Psoriatic arthropathy.  
o Vasculitis.  
o Systemic lupus erythematosus. 
o Dermatopolymyositis.  
o Systemic sclerosis.  
o Ankylosing spondylitis.  
o Primary sclerosing colangitis. 
o Autoimmune hepatitis. 
o Diabetes Mellitus.  
o Hypertension.  
o Dyslipidemia. 
 
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6.5.2 Clinical Data 
 Date of first UC signs/symptoms. 
 Date of UC diagnosis. 
 UC intestinal location/s (i.e., rectal and sigmoid colon only, left side of colon only, 
proximal to the splenic flexure only, all of the colon) and extraintestinal manifestations at 
baseline. 
 Partial or complete Mayo score at baseline and follow-up, respectively. This score 
comprises 4 sections assessing the severity and activity of UC in terms of: ‘stool pattern’, 
‘most severe rectal bleeding of the day’, ‘endoscopic findings’, and ‘global assessment by 
physician’. All 4 items are ranked based on severity with 0 being normal and 3 being 
most severe. Each item acquires 0-3 points, resulting in a maximum final score of 12. 
Partial score does not include endoscopic findings (Section 14.1 – Annex 1). 
 
6.5.3 Laboratory and Endoscopic Data 
 Clinical laboratory values: fecal calprotectin and C-reactive protein at baseline and 
follow-up. 
 Blood laboratory values: erythrocyte sedimentation rate, hemoglobin, albumin, platelet 
count and Clostridium difficile at baseline and follow-up. 
 Endoscopic data at baseline and follow-up. 
 Biopsy / histologic findings at baseline and follow-up. 
 
6.5.4 Treatment Data 
 UC medication history prior to start of vedolizumab IV (especially, TNF-α antagonist 
therapy). 
 UC-related hospitalizations, emergency department and outpatient medical visits. Note: 
planned hospital admissions for vedolizumab IV therapy are not to be considered AEs 
and not to be collected as hospitalizations. 
 UC-related surgeries. 
 Start and all dates of vedolizumab infusions, dose and dose escalation (if any). 
 Concurrent use of other UC medications at time of starting vedolizumab IV, including 
dates start / stop: 
o Other biologic agents (infliximab, adalimumab, golimumab). 
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o Immunomodulators. 
o 5-ASAs. 
o Corticosteroids. 
o Antibiotics. 
o Opioid pain medications. 
o Others. 
 Date and reasons for vedolizumab IV discontinuation, and type of medication switch. 
 
6.5.5 Adverse Events Data 
 
AESIs (including dates and pre-index occurrence, if any): 
o Serious infections. 
o Opportunistic infections, including but not limited to: TB infection or 
reactivation, including extrapulmonary TB, and PML. 
o Hepatitis viral infection. 
o GI infections. 
o Respiratory infections. 
o Malignancies. 
o Infusion-related reactions and hypersensitivity. 
o Hepatic injury. 
 SAEs. 
 Pregnancy outcomes. 
 
All AEs occurring on or after start of vedolizumab IV therapy will be abstracted from the 
medical charts and categorized as defined below. Events will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
 
Serious Infections 
Serious infection is defined as any event coded to MedDRA terms within the MedDRA SOC 
of Infections and Infestations that meets the seriousness definition (see Section 7.1.4). 
 
Opportunistic Infections 
Opportunistic infections include: 
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 Candidiasis of bronchi, trachea, esophagus, or lungs. This is defined as any events coded 
to a MedDRA term for candidiasis of the bronchi, trachea, esophagus, or lung. 
 Coccidioidomycosis. This is defined as any events coded to a MedDRA term for 
coccidioidomycosis, pulmonary coccidioidomycosis, cutaneous coccidioidomycosis or 
extrapulmonary coccidioidomycosis. 
 Cryptococcosis. This is defined as any events coded to a MedDRA term for 
cryptococcosis, pulmonary cryptococcosis, extrapulmonary cryptococcosis, disseminated 
cryptococcosis and recurrent cryptococcosis. 
 Cryptosporidiosis. This is defined as any events coded to a MedDRA term for 
cryptosporidiosis or recurrent cryptosporidiosis. 
 Cytomegalovirus (CMV) disease. This is defined as events coded to a MedDRA term for 
CMV disease, including CMV chorioretinitis, colitis, duodenitis, enteritis, gastritis, 
hepatitis, mononucleosis, mucocutaneous ulcer, myelomeningoradiculitis, myocarditis, 
esophagitis, pancreatitis, pericarditis, proctocolitis, urinary tract infection, encephalitis, 
CMV pneumonia, and CMV syndrome. 
 Encephalopathy-related infections. This is defined as encephalitis or encephalopathy due 
to infections, excluding those transmitted by arthropod (such as Japanese B encephalitis) 
or rodents, or due to influenza, measles, mumps, polio or rabies. Includes PML (see 
below). 
 Herpes simplex. This is defined as events coded to MedDRA terms for herpes simplex 
esophagitis, bronchitis, or pneumonitis, or to herpes esophagitis, bronchitis or pneumonia. 
 Histoplasmosis. This is defined as events coded to any MedDRA term for histoplasmosis, 
and includes both acute and chronic infections of any site. 
 Isosporiasis, chronic intestinal. This is defined as events coded to MedDRA terms for 
isosporiasis of the MedDRA high-level term (HLT) isospora infection. 
 Kaposi's sarcoma. This is defined as events coded to the MedDRA HLT Kaposi's 
sarcoma. 
 Mycobacterium avium complex. This is defined as events coded to the MedDRA term 
Mycobacterium avium complex infection. 
 TB: This is defined as all events coded to the MedDRA HLT TB infections, including 
new infections and reactivation of latent infections, of pulmonary and extrapulmonary 
sites. 
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 Pneumocystis carinii pneumonia. This is defined as events coded to the MedDRA terms 
Pneumocystis carinii pneumonia and acute Pneumocystis carinii pneumonia. 
 Pneumonia, recurrent. This is defined as events coded to the MedDRA term pneumonia 
recurrent. 
 PML: This includes events coded to the MedDRA terms PML, human polyomavirus 
infection, 
John 
Cunningham 
virus 
(JCV) 
infection, 
JCV 
test 
positive, 
leukoencephalopathy, and polyomavirus test positive. Cases of PML shall meet the 
histopathological, radiological, laboratory, and clinical criteria of the American Academy 
of Neurology guidelines for PML diagnosis [Berger JR 2013].  
 Salmonella septicemia, recurrent. This is defined as events coded to the MedDRA terms 
Salmonella sepsis or Salmonella septicemia. 
 Toxoplasmosis of brain. This is defined as events coded to MedDRA term cerebral 
toxoplasmosis. 
Other rare infections that are not normally seen in immunocompetent persons may also be 
considered as opportunistic infections. 
 
Hepatic Viral Infections 
This is defined as events within the Hepatitis viral infections MedDRA HLT, and includes all 
types of viral infections of the hepatic system. Where number of events permit, sub-analyses 
of specific types of infection (hepatitis B and hepatitis C) will be undertaken. 
 
Gastrointestinal Infections 
This is defined as events within the Infections and Infestation SOC that are coded to the 
MedDRA HLT GI infections. 
 
Respiratory Infections 
This is defined as events within the Respiratory, Thoracic and Mediastinal Disorders SOC 
that are coded to the MedDRA HLT respiratory tract infection. 
 
Malignancies 
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This is defined as all malignant and benign neoplasms within the MedDRA Malignant tumors 
sub-standardized MedDRA query (SMQ). This SMQ includes all malignancies and 
carcinomas in situ. 
 
Infusion-Related Reactions and Hypersensitivity 
This is defined as events occurring within 1 day after each vedolizumab IV administration 
that are coded to terms in the following MedDRA SMQs and will be considered as suspected 
reports of hypersensitivity: 
 Anaphylactic reaction SMQ. 
 Anaphylactic/anaphylactoid shock conditions SMQ. 
 Hypersensitivity SMQ. 
 Angioedema SMQ. 
 
Hepatic Injuries 
Events coded to terms in the following MedDRA SMQs will be considered as suspected 
reports of drug-induced liver injury: 
 Cholestasis and jaundice of hepatic origin SMQ. 
 Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions SMQ. 
 Hepatitis non-infectious SMQ. 
 Liver-related investigations signs and symptoms (Narrow SMQ). 
 Liver infections SMQ. 
 Abnormal liver function is defined as levels >2 × Upper Limit of Normal. 
 
Serious Adverse Events 
All AEs that meet the seriousness criteria (see Section 7.1.4). 
 
6.6 
Study Plan 
All eligible UC patient medical records will be identified, wherever feasible, through the 
following steps: 
1. Participating sites will be asked to list exhaustively all UC patients with at least 1 
prescription of vedolizumab IV up to site initation. 
2. Full eligibility criteria will be confirmed by the principal investigator or any designee. 
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3. Retrospecitve Patient’s data defiened per IRB policy will be abstracted only after 
reception of the waiver of requirement to obtain informed consent.  
4. Prospective Patient’s data defined per IRB policy will be abstracted only for patients 
who consented to participate in the study. 
 
The medical records data collection will follow this schedule (see Table 1): 
 
Table 1. Study data collection schedule.1 
 
Enrollment  
Baseline 2  
Follow-up period 3 
Review inclusion/exclusion 
criteria 
X 
 
 
Demographics and risk 
factors data 4 
 
X 
 
Clinical data 
(including Mayo score) 
 
X 
X 
Laboratory and endoscopic 
data 
 
X 
X 
UC medication and 
surgeries history 
 
X 
X 
UC current medications 
(including vedolizumab data) 
 
X 
X 
Adverse Events data 
 
X 
X 
1 Data will be collected only if available in the medical charts. 
2 Baseline refers to the start of vedolizumab treatment. Index date will be considered as the baseline patient data. 
3 The follow-up data for each patient will be data from index date until the occurrence of any of following: end 
of treatment, lost to follow up, or death. 
4 Demographics and risk factors data include year of birth, sex, body mass index, or height and weight at 
baseline (i.e., start of vedolizumab treatment), previous and current (at baseline) smoking status, and 
UC/Inflammatory Bowel Disease family history. 
 
 
 
 
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7 
Safety Reporting 
 
7.1 
Definitions 
 
7.1.1 Adverse Event  
An AE is any untoward medical occurrence in a subject administered a medicinal product and 
which does not necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, a new disease or worsening in severity or frequency of a concomitant 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. 
Although abnormal laboratory values are typically not considered AEs, the following 
considerations may result in an abnormal laboratory value being considered an AE: 
 A laboratory test result that meets the criteria for an SAE. 
 A laboratory test result that requires the subject / patient to receive specific corrective 
therapy. 
 A laboratory abnormality that leads to discontinuation of therapy. 
 A laboratory abnormality that the health care provider considers to be clinically 
significant. 
 
7.1.2 Adverse Drug Reaction 
An ADR is an AE for which there is at least a reasonable suspicion of a causal relationship 
between an AE and a suspected medicinal product. 
 
7.1.3 Special Situation Reports and Product Quality Issues 
A Special Situation Report (SSR) includes any of the following events: 
 Pregnancy: any case in which a pregnancy patient is exposed to a Takeda Product or in 
which a female patient or female partner of a male patient becomes pregnant following 
treatment with Takeda Product. Exposure is considered either through maternal exposure 
or via semen following paternal exposure. 
 Breastfeeding: infant exposure from breast milk. 
 Overdose: all information of any accidental or intentional overdose. 
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 Drug abuse, misuse or medication error: all information on medicinal product abuse, 
misuse or medication error (potential or actual). 
 Suspected transmission of an infectious agent: all information on a suspected (in the sense 
of confirmed or potential) transmission of an infectious agent by a medicinal product. 
 Lack of efficacy of Takeda Product. 
 Occupational exposure. 
 Use outside the terms of the marketing authorization, also known as “off-label”.  
 Use of falsified medicinal product. 
 
A Product Quality Issue refers to defects related to the safety, identity, strength, quality, or 
purity of the product or with the physical characteristics, packaging, labeling, or design of the 
product. 
 
7.1.4 Serious Adverse Event  
A SAE is any untoward medical occurrence that at any dose: 
 Results in death. Note that death is an outcome of an event, so the event(s) causing the 
death should be recorded. 
 In the view of the health care provider, places the subject / patient at immediate risk of 
death (a life threatening event); however, this does not include an event that, had it 
occurred in a more severe form, might have caused death. 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability / incapacity. 
 Results in a congenital anomaly / birth defect. 
 
A SAE may also be any other medically important event that, in the opinion of the health care 
provider, may jeopardize the subject / patient or may require intervention to prevent one of 
the other outcomes listed in the definition above. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or convulsions 
occurring at home that do not require an inpatient hospitalization and includes any event or 
synonym described in the Takeda Medically Significant AE List (see Table 2).  
 
 
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Table 2. Takeda medically significant AE list. 
 
Term 
General 
Hepatobiliary System 
Malignancy 
Acute hepatic failure 
Endotoxic shock 
Fulminant hepatitis 
Sepsis 
Immune system 
Transmission of an infectious agent by a medicinal 
product 
Anaphylaxis 
Necrotic conditions including Gangrene 
Progressive multifocal leukoencephalopathy  
Blood and Lymphatic System 
Transplant rejection 
Bone marrow failure 
Musculoskeletal System 
Disseminated intravascular coagulation 
Rhabdomyolysis 
Thrombotic thrombocytopenic purpura 
Nervous System 
Acquired hemoglobinopathies 
Cerebrovascular accident 
Hemolysis 
Coma 
Cardiovascular System 
Convulsive seizures 
Cardiac arrest 
Hyperthermia malignant 
Cardiac failure 
Macular edema 
Cardiomyopathy acute 
Psychosis 
Malignant hypertension 
Meningoencephalitis 
Ventricular arrhythmias 
Neuroleptic malignant syndrome 
Embolisms and infarctions 
Suicidal behavior 
Dissection and rupture of important vessels 
Reproductive System 
Endocrine System 
Abortion 
Adrenal crisis 
Uterine perforation 
Gastrointestinal System 
Respiratory System 
Acute pancreatitis 
Acute respiratory failure 
GI hemorrhage 
Pulmonary hypertension 
GI perforation 
Skin and subcutaneous tissue 
GI obstruction 
Toxic epidermal necrolysis 
Necrotizing colitis 
Stevens-Johnson syndrome 
Peritonitis 
Urinary System 
 
Acute renal failure 
GI: gastrointestinal 
 
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7.2 
Collection and Notification of Adverse Events, Special Situation Reports and 
Product Quality Issues to Takeda Pharmacovigilance  
Events / issues which are part of the study objectives or outcomes will be systematically 
identified and collected from medical records or other applicable source records, and 
summarized as part of any interim analysis and in the final study report. Such events do not 
need to be notified as individual reports to Takeda Korea Pharmacovigilance.  
 
If during the conduct of the study the investigator(s) or a member of the research team is 
spontaneously informed by a healthcare professional or patient of an SAE, AE, ADR, SSR or 
Product Quality Issue where the event / issue pertains to a Takeda product (or unbranded 
generic), such information should be notified to the local Takeda Pharmacovigilance 
department within 1 working day for fatal or life-threatening SAEs, within 4 calendar days 
for other SAEs, and within 7 calendar days for all other events. As such reports are 
spontaneously notified, causality of any AEs should be assumed unless there is evidence to 
the contrary. 
 
7.3 
Reporting of Adverse Drug Reactions and Special Situation Reports to Regulatory 
Agencies  
The expedited reporting of AEs and SSRs that are study endpoints to regulatory agencies is 
not required. Such events should be included in the Clinical Study Report.  
For spontaneously reported events that are not study endpoints, sponsor shall notify 
regulatory agencies in accordance with local regulatory requirements. 
 
 
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8 
Data Quality Control and Assurance 
 
8.1 
Quality Control 
Sponsor’s standard operating procedures for the analysis of observational studies shall be 
followed. Any deviation from the Statistical Analysis Plan (SAP) or additional unplanned 
analyses shall be identified as such in the study report. 
 
8.2 
Audit from Quality Assurance Unit 
The Quality Assurance unit may audit the study to ensure that study procedures comply with 
the protocol and standard operating procedures, and that collected data is correct and 
complete. 
 
8.3 
Inspection by Institutional Review Board / Institutional Ethics Committee or 
Competent Authority 
Representatives from IRB / IEC or CA may in rare cases wish to inspect the study on site. 
Upon receiving notification of such inspection, the Site Study Responsible must immediately 
contact the Sponsor and CRO, and must make the records available as requested. 
 
8.4 
Data Management 
Data management will be carried out according to a Data Management Plan, which must be 
written and approved before the design of the study database is finalized. The data 
management provider should approve all data formats before the data collection tools are 
made available to the sites. Collected data will be encrypted to ensure confidentiality and data 
protection. 
 
If the waiver of requirement to obtain informed consent or written informed consent required 
for collection of prospective data and of pregnancy-related data is known not to be available 
in spite of it being required, data is not entered into or is deleted from the database. 
  
If a patient is erroneously included in the study more than once only the data relating to the 
first inclusion will be kept in the database and be available for analysis. Data from later 
inclusions will be transferred to the first dataset when relevant (i.e., if collected within the 
time frame of the first follow-up period). 
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If a patient is included in the study in spite of being treated off-label (not according to the 
summary of product characteristics), data is kept in the database and analyzed separately and 
as part of the overall analyses as described in the SAP. 
 
The current Standard Coding Instructions for coding of medical history, concomitant illness 
(MedDRA), concomitant medication (WHO-Drug) and AEs/ADRs (MedDRA) must be 
followed. 
 
8.4.1 Data Collection Tools  
The Study Site will receive data collection tools (case report forms, access to electronic data 
capture, etc.) from Takeda. Whenever possible, complete data sets should be entered. Text 
field entries and any data collected on paper should be legible and follow the requested 
language standard. 
 
The Site Study Responsible must sign-off the complete data set for each patient, confirming 
the collected data. AEs data reported according to Section 7 and data on SAEs collected 
according to Section 6 should be signed-off separately by a physician who is involved in the 
study. 
 
 
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9 
Statistical Methods and Determination of Sample Size 
Statistical analysis will be performed using the SAS software (SAS Institute, North Carolina), 
version 9.4. A comprehensive SAP will be prepared before database lock. The SAP will 
detail the statistical analyses to be performed. It will describe the statistical analyses as 
foreseen at the time of planning the study. Any known deviations from the planned analyses, 
the reason for such deviations and all alternative / additional statistical analyses that may be 
performed, as well as the final statistical analysis, will be described in a revised SAP before 
database lock. All later deviations and / or alterations will be summarized in the final study 
report. 
 
Analyses will be performed using all available data. Due to the observational nature of the 
study, missing values are expected. However, no imputation of missing values will be 
considered unless otherwise stated in the SAP. 
 
9.1 
Description of Analysis Set 
The full analysis set will comprise all patients fulfilling all inclusion and exclusion criteria 
and any informed consent requirements. 
 
9.2 Method of Statistical Analysis 
All collected data will be presented using descriptive statistics because of the exploratory 
nature of this study. Continuous variables will be summarized as the number of patients (n), 
mean, standard deviation (SD), median, 1st and 3rd quartiles (Q1 and Q3), minimum and 
maximum. Summary for categorical variables will include frequency counts and percentages 
and number of missing data. Percentages will be based on the number of non-missing data as 
the denominator. 
 
Patient disposition will be presented, inclusive of discontinuation and reason for 
discontinuation. Patient demographics, risk factors, clinical characteristics and laboratory 
data (at baseline and follow-up, if applicable) will be summarized as descriptive statistics. 
 
9.3 Analysis of Study Outcomes 
 
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Study Protocol Final Ver. 4.1, 24-SEP-2018 
Page 43 of 47 
 
10 Reports 
Observational / non-interventional study reports will be prepared and submitted to Global 
Research for distribution. The interim and final study reports are planned to be available 
within a maximum of 3 months from collection of the last data point, and the participating 
sites should be informed about the results when the final report is finalized. 
 
11 Plans for Disseminating and Communicating Study Results 
Presentation of the study results in local, regional and / or international congresses, in 
addition to publication in a scientific journal, are envisaged as part as dissemination plans. 
 
12 Archiving of Study Documentation 
During the course of the study the Site Study Responsible must as a minimum file the below 
essential documents in the Study Site File: 
 Written agreement between the Sponsor or representative (CRO) and the Site Study 
Responsible. 
 The study protocol and any amendments. 
 Signed and dated protocol agreement and amendment agreements, if any, with the 
original signature of the Site Study Responsible. 
 Waiver of requirement to obtain informed consent (notified to / approved by IECs / IRBs, 
as locally required), including the original signed forms. 
 Signed informed consent forms, for prospective data collection from treatment baseline 
and follow up visits, according to IRB policy. 
 Signed informed consent forms of patient or of patient’s partner, for collection of 
pregnancy and pregnancy outcomes data. 
 The list of participating patients. 
 Written IEC / IRB approval / vote according to local regulations. 
 Authority approval according to local regulations, if required. 
 The completed clinical report forms. 
 
After final database lock the Site Study Responsible must at a minimum store the list of 
participating patients, the waiver of requirement to obtain informed consent and the signed 
informed consent forms for collection of pregnancy-related data and for prospective data 
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Study Protocol Final Ver. 4.1, 24-SEP-2018 
Page 44 of 47 
 
collection (according to IRB policy) from treatment baseline and follow up visits on site for 5 
years. The Site Study Responsible should store additional study documentation for a longer 
period of time as required by any local regulations and / or hospital requirement. 
Additionally, data collected via the clinical report forms and abstracted via Electronic Data 
Capture (EDC) must be archived by the site study responsible for 5 years after study 
completion. Data on the EDC will thereafter be destroyed, unless required to be store for a 
longer period of time by any local regulations and / or hospital requirement. The Sponsor, on 
top of the above onsite archiving requirements and according to local guidelines and standard 
operating procedures, will archive all study-related documentation and data (including data 
abstracted via an EDC) for 10 years after study completion. 
 
 
 
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Page 45 of 47 
 
13 References 
 
- 
Adams SM, Bornemann PH. Ulcerative colitis. Am Fam Physician. 2013 May 
15;87(10):699-705. 
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Ananthakrishnan AN, Xavier RJ, Podolsky DK. Biologic Therapies, in Inflammatory 
Bowel Diseases: A Clinician's Guide, John Wiley & Sons, Ltd, Chichester, UK. 2017. 
doi: 10.1002/9781119077633.ch8. 
- 
Baumgart DC, Bokemeyer B, Drabik A, Stallmach A, Schreiber S and Vedolizumab 
Germany Consortium. Vedolizumab induction therapy for inflammatory bowel disease in 
clinical practice a nationwide consecutive German cohort study. Aliment Pharmacol 
Ther. 2016 May;43(10):1090-102.  
- 
Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus 
statement from the AAN Neuroinfectious Disease Section. Neurology 2013;80(15):1430-
8. 
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Burisch J, Tine J, Martinato M, Lakatosdo PL. The burden of inflammatory bowel 
disease in Europe. Journal of Crohn's and Colitis. 2013;7(4):322-337. 
- 
Choi CH, Kim WM, Kim ES, et al. and IBD Study Group of the Korean Association for 
the Study of Intestinal Diseases. Second Korean guidelines for the management of 
ulcerative colitis. Intest Res. 2017 Jan;15(1):7–37. 
- 
Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical 
response and remission in patients with Crohn's disease: the CHARM trial. 
Gastroenterology 2007;132(1):52-65. 
- 
Colombel JF, Sands BE, Rutgeerts P, et al. The safety of vedolizumab for ulcerative 
colitis and Crohn's disease. Gut. 2017 May;66(5):839-851. 
- 
European Medicines Agency (EMA). Guideline on Good Pharmacovigilance Practices 
(GVP). Module VI – Management and reporting of adverse reactions to medicinal 
products (Rev 1). EMA/873138/2011 Rev 1. 8 September 2014. 
- 
Feagan B, Rutgeerts P, Sands B, et al. Vedolizumab as induction and maintenance 
therapy for ulcerative colitis. New Engl J Med. 2013;369(8):699–710. 
- 
Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's 
disease: the ACCENT I randomised trial. Lancet 2002;359(9317):1541-9. 
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Page 46 of 47 
 
- 
International Society for Pharmacoepidemiology (ISPE). Guidelines for Good 
Pharmacoepidemiology Practices (GPP).  Pharmacoepidemiol Drug Saf. 2016 
Jan;25(1):2-10. 
- 
Kim ES, Kim WH. Inflammatory bowel disease in Korea: epidemiological, genomic, 
clinical, and therapeutic characteristics. Gut Liver. 2010;4(1):1-14. 
- 
Kim HJ, Hann HJ, Hong SN, et al. Incidence and natural course of inflammatory bowel 
disease in Korea, 2006-2012: a nationwide population-based study. Inflamm Bowel Dis 
2015;21:623-630. 
- 
Lewis JD, Chuai S, Nessel L, Lichtenstein GR, Aberra FN, Ellenberg JH. Use of the 
noninvasive components of the Mayo score to assess clinical response in ulcerative 
colitis. Inflamm Bowel Dis 2008;14(12):1660-6. 
- 
Loftus EV. Update on the Incidence and Prevalence of Inflammatory Bowel Disease in 
the United States. Gastroenterol Hepatol. 2016 Nov;12(11):704–707. 
- 
Ng WK, Wong SH, Ng SC. Changing epidemiological trends of inflammatory bowel 
disease in Asia. Intest Res. 2016;14(2):111-9.  
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Rocchi A, Benchimol E, Bernstein CN, et al. Inflammatory bowel disease: A Canadian 
burden of illness review. Can J Gastroenterol. 2012 Nov;26(11):811–817. 
- 
Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance 
therapy for ulcerative colitis. N Engl J Med 2005;353(23):2462- 76. 
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World Medical Association (WMA). Declaration of Helsinki. Ethical principles for 
Medical Research Involving Human Subjects, Helsinki 1964, amended in Tokyo 1975, 
Venice 1983, Hong Kong 1989, South Africa 1996, Edinburgh 2000, and Seoul 2008. 
 
 
 
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14 Appendices 
14.1 Annex 1. Mayo Score. 
 
 
Source [Lewis 2008]. 
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