Vedolizumab and Anti-TNFs Outcomes in Real-World Biologic Ulcerative Colitis and Crohn's Disease Patients
Conditions: Colitis, Ulcerative, Crohn Disease
Sponsor: Takeda



Non-Interventional Study Protocol 
Title: Vedolizumab and anti-TNFs Outcomes in Real-World Biologic Ulcerative Colitis and 
Crohn’s Disease Patients (EVOLVE) – IBERIA 
Short title:  Vedolizumab and anti-TNFs Outcomes in Real-World Biologic Ulcerative Colitis 
and Crohn’s Disease Patients (EVOLVE) – IBERIA 
Spanish Health Authorities Study code: TAK-VEZ-2018-01 
Study ID: 
 Vedolizumab-5047 
Sponsor: 
Takeda Farmacéutica España SA 
C/ Alsasua 20, 28023 (Madrid) 
Phone: + 0034917149900 
Study phase: Medical Affairs, Post-Approval Company Sponsored (Observational) 
Protocol final version: 2.0, 23 May 2019 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may 
be administered. Furthermore, the information is only meant for review and compliance by the recipient, his or 
her staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study. 
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Vedolizumab-5047 
 
EVOLVE-IBERIA 
 
Protocol final Ver. 2.0, 23 May 2019 
Page 4 of 72 
 
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 subjects in 
accordance with the following: 
 The ethical principles that have their origin in the Declaration of Helsinki. 
 International Conference on Harmonization, 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)> 
 
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Vedolizumab-5047 
 
EVOLVE-IBERIA 
 
Protocol final Ver. 2.0, 23 May 2019 
Page 5 of 72 
 
STUDY SUMMARY 
 
Name of Sponsor(s): 
Takeda Farmacéutica España SA. 
Compound/Product: 
Vedolizumab, Adalimumab, golimumab, 
infliximab.  
 
Title of Protocol: VEDOLIZUMAB and anti-TNFs Outcomes in Real-World Biologic Ulcerative 
Colitis and Crohn’s Disease Patients (EVOLVE) -IBERIA 
 
Study Number: Vedolizumab-5047 
Phase: IV 
Study Design: 
Multicentre, retrospective cohort study of the medical charts of patients who were diagnosed 
with Crohn’s disease (CD) or ulcerative colitis (UC) and who initiated first-line or second-line 
treatment with vedolizumab (VDZ) or another biologic agent (infliximab, adalimumab, or 
golimumab [UC only]) (index event) during the eligibility period. 
 
Primary Objectives: 
 
Describe treatment patterns associated with first-line and second line biologic use (VDZ or 
other biologic: infliximab, adalimumab, or golimumab, [UC only]) (e.g., dose escalation, 
treatment discontinuation, and switching). 
 
Describe the real-world clinical effectiveness of the use (first-line and second line) VDZ vs. 
other biologics at least 6 months post-treatment initiation. 
 
Secondary Objectives: 
 
Characterize patients treated with VDZ or other biologics (infliximab, adalimumab, or 
golimumab [UC only]) as first and second line biologic therapy in terms of demographics, 
medical, and treatment histories. 
 
Describe the real world clinical effectiveness of VDZ vs. other biologics at least 12 months 
post-treatment initiation (in a subgroup of patients with adequate follow-up available). 
 
Describe the safety events occurring post biologic treatment initiation (VDZ or other 
biologics). 
 
Quantify healthcare resource utilization including the rates of healthcare professional (HCP) 
and emergency department (ED) visits, hospitalizations and Inflammatory Bowel Disease 
(IBD) related surgical procedures. 
 
 
 
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Vedolizumab-5047 
 
EVOLVE-IBERIA 
 
Protocol final Ver. 2.0, 23 May 2019 
Page 7 of 72 
 
1. The patient has a diagnosis of moderate to severe UC or CD documented in the medical 
chart. 
2. The patient received at least one dose of VDZ or other biologic (infliximab, adalimumab, or 
golimumab [UC only]) during the eligibility period. 
3. The patient was 18 years of age or older at the time of starting treatment with VDZ or other 
biologic (index event). 
4. The patient received the biologic treatment as first-line or second-line biologic for UC or 
CD. 
5. Patient has a minimum of six months of follow-up between date of starting biologic 
treatment (index event) and the date of completion of the patient pre-screening registry. 
Main Criteria for Exclusion: 
1. Patient received VDZ or another biologic as part of an interventional clinical trial ever in 
their lifetime (includes index treatment). 
2. Patient’s index treatment was another biologic therapy other than VDZ, infliximab, 
adalimumab, or golimumab [UC only]. 
3. Patient initiated index treatment as combination therapy with two biologic agents. 
4. The biologic was prescribed for the treatment of perianal disease. 
5. The patient has received a biologic prior to the index period for a disease other than 
inflammatory bowel disease. 
6. The patient’s clinical record is unavailable. 
 
Main Criteria for Evaluation and Analyses: 
The primary outcomes are the description of treatment patterns (changes in dose and regimen, 
concomitant treatments, discontinuation) and effectiveness (change in disease activity, 
biomarkers, qualitative outcomes) in patients with CD and UC following initiation of VDZ or 
other biologic therapy. 
Secondary outcomes include the description of demographic characteristics, frequency and type 
of adverse events, and the resource utilization during treatment with VDZ or other biologic 
therapies. 
 
Statistical Considerations: 
Data analysis will be primarily descriptive. Analysis will be conducted by index treatment cohort 
(VDZ vs. other biologics) and then further stratified (if sample size allows) by age and disease type 
(CD or UC). Simple statistical tests will be conducted to test for significant differences between 
cohorts (e.g., t-tests and chi-square tests). 
An interim analysis is planned prior to database lock. The interim analysis is foreseen by October 
2019, although timing may depend on the number of patients included (and data abstracted) as well 
as deadlines for submission to congresses of interest. Final analyses will be performed once the data 
from all patients has been collected in the database, cleaned, and database has been lock. 
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Protocol final Ver. 2.0, 23 May 2019 
Page 8 of 72 
 
A statistical analysis plan (SAP) will be developed that defines all analytic populations and 
subpopulations, including definition of treatment response and effectiveness. The SAP will further 
provide a detailed description of analyses to be performed and describe methods to deal with missing 
data and censoring. The final SAP will include (empty) table shells to be populated during the final 
data analysis. 
 
Sample Size Justification: 
As the primary objective is descriptive, the sample size will be estimated based on the precision of 
a confidence interval estimation of a proportion. Assuming the scenario of maximum 
indetermination (i.e., an expected proportion of 50%), to obtain a confidence interval of 95% of this 
proportion with a precision of 7.5% is necessary to recruit 171 patients. We expect a 10% of non-
valid data so we will recruit 200 patients per group (400 patients in total). 
 
 
 
 
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Protocol final Ver. 2.0, 23 May 2019 
Page 9 of 72 
 
Table of Contents 
1 
Administrative information ................................................................................................. 2 
1.1 
Contacts ..................................................................................................................... 2 
1.2 
Approval .................................................................................................................... 3 
2 
Introduction ....................................................................................................................... 18 
3 
Study Objective(s) and Outcome(s) .................................................................................. 21 
3.1 
Objective(s) .............................................................................................................. 21 
3.1.1 
Primary Objective ...................................................................................... 21 
3.1.2 
Secondary Objective(s) .............................................................................. 21 
3.1.3 
Exploratory Objective(s) ........................................................................... 22 
3.2 
Outcome(s) ............................................................................................................... 22 
3.2.1 
Primary Outcome ....................................................................................... 22 
3.2.2 
Secondary Outcome(s)............................................................................... 22 
3.2.3 
Exploratory Outcome(s) ............................................................................ 23 
4 
Study Administrative Structure ......................................................................................... 23 
4.1 
Study Sites ............................................................................................................... 23 
4.2 
Sponsor personnel .................................................................................................... 23 
4.2.1 
Sponsor responsible persons ...................................................................... 23 
4.3 
Contract Research Organisation (CRO) .................................................................. 24 
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Protocol final Ver. 2.0, 23 May 2019 
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4.3.1 
CRO responsible persons ........................................................................... 24 
5 
Ethics ................................................................................................................................. 26 
5.1 
Ethical conduct of the Study .................................................................................... 26 
5.2 
Independent Ethics Committee / Institutional Review Board and Authorities ........ 27 
5.3 
Authorities ............................................................................................................... 28 
5.4 
Subject Information and Written Informed Consent ............................................... 28 
5.4.1 
Informed Consent Procedures ................................................................... 29 
5.5 
Participant Confidentiality ....................................................................................... 29 
6 
Study Design and Plan ...................................................................................................... 31 
6.1 
Study Period ............................................................................................................. 32 
6.2 
Study Schedule ........................................................................................................ 33 
6.3 
Discussion of Study Design ..................................................................................... 34 
6.3.1 
Limitations ................................................................................................. 34 
6.4 
Site selection ............................................................................................................ 36 
6.5 
Selection of Study Population .................................................................................. 36 
6.5.1 
Inclusion Criteria ....................................................................................... 36 
6.5.2 
Exclusion Criteria ...................................................................................... 37 
6.6 
Patient selection ....................................................................................................... 37 
6.6.1 
Sampling Frame Identification .................................................................. 37 
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Protocol final Ver. 2.0, 23 May 2019 
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6.6.2 
Preliminary Target Cohort Selection ......................................................... 38 
6.6.3 
Screening for Eligibility ............................................................................ 39 
6.7 
Treatments ............................................................................................................... 41 
6.8 
Premature Termination or Suspension of Study or Investigational Site .................. 41 
6.8.1 
Criteria for Premature Termination or Suspension of the Study ............... 41 
6.8.2 
Criteria for Premature Termination or Suspension of Investigational Sites
 ................................................................................................................... 41 
6.8.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) ...................................................... 41 
6.9 
Study Plan ................................................................................................................ 41 
7 
Safety Reporting ................................................................................................................ 42 
7.1 
Definitions ............................................................................................................... 42 
7.1.1 
Adverse Event ............................................................................................ 42 
7.1.2 
Serious Adverse Events ............................................................................. 43 
7.1.3 
Adverse Drug Reactions ............................................................................ 43 
7.1.4 
Product Quality Issues ............................................................................... 44 
7.1.5 
Special Situation Reports ........................................................................... 44 
7.2 
Collection and notifying of Adverse Events, Special Situation Reports and Product 
Quality Issues to Takeda Pharmacovigilance .......................................................... 45 
7.3 
Reporting of Adverse Drug Reactions and Special Situation Reports to Regulatory 
Authorities ............................................................................................................... 46 
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Protocol final Ver. 2.0, 23 May 2019 
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8 
Data Quality Control and Assurance ................................................................................. 47 
8.1 
Quality Control ........................................................................................................ 47 
8.2 
Audit from Quality Assurance Unit ......................................................................... 47 
8.3 
Inspection by IRB/IEC or Competent Authority ..................................................... 48 
8.4 
Data Management .................................................................................................... 48 
8.4.1 
Data Collection Tools and Flow ................................................................ 49 
8.4.2 
Data Monitoring......................................................................................... 50 
8.4.3 
Data Cleaning ............................................................................................ 51 
8.4.4 
Data Retention ........................................................................................... 51 
8.4.5 
Study Variables .......................................................................................... 51 
9 
Statistical Methods and Determination of Sample Size .................................................... 58 
9.1 
Foreseen analyses .................................................................................................... 58 
9.1.1 
Primary outcomes ...................................................................................... 59 
9.1.1.1 
Treatment Patterns ..................................................................................... 59 
9.1.1.2 
Time-to-Event Analysis ............................................................................. 59 
9.1.1.3 
Clinical Effectiveness at Least Six Months Post-Treatment Initiation ...... 60 
9.1.2 
Secondary outcomes .................................................................................. 60 
9.1.2.1 
Patient Populations .................................................................................... 60 
9.1.2.2 
Clinical Effectiveness at Least 12 Months Post-Treatment Initiation ....... 61 
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9.1.2.3 
Safety Events ............................................................................................. 61 
9.1.3 
Exploratory outcomes ................................................................................ 62 
9.1.3.1 
Predictors of Response to VDZ ................................................................. 62 
9.1.3.2 
Treatment Patterns, Clinical Effectiveness, and Safety Events for Second-
Line Biologic for Switch Patients ................................................................................. 62 
9.2 
Interim Analyses ...................................................................................................... 63 
9.3 
Determination of Sample Size ................................................................................. 63 
10 Reports .............................................................................................................................. 64 
11 Publication, Disclosure, and Clinical Trial Registration Policy ........................................ 64 
12 Archiving of Study Documentation .................................................................................. 65 
13 References ......................................................................................................................... 66 
14 Appendices ........................................................................................................................ 70 
 
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APPENDICES 
1. Takeda AE Reporting Form 
2. Study Investigator Agreement 
3. Case Report Form 
4. Ethics Comitee Approval 
5. Summary of Products Characteristics 
6. Patient Information Sheet  
7. Informed Consent Form 
8. Economic Details 
 
 
 
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List of Abbreviations and Definition of Terms 
ADR 
Adverse drug reaction 
AE 
Adverse event 
Anti-TNF 
Anti-tumour necrosis factor 
Anti-TNFα 
Anti-tumour necrosis factor –alpha 
BMI 
Body mass index 
CD 
Crohn’s disease 
CDAI 
Crohn's Disease Activity Index 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF 
Case report form 
CRO 
Contract research organization 
CRP 
C reactive protein 
CT 
Computerized tomography 
DRG 
Diagnosis-related group 
eCRF 
Electronic case report form 
ED 
Emergency Department 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
ENCePP 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance 
ESR 
Erythrocyte sedimentation rate 
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EU 
European Union 
FCP 
Fecal calprotectin 
GCP 
Good Clinical Practice 
GEP 
Good Epidemiological Practice 
GPP 
Good Pharmacoepidemiology Practices 
GVP 
Good Pharmacovigilance Practices 
HBI 
Harvey-Bradshaw Index 
HCP 
Healthcare professional 
HRQoL 
Health-related quality of life 
HRU 
Healthcare resource utilization 
IBD 
Inflammatory bowel disease 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
ICU 
Intensive care unit 
ID 
Identification 
IEA 
International Epidemiological Association 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISPE 
International Society for Pharmacoepidemiology 
ISPOR 
International Society for Pharmacoeconomics and Outcomes Research 
MedDRA 
Medical Dictionary for Regulatory Activities 
PDL 
Patient disposition log 
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Protocol final Ver. 2.0, 23 May 2019 
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PGA 
Physician Global Assessment 
PI 
PQI 
Principal investigator 
Product Quality Issue 
SAE 
SAP 
Serious Adverse Event  
Statistical analysis plan 
SD 
Standard deviation 
SDV 
Source data verification 
SES-CD 
Simple Endoscopic Index for Crohn's Disease 
SOPs 
Standard operation procedures 
SSRs 
Special Situation Reports 
TNFα 
Tumour necrosis factor –alpha 
UC 
Ulcerative colitis 
UK 
United Kingdom 
US 
United States of America 
VDZ 
Vedolizumab 
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2 
Introduction 
Inflammatory bowel disease (IBD) is a collective term for a number of conditions that manifest 
through the inflammation of the gastrointestinal tract. The most common forms of IBD are 
Crohn’s disease (CD) and ulcerative colitis (UC), which can be differentiated by the areas of 
the gastrointestinal tract that are affected (other important pathological and diagnostic 
differences also occur). 
There is evidence that the worldwide incidence and prevalence of IBD is increasing.1 There is 
considerable geographic variation in both the prevalence and incidence of CD and UC across 
Europe, with the highest rates of IBD reported in Northern Europe, especially Scandinavia and 
the United Kingdom  (UK), while IBD is relatively rare in Eastern Europe.2 In the United States 
(US), the prevalence of CD in adults has been estimated to be 201 (95% CI: 197, 204) per 
100,000, and of UC to be 238 (95% CI: 234, 241);3 the US average annual age/gender-
standardised incidence is estimated to be 33 (range: 27–40) per 100,000, and 50 (range: 36–
55) per 100,000 respectively.3 An estimated 2.5–3 million people in Europe are affected by 
IBD, with a direct healthcare cost of 4.6–5.6 bn Euros/year.2 
IBD is associated with significant patient morbidity and negatively impacts HRQoL.4 
Furthermore, patients with IBD consume substantial health care resources, with increased 
hospitalizations, ED visits, and clinician office-based visits.5 
Traditionally, patients with mild or moderate IBD are treated with aminosalicylates as first-
line therapy, with progression to second-line/add-on therapy comprising of glucocorticoids or 
immunomodulators if symptoms persist or intensify. Patients with moderately or severely 
active disease may be treated with tumour necrosis factor-alpha (TNFα) antagonist therapies 
such as infliximab, adalimumab, and golimumab. However, due to safety risks associated with 
systemic immunosuppression and the significant primary non-response and secondary loss of 
response experienced on these current therapies, novel treatments are warranted. Patients with 
a diagnosis of UC who do not respond to treatment, have waning response to treatment, or 
whose symptoms intensify, may also undergo surgery. Maintenance therapy following 
remission of symptoms varies but typically includes the use of biologics (e.g., anti-TNFα).6,7 
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However, due to the significant failure rate and side effects associated with current IBD 
therapies, novel therapies for the treatment of IBD are warranted. New biologic agents are 
being investigated for use in patients with IBD.8 
Vedolizumab (VDZ; originator product name: ENTYVIO®) is the first gut-selective 
monoclonal antibody developed by Takeda for the treatment of both UC and CD that targets 
α4β7 integrin, blocking lymphocyte trafficking to the gut, which differentiates its mechanism 
of action compared to the other biologic   therapies listed above. In the double-blind randomised 
GEMINI clinical trials, VDZ was shown to maintain clinical remission and improve HRQoL 
at 52 weeks and 152 weeks post-treatment initiation in patients with moderately-to-severely 
active UC.9–11VDZ was licensed for the treatment of CD and UC by the US Food and Drugs 
Agency.7and by the European Medicines Agency.12 VDZ was launched in Spain and Portugal 
on 30 June 2014 and January of 2017 respectively for the treatment of adult patients with 
moderately to severely active UC who have had an inadequate response, loss of response, or 
are intolerant to conventional treatment or with an antagonist of tumor necrosis factor alpha 
(TNFα); for CD, VDZ is approved for use in adult patients who have had an inadequate 
response, loss of response, or are intolerant to conventional treatment or with an antagonist of 
tumor necrosis factor alpha (TNFα) (ENTYVIO® EMA Technical Data Sheet or Summary of 
Product Characteristics).13 VDZ can be used in patients who are naïve to prior biologics as well 
as patients who received one or more prior biologic regimens.12 In the real-world, there are 
only a few reports on the comparative effectiveness of VDZ to other biologics in UC and CD 
patients, especially in those naïve to prior biologic therapy. The majority of real-world data 
generated to date on VDZ has primarily focused on anti-TNF refractory cohorts;14,15 hence, 
there is a need to generate additional evidence on outcomes in bio-naïve cohorts, where 
preliminary observations may suggest improved outcomes relative to patients on anti-TNF 
therapies.2 These data will be important to understand positioning of VDZ in the treatment 
pathway as well as supporting the development of treatment guidelines and informing clinical-
decision making. 
The efficacy and safety of VDZ for the treatment of UC and CD was demonstrated in the 
GEMINI clinical trial programmes,9–11,14,16 which included both biologic-naïve patients and 
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patients who had failed prior anti-TNFα treatment. In the real-world, there are only a few 
reports on the comparative effectiveness of VDZ to other biologics in UC and CD patients, 
especially in those naïve to prior biologic therapy. The majority of real-world data generated 
on VDZ to date has primarily focused on anti-TNF refractory cohorts17–19; hence, there is a 
need to generate additional evidence on outcomes in bio-naïve cohorts, where preliminary 
observations may suggest improved outcomes relative to anti-TNFα experienced patients. 
 
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3 
Study Objective(s) and Outcome(s) 
3.1 
Objective(s) 
The overall purpose of the study is to evaluate treatment effectiveness, treatment patterns, 
health care resource utilization, and safety of VDZ in patients with UC and CD as first line 
(patients who were biologic-naïve at the start of therapy) or second-line biologic therapy 
(patients who discontinued treatment with first TFNα inhibitor). A cohort of patients with UC 
or CD who were prescribed an anti-TNFα will also be included in this study to facilitate the 
descriptive analysis of treatment effectiveness in the VDZ cohort. In order to evaluate VDZ 
and provide a real-world treatment landscape with anti-TNFα therapies in Spain and Portugal, 
data will be collected retrospectively from the patients’ medical charts. 
3.1.1 Primary Objective(s) 
1. Describe treatment patterns associated with first-line and second line biologic use 
(VDZ or other biologic: infliximab, adalimumab, or golimumab [UC only]) (e.g., dose 
escalation, treatment discontinuation, and switching). 
2. Describe the real-world clinical effectiveness of the use (first-line and second line) 
VDZ vs. other biologics at least 6 months post-treatment initiation. 
3.1.2 Secondary Objective(s) 
1. Characterize patients treated with VDZ or other biologics (infliximab, adalimumab, or 
golimumab [UC only]) as first and second line biologic therapy in terms of 
demographics, medical, and treatment histories. 
2. Describe the real world clinical effectiveness of VDZ vs. other biologics at least 12 
months post-treatment initiation (in a subgroup of patients with adequate follow-up 
available). 
3. Describe the safety events occurring post biologic treatment initiation (VDZ or other 
biologics). 
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5 
Ethics 
Owing to the retrospective design, this study does not result in interference with standard 
medical care and, therefore, it will not affect treatment of study participants. The study will be 
managed by Bioclever 2005 S.L (Spain) and EUROTRIALS-Consultores Científicos, S.A. 
(Portugal), hereinafter referred to as Contract Research Organizations (CRO). The study is 
sponsored by Takeda Farmacéutica España SA., hereinafter referred to as the Sponsor. No 
patient-identifying information will be transferred to the Sponsor or to the CRO. All data 
collected will be managed in accordance to local and European laws for personal data 
protection in force at the moment of protocol approval by the competent independent ethics 
committee (IEC)/international review board (IRB). 
 
5.1 
Ethical conduct of the Study 
The study will be conducted in accordance with International Conference on Harmonization 
(ICH) Good Clinical Practice (GCP) (as applied to observational research), all applicable 
patient privacy requirements, and the ethical principles that are outlined in the Declaration of 
Helsinki 2013,20 including, but not limited to: 
 Central IRB and local IEC review and approval of study protocol and any subsequent 
amendments 
 Investigator reporting requirements. 
The study will be conducted in accordance with legal and regulatory requirements in force in 
Spain and Portugal, as well as with scientific purpose, value and rigor and will follow generally 
accepted research practices described in Good Pharmacoepidemiology Practices (GPP)21 
issued by the International Society for Pharmacoepidemiology (ISPE), Good Epidemiological 
Practice (GEP) guidelines issued by the International Epidemiological Association (IEA), 
Good 
Outcomes 
Research 
Practices 
issued 
by 
the 
International 
Society 
for 
Pharmacoeconomics and Outcomes Research (ISPOR), International Ethical Guidelines for 
Epidemiological Research issued by the Council for International Organizations of Medical 
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Sciences (CIOMS), European Medicines Agency (EMA), European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance (ENCePP), Guide on Methodological 
Standards 
in 
Pharmacoepidemiology, 
and 
FDA 
Guidance 
for 
Industry: 
Good 
Pharmacovigilance and Pharmacoepidemiologic Assessment, FDA Draft Guidance for 
Industry 
and 
FDA 
Staff: 
Best 
Practices 
for 
Conducting 
and 
Reporting 
of 
Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data Sets (February 
2011). Data will be managed in accordance to the General Data Protection Regulation 
2016/679 on data protection and privacy for all individuals within the European Union.22 
The Sponsor and/or the appointed CRO will ensure that the protocol, any amendments and the 
Subject Information Sheet/Informed Consent Form 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 IEC/ 
IRB 
Before study initiation, the protocol will be submitted for review and approval to the 
appropriate IEC/IRB or equivalent group charged with this responsibility in Spain and 
Portugal, respectively. The CRO will provide assistance in IEC/IRB submission. When local 
approval is obtained, the CRO will send the documentation indicating the IEC/IRB (if 
applicable) Committee's approval or favorable opinion to the study Sponsor before the 
recruitment process begins.  
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, as well as any 
amendments, and 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 
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The Sponsor or the appointed 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 Responsible with 
a copy of this list. Copies of the documentswill be distributed upon request. 
5.3 
Authorities 
The Sponsor or the appointed CRO will send required documents to the competent authority 
and/or other national or regional authorities. The Sponsor or the appointed will keep an updated 
list of submission and approval dates and a copy of all documents submitted.   
5.4 
Subject Information and Written Informed Consent 
The Site Study Responsible must give the subject (and if applicable, parent or legal guardian) 
oral and written information about the study in a form that the subject (and if applicable, the 
parent or legal guardian) can understand, and obtain the subject’s (and if applicable, the 
subject’s assent and the parent’s or legal guardian’s) written consent before collection of 
identifiable subject information (hereinafter referred to as personal data). Before consenting, 
the subject (and if applicable, parent or legal guardian) must be left with ample time to consider 
and to pose questions. Since the study is retrospective, the consent only concerns the data 
collection per se and it does not consent to any interventional procedure or treatment.  
The subject must agree that sponsor personnel, their representatives or IEC/IRB or competent 
authority personnel (national or other) may require direct access to the subject’s data / personal 
records which were collected, processed and stored in an anonymous form.  
The subject must agree that his / her data will be processed and stored in an anonymous form 
for evaluation of this study and any later overviews. Data may also be transferred in anonymous 
form to third parties, e.g. other companies or authorities, that may be located in other countries 
with potentially different regulations for data.  
The subject and parent or legal guardian, if applicable, has the right to withdraw his/her consent 
at any time without prejudice. In the Informed Consent Form it is stated that if consent is 
withdrawn, any data collected before withdrawal of consent will be kept. The original, signed 
Informed Consent Forms must be kept on the Site. 
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For details, see the Subject Information Sheet and Informed Consent Form. 
5.4.1 Informed Consent Procedures 
Data chart abstraction will not begin until the patient has signed the informed consent in which 
he/she accepts to participate in the study.  
In sites in Spain, in case of deceased patients, the signature of the informed consent will not be 
necessary. Nevertheless, for these cases, the IEC/IRB involved in the study approval will be 
informed of the signature exemption of the informed consent, and the use of the data of these 
patients for the study will be documented in the medical chart by the principal investigator. 
In Portuguese sites, in the case of deceased patients, informed consent will be requested from 
a family member, legal representative or heir, and the use of the data of these patients for the 
study will be documented in the medical chart. The person obtaining consent is responsible for 
ensuring that each participant fully understands the nature, purpose, procedures, risks, and 
benefits of the study. Each participating patient will be provided with a copy of his/her signed 
informed consent form. 
5.5 
Participant Confidentiality 
All data collected in this study will be strictly confidential in accordance with Spanish and 
Portuguese regulations, as well as the General Data Protection Regulation 2016/679 on data 
protection and privacy for all individuals within the European Union.22 Personnel from the 
following organizations may examine the research study records: CRO and regulatory 
agencies. To safeguard patient confidentiality, the eCRF in the EDC system will record subjects 
only by means of an anonymous, unique identification code assigned by the EDC system. No 
information such as initials, date of birth, or local case study identification number that could 
subsequently be used to identify patients will be entered into the EDC system. Only Principal 
Investigators, or site personnel delegated by him/her, will have the possibility of associating 
the de-identified assigned identification code to a specific subject. 
It is the participating site’s responsibility that sufficient information related to the identity of 
the patients will be retained. Site study staff will be instructed to maintain complete 
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confidentiality of all collected data. The data must be collected and processed with adequate 
precautions to ensure confidentiality and compliance with applicable data privacy protection 
laws and regulations. By signing the protocol, the Institution and/or PI commit to complying 
with all related applicable local laws and regulations as well as any applicable Spanish and 
Portuguese regulations, as well as the General Data Protection Regulation 2016/679 on data 
protection and privacy for all individuals within the European Union. 
The summary report generated from the eCRF will not contain any participant identifying 
information. 
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6 
Study Design and Plan 
This study is a ‘non-interventional study’ as defined in Directive 2001/20/EC,23 and will follow 
the guidelines for GPP.  
This means that: 
 The assignment of a subject to a particular therapeutic strategy is not decided in advance 
by the study protocol but falls within current practice. 
 No additional diagnostic or monitoring procedures shall be applied to the subjects. 
 Epidemiological methods shall be used for the analysis of collected data. 
The study is an ethics-approved, designed as a multicentre, retrospective cohort study of the 
medical charts of patients who were diagnosed with CD or UC and who initiated first- or 
second-line biologic treatment with VDZ or another biologic (infliximab, adalimumab, or 
golimumab [UC only]) (index event) during the eligibility period: January 2017 to date of site 
initiation. 
The target sample size is approximately 400 patientsa (200 patients per treatment cohort: 1) 
VDZ and 2) other biologics. It is estimated that these patients will be included from across ~25 
sites (20 in Spain and 5 in Portugal), resulting on average in ~8 patients per treatment 
cohort/siteb. The medical charts of patients with UC or CD who initiated first-line or second-
line biologic treatment with VDZ or another biologic (infliximab, adalimumab, or golimumab 
[UC only]) during the eligibility period will be identified for potential enrolment. 
                                                 
 
a Final sample size may vary depending on number of eligible patients available for inclusion at participating 
sites. 
b Based on interest in participation and the number of eligible patients each site can contribute, the total number 
of sites enrolled as well as patients per site could increase/decrease. 
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6.1 
Study Period 
The study eligibility period will be between January 2017 until date of site initiation and is 
defined as the period of time within which patients with UC or CD who initiated first or second-
line treatment with VDZ or other biologic (index event) are identified for enrolment into the 
chart review study. 
Data collection spans two main periods anchored to the date of index event: 
 Pre-Index Event Period:  Begins on the date of diagnosis of UC/CD and ends one day 
prior to the date of index VDZ or other biologic treatment initiation during the 
eligibility period. 
 Post-index Event Period: Begins on the date of index VDZ or other biologic treatment 
initiation during the eligibility period and ends at the earliest of 6 months -post-index 
treatment discontinuation, death, loss to follow-up, or date of chart abstraction 
initiation. 
It is estimated that data abstraction will be completed over a 12 month period between February 
2019 and February 2020. In order to avoid selection bias, sites may be instructed to start data 
abstraction selecting a random sample of all eligible patients with at least six months duration 
between date of index treatment initiation and date of chart abstraction (see section 6.6.3). It is 
anticipated that, at a minimum, patients will contribute six months of data -post-index treatment 
initiation and a maximum of approximately 23.5 months. 
Data collection is estimated to be completed by February 2020. This date is subject to change 
pending duration of study start-up activities (IEC/IRB approvals) and the date that sites are 
eventually initiated. 
Figure 1 shows an overview of the eligibility and study periods. According to the proposed 
design: 
 All medicinal products were prescribed in accordance with the terms of the marketing 
authorisation(s) 
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 The prescription of is clearly separated from the decision to include the subject in the 
study 
 
Figure 1. Study design overview 
 
6.2 
Study Schedule 
Planned Start of Study: 
 
 
 
February 2019 
Planned collection of first data point:  
 
May 2019 
Planned End of Study:  
 
 
 
February 2020 
Planned collection of the last data point: 
 
February 2020 
Planned completion of the Statistical Analysis: 
April 2020 
Planned completion of the Study Report: 
 
June 2020 
 
The Start of Study is defined as the date the first IEC/IRB approves the study protocol. The 
End of study is defined as last data point collected. 
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The Sponsor will ensure that End-of-Study notification is submitted to the concerned 
authorities and IEC/IRB for each site, for each country and for the complete study, as locally 
required. 
The Sponsor will ensure that results are posted on “clinicaltrials.gov” and as required by local 
authorities.  
Based on upcoming knowledge, the Sponsor might choose to terminate the study prematurely. 
In such case the Committee(s), study sites, IECs/IRBs and authorities will be informed 
promptly. 
6.3 
Discussion of Study Design 
The study is aimed to gather real-world data of patients treated with first-and second-line 
biologic therapies for UC and CD. Therefore, the retrospective design is considered most 
appropriate to capture the actual scenario of routine clinical practice in the management of 
patients with UC or CD who start biologic therapies. 
Although the study objectives are mainly descriptive and do not rely on comparisons, two 
cohorts have been established based on the type of biologic agent. The rationale for the double 
cohort is the different mechanism of action of these agents, which is likely to bias the study 
results in case a single study group is considered. 
The number of included sites (25 sites foreseen) is deemed high enough to achieve a reasonable 
generalizability of the results. 
6.3.1 Limitations 
This retrospective study design is associated with some methodological limitations. 
To start, the quality of the data is dependent on completeness and accuracy of the data 
documentation available in the medical records. Existing medical chart data may not contain 
all of the information required to address the study objectives; data availability as a result of 
differences in HCP usual care documentation may vary across charts. However, it is expected 
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that data supporting the primary and secondary objectives should be of reasonably good quality 
across sites. This will be evaluated during the feasibility assessment phase of the study. 
It may be possible that sites included in the study may not be fully representative of usual care 
patterns of UC and CD in Spain and Portugal. Additionally, variation in patient identification 
procedures by the sites could also lead to selection bias. To address these issues, efforts will be 
made to include sites in this study that vary by geographical location (different provinces) and 
institution type to increase generalizability of the data. In addition, the patient identification 
process at the sites will be documented and monitored by the CRO to reduce this risk of bias. 
Sample size targets will be set for each site and for sites with sampling frames larger than set 
targets for VDZ and other biologic cohorts, random sampling will be undertaken by the CRO. 
Subgroup analyses by IBD type (UC vs. CD) and treatment lines (first vs second) will depend 
on the actual distribution of these patients in usual care, which may limit the robustness of the 
analysis. If a particular cohort is under-represented in the population, best attempts will be 
made during patient recruitment to enroll these patients. Other sub-group analyses may be 
identified post-hoc during analysis. 
Similarly, due to the chart review study paradigm, applying 1:1 matching techniques to conduct 
a comparative analysis between VDZ and other biologic patients at time of enrolment is not 
feasible. Matching will be limited to post-hoc analytic techniques which may require an over-
sampling of patients from the other biologic reference cohort. There will also be limitations to 
the extent of 1:1 matching of characteristics between subjects which may impact the 
comparativeness of the two cohorts. 
In addition to the design-specific limitations, the limited time period since VDZ approval in 
Portugal (January 2017), may jeopardize patient recruitment in this country, leading to a biased 
study cohort (i.e., according to the study protocol, patients must have been followed up for at 
least six months since treatment start). This potential risk will be addressed during the 
feasibility assessment phase of the study.   
 
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6.4 
Site selection 
Approximately 25 sites, 20 in Spain and 5 in Portugal, that treat patients with UC and CD with 
VDZ and other biologics (infliximab, adalimumab, or golimumab [UC only]) will be selected 
for participation in this study. To represent variations in current real-world patterns of care, 
where possible, sites will be selected on the basis of geographic region (e.g., different 
provinces), and institution size and type (e.g., academic vs. community). 
The clinical sites will be evaluated prior to enrolment into the study through a structured 
feasibility process. As part of the feasibility process, centres will complete a feasibility 
questionnaire to evaluate the number of potentially eligible patients, data availability, staff 
resourcing, etc.  
6.5 
Selection of Study Population 
The study population consists of two distinct first-line and second-line biologic treatment 
cohorts: 
 VDZ Cohort: Patients with UC or CD who have initiated VDZ as a first-or second-line 
biological treatment. 
 Other Biologic Cohort: Patients with UC or CD who have initiated other biologic 
treatment (infliximab, adalimumab, or golimumab [UC only]) as first-or second-line 
biological treatment. 
Irrespective of the biological therapy prescribed for UC or CD, patients must meet all selection 
criteria. 
6.5.1 Inclusion Criteria 
To be considered eligible, the subject must meet the following inclusion criteria: 
1. Patient has a diagnosis of moderate to severe UC or CD documented in the medical chart. 
2. Patient received at least one dose of VDZ or other biologic (infliximab, adalimumab, or 
golimumab [UC only]) during the eligibility period. 
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3. Patient was 18 years of age or older at the time of treatment initiation with VDZ or other 
biologic (index event). 
4. Patient received the biologic treatment as first-line or second line biologic for UC or CD. 
5. Patient has a minimum of six months of follow-up between date of starting biologic therapy 
(index event) and the date of completion of the patient pre-selection registry. 
6.5.2 Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. Patient received VDZ or another biologic as part of an interventional clinical trial ever 
in their lifetime (includes index treatment). 
2. Patient’s index treatment was another biologic therapy other than VDZ, infliximab, 
adalimumab, or golimumab [UC only]. 
3. Patient initiated index treatment as combination therapy with two biologic agents. 
4. The biologic was prescribed for treatment of perianal disease. 
5. The patient received biologic therapy before the index period for a disease other than 
inflammatory bowel disease. 
6. Patients’ medical chart is unavailable. 
 
Patients should be included in the study only once.  
Data erroneously collected from subjects for which written consent is not available will not be 
included in or will be deleted from the database. 
6.6 
Patient selection 
6.6.1 Sampling Frame Identification 
All patients 18 years of age or older with UC or CD who initiated first-line or second-line 
biologic treatment with VDZ or one of 4 other biologics (infliximab, adalimumab, or 
golimumab [UC only]) during the eligibility period (refer to section 6.1) (index event) and meet 
all selection criteria (refer to sections 6.5.1 and 6.5.2) will be identified at each of the study 
sites. The sampling frame will comprise these patients. Site staff will record sampling frame 
patients directly into a Pre-Screening Log, where each patient will be assigned a sequential pre-
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screening identification (ID) number. For each patient, site staff will indicate age at index 
event, date of index event, index treatment type (VDZ, infliximab, adalimumab, or golimumab 
[UC only]), disease type (UC or CD) and date of most recent visit prior to chart abstraction 
initiation. The site staff will also receive a file (patient key) where they will record the pre-
screening ID and their local patient ID number. This file will be kept at the site and used as a 
patient key to link the site patient ID number to the study ID number using the pre-screening 
ID. 
6.6.2 Preliminary Target Cohort Selection 
The pre-screening log, in which patients are identified by the pre-screening ID only, will be 
transferred to the CRO, which will create the target cohort of patients at each site following 4-
block randomization procedure in which patients will be stratified according to the type of 
treatment (i.e., VDZ vs. other biologic) and diagnosis (i.e., UC vs. CD). The target cohort will 
consist of 16 patients per site, balanced in terms of type of treatment and diagnosis. In the event 
that at any site the number of patients who are possible candidates for inclusion is less than the 
four patients planned per cohort, the randomization process will not be conducted in that 
cohort, although this procedure will be performed for the remaining cohorts.  
For the preliminary identification of the cohort of interest, consideration shall be given to 
whether pre-screened patients have been followed up for least 6 months during the eligibility 
period of the study. Patients who at the time of pre-screening have not been followed up for 
this period will not be included as potential candidates and will not be taken into account for 
randomization.  
Each site will be provided with the pre-screening IDs of patients selected for the target cohort, 
who will be offered to enrol the study. In case the patient accepts, he/she will sign the informed 
consent and a study ID will be assigned to the patient. The study ID of patients who have 
enrolled the study shall be recorded in the excel-based patient key, which will link the patient’s 
local ID, the pre-screening ID, and the study ID. 
In case a patient reject to participate in the study or a screening failure occurs (e.g., the patient 
does not meet a given inclusion/exclusion criteria), the CRO will randomly select another 
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patient in the corresponding site following the same procedure. This procedure will be 
conducted recursively until the final target cohort is achieved or there are no patients left in the 
sampling frame of the given site. If a site cannot meet the site target, another site may enroll 
additional cases to make up for deficit. 
6.6.3 Screening for Eligibility 
Site staff will review the medical charts for all patients in order to determine the sampling 
frame. Once the patient has been selected and has signed the informed consent, the site staff 
will record the fulfilment of each inclusion/exclusion criteria in the eCRF. Screen failures (e.g., 
patients considered for the sampling frame who do not meet the eligibility criteria) will be also 
recorded in the eCRF. 
The overview of the entire patient selection process is represented in Figure 2. 
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6.7 
Treatments 
Owing to the retrospective design, treatments no treatments are instructed by the study 
protocol. 
6.8 
Premature Termination or Suspension of Study or Investigational Site 
6.8.1 Criteria for Premature Termination or Suspension of the Study 
As this is a retrospective study, patients have already received treatment at the moment of 
initiating data collection. Hence, the changes in the use of medications due to safety concerns 
shall not affect the conduct of the study, which will be completed as planned unless significant 
violation of Good Clinical Practice (GCP) that compromises the ability to achieve the primary 
study objectives. 
6.8.2 Criteria for Premature Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of GCP/GPP, protocol, or contractual agreement, is unable to 
ensure adequate performance of the study, or as otherwise permitted by the contractual 
agreement. 
6.8.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) 
In the event that the Sponsor, an IEC/IRB or regulatory authority elects to terminate or suspend 
the study or the participation of an investigational site, a study-specific procedure for early 
termination or suspension will be provided by the sponsor; the procedure will be followed by 
applicable investigational sites during the course of termination or study suspension. 
6.9 
Study Plan 
As this is a retrospective study, only remote monitoring visits are foreseen. Once the study sites 
have been selected based on the feasibility plan (see section 6.4) and the study protocol has 
been approved by the competent IRB/IEC, investigators in each site will initiate the patient 
selection process as described in section 6.6). 
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7 
Safety Reporting 
7.1 
Definitions 
7.1.1 Adverse Event 
An adverse event (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 
Descriptive statistics will be used to describe all safety events reported during the chart review. 
Safety data described will include: 
 Number and types of AEs associated with medical treatment vs. non-treatment related 
events 
 Number of non-serious and serious AEs documented to be related to treatment 
 Number of treatment alterations (withdrawn, reduced, increased) as a result of AEs 
 AE duration (based on information on date of onset and date of resolution) 
 AE outcome 
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Safety outcomes will be evaluated from VDZ or other biologic initiation to 6 months -post-
index treatment discontinuation. For subjects who are not 6 months post-treatment 
discontinuation at the time of chart abstraction initiation, the end date will be the date of chart 
abstraction initiation. All analyses will be finalized in the SAP. 
7.1.2 Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
 Results in death. Note that death is an outcome of an event. The event(s) causing 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. 
 An 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.). 
 
7.1.3 Adverse Drug Reactions 
An adverse drug reaction (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. 
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7.1.4 Product Quality Issues 
A Product Quality Issue (PQI) 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. 
Note: All Special Situation (SS) reports and product quality issues will be sent to Takeda, with 
or without an associated adverse event, as described in section 7.2. 
7.1.5 Special Situation Reports 
A Special Situation Report (SSR) includes any of the following events: 
 Pregnancy:  
o 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:  
o Infant exposure from breast milk. 
 Overdose:  
o All information of any accidental or intentional overdose. 
 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:  
o 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 SSR should be reported even if there is no associated AE (see section 7.2). 
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7.2 
Collection and notifying of Adverse Events, Special Situation Reports and Product 
Quality Issues to Takeda Pharmacovigilance 
 SAEs, AEs, ADRs, SSRs and PQIs in the medical record/source data that are part 
of the study objectives or outcomes 
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 Pharmacovigilance.  
 SAEs, AEs, SSRs and PQIs in the medical records/other applicable source data 
that are not part of the study objectives and outcomes 
Events/Issues which are not part of the study objectives and outcomes will not be 
abstracted or collected from medical records/ source records.  
 SAEs, AEs, ADRs, SSRs and PQIs spontaneously reported to the investigator(s). 
If during the conduct of the study the investigator(s) is spontaneously informed by a 
healthcare professional or patient of an SAE, AE, ADR, SSR or PQI where the 
event/issue pertains to a Takeda product (or unbranded generic), such information 
should be forwarded to the local Takeda Pharmacovigilance department within 24 hours 
from reception. This included events spontaneously notified to the investigator(s) which 
are study endpoints and also events spontaneously notified which are not study 
endpoints. As such reports are spontaneously notified, causality of any adverse events 
should be assumed unless there is evidence to the contrary. 
In the event that for the assessment of any adverse reaction, Takeda requires additional 
information and submit questions to the investigator of the corresponding center, the 
information answered by the investigator will be considered as follow-up information 
of the reported adverse events and therefore it will have to be notified to Takeda who 
requested said information, referring to the adverse reaction initially reported. Such 
notification to Takeda will be done as described throughout this section. 
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On a quarterly basis Takeda Pharmacovigilance will send a list of the adverse events 
received to the CRO in order to perform the corresponding reconciliation process. Then 
the CRO will send back the discrepancies to Takeda Pharmacovigilance for resolution.  
Takeda Contact Information 
Spontaneous reports are notified to the local Pharmacovigilance Department in Spain, 
within 
24 
hours 
from 
reception 
through 
the 
email 
address 
farmacovigilancia@takeda.com using the Takeda AE reporting form (ANNEX 1). 
 
7.3 
Reporting of Adverse Drug Reactions and Special Situation Reports to Regulatory 
Authorities 
The expedited reporting of AEs and SSRs that are study outcomes to regulatory agencies is not 
required. Such events should be included in the interim analysis and the Final Study Report. 
For spontaneously reported events that are not study outcomes, the Sponsor shall notify 
regulatory agencies in accordance with local regulatory requirements or Sponsor’s post-
marketing commitments. 
 
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8 
Data Quality Control and Assurance 
8.1 
Quality Control 
Systems with procedures will be implemented to ensure the quality of every aspect of the study. 
The development of the protocol and SAP will follow internal standard operating procedures 
(SOPs) of the CRO, which include detailed review rounds. Quality control of the statistical 
programming will follow the CRO’s SOPs. 
The EDC system meets approved established standards for the security of health information, 
is validated and is 21 CFR Part 11/EudraLex Annex 11 compliant. In order to ensure that 
patient data (as well as other confidential data) remain secure and intact, the CRO follows SOPs 
and quality control processes that address patient data security. The EDC system has built in 
edit checks and validations and supports electronically generated and manual queries. 
Patient confidentiality will be strictly maintained. Access to the EDC system will be regulated 
via a hierarchical user-name and password control. Subject data will be de-identified through 
design of data entry fields that do not permit the entry of identifying information such as 
initials, date of birth, or centre- assigned patient identifiers. Only trained site staff will enter 
data into the eCRFs. Patients’ ages in whole years, but not date of birth, will be entered. No 
patient identifiers used by sites will be entered; rather the EDC program will automatically 
assign a study ID to each patient. The de-identified data as entered into the EDC system will 
be visible to the CRO and the Sponsor, but only centre staff will be able to trace a study ID 
number back to a patient identity, a necessary measure to allow centre staff to respond to data 
queries raised by the CRO later. 
8.2 
Audit from Quality Assurance Unit 
The Quality Assurance (QA) 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. 
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8.3 
Inspection by IRB/IEC or Competent Authority 
Representatives from IEC/IRB or Competent Authority may in rare cases wish to inspect the 
study on site. Upon receiving notification of such inspection, the Study Site Responsible must 
immediately contact Global Research and must make the records available as requested. The 
Inspector must be reminded up front that consent to access to personal data of deceased patients 
has not been obtained and that the corresponding IEC/IRB has been informed of the signature 
exemption of informed consent. 
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 finalised. The data management 
provider should approve all data formats before the data collection tools are made available to 
the sites. 
If the written informed consent of a subject is known not to be available in spite of it being 
required, data for this subject is not entered into or is deleted from the database. This will not 
apply to deceased patients with exemption of informed consent signature. 
If a subject 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. 
If a subject is included in the study in spite of being treated off-label (not according to the 
SPC), data is kept in the database and analysed separately and as part of the overall analyses as 
described in the Statistical Analysis Plan.  
The current Standard Coding Instructions for coding of medical history, concomitant illness 
(MedDRA), concomitant medication (WHO-Drug) and adverse events/reactions (MedDRA) 
must be followed. 
The study patients will be identified in the database only by Study ID, which may contain 
information regarding the study site.  
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8.4.1 Data Collection Tools and Flow 
The study site will receive data collection tools (CRFs, access to electronic data capture, etc) 
from the CRO. 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 study site responsible must sign off the complete data set for each subject, confirming the 
collected data. ADR data reported according to section 7 and data on serious AE/ADR reactions 
collected according to section 7 should be signed off separately by a physician who may or 
may not be involved in the study. 
De-identified data (anonymous to non-site staff) from enrolled patients’ medical charts will be 
abstracted by site staff and entered at the site into the electronic CRFs (eCRFs) of the EDC 
system. 
Over the course of the study, the patient study status (e.g., selected and waiting confirmation 
of eligibility, enrolled and waiting completion of forms) will be updated automatically within 
the EDC system. The EDC system will also facilitate the monitoring of the completeness and 
quality of study data as the study data accrue. 
The CRO will provide a web-based EDC system (ENNOV EDC v.8.0.130) to serve as an 
integrated, transparent tool to collect and manage data and track study progress at the site and 
patient level.  
Screening results for inclusion and exclusion criteria will be captured in the EDC system for 
all patients in the preliminary target cohort. One eCRF will be completed in the EDC system 
for each enrolled patient. The completed original eCRFs are the sole property of the study 
Sponsor and will not be made available in any form to third parties without written permission 
from the Sponsor, except for authorized representatives of the Sponsor or appropriate 
regulatory authorities. 
Each study investigator has ultimate responsibility for the collection and reporting of all data 
entered on the eCRFs and any other data collection forms (source documents) and ensuring 
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that they are accurate, authentic/original, attributable, complete, consistent, legible, timely 
(contemporaneous), enduring, and available when required. The eCRFs must be electronically 
signed prior to database lock by the study investigator or by an authorized staff member to 
attest that the data contained on the eCRFs are correctly recorded. The CRO will inform sites 
when it is time for eCRF sign-off to occur. 
In the present case, the source documents are the patients’ medical charts and, therefore, data 
collected on the eCRFs should match the data in the charts. 
Site staff will be trained by the CRO to perform the chart abstraction, including data entry and 
how to retrieve and respond to data queries in the EDC system. It is assumed that all sites will 
be able to complete data entry into the CRFs via the EDC system. 
The EDC system includes logic checks to minimize data entry errors. Data inconsistencies 
outside the logic checks will be managed by manual queries issued by data management within 
the EDC system for site completion. All queries will be monitored until resolution within the 
EDC through the electronic query report. 
8.4.2 Data Monitoring 
The CRO will provide a web-based EDC system (ENNOV EDC v.8.0.130) to serve as an 
integrated, transparent tool to collect and manage data and track study progress at the site and 
patient level.  
Quality control mechanisms (e.g., verification of data completeness, validations, and edit 
checks), which will be automated at time of data entry, will be built into the EDC, and listed in 
the study Data Management Plan (DMP). Queries will be generated by the CRO for resolution 
by site staff within the EDC system. 
If necessary, a small percent of routine on-site monitoring visits and “For cause” visits (utilised 
based on pre-agreed triggers) will be performed to ensure appropriate study procedures are 
being followed and ensure regulatory compliance. 
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8.4.3 Data Cleaning 
In accordance with the DMP, the EDC system will have built-in methods for data validation 
(e.g., drop down lists, value range controls, and standardised response formats). However, a 
data cleaning method will furthermore be employed in order to correct inconsistencies or errors 
that were not captured during data entry (e.g., outliers or conflicting data). Data queries will be 
identified on an ongoing basis during data collection. Queries will be generated for site 
completion within the EDC system. Sites will have approximately 5 business days to resolve 
queries. As database lock approaches, the duration to resolve queries may be less than 5 
business days. There will be no formal source data verification (SDV) as data will be de-
identified (anonymous to all non-site personnel). 
8.4.4 Data Retention 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient information 
to link records, e.g., eCRFs and medical charts), source documents, detailed records of patient 
disposition, and adequate documentation of relevant correspondence (e.g., letters, meeting 
minutes, telephone calls reports). The records should be retained by the investigator for the 
length of time specified in local regulations, or in the Site Contract Agreement (whichever time 
period is longer).  
If the investigator becomes unable for any reason (e.g., retirement or relocation) to continue to 
retain study records for the required period, the Sponsor should be prospectively notified. The 
study records must be transferred to a designee acceptable to the Sponsor, such as another 
investigator, another institution, or to an independent third party arranged by the Sponsor. The 
investigator must obtain the Sponsor's written permission before disposing of any records, even 
if retention requirements have been met. 
8.4.5 Study Variables 
Variables including but not limited to the following will be collected, if available. Table 1 
summarizes the variable groups and the corresponding timelines in the medical charts. 
Table 1. Overview of study variables 
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Demographics and medical history 
 Age. 
 Sex. 
 Weight 
 Height 
 Smoking status (never, former, current, unknown, including number of years smoked, 
number of cigarettes smoked per day). 
Disease characteristics 
 IBD diagnosis characteristics. 
o Date of first-ever diagnosis with IBD (UC or CD diagnosis). 
o Age at first-ever diagnosis (if date is not known). 
o Type of IBD (CD vs. UC). 
 UC characteristics at diagnosis  
(Closest assessment to diagnosis, within 3 months post-diagnosis). 
o Location of UC 
 CD characteristics at diagnosis  
(Closest assessment to diagnosis, within 3 months post-diagnosis). 
o Location of intestinal involvement 
o Disease behaviour 
o Number and type of active fistulae (if active) 
Systemic drug therapy history 
 Non-biologic drug therapies (e.g., immune modulators, corticosteroids, antibiotics, 5-
ASA): start date, end date, or ongoing at time of index event). 
(Within  6 months prior to the index event) 
 Biologic drug therapies  
(Since diagnosis until the index event) 
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o Therapy type and dosing information (e.g., dose increase or decrease in dosing 
frequency, date of intensification, discontinuation, date of discontinuation, main 
reason for discontinuation) 
 Laboratory measures 
(Most recent measure within 6 months prior to index event and during the post-index event period 
(including dates of tests and up to 6 months post-index treatment for patients who discontinued their 
index treatment). 
o C-Reactive Protein (CRP), erythrocyte sedimentation rate (ESR), fecal 
calprotectin (FCP), albumin, hemoglobin, and liver profile [aspartate 
aminotransferase 
(AST), 
alanine 
aminotransferase 
(ALT), 
alkaline 
phosphatase, bilirubin, serum creatinine, blood urea nitrogen (BUN)]).  
Disease activityc, ‘flare-ups’ and treatment response 
 UC disease activity  
(Closest assessment within 6 months prior to index event, and all assessments during the post-index event 
period (including dates of all assessments and up to 6 months post-index treatment discontinuation for 
patients who discontinued their index treatment). 
 CD disease activity  
(Closest assessment within 6 months prior to index event, and all assessments during the post-index event 
period (including dates of all assessments and up to 6 months post-index treatment discontinuation for 
patients who discontinued their index treatment). 
 UC and CD treatment response.   
(Assessments during the post-index event period (including dates of all assessments) up to 6 months 
post-index treatment discontinuation for patients who discontinued their index treatment). 
o Complete response (remission), partial response, no response (no remission), 
response not assessed, or  unknown. 
                                                 
 
c Note that the timing of disease activity score assessments and level of documentation in the medical charts is 
expected to vary.Data availability will be assessed as part of the formal site feasibility assessment. 
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 Diagnostic evaluations (endoscopic) related to UC or CD during post-index event 
period.  
(All diagnostic evaluations within 6 months prior to index event, and during the post-index event period 
(including dates of all assessments) up to 6 months post-index treatment discontinuation for patients who 
discontinued their index treatment). 
o Disease status after diagnostic evaluation (complete remission, partial 
remission, no remission). 
Comorbid medical conditions 
 Comorbid medical conditions (includes: chronic conditions, acute events, reactions to 
prior treatment, and extra intestinal manifestations)  
(Within 6  months prior to index event and pre-existing at time of index event). 
o Type of comorbidity and date of diagnosis. 
o Extra intestinal manifestations change in severity/resolution status post-index 
event. 
 New-onset comorbid conditions (chronic and acute) including extra intestinal 
manifestations. 
(During the post-index event period up to 6 months post-index treatment discontinuation for patients who 
discontinued their index treatment). 
o Type of comorbidity and date of diagnosis. 
o Extra intestinal manifestations - change in severity/resolution status. 
VDZ or other biologic index treatment 
 Treatment overview. 
o Type of index treatment (induction and maintenance), type of drug (originator 
product or biosimilar), date of initiation, steroid dependency status at start of 
treatment, primary and secondary reasons for selecting treatment. 
 Modifications to VDZ/other biologic treatment administration 
o Modification type (e.g., dose increase or decrease in dosing frequency, date of 
intensification, discontinuation, date of discontinuation, primary reason for 
discontinuation). 
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Biologic drug therapy switching  
(Only for subjects who discontinued index VDZ/other biologic treatment during the post-index event period:  
treatment patterns during the post-index event period up to 6 months post-index treatment discontinuation). 
 Biologic drug. 
o Type of drug, date of initiation, steroid dependency status at treatment start. 
 Treatment overview. 
o Type of index treatment, type of drug (originator product or biosimilar), date of 
initiation, steroid dependency status at start of treatment, primary and secondary 
reasons for selecting treatment. 
 Modifications to VDZ/other biologic treatment administration 
o Modification type (e.g., dose increase or decrease in dosing frequency, date of 
intensification, discontinuation, date of discontinuation, primary reason for 
discontinuation). 
 
 
Concomitant non-biologic drug therapies  
(During the -post-index event period up to 6 months -post-index treatment discontinuation for patients who 
discontinued their index treatment). 
 Type of concomitant non-biologic drug therapy during induction and maintenance, start 
and end dates, route of administration, administration site. 
Adverse events during VDZ and other biologic therapy 
(All AEs regardless of seriousness or relation to index therapy that occurred during the post-index event period 
up to 6 months post-index treatment discontinuation for patients who discontinued their index treatment). 
o Type of AE, whether subject also had this AE within 12 months prior to 
initiation of VDZ or other biologic, severity, AE seriousness criteria 
assessment, documented relation to index drug noted in chart, date of onset and 
resolution, action taken with VDZ or other biologic therapy, and outcome. 
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Healthcare Resource Utilization 
 Work status  
At time of the index event 
o Status (e.g., retired, full-time employee) 
o Days of sick leave 
 HCP visits/referrals related to UC or CD management. 
o Number of UC/CD-related HCP visits within 12 months prior to index event by 
HCP type. 
o UC/CD-related HCP visits during the post-index event period up to 6 months 
post-index treatment discontinuation for patients who discontinued their index 
treatment. 
▪ Type of HCP, type of visit, date and reason for visit 
 
 ED visits and hospitalizations for any reason (includes UC/CD related reasons and non-
UC/CD related reasons). 
(Within 12 months prior to index event and during the post-index event period up to 6 months post-index 
treatment discontinuation for patients who discontinued their index treatment). 
o Number of ED  and/or Hospitalizations referrals/visits. 
 UC/CD-related surgical procedures. 
(During the pre-index event period (from the point of UC/CD diagnosis) and during the post-index event 
period up to 6 months -post-index treatment discontinuation for patients who discontinued their index 
treatment). 
o Type of surgical procedure. 
Survival status 
 Date of death (including primary cause) or last day subject was known to be alive (last 
contact with site) on date of chart abstraction initiation. 
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9 
Statistical Methods and Determination of Sample Size 
This section describes 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 
must be described in a revised Statistical Analysis Plan (SAP) before completion of data 
collection. All later deviations and / or alterations will be summarised in the Clinical Study 
Report. 
All final analyses will be performed once the data from all patients has been collected in the 
database, cleaned, and database lock has occurred. 
9.1 
Foreseen analyses 
This study is observational and epidemiological methods will be employed for data analyses. 
Descriptive analysis will be performed of all collected data except data collected only for the 
purpose of data cleaning. The following descriptive analyses are foreseen: 
 Continuous data will be described by their mean, median, standard deviation (SD), 
minimum, and maximum. 
 Categorical variables will be described by frequency and percentages (n, %). 
 Kaplan-Meier curves will be presented to describe time-to-event analyses (e.g., time to 
first dose escalation, time to discontinuation). 
Treatment patterns will be analysed by index treatment cohort (VDZ vs. other biologic) and 
then sub-stratified disease type (CD or UC). Simple statistical tests will be conducted (in case 
data are available) to test for significant differences between cohorts. Appropriate tests (e.g., t-
test, Mann Whitney-U test, and chi-square test) will be used for comparison between cohorts. 
The following study outcomes have been defined: 
 
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9.1.1 Primary outcomes 
9.1.1.1 Treatment Patterns 
Changes in patients’ biologic treatment following initiation of the index treatment will be 
described across treatment cohorts. Type of treatment will be defined in the SAP. The 
descriptive analysis will examine: 
 Changes in index treatment intensity, such as: 
o Changes in dose (increase or decrease) and frequency of dose intervals (increase 
or decrease) 
 Modifications to planned treatment, such as: 
o Reason for treatment modification related to AEs versus related to disease 
management 
 Concomitant (non-biological) drug treatment 
o Prescribed non-biological drug therapy during post-index period 
 Discontinuation of index therapy 
 Discontinuation of index therapy with subsequent implementation of another biologic 
therapy (VDZ, infliximab, adalimumab or golimumab [UC only], tofacitinib, 
certolizumab and ustekinumab); 
o Switch to either VDZ, infliximab, adalimumab, or golimumab [UC only], 
tofacitinib, certolizumab and ustekinumab. 
Description of specific treatment pattern measures will be further defined in the SAP. 
9.1.1.2 Time-to-Event Analysis 
Time-to-events (e.g., time-to-switch) will be analysed using survival analysis techniques and 
Kaplan-Meier curves will be presented. This will allow different follow-up periods for different 
patients to be accounted for, and for censoring at the end of the observation period (i.e., death 
and loss to follow-up). The main events evaluated will include: 
Time to switching: defined as time from index treatment initiation until a patient initiates 
another biologic treatment (VDZ, infliximab, adalimumab, or golimumab [UC only], 
tofacitinib, certolizumab and ustekinumab) 
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Time to discontinuation: defined as time from index treatment initiation until patient 
discontinues index treatment without switching to another biologic therapy 
Time-to-events analyses will be described across treatment cohorts and by subgroups (i.e., age, 
disease type, and treatment history) dependent on data availability. 
9.1.1.3 Clinical Effectiveness at Least Six Months Post-Treatment Initiation 
Clinical effectiveness will be defined by changes in disease measures and outcomes from 
diagnostic procedures conducted closest to the date of index event, and all assessments during 
the -post-index event period. All analyses will take into account variations in clinical evaluation 
time periods to ensure cohorts are comparable. Clinical effectiveness will be described across 
treatment cohorts and descriptive analysis will examine: 
 Changes in disease activity indicators such as changes in scores of the Mayo score, the 
simple endoscopic index for Crohn's disease (SES-CD), HBI, or CDAI, and/or change 
to individual components of scores (e.g., change in abdominal pain, change in physician 
global assessment [PGA], change in abdominal mass, change in stool frequency, or 
rectal bleeding). 
 Changes in clinical assessments such as change in CRP, ESR, FCP. 
 Changes based on the evaluation of outcomes associated with diagnostic procedures 
such as endoscopic findings or other qualitative outcomes provided by HCPs 
Definitions of treatment response will be included in the SAP and determined based on the 
abstracted data variables. Treatment response and clinical effectiveness will be described 
across treatment cohorts and by subgroups (i.e., IBD type) dependent on data availability. 
9.1.2 Secondary outcomes 
9.1.2.1 Patient Populations 
Patient demographics (e.g., age, smoking status, body mass index, etc.), treatment histories 
(i.e., prior non-biologic use) and IBD type (UC vs. CD) and disease characteristics (CD/UC) 
will be summarized. 
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Sample characteristics will be used to stratify the data into subgroups (i.e., age, diagnosis, 
treatment, treatment history, treatment lines etc.); subgroup analyses will be conducted 
throughout as permitted by the availability of data. Variables used in the analysis will be 
defined further in the SAP. 
9.1.2.2 Clinical Effectiveness at Least 12 Months Post-Treatment Initiation 
The same analyses conducted at 6 months will be conducted on the sub-set of patients with 12 
or more months based on data availability. Treatment response will also be evaluated at 12 
months. Definitions of clinical effectiveness and treatment response will be included in the 
SAP and determined based on the abstracted data variables. Treatment response and clinical 
effectiveness will be described across treatment cohorts and by subgroups (i.e., IBD type) 
dependent on data availability. 
9.1.2.3 Safety Events 
Descriptive statistics will be used to describe all safety events reported during the chart review. 
Safety data described will include: 
 Number and types of AEs associated with medical treatment vs. non-treatment related 
events 
 Number of non-serious and serious AEs documented to be related to treatment 
 Number of treatment alterations (withdrawn, reduced, delayed, increased) as a result of 
AEs 
 AE duration (based on information on date of onset and date of resolution) 
 AE outcome 
Safety outcomes will be evaluated from VDZ or other biologic initiation to 6 months -post-
index treatment discontinuation. For subjects who are not 6 months post-treatment 
discontinuation at the time of chart abstraction initiation, the end date will be the date of chart 
abstraction initiation. All analyses will be further defined in the SAP. 
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9.2 
Interim Analyses 
An interim analysis will be performed sometime prior to database lock. Interim analysis timing 
will be determined during the data collection period and will be dependent on the number of 
patients included (and data abstracted) as well as target congress submission deadlines. The 
analysis is likely to provide an evaluation of data quality as well as provide an understanding 
of the VDZ study population. Furthermore, the analysis may also examine key study outcomes 
as well as characterise the populations. 
9.3 
Determination of Sample Size 
The primary objective of the study is descriptive. Therefore, the sample size calculation is 
based in the precision of a confidence interval estimation of a proportion. The study will recruit 
two types of patients; the distribution will be 1:1. Both groups will be evaluated separately in 
consequence we calculated a sample size calculation for each group. 
We assumed the scenario of maximum indetermination (i.e., an expected proportion of 50%). 
To obtain a confidence interval of 95% of this proportion with a precision of 7.5% is necessary 
to recruit 171 patients. We expect a 10% of non-valid data so we will recruit 200 patients per 
group (400 patients in total). 
 200 patients treated with a first-line or second-line VDZ. 
 200 patients treated with first-line or second-line of other biologics (infliximab,  
adalimumab, golimumab). 
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10 Reports 
A Non-Interventional Study Report based on the results obtained will be prepared and 
submitted to Global Research for distribution. The Final Study Report should be available 
within one year from collection of the last data point, and the participating sites should be 
informed about the results when the report is finalised. 
11 Publication, Disclosure, and Clinical Trial Registration Policy 
The Sponsor aims to have the results of this study published. 
The Sponsor has the right to use the data and results for regulatory purposes and for internal 
presentation within the company and to partners. 
Takeda may post the results of the study on ClinicalTrials.gov and/or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations. 
The study team plans to disseminate the results of the study through the development of an 
abstract, poster/presentation (if selected), final study report, and manuscript. 
 Final Study Report: A final study report will be developed based on analysis of the 
final locked dataset. The final study report will include all final study tables. 
 Abstract/Poster: In the case that results yield material suitable for generation of a 
conference abstract, an abstract will be prepared. If selected, the study results (either 
interim or final) will be used to develop a poster/presentation for the conference. 
 Manuscript: In the case that results yield material suitable for publication of a 
manuscript in a peer- reviewed journal, a manuscript will be developed. All authors will 
have to meet the International Committee of Medical Journal Editors (ICMJE) 
guidelines for authorship. 
An authorship plan will be developed to establish the authorship criteria for publication of the 
results obtained in this study. To be considered as authors, all investigators should accept and 
sign the authorship plan. 
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12 Archiving of Study Documentation 
During the course of the study the Site Responsible must as a minimum file the below essential 
documents in the Study Site File: 
 Written agreement between the Sponsor or its representative (e.g., CRO) and the Study 
Site Responsible/Clinic/Hospital/Trust as locally applicable. 
 The study protocol and any amendments. 
 Signed and dated protocol agreement and amendment agreements, if any, with the 
original signature of the Site Responsible. 
 Subject Information Sheet and Informed Consent Form in local language (notified to / 
approved by IEC/IRB, including the original signed Forms. 
 The list of participating subjects. 
 Written IEC / IRB approval / vote according to local regulations. 
 Authority approval according to local regulations. 
 The completed CRFs. 
 The progress reports. 
 
After final database lock the Site Responsible must as a minimum store the list of participating 
subjects and the signed Informed Consent Forms on site for 5 years. The Site Responsible 
should store additional study documentation for a longer period of time as required by any local 
regulations and/or hospital requirement. 
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13 References 
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Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing 
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Burisch J, Jess T, Martinato M, Lakatos PL. The burden of inflammatory bowel disease 
in Europe. J Crohn’s Colitis. 2013 May 1;7(4):322–37.  
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Kappelman MD, Rifas–Shiman SL, Kleinman K, Ollendorf D, Bousvaros A, Grand RJ, 
et al. The Prevalence and Geographic Distribution of Crohn’s Disease and Ulcerative 
Colitis in the United States. Clin Gastroenterol Hepatol. 2007 Dec;5(12):1424–9.  
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Blondel-Kucharski F, Chircop C, Marquis P, Cortot A, Baron F, Gendre JP, et al. Health-
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Kappelman MD, Porter CQ, Galanko JA, Rifas-Shiman SL, Ollendorf DA, Sandler RS, 
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782/human_med_001751.jsp&mid=WC0b01ac058001d124 
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US Food and Drug Administration (FDA). Drugs @ FDA - FDA Approved Drug 
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Ungar B, Kopylov U. Advances in the development of new biologics in inflammatory 
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Feagan BG, Patel H, Colombel J-F, Rubin DT, James A, Mody R, et al. Effects of 
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vedolizumab on health-related quality of life in patients with ulcerative colitis: results 
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Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel J-F, Sandborn WJ, et al. 
Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J 
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Loftus E V., Colombel J-F, Feagan BG, Vermeire S, Sandborn WJ, Sands BE, et al. 
Long-term Efficacy of Vedolizumab for Ulcerative Colitis. J Crohn’s Colitis. 2016 Sep 
28;11(4):jjw177.  
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Barré A, Colombel JF, Ungaro R. Review article: predictors of response to vedolizumab 
and ustekinumab in inflammatory bowel disease. Vol. 47, Alimentary Pharmacology 
and Therapeutics. Wiley/Blackwell (10.1111); 2018. p. 896–905.  
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European Medicines Agency. Entyvio -Vedolizumab [Internet]. Agencia Europea de 
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Vermeire S, Loftus E V., Colombel J-F, Feagan BG, Sandborn WJ, Sands BE, et al. 
Long-term Efficacy of Vedolizumab for Crohn’s Disease. J Crohn’s Colitis. 2016 Sep 
28;11(4):jjw176.  
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Raluy M, Alam N, Donaldson R, Smyth M, Khalid JM. A real-world study of outcomes 
in biologic-naive patients with Crohn’s disease and ulcerative colitis initiating 
vedolizumab. In: JOURNAL OF CROHNS & COLITIS. OXFORD UNIV PRESS 
GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND; 2016. p. S238–S238.  
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Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel J-F, Sands BE, et al. 
Vedolizumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J 
Med. 2013 Aug 22;369(8):711–21.  
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Baumgart DC, Bokemeyer B, Drabik A, Stallmach A, Schreiber S, Vedolizumab 
Germany Consortium. Vedolizumab induction therapy for inflammatory bowel disease 
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in clinical practice -a nationwide consecutive German cohort study. Aliment Pharmacol 
Ther. 2016 May;43(10):1090–102.  
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Dulai PS, Singh S, Jiang X, Peerani F, Narula N, Chaudrey K, et al. The Real-World 
Effectiveness and Safety of Vedolizumab for Moderate–Severe Crohn’s Disease: 
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Stallmach A, Langbein C, Atreya R, Bruns T, Dignass A, Ende K, et al. Vedolizumab 
provides clinical benefit over 1 year in patients with active inflammatory bowel disease 
-a prospective multicenter observational study. Aliment Pharmacol Ther. 2016 
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The World Medical Association I. WMA Declaration of Helsinki – Ethical Principles 
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Association [Internet]. Declaration of Helsinki. 2013 [cited 2018 Jul 18]. p. 3. Available 
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Epstein M, International Society of Pharmacoepidemiology. Guidelines for good 
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Regulation) -fir [Internet]. VoteWatch Europe. 2016 [cited 2018 Jul 18]. Available from: 
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European Commission. Clinical trials - Directive 2001/20/EC - European Commission 
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14 Appendices - List of Stand –alone Documents 
1. Takeda AE Reporting Form 
2. Study Investigator Agreement 
3. Case Report Form 
4. Ethics Comitee Approval 
5. Summary of Products Characteristics 
6. Patient Information Sheet  
7. Informed Consent Form 
8. Economic Details 
 
 
 
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ANNEX 1: TAKEDA AE REPORTING FORM 
 
 
 
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ANNEX 2: STUDY INVESTIGATOR AGREEMENT 
ANNEX 3: CASE REPORT FORM 
ANNEX 4: ETHICS COMITEE APPROVAL 
ANNEX 5: SUMMARY AND PRODUCT CARACTERISTICS OF 
ANNEX 6: PATIENT INFORMATION SHEET  
ANNEX 7: INFORMED CONSENT FORM 
ANNEX 8: ECONOMIC DETAILS 
 
 
 
 
 
 
 
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