The Relationship Between Vedolizumab Therapeutic Drug Monitoring, Biomarkers of Inflammation and Clinical Outcomes in the Real World Setting (VEDO TDM RWE)
Conditions: Inflammatory Bowel Diseases, Colitis, Ulcerative, Crohn Disease
Sponsor: Takeda



Vedolizumab-5062 
VEDO TDM RWE 
Study Protocol Ver. 1.0 11-JUNE-2020 
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<GMA NIS Protocol Template for Takeda Sponsored Studies, version 1.0 (02-Mar-2018)> 
Non-Interventional Study Protocol 
Title: The Relationship Between Vedolizumab Therapeutic Drug Monitoring, 
Biomarkers of Inflammation and Clinical Outcomes in the Real World Setting (VEDO 
TDM RWE) 
Short title: 
VEDO TDM RWE 
Study ID: 
Vedolizumab-5062 
Sponsor: 
Takeda Canada Inc. 
Bay Adelaide Centre 
22 Adelaide Street West, Suite 3800 
Toronto, ON M5H 4E3 
Phone: +1 (647) 798-2200 
Study phase:  Medical Affairs, Post-Approval Company Sponsored (Observational) 
Date of draft version 1.0 of protocol: 22-July-2020  
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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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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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 Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline. 
- 
All applicable laws and regulations, including, without limitation, data privacy laws 
and regulations. 
- 
Regulatory requirements for reporting serious adverse events as defined in this 
protocol. 
 
 
 
Signature of Investigator 
Date 
 
<Investigator Name (print or type)> 
 
<Investigator’s Title> 
 
<Location of Facility (City, State/Provence)> 
 
<Location of Facility (Country)> 
 
 
 
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STUDY SUMMARY 
Name of Sponsor(s): 
Takeda Canada Inc.
Compound/Product: 
Vedolizumab (ENTYVIO)
Title of Protocol: The Relationship Between Vedolizumab Therapeutic Drug Monitoring, 
Biomarkers of Inflammation and Clinical Outcomes in the Real-World Setting (VEDO TDM RWE)
Study Number: Vedolizumab-5062
Phase: N/A 
Study Design: 
The proposed study is a retrospective, longitudinal analysis of data collected in a subset of Takeda 
Canada PSP, specifically those patients on vedolizumab, some of which received biomarker testing 
and Therapeutic Drug Monitoring (TDM) at pre-specified intervals during their treatment. 
Primary Objectives: 
To determine if a relationship exists between week 6 vedolizumab TDM and week 30 Faecal 
calprotectin (FCP).
Secondary Objectives: 
x
To assess the longitudinal relationship between TDM at week 6, week 14, week 22, and 
week 30 with baseline characteristics (albumin, CRP, FCP, line of therapy, disease subtype, 
disease duration, concomitant immunomodulator use). 
x
To assess the relationship between week 6 TDM and week 30 CRP, disease scores, dose 
escalation, and treatment persistence.   
x
To assess the relationship between week 14 TDM and week 30 FCP.   
x
To assess the relationship between week 14 TDM and week 30 CRP, disease scores, dose 
escalation, and/or treatment persistence. 
x
To assess the longitudinal relationship between TDM at week 6, week 14, week 22 and week 
30 and week 30 FCP, CRP, disease scores, dose escalation and treatment persistence. 
x
To assess vedolizumab drug concentration by quartile analysis, at week 6, 14, 22 and 30. 
x
To assess relationships between therapy discontinuation and baseline characteristics 
(albumin, CRP, FCP, line of therapy, disease subtype, disease duration, concomitant 
immunomodulator use). 
x
To assess relationships between dose escalation and baseline characteristics (albumin, CRP, 
FCP, line of therapy, disease subtype, disease duration, concomitant immunomodulator 
use). 
x
To assess the longitudinal relationships of FCP, CRP, disease scores, therapy 
discontinuation, dose escalation with baseline characteristics (albumin, disease subtype, 
disease duration, line of therapy). 
x
To assess the relationship between TDM (at week 6 and longitudinally) and therapy 
discontinuation. 
x
To assess the relationship between TDM (at week 6 and longitudinally) and dose escalation.
x
To assess the relationship between any primary or secondary endpoint in patient subgroups, 
including by disease subtype, disease severity, disease localization/extension (if provided), 
line of therapy, line of therapy by disease subtype, and by baseline disease characteristics 
(albumin, CRP, FCP, disease duration, concomitant immunomodulator use).
Exploratory Objectives: 
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Subject Population: Subjects aged >18 years, with Inflammatory Bowel Disease (IBD) (Ulcerative 
colitis (UC) or Crohn’s Disease (CD)). 
Number of Subjects: 
TDM cohort: ~500
Historical cohort: ~5,000
Study Sites:  
N/A. Data is generated from Takeda Canada 
Patient Support Program
Dose Level(s): 
Vedolizumab, 300 mg at (induction) week 0, 
week 2, week 6 and (maintenance) every 8 weeks 
thereafter as per product Health Canada Product 
Monograph, or every 4 or 6 weeks thereafter if 
requested by treating physician as per local 
practice.
Route of Administration: 
Intravenous (IV) infusion over 30 minutes.
Duration of Study: 
Data extract is from the Takeda Patient Support Program from 2015 to 2020.  Data analysis and 
reporting is from August 2020 to March 2021.
Criteria for Inclusion: 
Subjects who are: 
x
Adult patients (18 years) diagnosed with IBD (UC or CD)
x
Enrolled in the Takeda Canada PSP  
x
Received or receiving vedolizumab between the years 2015 and 2020 
x
Provided consent for secondary use of their data 
Criteria for Exclusion: 
No exclusion criteria were applied. 
Criteria for Evaluation and Analyses: 
TDM cohort: 
The available data include (but are not limited to):
x
Baseline characteristics: age, sex, disease type (CD/UC), disease duration, prior 
immunomodulator therapy, prior biologic therapy, CRP, FCP, albumin and disease scores 
x
Vedolizumab treatment: Start date, end date, dose, frequency, reason for discontinuation 
x
Biochemical markers of inflammation: FCP, CRP at week 0, week 6, week 14, week 22, and 
week 30 
x
Vedolizumab therapeutic drug monitoring (TDM) at week 6, week 14, week 22 and week 
30 
x
Disease scores (CD:HBI, UC:partial Mayo) at baseline (week 0) and week 6, week 14, week 
22 and week 30 
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Statistical Considerations: 
Receiver-operating characteristic (ROC) curve analysis will be used to establish the best 
cut-off for vedolizumab TDM at week 6 and its corresponding performance for the 
prediction of Faecal calprotectin (FCP) at week 30. Kaplan-Meier survival curves and the 
log-rank test will be used to obtain treatment persistence curves. A two-sided p-value of 
<0.05 will be considered statistically significant.  
Sample Size Justification: The retrospective data extraction will include up to 5500 patients (~550 
in the TDM cohort and ~5000 in the historical control) with IBD. This study size is based on all 
patients within the Takeda Canada PSP Group that received vedolizumab between the years 2015 
and 2020 and provided consent for secondary data usage.
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Table of Contents 
1 
Administrative information ................................................................................................ 2 
1.1 
Contacts .................................................................................................................. 2 
1.2 
Approval ................................................................................................................. 3 
2 
Introduction .................................................................................................................... 11 
3 
Study Objective(s) and Endpoint(s) ................................................................................... 13 
3.1 
Objective(s) ........................................................................................................... 13 
3.1.1 
Primary Objective .................................................................................... 13 
3.1.2 
Secondary Objectives................................................................................ 13 
3.1.3 
Exploratory Objective(s) ........................................................................... 14 
3.2 
Endpoint(s) ........................................................................................................... 15 
3.2.1 
Primary Endpoint ..................................................................................... 15 
3.2.2 
Secondary Endpoints ................................................................................ 15 
3.2.3 
Exploratory Endpoints .............................................................................. 15 
4 
Study Administrative Structure ......................................................................................... 16 
4.1 
Sponsor Personnel .................................................................................................. 16 
4.2 
Contract Research Organisation (CRO) .................................................................... 16 
4.3 
Steering Committee ................................................................................................ 16 
5 
Ethics ............................................................................................................................ 17 
5.1 
Ethical conduct of the Study .................................................................................... 17 
5.2 
Independent Ethics Committee / Institutional Review Board and Authorities ................. 17 
5.3 
Subject Information and Written Informed Consent .................................................... 18 
6 
Study Design and Plan ..................................................................................................... 19 
6.1 
Study Schedule ...................................................................................................... 19 
6.2 
Discussion of Study Design ..................................................................................... 20 
6.3 
Selection of Study Population .................................................................................. 21 
6.3.1 
Inclusion Criteria ...................................................................................... 21 
6.3.2 
Exclusion Criteria ..................................................................................... 21 
6.4 
Treatments ............................................................................................................ 21 
6.5 
Criteria for Premature Termination or Suspension of Study ......................................... 21 
6.5.1 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) ......................................................... 22 
6.6 
Study Plan ............................................................................................................. 23 
7 
Safety Reporting ............................................................................................................. 25 
7.1 
Definitions ............................................................................................................ 25 
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7.1.1
Adverse Event.......................................................................................... 25
7.1.2
Serious Adverse Events ............................................................................. 25
7.1.3
Adverse Drug Reactions ............................................................................ 26
7.1.4
Product Quality Issues .............................................................................. 26
7.1.5
Special Situation Reports........................................................................... 26
7.2
Collection and notifying of Adverse Events, Special Situation Reports and Product Quality
Issues to Takeda Pharmacovigilance......................................................................... 27
8
Data Quality Control and Assurance .................................................................................. 28
8.1
Quality Control ...................................................................................................... 28
8.2
Audit from Quality Assurance Unit .......................................................................... 28
8.3
Inspection by IRB/IEC or Competent Authority ......................................................... 28
8.4
Data Management .................................................................................................. 28
8.4.1
Data Flow................................................................................................ 29
9
Statistical Methods and Determination of Sample Size......................................................... 30
9.1
Statistical Analysis Plan .......................................................................................... 30
9.1.1
Main primary outcome .............................................................................. 30
9.1.2
Main secondary outcomes ......................................................................... 30
9.1.3
Methods for handling missing data ............................................................. 31
9.1.4
Data analysis ........................................................................................... 31
9.1.5
34
9.2
Interim Analyses .................................................................................................... 35
9.3
Determination of Sample Size ................................................................................. 35
10 Reports .......................................................................................................................... 36
11 Publication, Disclosure, and Clinical Trial Registration Policy.............................................. 36
12 Archiving of Study Documentation ................................................................................... 36
13 References ..................................................................................................................... 37
 
 
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List of Abbreviations and Definition of Terms 
 
AE: 
 
Adverse Event 
AI: 
 
Artificial Intelligence 
ADR:  
Adverse Drug Reaction 
AUROC: 
Area under the Tececiver-operating characteristic curve 
CD: 
 
Crohn’s Disease 
CI: 
 
Confidence Interval 
CRP:  
C-Reactive Protein 
CRO:  
Contract Research Organisation 
EC: 
 
Ethics Committee 
FCP:  
Faecal Calprotectin 
FTP:   
File Transfer Protocol 
GCP:  
Good Clinical Practice 
GPP:  
Good Pharmacoepidemiology Practices 
HBI:  
Harvey-Bradshaw Index 
IBD:   
Inflammatory Bowel Disease 
ICH:  
International Conference on Harmonisation 
IEC: 
 
Independent Ethics Committee 
IQR:  
Inter-Quartile Range 
IRB:  
Institutional Review Board 
ISPE:   
International Society of Pharmacoepidemiology 
MAR:  
Missing at random 
MCAR:  
Missing completely at random 
MNAR: 
Missing not at random 
NLP:  
Natural Language Processing 
PSP:  
Patient Support Program 
ROC:  
Receiver-operating characteristic 
RWE:   
Real-world evidence 
SAE:  
Serious Adverse Event 
SAP:  
Statistical Analysis Plan 
TDM:  
Therapeutic Drug Monitoring 
UC: 
 
Ulcerative Colitis 
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2
Introduction 
Disease background and rationale: 
Inflammatory Bowel Disease (IBD) refers to a group of serious, chronic conditions that affect 
more than five million people worldwide (1,2). Although it can affect people at any age it has 
a propensity to strike teenagers and those in their twenties with unpredictable symptoms and 
significant morbidity and mortality (3). Currently the cause for either Ulcerative Colitis or 
Crohn’s Disease are poorly understood, however, significant advances have been made in the 
treatment of these diseases including the biologic vedolizumab (4-7). 
Takeda is conducting a retrospective study which seeks to leverage the data generated as part 
of the Takeda Canada Patient Support Program to determine the real-world evidence (RWE) 
of vedolizumab, its relationship with Therapeutic Drug Monitoring (TDM), biomarkers of 
inflammation, and its effect on clinical outcomes in a real-world setting.  
Study design:  
The study is retrospective and longitudinal by design, conducted on data collected as part of 
the cross-Canada PSP group, and will include IBD patients receiving vedolizumab between the 
years 2015 and 2020.  
A total of approximately 5,500 patients will be included. The main study cohort consists of 
~500 patients who received TDM during their treatment (“TDM cohort”). The remaining 
~5,000 patients received vedolizumab but did not receive TDM during the course of their 
treatment (“Historical cohort”).
The TDM cohort includes the following data points:  
x
Baseline characteristics: age, sex, disease type (CD/UC), disease duration, prior 
immunomodulator therapy, prior biologic therapy, CRP, FCP, albumin and disease 
scores 
x
Vedolizumab treatment: Start date, end date, dose, frequency, reason for 
discontinuation 
x
Biochemical markers of inflammation: FCP, CRP at w0, w6, w14, w22, and w30 
x
Vedolizumab therapeutic drug monitoring (TDM) at w6, w14, w22 and 30 
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x Disease scores (CD:HBI, UC:partial Mayo) at baseline and w6, w14, w22 and w30 
 
The Historical cohort includes the following data points: 
x Baseline characteristics: age, sex, disease type (CD/UC), disease duration 
x Vedolizumab treatment: Start date, end date, dose, frequency, reason for 
discontinuation 
 
 
 
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3 
Study Objective(s) and Endpoint(s) 
 
3.1 
Objective(s) 
The goal of the study is to determine whether there is a relationship between TDM of patients 
on vedolizumab and their clinical outcomes to generate hypotheses for future testing. 
 
3.1.1 Primary Objective  
x Determine if a relationship exists between week 6 vedolizumab TDM and week 30 
FCP. Subgroup analyses of the primary outcome will include by disease subtype (UC, 
CD), line of therapy (bionaive, failure on > 1 previous biologic therapy), line of therapy 
by disease subtype, and by baseline disease characteristics (albumin, CRP, FCP, disease 
duration and concomitant immunomodulator use). 
 
3.1.2 Secondary Objectives  
x Assess the longitudinal relationship between TDM at week 6, week 14, week 22, and 
week 30 with baseline characteristics (albumin, CRP, FCP, line of therapy, disease 
subtype, disease duration, concomitant immunomodulator use). 
x Assess the relationship between week 6 TDM and week 30 CRP, disease scores, dose 
escalation, and treatment persistence. 
x Assess the relationship between week 14 TDM and week 30 FCP.   
x Assess the relationship between week 14 TDM and week 30 CRP, disease scores, dose 
escalation, and/or treatment persistence. 
x Assess the longitudinal relationship between TDM at week 6, week 14, week 22 and 
week 30 and week 30 FCP, CRP, disease scores, dose escalation and treatment 
persistence. 
x Assess vedolizumab drug concentration by quartile analysis, at week 6, 14, 22 and 30. 
x Assess relationships between therapy discontinuation and baseline characteristics 
(albumin, CRP, FCP, line of therapy, disease subtype, disease duration, concomitant 
immunomodulator use). 
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x
Assess relationships between dose escalation and baseline characteristics (albumin, 
CRP, FCP, line of therapy, disease subtype, disease duration, concomitant 
immunomodulator use). 
x
Assess the longitudinal relationships of FCP, CRP, disease scores, therapy 
discontinuation, dose escalation with baseline characteristics (albumin, disease 
subtype, disease duration, line of therapy). 
x
Assess the relationship between TDM (at week 6 and longitudinally) and therapy 
discontinuation. 
x
Assess the relationship between TDM (at week 6 and longitudinally) and dose 
escalation.  
x
Assess the relationship between TDM (at week 6 and longitudinally) and treatment 
duration. 
x
To assess the relationship between any primary or secondary endpoint in patient 
subgroups, including by disease subtype, line of therapy, line of therapy by disease 
subtype, and by baseline disease characteristics (albumin, CRP, FCP, disease duration, 
concomitant immunomodulator use). 
3.1.3
Exploratory Objective(s)  
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3.2
Endpoint(s) 
3.2.1
Primary Endpoint
The primary endpoint for this study is the correlation between week 6 vedolizumab TDM and 
week 30 FCP.   FCP is being used as a surrogate marker for disease severity, and by extension 
drug efficacy, with higher levels indicating poor drug efficacy, and low to non-detectable levels 
indicating increased drug efficacy. 
3.2.2
Secondary Endpoints  
Secondary endpoints for this study are CRP levels at week 30, disease scores (HBI and Partial 
Mayo), dose escalation, and treatment persistence, each of which are being used as surrogates 
for treatment efficacy. Similar to FCP, decreased levels of CRP, HBI and Partial Mayo disease 
scores, and less dose escalation will each be interpreted to indicate increased drug efficacy. 
Treatment persistence and longer treatment duration will each be interpreted to indicate drug 
efficacy.  
3.2.3
Exploratory Endpoints  
  
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4 
Study Administrative Structure 
Takeda Canada Inc. is the study sponsor. They have contracted Pentavere Research Group Inc. 
(hereafter referred to as Pentavere) to act as CRO and conduct all study activities related to the 
proposed secondary data analysis, including drafting of protocols, Statistical Analysis Plan 
(SAP), Data management plans, submission to IRB/IEC, analysis of data and reporting of study 
results. Pentavere will maintain records of generated study material, excluding patient informed 
consent, as these were collected by the PSP provider at the time of patient enrollemnt. 
 
4.1 
Sponsor Personnel 
 The Sponsor (Takeda Canada Inc.) will keep a record of all relevant sponsor personnel.  
 
4.2 
Contract Research Organisation (CRO) 
Pentavere is a Healthcare Technology Research group, which provides CRO services along 
with proprietary AI and NLP data curation engine DARWENTM, which transforms structured 
and unstructured healthcare information into analysis-ready structured and curated datasets. 
Pentavere’s clinical, research and data science teams will perform all study-related activities to 
execute the proposed retrospective, longitudinal analysis of data collected in a subset of 
Takeda’s Canada Patient Support Program. Pentavere will keep a record of all involved 
Pentavere personnel. 
 
4.3 
Steering Committee 
Three IBD Thought Leaders, external to Takeda Canada Inc and Pentavere, and practicing 
gastroenterologists from across Canada, will form the study’s Steering Committee and will 
help guide the research project, ensuring the project outputs are clinically relevant, meaningful 
and credible. 
 
 
 
 
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5 
Ethics 
This study is a retrospective observational study where the existence of the study has no impact 
on the subject except for collection of informed consent to use of the subject’s data.  
 
5.1 
Ethical conduct of the Study 
This study will be conducted in accordance with the protocol, the current version of the 
Declaration of Helsinki, Good Pharmacoepidemiology Practices (GPP), ISPE GPP guideline 
and any local regulations (8-11). Data protection and privacy regulations will be observed in 
capturing, forwarding, processing, and storing patient data, in accordance with local applicable 
privacy and confidentiality requirements. 
 
The appointed CRO will ensure that the protocol, any amendments are submitted to the relevant 
Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) according to local 
requirements. 
 
The appointed CRO 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 
According to applicable regulations, the appointed CRO will: 
x notify or obtain approval from the relevant IEC/IRB of the protocol and any amendments  
 
The appointed CRO will submit required documents to the IEC / IRB, such as: 
x periodic updates on the progress of the study 
x notification of the end-of-study 
x a summary of the study results 
 
The appointed CRO will keep an updated list of all submission and approval dates of all 
documents submitted to the IEC / IRB. Copies of the documents will be distributed upon 
request. 
 
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5.3 
Subject Information and Written Informed Consent 
The proposed study is a retrospective, secondary data analysis. Takeda Canada has ensured 
that the patients in this study have explicitly agreed to any secondary use of their data by 
following the below guidelines: 
 
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 observational the consent only concerns the data 
collection per se and is 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. 
 
For details, see the Subject Information Sheet and Informed Consent Form. 
 
 
 
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6 
Study Design and Plan 
This study is a ‘non-interventional study’ as defined in Directive 2001/20/EC and will follow 
the guidelines for GPP (9,11).  
 
This means that: 
x The assignment of a subject to a particular therapeutic strategy is not decided in advance 
by the study protocol but falls within current practice. 
x No additional diagnostic or monitoring procedures shall be applied to the subjects. 
x Epidemiological methods shall be used for the analysis of collected data. 
x Vedolizumab was prescribed in accordance with the terms of the marketing authorisation(s) 
x The prescription of vedolizumab is clearly separated from the decision to include the 
subject in the study 
 
The proposed study is a retrospective, longitudinal analysis of data collected in a subset of 
Takeda Canada PSP, specifically those patients on vedolizumab, some of which received 
biomarker testing and TDM at pre-specified intervals during their treatment. This activity aims 
to investigate whether there are relationships between the proposed variables and clinical 
outcomes, and whether there is a benefit of early therapeutic drug monitoring for patients 
receiving vedolizumab.  
 
6.1 
Study Schedule 
Start of Historical Cohort 
 
 
 
May 2015 
Start of TDM Cohort  
 
 
 
March 2018 
Planned Start of Analysis: 
 
 
 
August 2020 
Planned completion of the Study Report: 
 
November 2020 
Planned End of Study: 
 
 
 
November 2020 
 
The Start of Study is defined as defined as the date that IRB/IEC was obtained. The End of 
study is defined as first study publication submitted.  
 
The Sponsor will ensure that End-of-Study notification is submitted to the concerned 
authorities and IEC/IRB, as locally required. 
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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), IECs/IRBs and authorities will be informed promptly. 
6.2
Discussion of Study Design   
The proposed study is a retrospective, longitudinal analysis of data collected in a subset of 
Takeda Canada PSP. A total of approximately 5,500 patients will be included. The main study 
cohort consists of 500 patients which received TDM during their treatment (“TDM cohort”). 
The remaining ~5,000 patients received vedolizumab but did not receive TDM during the 
course of their treatment (“Historical cohort”).
. 
In addition, as the TDM and biomarker data comes from only 500 patients, the cohort may not 
accurately represent the Canadian population, and may be subject to issues in reproducibility. 
Moreover, treatment is not reflective of the entire care pathway as information may not be 
linked between healthcare providers. As the data is coming from the Takeda Canada Patient 
Support Group database, assumptions are based on the PSP’s team and are potentially 
imprecise.  
Results from the currently proposed comparison of dose frequency escalations and treatment 
persistence between cohorts should be interpreted with caution as this is only a proxy of disease 
severity. Furthermore, bias may exist due to data collection occurring for both cohorts occurred 
during different periods of time, and thus disease management may have differed. Additionally, 
there may be selection bias as patients in the TDM cohort agreed to extensive disease 
monitoring, whereas patients in the Historical cohort were not offered a similar option. Lastly, 
no causal conclusions will be drawn from the proposed analyses, only correlations will be 
investigated. 
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6.3 
 Selection of Study Population 
This is a retrospective longitudinal study being conducted on data collected as part of a cross-
Canada PSP group, and will include IBD patients receiving vedolizumab between years 2015 
and 2020.  
6.3.1 Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. The subject or, when applicable, the subject’s legally acceptable representative signed and 
dated a written, informed consent form, which specified secondary use of their data, and 
any required privacy authorization as part of their enrollment in Takeda Canada’s PSP.  
2. Adult patients (≥18 years) diagnosed with IBD (UC or CD) 
3. Received or receiving vedolizumab between the years 2015 and 2020 
 
6.3.2 Exclusion Criteria 
No exclusion criteria were applied. 
Subjects 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. 
 
6.4 
Treatments 
Non-interventional/observational – no treatments/pharmacotherapy are instructed by the study 
protocol. 
 
6.5 
Criteria for Premature Termination or Suspension of Study 
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study. 
x If the Sponsor and/or CRO 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. 
 
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6.5.1 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) 
In the event that the Sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) 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. 
 
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The following data has been collected as part of the Takeda Canada PSP and will be analysed 
for this study: 
 
TDM cohort: 
Approximately 500 patients from the Takeda Canada PSP patients receiving vedolizumab with 
biomarker and TDM data will be analysed. 
The available data include (but are not limited to): 
• 
Baseline characteristics: age, sex, disease type (CD/UC), disease duration, prior 
immunomodulator therapy, prior biologic therapy, CRP, FCP, albumin and disease 
scores 
• 
Vedolizumab treatment: Start date, end date, dose, frequency, reason for 
discontinuation 
• 
Biochemical markers of inflammation: FCP, CRP at week 0, week 6, week 14, week 
22, and week 30 
• 
Vedolizumab therapeutic drug monitoring (TDM) at week 6, week 14, week 22 and 
week 30 
• 
Disease scores (CD:HBI, UC:partial Mayo) at baseline (week 0) and week 6, week 
14, week 22 and week 30 
 
Historical cohort: 
Approximately 5,000 patients from the Takeda Canada Patient Support Program patients who 
received/are receiving vedolizumab but did not undergo biomarker or TDM monitoring will be 
analysed. 
The available data include (but may not be limited to): 
x Baseline characteristics: age, sex, disease type (CD/UC), disease duration 
x Vedolizumab treatment: Start date, end date, dose, frequency, reason for 
discontinuation 
 
 
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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: 
 
x A laboratory test result that meets the criteria for an SAE 
x A laboratory test result that requires the subject/patient to receive specific corrective therapy 
x A laboratory abnormality that leads to discontinuation of therapy 
x A laboratory abnormality that the health care provider considers to be clinically significant 
 
7.1.2 Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
 
x Results in death. Note that death is an outcome of an event. The event(s) causing death 
should be recorded. 
x 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 
x Requires inpatient hospitalization or prolongation of existing hospitalization 
x Results in persistent or significant disability/incapacity 
x Results in a congenital anomaly/birth defect 
x 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 
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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. 
 
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. 
 
7.1.5 Special Situation Reports 
A Special Situation Report (SSR) includes any of the following events: 
 
x Pregnancy: Any case in which a pregnancy patient is exposed to a Takeda Product or in 
which a female patient or female partner of a male patient becomes pregnant following 
treatment with Takeda Product. Exposure is considered either through maternal exposure or 
via semen following paternal exposure. 
x Breastfeeding: Infant exposure from breast milk 
x Overdose: All information of any accidental or intentional overdose 
x Drug abuse, misuse or medication error: All information on medicinal product abuse, misuse 
or medication error (potential or actual) 
x Suspected transmission of an infectious agent: All information on a suspected (in the sense 
of confirmed or potential) transmission of an infectious agent by a medicinal product.  
x Lack of efficacy of Takeda Product 
 
x Accidental exposure 
x Use outside the terms of the marketing authorization, also known as “off-label” 
x Use of falsified medicinal product 
x Unintended benefit 
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A SSR should be reported even if there is no associated AE. 
 
 
7.2 
Collection and notifying of Adverse Events, Special Situation Reports and Product 
Quality Issues to Takeda Pharmacovigilance 
x 
SAEs, AEs, ADRs, SSRs and PQIs in the healthcare record or other applicable source 
data that are part of the study objectives or endpoints 
Events/issues which are part of the study objectives or endpoints will be systematically 
identified and collected from healthcare 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. 
x 
SAEs, AEs, SSRs and PQIs in the healthcare records or other applicable source data 
that are not part of the study objectives and endpoints 
Events/Issues which are not part of the study objectives and endpoints will not be  
abstracted or collected from healthcare records or other applicable source records. 
 
 
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8 
Data Quality Control and Assurance 
 
8.1 
Quality Control 
The proposed study is a secondary data analysis. No Manual Data Monitoring or source data 
verification will be performed. Informed consent has already been obtained when patients 
enrolled into the PSP. 
Pentavere will comply with Takeda’s procedures regarding content, archiving and records 
management of process documents. 
Pentavere shall ensure that the datasets and statistical programs used for generating the data 
included in the final study report are kept in electronic format and are available for auditing 
and inspection. 
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. 
 
8.3 
Inspection by IRB/IEC or Competent Authority 
Representatives from IRB/IEC 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 has not been 
obtained from the participants in this study. 
 
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.  
  
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 
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inclusions will be transferred to the first dataset when relevant, i.e. if collected within the time 
frame of the first follow-up period.  
 
The subjects will be identified in the database only by their unique Takeda Canada Patient 
Support Program reference number. 
 
8.4.1 Data Flow 
Takeda Canada will extract the required data from their PSP Group and provide it to Pentavere. 
Following the extraction from the data source, anonymized data will be transferred 
electronically to Pentavere, and Pentavere’s standard procedures will be used to handle and 
process the electronic transfer of these data. The anonymized data will be transferred and stored 
at Pentavere using a zero-knowledge cloud-based data store which maintains compliance with 
the strictest standards to ensure privacy and data protection. Access to the data will be restricted 
to only those members at Pentavere working on the study and who will have access.  
Further data management procedures are as follows: 
x Pentavere will produce a Quality Assurance Plan that is approved by Takeda and 
describes the quality checking to be performed on the data. Correction documentation 
will be maintained following Pentavere’s standard procedures.   
x System backups for data stored at Pentavere and records retention for the study data 
will be consistent with Pentavere’s standard procedures. 
It is assumed that safety reporting of data which are going to be analysed as part of this study 
have been appropriately performed and documented at the time this data was collected through 
primary data collection mechanism (PSP). 
 
 
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9 
Statistical Methods and Determination of Sample Size 
The data will be analysed by Pentavere statisticians and machine learning engineers.  The 
database will be imported into a statistical analysis tool such as SAS (version 9.4), Stata 
(version 16), or R (version 3.6.3) for data analysis. 
 
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 SAP before starting analysis. All later deviations and / or 
alterations will be summarised in the Clinical Study Report. 
 
9.1 
Statistical Analysis Plan 
This study is observational and epidemiological methods will be employed for data analyses. 
The following statistical analysis plan will be conducted on the TDM cohort only, unless 
inclusion of the historical cohort has been explicitly stated. 
 
9.1.1 Primary outcome  
The primary outcome of the study is Week 30 FCP, which will be defined as the level of FCP 
detected within patient’s stool 30 weeks after the patient’s first dose of vedolizumab. This will be 
measured in the TDM cohort only. 
 
9.1.2 Secondary outcomes 
FCP, CRP, HBI/Partial Mayo scores are for the TDM cohort only. The secondary outcomes of 
the study are: 
x Week 30 CRP, which will be defined as the level of CRP detected within patient’s blood 
30 weeks after that patient’s first dose of vedolizumab. 
x Week 30 Disease score, which will be defined as the HBI (for CD patients) or Partial 
Mayo score (for UC patients) measured 30 weeks after the patient’s first dose of 
vedolizumab. 
x Dose escalation, which will be defined as a change from doses every 8 weeks to every 
6 or 4 weeks.  
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x Treatment persistence, which will be defined whether the patient is still on the treatment 
at the end of the TDM study (week 30). 
x Treatment duration, which will be defined as the length of time a patient remains on 
treatment. 
 
9.1.3 Methods for handling missing data 
Summary statistics for the interim and entire dataset will be calculated by Pentavere’s 
Biostatistician to identify inconsistent and/or missing data patterns, outliers, and potential 
selection and information biases. For all numerical features the min, max, median, Q1, Q3 and 
number missing will be included. For all categorical features the count, % and number missing 
will be included. 
 
The cause of missing data will be investigated, and Little’s test will be used to examine if data 
is missing completely at random (MCAR). If data is missing completely at random (MCAR) 
and the percentage of missing data is less than 5% of all observations, complete case analysis 
will be carried out. If the data is missing at random (MAR) or missing not at random (MNAR), 
best-worst and worst-best case analyses will be carried out to account for the range of 
uncertainty due to missing data. The extent of missing data and the limitations will be 
discussed. No missing data imputation will be performed on patient baseline characteristics. 
 
9.1.4 Data analysis 
Data analysis can be split into two major sections: 
 
Cohort characterization and comparisons 
We will carry out descriptive statistics to characterize the TDM and Historical cohorts.  
x Continuous data (depending on the data distribution) will be described as: 
o median and interquartile range (IQR) 
o mean and 95% confidence interval (CI) 
x Discrete data will be described as: 
o frequencies and proportions  
 
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Comparisons of TDM and Historical cohort clinico-demographics will be carried out.  
x Continuous variables (depending on the data distribution) will be described as: 
o Parametric test (such as ANOVA, t-test)  
o Non-parametric test (such as Kruskall-Wallis test or Wilcoxon rank-sum 
test)  
x Discrete variables (depending on the expected value) 
o χ2 test  
o Fisher’s exact test 
 
Outcome Analyses 
The relationship between TDM at week 6 and FCP levels at week 30 will be studied using 
univariate logistic regression models. Multivariate analyses will be performed to control for 
confounding factors. Possible confounding factors which will be examined are age, sex, disease 
type (CD/UC), duration, prior immunomodulator/biologic therapy, vedolizumab start and end 
dates, vedolizumab dose, vedolizumab frequency, and albumin. Both Univariate and 
Multivariate logistic regression models will be perfoemed using the SAS GENMOD procedure, 
or similar package in another software.  
 
For an initial investigation of relationships described in the primary and secondary 
objectives, correlations will be explored using the following (as appropriate): 
x Pearson correlation coefficient 
x Spearman’s rank test 
 
For the described subgroup analyses, the following tests will be used to compare data 
within subgroups: 
x Continuous variables (depending on the data distribution): 
o Parametric tests (such as ANOVA, t-test) 
o Non-parametric tests (such as Kruskal-Wallis test or Wilcoxon rank-sum 
test) 
x Discrete variables (depending on the expected value): 
o χ2 test  
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o Fisher’s exact test  
 
Next, to further explore the relationships between TDM intervals and outcomes described 
in the primary and secondary objectives, the vedolizumab TDM cut-off level that predicts 
the outcomes will be determined using:  
x Receiver-operating characteristic (ROC) curve analysis; the following will be 
reported: 
o Sensitivity 
o Specificity  
o Area under the curve (AUROC)  
o 95% CI  
o We will also use the SAS procedure GLIMMROC (or similar package in 
another software) to explore estimating the AUROC for repeated measures 
analyses with TDM as time-dependent covariate.  
x Kaplan Meier survival analysis and Log-Rank test using the SAS procedure 
PHREG (or similar package in another software) will be done to obtain treatment 
persistence curves; the following will be reported: 
o Hazard ratios 
o 95% CIs 
o We will also use PHREG (or similar package in another software) to 
explore survival analyses with TDM as a time-dependent covariate. 
x Univariate and multivariate analysis by logistic regression, using the determined 
cut-off levels, will be carried out using either the SAS procedure GENMOD or 
GLIMMIX (or similar package in another software). From this analysis, the 
following will be reported:  
o Odds ratios  
o 95% CIs  
x A two-sided p value of <0.05 will be considered statistically significant.  
x Benjamini & Hochberg procedure will be applied to correct for multiple testing. 
 
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We may leverage the concept of unsupervised clustering of data to find any new patterns 
which have not yet been explored and are not very obvious in the data set. To do this we 
will perform: 
x
Dimensionality reduction (such a principal component analysis) to get a list of 
linearly uncorrelated features  
x
Perform clustering (exploring various algorithms) on these features  
The entire act of monitoring patients during treatment, instead of any one variable, may 
actually be related to outcome. To investigate this potential phenomenon, we will first: 
x
Compare dose frequency escalations (i.e. switching from 8-weeks to 4- or 6- week 
frequencies) and treatment persistence between cohorts as a proxy-outcome for 
worsening disease.  
x
Proportions of dose frequency escalations or treatment persistence (yes/no) will be 
compared between the TDM and Historical cohort using Ȥ2 test  
x
Perform Kaplan Meier survival analysis and Log-Rank test as described above on 
both cohorts separately to obtain treatment persistence curves and dose escalation 
curves (one for time from treatment initiation to dose escalation, another for time 
from dose escalation to treatment discontinuation). For each cohort, subgroup 
analyses will be performed using clinico-demographic variables such as: 
o
Disease subtype (UC vs CD) 
o
Line of therapy (Bionaive, 2nd line, 3rd line, 3+ lines) 
o
Disease subtype and line of therapy 
o
Hazard ratios and 95% CIs will be reported for all analyses and compared 
between cohorts. 
9.1.5
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9.2
Interim Analyses 
An interim analysis will be performed to identify missing data and potential general sources of 
missing data, following the “Methods for handling missing data” section of the SAP. Cohort 
characterization will be carried out following the “Cohort characterization and comparisons” 
section of the SAP. 
Any deviations from the planned analyses triggered by this interim analysis (e.g. controlling 
for major demographic imbalances between cohorts), 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 SAP before starting analysis. All later deviations and / 
or alterations will be summarised in the Clinical Study Report. 
9.3
Determination of Sample Size 
The retrospective data extraction will include up to 5,500 patients with IBD. This study size is 
based on all patients within the Takeda Canada PSP Group that received vedolizumab between 
years 2015 and 2020 and provided consent for secondary data usage. 
 
 
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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. 
 
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. 
 
12 Archiving of Study Documentation 
During the course of the study the CRO must as a minimum file the below essential documents 
in the Study Management File: 
x Written agreement between the Sponsor and the CRO 
x The study protocol and any amendments 
x Signed and dated protocol agreement and amendment agreements, if any 
x Written IEC / IRB approval / vote according to local regulations 
x The progress reports 
 
After study completion the CRO must as a minimum store the study data for 25 years, in 
keeping with Sponsor and CROs SOPs.  
 
No data may be disposed of without the written approval of the Sponsor.  Written notification 
will be provided to the Sponsor prior to transferring any data to another party or moving them 
to another location. 
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13 References 
1. Torres J, Mehandru S, Colombel J-F, Peyrin-Biroulet L. Crohn's disease. Lancet. 
2017;389(10080):1741-55. 
2. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel J-F. Ulcerative colitis. 
Lancet. 2017;389(10080):1756-70. 
3. Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol. 
2015;12(12):720-7. 
4. 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 Med. 
2013;369(8):699-710. 
5. 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;369(8):711-21. 
6. Sands BE, Peyrin-Biroulet L, Loftus EV, Jr., Danese S, Colombel J-F, Törüner M, et al. 
Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis. N Engl J 
Med. 2019;381(13):1215-26. 
7. Olivera P, Danese S, Jay N, Natoli G, Peyrin-Biroulet L. Big data in IBD: a look into the 
future. Nat Rev Gastroenterol Hepatol. 2019;16(5):312-21. 
8. World Medical Association Declaration of Helsinki. Ethical principles for Medical 
Research Involving Human Subjects, Helsinki 1964, amended in Tokyo 1975, Venice 
1983, Hong Kong 1989, South Africa 1996, Edinburgh 2000, and Seoul 2008. 
9. Epstein, M on behalf of ISPE. Guidelines for Good Pharmacoepidemiology Practices 
(GPP). Pharmacoepidemiology and Drug Safety 2005;14:589-95.  
10. Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on 
the Protection of Individuals with Regard to the Processing of Personal Data and on the 
Free Movement of Such Data. Official Journal of the European Communities L281/31 
23.11.1995. 
11. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on 
the approximation of the laws, regulations and administrative provisions of the Member 
States relating to the implementation of good clinical practice in the conduct of clinical 
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trials on medicinal products for human use. Official Journal of the European Communities 
L/21/34 1.5.2001. 
12. Peyrin-Biroulet L, Panes J, Sandborn WJ, Vermeire S, Danese S, Feagan BG, et al. 
Defining Disease Severity in Inflammatory Bowel Disease: Current and Future Directions. 
Clin Gastroenterol Hepatol. 2016;14(3):348-354.e17 
 
 
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