Special Drug-Use Surveillance Study on Entyvio for IV Infusion 300 mg [Ulcerative Colitis]
Conditions: Ulcerative Colitis
Sponsor: Takeda

Clinical Study Protocol 
NCT Number: NCT03824561 
Title: Special Drug-Use Surveillance Study on Entyvio for IV Infusion 300 mg 
[Ulcerative Colitis] 
Study Number: Vedolizumab-5033 
Document Version and Date: Version 9 / 29-JUL-2024 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 
A summary of changes to previous protocol versions is appended to the end of the 
document. 
Note; This document was translated into English as the language on original version 
was Japanese. 

Protocol for Special Drug Use-Results Surveillance 
Study 
Entyvio for IV Infusion 300 mg 
Special Drug Use-Results Surveillance Study 
[Ulcerative Colitis] 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol No.
Vedolizumab-5033 
Version No.
Version 9 
Date of 
preparation 
July 29, 2024
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

 
 
 
Table of Contents 
1.0 
BACKGROUND ................................................................................................................................ 1 
2.0 
OBJECTIVES ..................................................................................................................................... 1 
3.0 
PLANNED SAMPLE SIZE AND RATIONALE .............................................................................. 1 
3.1 PLANNED SAMPLE SIZE ..................................................................................................................... 1 
3.2 RATIONALE ....................................................................................................................................... 1 
4.0 
STUDY POPULATION ..................................................................................................................... 2 
4.1 INCLUSION CRITERIA......................................................................................................................... 2 
4.2 EXCLUSION CRITERIA ....................................................................................................................... 2 
5.0 
DOSAGE AND ADMINISTRATION ............................................................................................... 2 
6.0 
PLANNED NUMBER OF MEDICAL INSTITUTIONS BY DEPARTMENT ................................ 2 
7.0 
METHODS ......................................................................................................................................... 2 
7.1 OBSERVATION PERIOD ...................................................................................................................... 2 
7.2 DATA COLLECTION METHOD ............................................................................................................ 3 
7.3 PARTICIPANT REGISTRATION METHOD ............................................................................................. 3 
7.4 ENTRY IN THE SURVEY FORM (ELECTRONIC) AND ELECTRONIC SIGNATURE .................................... 3 
8.0 
SCHEDULED IMPLEMENTATION PERIOD ................................................................................. 3 
9.0 
ITEMS ................................................................................................................................................ 4 
9.1 INFORMED CONSENT ......................................................................................................................... 4 
9.2 PARTICIPANT REGISTRATION ............................................................................................................ 4 
9.3 PARTICIPANT BACKGROUND ............................................................................................................. 4 
9.4 TREATMENT DETAILS ........................................................................................................................ 4 
9.5 EXAMINATION/OBSERVATION ITEMS ................................................................................................ 4 
 
Presence or Absence of Therapeutic Response and Continuation of Treatment .......... 4 
 
Complete Mayo Score .................................................................................................. 5 
 
QOL Survey ................................................................................................................. 5 
 
Laboratory Test Values ................................................................................................. 5 
 
Other Items for Observation ........................................................................................ 5 
9.6 ADVERSE EVENTS ............................................................................................................................. 5 
10.0 
ANALYSIS ITEMS AND METHODS .............................................................................................. 7 
10.1 STATISTICAL ANALYSIS PLAN ........................................................................................................... 7 
10.2 ANALYSIS SETS ................................................................................................................................. 7 
10.3 ITEMS RELATED TO PARTICIPANT DISPOSITION ................................................................................ 7 
10.4 PARTICIPANT BACKGROUND ............................................................................................................. 7 
10.5 TREATMENT DETAILS ........................................................................................................................ 7 
10.6 ITEMS RELATED TO SAFETY .............................................................................................................. 8 
 Status of Adverse Events ............................................................................................. 8 
 Factors That May Affect Safety ................................................................................... 8 
10.7 ITEMS RELATED TO EFFICACY ........................................................................................................... 8 
 Presence or Absence of Therapeutic Response and Continuation of Treatment .......... 8 
 Time Course of Complete Mayo Score and Partial Mayo Score ................................. 8 
 QOL Survey ................................................................................................................. 8 
 Calprotectin .................................................................................................................. 8 
10.8 INTERIM ANALYSIS ........................................................................................................................... 8 
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11.0 
REGISTRATION OF STUDY INFORMATION .............................................................................. 8 
12.0 
ORGANIZATIONAL STRUCTURE................................................................................................. 9 
12.1 ORGANIZATIONAL CHART FOR OPERATIONS FOR POST-MARKETING SURVEILLANCE ....................... 9 
13.0 
MEDICAL ADVISOR........................................................................................................................ 9 
14.0 
CONTRACT RESEARCH ORGANIZATION .................................................................................. 9 
15.0 
OTHER NECESSARY MATTERS ................................................................................................. 10 
15.1 REVISION OF PROTOCOL .................................................................................................................. 10 
15.2 MEASURES TO BE TAKEN IN CASES OF PROBLEMS OR QUESTIONS ................................................. 10 
APPENDIX 1  OBSERVATION SCHEDULE ............................................................................................ 11 
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1.0 
BACKGROUND 
Ulcerative colitis (UC) is an inflammatory bowel disease that relapses and remits 
repeatedly. Since no radical treatment has been established, the basic medical treatment 
strategy is to promptly induce remission by drugs and maintain remission for a long 
period of time (remission maintenance). 
Entyvio for intravenous (IV) infusion 300 mg (hereafter referred to as ”Entyvio”) is a 
recombinant humanized immunoglobulin G1 monoclonal antibody that binds specifically 
to α4β7 integrin on human lymphocytes and inhibits the binding of α4β7 integrin to the 
mucosal addressin cell adhesion molecule 1 (MadCAM1) ligand on the vascular 
endothelium of the intestine, thereby inhibiting the entry of pro-inflammatory memory 
T-cells into the intestinal mucosa. Entyvio, thus, inhibits intestinal inflammation with its
gut-selective immunomodulatory activity not associated with systemic
immunosuppression. Based on shipment data, the cumulative number of patients using
Entyvio after the first marketing approval in May 2014 is estimated to be approximately
510,259 patient-years overseas as of May 19, 2020. The evidence of statistically
significant and clinically meaningful efficacy of Entyvio has been demonstrated through
multiple clinical studies in participants with moderate to severe active UC.
Therefore, a special drug use-results surveillance study (hereafter referred to as this
study) was planned to investigate the safety and effectiveness of the long-term use of
Entyvio in participants with UC during actual and the routine clinical setting in Japan.
This study will be conducted in compliance with the applicable regulatory requirements,
including the Good Post-marketing Study Practice (GPSP) Ordinance.
2.0 
OBJECTIVES 
To examine and evaluate the safety and effectiveness of Entyvio in UC participants for 
long-term and actual use during the routine clinical setting in Japan. 
3.0 
PLANNED SAMPLE SIZE AND RATIONALE 
3.1 
PLANNED SAMPLE SIZE 
1,000 participants including: 
≥ 300 participants with a history of treatment with anti-tumor necrosis factor alpha 
(TNFα) antibody, and 
≥ 300 participants without any history of treatment with anti-TNFα antibody 
3.2 
RATIONALE 
In the 300 mg group of Entyvio during the CCT-101 study, the incidence of adverse 
events related to infusion-related reactions was 4.2% (12/287 participants) and the 
incidence of adverse events in the infections and infestations system organ class (SOC), 
was 67.6% (194/287 participants). Adverse events in the infections and infestations SOC 
occurred in ≥3% of participants by preferred term were nasopharyngitis (45.6%, 131/287 
participants), gastroenteritis (6.6%, 19/287 participants), influenza (4.9%, 14/287 
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participants), bronchitis (3.8%, 11/287 participants), pharyngitis (3.5%, 10/287 
participants), enteritis infectious (3.5%, 10/287 participants), and tonsillitis (3.1%, 9/287 
participants). 
To examine these safety specifications and the other adverse drug reactions in the routine 
clinical setting, the sample size was set at 1,000 participants. A sample size of 1,000 
participants will provide the power to detect at least one adverse drug reaction with an 
incidence of ≥ 0.3% with a confidence level over 95%. 
Of the planned 1,000 participants, ≥ 300 participants each with or without a history of 
treatment with anti-TNFα antibody will be enrolled to evaluate the safety and 
effectiveness of long-term administration of Entyvio. As an interim analysis, the 
effectiveness of induction therapy with Entyvio in the induction phase will be evaluated 
when the evaluable data after 3 doses of Entyvio are obtained from ≥ 90 participants each 
with or without a history of treatment with anti-TNFα antibody, along with the safety as 
necessary. 
4.0 
STUDY POPULATION 
Target population is patients with UC. Participants must meet all of the following 
inclusion criteria and none of the exclusion criteria. Refer to the precautions in the 
package insert. 
4.1 
INCLUSION CRITERIA 
Patients who meet both of the following criteria will be included. 
[1] Patients in the active phase of moderate or severe UC.
[2] Patients with an inadequate response to conventional therapy.
4.2 
EXCLUSION CRITERIA 
Patients who meet the following criterion will not be included. 
Patients for whom Entyvio is contraindicated. 
5.0 
DOSAGE AND ADMINISTRATION 
The usual dose is 300 mg of vedolizumab (recombinant) per administration via 
intravenous infusion for adults. Entyvio should be administered at Week 2 and Week 6 
after receiving the initial dose, and then every 8 weeks thereafter. Refer to the precautions 
in the package insert for details. 
6.0 
PLANNED NUMBER OF MEDICAL INSTITUTIONS BY DEPARTMENT 
Department of gastroenterological medicine and others Approximately 250 institutions 
7.0 
METHODS 
7.1 
OBSERVATION PERIOD 
54 weeks 
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7.2 
DATA COLLECTION METHOD 
Web-based Electronic Data Capture (EDC) system will be used. Data on stool frequency 
and rectal bleeding as part of Quality of life (QOL) and Mayo scores will be collected via 
the participant diary (Medidata ePRO) in principle. 
7.3 
PARTICIPANT REGISTRATION METHOD 
The “central registration system” will be used. The investigator or a person appointed by 
the investigator will enter participant registration information into the EDC system and 
electronically sign it within 14 days after the start of the treatment with Entyvio (the day 
of treatment initiation is defined as “Day 0” and the day after initiation is defined as “Day 
1”). 
7.4 
ENTRY IN THE SURVEY FORM (ELECTRONIC) AND ELECTRONIC SIGNATURE 
The investigator or a person appointed by the investigator will enter the participant's 
background and treatment information into the EDC system after 3 doses of Entyvio and 
within approximately 1 month after the end of observation at Week 54. The investigator 
will then electronically sign it. 
For participants who discontinue the treatment during observation period for any reasons, 
the investigator or a person appointed by the investigator will enter the participant's 
background and treatment information into the EDC system within approximately 1 
month after the completion of the observation required. The investigator will then 
electronically sign it. However, for participants who discontinue treatment due to adverse 
events, the investigator will continue to observe until the adverse event has resolved or is 
alleviated or until the end of the observation period, to the extent possible even after 
treatment discontinuation. The investigator or a person appointed by the investigator will 
enter the observation results into the EDC system, and the investigator will electronically 
sign it. 
8.0 
SCHEDULED IMPLEMENTATION PERIOD 
Study period: February 2019 to October 31, 2024 
Participant registration period: February 2019 to June 30, 2023*
Date of study completion (date of completion of the final analysis): June 30, 2025 
(planned) 
* Even for patients for whom Entyvio has been prescribed by June 30, 2023, registration
(entry into the EDC system) will not be accepted from July 1, 2023.
If the number of participants registered for the study reaches the planned number before
June 30, 2023, the registration will be closed before the end of the participant
registration period. If the participant registration period is shortened, the study period
will be changed accordingly.
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9.0 
ITEMS 
The investigator or a person appointed by the investigator will enter the following items 
into the EDC system. The schedule of the study is shown in Appendix 1. 
 
9.1 
INFORMED CONSENT 
The investigator will obtain informed consent from the participant or a legally acceptable 
representative before registration. Patients who provide informed consent will be 
assigned an identification number. 
 
9.2 
PARTICIPANT REGISTRATION 
1) Items 
Presence or absence of consent, start date of treatment with Entyvio, participant 
identification number, sex, month and year of birth, assessment of inclusion criteria, 
assessment of exclusion criteria, presence or absence of history of treatment with anti-
TNFα antibody, and severity of UC. 
2) Timing 
At participant registration. 
 
9.3 
PARTICIPANT BACKGROUND 
1) Items 
Time of UC diagnosis, range of UC lesions, medical history/complications, familial 
history, history of tuberculosis infection, steroid resistance/dependence/intolerance, 
presence or absence and details of previous therapies for UC other than Entyvio within 
3 months before the start of treatment with Entyvio (excluding anti-TNFα antibody 
drugs), and details of history of treatment with anti-TNFα antibody. 
2) Timing 
At the start of treatment with Entyvio. 
 
9.4 
TREATMENT DETAILS 
1) Items 
Status of treatment with Entyvio, lot number, status of treatment with concomitant 
medicines, implementation status of concomitant therapies, and implementation status 
of surgical procedures. 
2) Timing 
From the start of treatment with Entyvio to Week 54 (or treatment discontinuation). 
 
9.5 
EXAMINATION/OBSERVATION ITEMS 
Each test/observation results will be recorded at each timing if performed in the 
routine clinical settings on treatment with Entyvio. 
 
 Presence or Absence of Therapeutic Response and Continuation of Treatment 
1) Observation Items 
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Presence or absence of therapeutic response and continuation or discontinuation of 
treatment. 
2) Timing 
After 3 doses of Entyvio. 
 
 Complete Mayo Score 
1) Observation Items 
Endoscopy findings and physician's global assessment (stool frequency and rectal 
bleeding will be automatically entered from the participant diary, in principle). 
2) Timing 
Measurement timepoints at the start of treatment with Entyvio, after 3 doses, and at 
Week 54 (or treatment discontinuation). 
 
 QOL Survey 
1) Observation Items 
Short Inflammatory Bowel Disease Questionnaire (SIBDQ) (QOL survey form for 
inflammatory bowel disease). 
2) Timing 
Measurement timepoints at the start of treatment with Entyvio, after 3 doses, and at 
Week 54 (or treatment discontinuation). 
 
 Laboratory Test Values 
1) Observation Items 
Hemoglobin, white blood cell count, lymphocytes, albumin, C-reactive protein (CRP), 
and calprotectin. 
2) Timing 
From the start of treatment with Entyvio to Week 54 (or treatment discontinuation). 
 
 Other Items for Observation 
1) Observation Items 
Pregnant or not pregnant during the observation period (women only) and withdrawal 
of consent. 
2) Timing 
From the start of treatment with Entyvio to Week 54 (or treatment discontinuation). 
 
9.6 
ADVERSE EVENTS 
1) Items 
Presence or absence of adverse events (see Table 1), name of adverse event, date of 
onset, time of onset after administration (only for infusion reactions including 
hypersensitivity reactions), seriousness and reasons for seriousness (see Table 2), 
cause of discontinuation of treatment with Entyvio, actions taken at the onset, date of 
outcome assessment, outcome, and causal relationship with Entyvio (see Table 3). 
 
Table 1  Definition of Adverse Events 
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will be collected to the extent as possible at the time of onset. 
 
Infusion reactions including hypersensitivity reactions. 
 
Infections (other than progressive multifocal leukoencephalopathy). 
 
Rationale for Safety Specifications 
 
Infusion reactions including hypersensitivity reactions. 
Infusion reactions are known as adverse reactions to biological products. Infusion 
reactions including hypersensitivity reactions to Entyvio have also been reported. 
Although most of symptoms have been reported to be mild or moderate and 
transient, and to resolve spontaneously, serious events such as anaphylaxis may 
occur. Therefore, these reactions were specified as safety specifications. 
 
 
Infections (other than progressive multifocal leukoencephalopathy). 
Entyvio is a gut-selective integrin antagonist and may impair immune functions in 
the gastrointestinal tract. However, infections outside the gastrointestinal tract 
have also been reported. Based on these, infection was specified as safety 
specifications. 
 
3) Study period 
From the start of treatment with Entyvio to Week 54 (or treatment discontinuation). 
 
10.0 
ANALYSIS ITEMS AND METHODS 
10.1 
STATISTICAL ANALYSIS PLAN 
A statistical analysis plan will be prepared before data lock. It will provide further details 
regarding the definition of endpoints and the analysis methods. 
 
10.2 
ANALYSIS SETS 
“Participants included in the safety evaluation” set will be identified for analysis. 
 
10.3 
ITEMS RELATED TO PARTICIPANT DISPOSITION 
The number of registered participants, number of participants from whom survey forms 
(electronic) were collected, number of participants included in the safety evaluation, 
number of participants excluded from the evaluation, and reasons for exclusion will be 
tabulated. 
 
10.4 
PARTICIPANT BACKGROUND 
As participant background, sex, age, disease duration, complications, presence or absence 
of history of treatment with anti-TNFα antibody, and severity of UC will be tabulated. 
 
10.5 
TREATMENT DETAILS 
Status of treatment with Entyvio, status of treatment with concomitant medicines, 
implementation status of concomitant therapies, and implementation status of surgical 
procedures will be tabulated. 
 
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10.6 
ITEMS RELATED TO SAFETY 
The following tabulation will be performed for participants included in the safety 
evaluation. 
 Status of Adverse Events 
For adverse events that occur during the observation period, frequency tabulation will 
be performed by type, time of onset, seriousness, and causal relationship with Entyvio. 
 
 Factors That May Affect Safety 
The frequency of adverse drug reactions that occur during the observation period will 
be tabulated by participants’ background factors. 
 
10.7 
ITEMS RELATED TO EFFICACY 
The following tabulation will be performed. 
 Presence or Absence of Therapeutic Response and Continuation of Treatment 
Presence or absence of therapeutic response and continuation or discontinuation of 
treatment will be tabulated. 
 
 Time Course of Complete Mayo Score and Partial Mayo Score 
The value, changes, remission rate, and improvement rate of complete and partial 
Mayo scores at each test time point will be tabulated. 
 
 QOL Survey 
The QOL survey scores and changes at each test time point will be tabulated. 
 
 Calprotectin 
The laboratory values and changes at each test time point will be tabulated. 
 
10.8 
INTERIM ANALYSIS 
For early evaluation and analysis of the efficacy data obtained in this study, interim 
analysis will be performed when the evaluable data after 3 doses of Entyvio are obtained 
from ≥ 90 participants each with or without a history of treatment with anti-TNFα 
antibody. In interim analysis, the same analyses as in Sections 10.7.1–10.7.2 will be 
performed, along with the same analyses as in Sections 10.3–10.5 and 10.6.1 as 
necessary. 
 
11.0 
REGISTRATION OF STUDY INFORMATION 
Prior to its start, the study information will be registered on the following public 
websites. 
 Japan Pharmaceutical Information Center-Clinical Trials Information JapicCTI-194603 
 Clinical study registration system of the United States National Institutes of Health: 
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ClinicalTrials.gov NCT03824561 
 
 
12.0 
ORGANIZATIONAL STRUCTURE 
12.1 
ORGANIZATIONAL CHART FOR OPERATIONS FOR POST-MARKETING SURVEILLANCE 
See Appendix. 
 
13.0 
MEDICAL ADVISOR 
 Tasks to Be Delegated 
 Advice on the preparation and revision of this protocol. 
 Advice on the preparation and revision of the statistical analysis plan 
(tabulation/analysis items and methods). 
 Advice on the preparation and revision of the clinical study report (safety and 
effectiveness conclusions and discussion). 
 Advice on the preparation of feedback materials for medical institutions. 
 Advice on journals/academic conferences in/at which the data could be published (if 
the data will be published outside the company). 
 Further advice regarding implementation of this study requires various medical 
judgments. 
Affiliation and Name 
 
 
 
 
(random order) 
 
14.0 
CONTRACT RESEARCH ORGANIZATION 
 
 
Service: Setting and management of the EDC related to the study. 
 
 
 
Service: Statistical analysis, construction of the EDC system, database creation, and 
medical writing. 
 
 
 
Service: Data management, construction and operation of the EDC system, and 
storage of records. 
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Service: Operations related to monitoring. 
 
 
15.0 
OTHER NECESSARY MATTERS 
15.1 
REVISION OF PROTOCOL 
During the implementation period, the status of progress, adverse drug reactions that 
cannot be predicted from precautions and serious adverse drug reactions, increase or 
stability in the incidence of specific adverse drug reactions, and appropriateness of items 
will be monitored and, if necessary, this protocol will be reviewed and revised. 
Additionally, when the application of partial changes in dosage and administration or 
indications are approved during the implementation period, the necessity for the revision 
of this protocol will be examined and the protocol will be revised if necessary. 
 
15.2 
MEASURES TO BE TAKEN IN CASES OF PROBLEMS OR QUESTIONS 
If any safety and efficacy issue is identified, the data will be closely examined and 
corrective measures will be considered. 
 
 
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Document History 
 
Version 
Date 
Comments 
original version 
December 6, 2018 
New document 
Version 2 
January 7, 2019 
7.3 Participant Registration Method 
9.5.5 Other Items for Observation 
Version 3 
June 1, 2019 
11.0 REGISTRATION OF STUDY INFORMATION 
12.0 ORGANIZATIONAL STRUCTURE 
12.1 Persons Responsible for Management 
13.0 CONTRACT RESEARCH ORGANIZATION 
Version 4 
October 14, 2020 
8.0 SCHEDULED IMPLEMENTATION PERIOD 
13.0 CONTRACT RESEARCH ORGANIZATION 
Version 5 
January 15, 2021 
9.4 Treatment Details 
9.6 Adverse Events 
13.0 CONTRACT RESEARCH ORGANIZATION 
Appendix 1 Observation Schedule 
Appendix 2 Takeda Medically Significant AE List 
Version 6 
July 5, 2021 
1.0 BACKGROUND 
3.2 Rationale 
9.6 Adverse Events 
Table 2 Criteria for Seriousness 
10.8 Interim Analysis 
13.0 CONTRACT RESEARCH ORGANIZATION 
Version 7 
March 25, 2022 
8.0. SCHEDULED IMPLEMENTATION PERIOD 
11.0 REGISTRATION OF STUDY INFORMATION 
12.0 ORGANIZATIONAL STRUCTURE 
12.2 Medical Advisor 
Version 8 
April 28, 2022 
12 0 ORGANIZATIONAL STRUCTURE 
Version 9 
July 29, 2024 
8.0 SCHEDULED IMPLEMENTATION PERIOD 
9.6 ADVERSE EVENTS 
Table 2 Criteria for Seriousness 
14.0 CONTRACT RESEARCH ORGANIZATION 
 
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