Clinical trial NCT00790933
Conditions: Ulcerative Colitis Crohn's Disease
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2009-05-22; Completion date: 2017-10-31
Enrollment: 2243 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this multicenter, open-label study is to collect data on the occurrence of important clinical safety events resulting from chronic vedolizumab (MLN0002) administration.

Detailed description:
The drug being tested in this study is called vedolizumab. Vedolizumab is being tested to treat people who have ulcerative colitis or Crohn's disease. This study will determine the safety profile of long-term vedolizumab treatment.

The study enrolled 2243 patients. Participants who received either placebo or vedolizumab 300 mg IV infusion every 4 or 8 weeks in previous vedolizumab studies received:

• Vedolizumab 300 mg

All participants received vedolizumab intravenous infusion every 4 weeks for approximately up to 510 weeks.

This multicenter trial is being conducted worldwide. The overall time to participate in this study was up to October 2017 until vedolizumab was available in the country in which the participant resided, or until participant withdrawal, whichever came first. Participants made multiple visits to the clinic up to 16 weeks after receiving their last dose of vedolizumab and were being followed up for 2-years during which a safety questionnaire was administered by telephone for follow-up assessments.

Arms: arm 1: Vedolizumab 300 mg, 30-minute intravenous (IV) infusion every 4 weeks, starting at Week 0 for approximately up to 510 weeks.
Interventions: intervention 1: Vedolizumab
Intervention descriptions: intervention 1: Vedolizumab intravenous infusion

Protocol documents:
Prot_001.pdf: 
This may include, but is not limited to, redaction of the following: 


•
Title: A  Phase 3, Open-label Study to Determine the Long-term Safety and Efficacy of 
Vedolizumab (MLN0002) in Patients With Ulcerative Colitis and Crohn’s Disease
NCT Number: NCT00790933
Protocol Approve Date: 22 August 2016
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.


Vedolizumab (MLN0002)
Clinical Study Protocol C13008 Amendment 20
Confidential
1
CLINICAL STUDY PROTOCOL C13008
Vedolizumab (MLN0002)
A Phase 3, Open-label Study to Determine the Long-term Safety and Efficacy of 
Vedolizumab (MLN0002) in Patients With Ulcerative Colitis and Crohn’s Disease
Protocol Number:
C13008
Indication:
Ulcerative colitis and Crohn’s disease
Phase:
3
Sponsor:
Takeda Development Center Americas, Inc., 
Takeda Development Centre Europe, Ltd., 
Takeda Development Center Asia Pte. Ltd
EudraCT Number:
2008-002784-14
Therapeutic Area:
Inflammation
Protocol History
Original
26 June 2008
Amendment 1
14 October 2008
Amendment 2
28 April 2009
Amendment 3
for use only outside of the US
28 April 2009
Amendment 4
for use only in Norway and the United Kingdom
17 November 2009
Amendment 5
for use in all countries except the US, Norway, and the 
United Kingdom
23 November 2010
Amendment 6
for use in the US only
23 November 2010
Amendment 7
for use only in Norway and the United Kingdom
21 January 2011
Amendment 8
for use in all countries outside the US 
15 February 2012
Amendment 9
for use in the US only
15 February 2012
Amendment 10
for use in all countries outside the US that are 
enrolling de novo patients
15 February 2012
Amendment 11
for use in Germany only
04 May 2012
Amendment 12
for use only in Norway and the United Kingdom
11 May 2012
Amendment 13
for use in Spain only
05 November 2012
Amendment 14
for use in all countries currently/previously working to 
Amendment 8 where vedolizumab is either not 
commercially available or is not reimbursed
26 November 2015
Amendment 15
for use in the US only
26 November 2015
Amendment 16
for use in all countries currently/previously working to 
Amendment 10 where vedolizumab is either not 
commercially available or is not reimbursed
26 November 2015


Vedolizumab (MLN0002)
Clinical Study Protocol C13008 Amendment 20
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Amendment 17
for use in the US only
19 February 2016
Amendment 18
for use in all countries currently/previously working to 
Amendment 14 where vedolizumab is either not 
commercially available or is not reimbursed
22 August 2016
Amendment 19
for use in India only
22 August 2016
Amendment 20
for use in all countries currently/previously working to 
Amendment 16 where vedolizumab is either not 
commercially available or is not reimbursed
22 August 2016
Takeda Development Centre Europe Ltd
61 Aldwych 
London WC2B 4AE
Tel: +44 (0)203 116 8300
Takeda Development Center Asia Pte. Ltd.
Biopolis Road, Nucleos North Tower, Level 4, 
Singapore 138567
Tel: +65 6808 9500
Confidentiality Statement
The information contained herein is confidential and the proprietary property of Takeda 
Pharmaceuticals and any unauthorized use or disclosure of such information without the prior written 
authorization of Takeda Pharmaceuticals is expressly prohibited.


Vedolizumab (MLN0002)
Clinical Study Protocol C13008 Amendment 20
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Approval Page
Note:  If this document was approved electronically, the electronic approval signatures may 
be found at the end of the document.
, 
Gastroenterology 
Signature
Date DD Month YYYY
(or designee)
Signature
Date DD Month  YYYY
Global Statistics and Statistical 
Programming
Signature
Date DD Month YYYY
PPD
PPD
PPD


Vedolizumab (MLN0002)
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Rationale for Amendment 20
Amendment 20 is an update to Amendment 16 of the C13008 protocol to be implemented in 
countries where vedolizumab is either not commercially available or is not reimbursed. With 
this amendment, patients participating in these countries will have continued access to 
vedolizumab in Study C13008 until either:

July 2017, or 

The Extended Access Program (XAP) study is available at the site, or 

Patient withdrawal, or 

Vedolizumab is available to the patient through commercial channels (including 
reimbursement) for the patient’s clinical scenario, or

The study is terminated early by the sponsor, as described in Section 11.12,
whichever comes first.
Purposes for Amendment 20
The purpose of this amendment is to:

Extend the duration of this study to allow all patients in countries where vedolizumab 
is either not commercially available or is not reimbursed continued access to 
vedolizumab until July 2017, or until the XAP study is available at the site, or until 
patient withdrawal, or until vedolizumab is available to the patient through commercial 
channels (including reimbursement) for the patient’s clinical scenario, or unless the 
study is terminated early by the sponsor, as described in Section 11.12, whichever 
comes first. 

Remove the requirement for patients who transition into the XAP study to attend the
Final Safety Visit in the C13008 study. The safety of these patients will be monitored 
as part of the XAP study.

Amendment of the pregnancy and contraception language in line with updated safety 
information.

Amend the adverse event, serious adverse event, and concomitant medication reporting 
instructions for patients in Study C13008 who transition into the XAP study, such that 
the C13008 collection period ends at the time the patient is consented into the XAP 
study.
For specific examples of changes in text and where the changes are located, see 
Section 15.14.


Vedolizumab (MLN0002)
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PROTOCOL SUMMARY
Study Title:  A Phase 3, Open-label Study to Determine the Long-term Safety and Efficacy of 
Vedolizumab (MLN0002) in Patients With Ulcerative Colitis (UC) and Crohn’s Disease (CD)
Study Phase:  Phase 3
Number of Patients:  up to approximately 2200
Study Objectives:
Primary Objective

To determine the safety profile of long-term MLN0002 treatment 
Resource Utilization and Patient-Reported Outcome Objectives

To determine the effect of long-term MLN0002 treatment on time to major 
inflammatory bowel disease (IBD)-related events (hospitalizations, surgeries, and 
procedures)

To examine the effect of long-term MLN0002 treatment on health-related quality 
of life (QOL) measurements
Exploratory Objective

To obtain data regarding the effect of long-term MLN0002 treatment on 
maintaining clinical response and remission
Overview of Study Design:
Enrolled patients will receive 300 mg MLN0002 every 4 weeks, starting at Week 0, until July 
2017, or until an Extended Access Program (XAP) study is available at the site, or until patient 
withdrawal, or until vedolizumab is available to the patient through commercial channels 
(including reimbursement) for the patient’s clinical scenario, unless the study is terminated early 
by the sponsor, as described in Section 11.12, whichever comes first. For subjects who do not 
transition into the XAP study, the dosing period will be followed by a 16-week posttreatment 
observation and safety assessment period.  
Patients may receive allowed concomitant medications for the treatment of IBD as detailed in 
Section 6.2.1, as determined by the principal investigator, at any time point during the 
study. Medications may be discontinued during the study, but if discontinuation is planned, it 
should be done prior to the first dose of vedolizumab. 
It is strongly recommended that patients receiving oral corticosteroids should begin an oral 
corticosteroid tapering regimen once they achieve clinical response or if, in the opinion of the 
investigator, they demonstrate sufficient improvement in clinical signs and symptoms.  
Patients who require rescue medication or major surgery for the treatment of their IBD (as defined 
in Section 6.4.9) or who, in the opinion of the investigator or patient, are not benefiting from 
therapy will be withdrawn from the study. Investigators should also strongly consider 
withdrawing patients who require recurrent courses of oral corticosteroids with an inability to 
taper.


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Safety assessments, including safety labs, and exploratory efficacy assessments (using the partial 
Mayo Score [for patients with UC] or the Harvey-Bradshaw Index (HBI) score [for patients with 
CD]) will be made throughout the treatment period, and at the Final Safety visit.  Serious adverse 
events (SAEs) and adverse events (AEs) will be collected throughout the study (as applicable).  
For patients enrolling to the XAP study, AEs/SAEs and concomitant medications will be collected 
until in Study C13008 the patient is consented into the XAP study.  Data pertaining to health care 
utilization and patient-reported outcomes will also be collected regularly throughout the study.  In 
addition, safety data from this study will be benchmarked with data from external databases.
Study Population:
Most patients enrolling in this study will have participated in a previous qualifying MLN0002 
study (rollover patients):

Patients with UC or CD who participated in the phase 2, open-label, long-term 
safety study (Study C13004) 

Patients who withdrew early from a phase 3 UC or CD induction and maintenance 
study (Study C13006 or Study C13007)  due to sustained nonresponse, disease 
worsening, or the need for rescue medications

Patients who completed Study C13006, Study C13007, or Study C13011
In addition, up to 400 patients without previous treatment with vedolizumab may be enrolled 
directly  (de novo patients):

Patients with UC or CD who meet the inclusion/exclusion criteria for de novo 
patients
Number of Study Center(s):  approximately 400 sites worldwide; de novo patients will be 
enrolled at approximately 150 of the existing sites.
Duration of Study:
It is anticipated that the duration of MLN0002 treatment will vary by patient based on continued 
benefit.  Treatment duration may continue until July 2017, or until XAP study is available at the 
site, or until patient withdrawal, or until vedolizumab is available to the patient through 
commercial channels (including reimbursement) for the patient’s clinical scenario, or unless the 
study is terminated early by the sponsor, as described in Section 11.12, whichever is sooner.  After 
the final dose of MLN0002, patients who do not transition into the XAP study will complete the 
16-week post treatment observation and assessment period.  Additionally, upon completion of or 
termination from this study, patients will participate in a 2-year follow-up survey during which 
time a safety questionnaire will be administered by telephone. Patients who transition into the 
XAP study are not required to attend the Final Safety Visit of C13008.  The safety of these 
patients will be monitored as part of the XAP study.


Vedolizumab (MLN0002)
Clinical Study Protocol C13008 Amendment 20
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Study Diagram:  Sources of Study Participants
Study C13004
patients with UC or CD; up to 78 weeks open-label MLN0002
Study
C13008
Open-label 
MLN0002 
treatment
completersa
Study C13006 or Study C13007
patients with UC (C13006) or CD (C13007); 
50 weeks study drug treatment (placebo vs MLN0002)
completersa
Study C13011
patients with CD; 6 weeks study drug treatment (placebo vs MLN0002)
early withdrawalsb
De Novo Enrollment
Patients with UC or CD, not previously treated with MLN0002
a Patients who completed the Week 52 assessments in Study C13006 or Study C13007, or the Week 10 
assessments in Study C13011.
B Patients who met the criteria for sustained nonresponse or disease worsening, or required rescue 
medications in a phase 3 UC or CD induction and maintenance study (Study C13006 or Study C13007) and 
withdrew early from that study.


Vedolizumab (MLN0002)
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Schedule of Events:  Pre-enrollment Through Year 2
Study 
Procedures
Pre-
enrollment
Treatment
Unscheduled Visit 
(Disease Exacerbation)
Rollover Patientsa
(P) = obtained from 
prior study
De Novo Screeningb
YEAR 1
YEAR 2
Weeks (1 week)
Weeks (1 week)
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
84
88
92
96
100
Informed 
consent
X
X
Wallet card
X
X
Demographics
(P)
X
Tobacco use
(P)
X
Medical history
(P)
X
Prior therapies
(P)
X
UC/CD Disease 
history
(P)
X
Physical examc
(P)
X
X
X
X
X
X
X
X
X
Neurological 
examc
(P)
X
X
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weightd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PML checklist
X
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Patient 
assessment of 
disease activity
X
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
X
Concomitant 
medicationse
(P)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Vedolizumab (MLN0002)
Clinical Study Protocol C13008 Amendment 20
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Study 
Procedures
Pre-
enrollment
Treatment
Unscheduled Visit 
(Disease Exacerbation)
Rollover Patientsa
(P) = obtained from 
prior study
De Novo Screeningb
YEAR 1
YEAR 2
Weeks (1 week)
Weeks (1 week)
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
84
88
92
96
100
Concomitant 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Enrollment
X
Dosing
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Partial Mayo 
scoref
X
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
X
HBIh
X
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
X
IBDQ
(P)
X
Xg
Xg
Xg
Xg
SF-36
(P)
X
Xg
Xg
Xg
Xg
EQ-5D
(P)
X
Xg
Xg
Xg
Xg
12-lead ECG
(P)
X
Xg
TB Screening
X
Chest X-ray
X
AEsi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAEsi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Samples for:  
Pregnancy 
testj
X
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Clinical 
chemistry
(P)
X
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
X
HBV, HCV, 
HIV screening
X
Hematology
(P)
X
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
X
Coagulation
(P)
X
Xg


Vedolizumab (MLN0002)
Clinical Study Protocol C13008 Amendment 20
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Study 
Procedures
Pre-
enrollment
Treatment
Unscheduled Visit 
(Disease Exacerbation)
Rollover Patientsa
(P) = obtained from 
prior study
De Novo Screeningb
YEAR 1
YEAR 2
Weeks (1 week)
Weeks (1 week)
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
84
88
92
96
100
Urinalysis
(P)
X
Xg
CRP
(P)l
X
Xg
Xg
Xg
HAHAm
(P)
X
Xg
Xg
Xg
Xg
Xg
Xg
Xg
X
Fecal 
calprotectin
Xo
Stool samplek
X
Xk
End-of-study 
eCRF
p
p
Abbreviations:  AEs = adverse events, CD = Crohn’s disease, CRP = C-reactive protein, EQ-5D = EuroQual, ECG = electrocardiogram, HAHA = human anti-human 
antibodies, HBV = hepatitis B virus, HCV = hepatitis C virus, HIV = human immunodeficiency virus, IBDQ = Inflammatory Bowel Disease Questionnaire, HBI = 
Harvey-Bradshaw Index, PML = progressive multifocal leukoencephalopathy, SAEs = serious adverse events, SF-36 = Short Form-36, TB = tuberculosis, UC = 
ulcerative colitis.
Note: Patients will return 16 weeks after the last dose of MLN0002 for final safety assessments at the Final Safety visit, as described in the Schedule of Events for Years 5 
and beyond.  This visit is not required for patients transitioning from Study C13008 into the XAP study.
a For rollover patients, the first dose of MLN0002 in this study (ie, Week 0) should occur no more than 9 weeks after the last dose of study drug in the previous study; 
the preferable period is within 3 to 5 weeks after the last dose in the previous study.  Pre-enrollment procedures marked with an X will be completed within 5 weeks 
prior to Week 0 for rollover patients.  Pre-enrollment assessments marked with (P) will not be performed; data for these assessments will be obtained from the previous 
study.
b For de novo patients, all screening procedures will be done between Day -21 and Day -1.
c Clinically significant findings will be recorded as AEs.
d On dosing days, vital signs and weight will be obtained prior to dosing.
e For rollover patients, any medications that are ongoing at the end of the previous study and that are still present at the time of enrollment into the C13008 study will be 
recorded in the eCRF for Study C13008.
f
For patients with UC. 
g To be performed prior to dosing.  


Vedolizumab (MLN0002)
Clinical Study Protocol C13008 Amendment 20
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Study 
Procedures
Pre-
enrollment
Treatment
Unscheduled Visit 
(Disease Exacerbation)
Rollover Patientsa
(P) = obtained from 
prior study
De Novo Screeningb
YEAR 1
YEAR 2
Weeks (1 week)
Weeks (1 week)
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
84
88
92
96
100
h For patients with CD.  
i
AE and SAE collection will begin at the time of enrollment (with the exception of SAE collection for de novo patients, which will begin at the signing of informed 
consent).    
j
All females must have a serum pregnancy test at screening for de novo patients and at the Final Safety visit for all patients (as applicable).  A urine pregnancy test will 
be performed prior to each dose of MLN0002.
k A stool sample for culture, ova and parasite evaluation, and C. difficile assay will be obtained at screening for de novo patients and (if indicated) at any point during the 
study when a patient becomes symptomatic, including worsening or return of disease activity.
l
For rollover patients, CRP results will be obtained from previous study as applicable.
m Drug concentration may be determined as part of the HAHA testing.
n Patients with no history of TB will have either a QuantiFERON test or a tuberculin skin test within 1 month of enrollment.
o As needed for study eligibility.
p If the patient is transitioning from Study C13008 into the XAP study, complete the end-of-study eCRF page at their last dosing visit in C13008.  For all other patients, 
complete the end-of-study page at the Final Safety Visit.


Vedolizumab (MLN0002)
Clinical Study Protocol C13008 Amendment 20
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Schedule of Events:  Years 3 and 4
Study Proceduresa
Treatment
Unscheduled Visit 
(Disease Exacerbation)
YEAR 3
YEAR 4
Weeks (1 week)
Weeks (1 week)
104
108
112
116
120
124
128
132
136
140
144
148
152
156
160
164
168
172
176
180
184
188
192
196
Physical examb
X
X
X
X
X
X
X
Neurological examb
X
X
X
X
X
X
Vital signsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weightc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PML checklist
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Patient assessment of 
disease activity
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dosing
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Partial Mayo scoree
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
X
HBIf
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
X
IBDQ
Xd
Xd
Xd
Xd
SF-36
Xd
Xd
Xd
Xd
EQ-5D
Xd
Xd
Xd
Xd
12-lead ECG
Xd
Xd
AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Samples for:  
Pregnancy testg
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Clinical chemistry
Xd
Xd
Xd
Xd
Xd
Xd
X
Hematology
Xd
Xd
Xd
Xd
Xd
Xd
X
Coagulation
Xd
Xd


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Study Proceduresa
Treatment
Unscheduled Visit 
(Disease Exacerbation)
YEAR 3
YEAR 4
Weeks (1 week)
Weeks (1 week)
104
108
112
116
120
124
128
132
136
140
144
148
152
156
160
164
168
172
176
180
184
188
192
196
Urinalysis
Xd
Xd
CRP
Xd
Xd
Xd
HAHAh
Xd
Xd
Xd
Xd
Xd
Xd
X
Stool samplei
Xi
End-of-study eCRF
j
j
Abbreviations:  AEs = adverse events, CD = Crohn’s disease, CRP = C-reactive protein, EQ-5D = EuroQual, ECG = electrocardiogram, HAHA = human anti-
human antibodies, IBDQ = Inflammatory Bowel Disease Questionnaire, HBI = Harvey-Bradshaw Index, HBV = hepatitis B virus, HCV = hepatitis C virus, HIV 
= human immunodeficiency virus, PML = progressive multifocal leukoencephalopathy, SAEs = serious adverse events, SF-36 = Short Form-36, UC = ulcerative 
colitis.
a Patients will return 16 weeks after the last dose of MLN0002 for final safety assessments at the Final Safety visit, as described in the Schedule of Events for 
Years 5 and beyond.  This visit is not required for patients transitioning from Study C13008 into the XAP study.
b Clinically significant findings will be recorded as AEs.
c On dosing days, vital signs and weight will be obtained prior to dosing.
d To be performed prior to dosing.  
e For patients with UC. 
f
For patients with CD.  
g All female subjects of childbearing potential must have a serum pregnancy test at the Final Safety visit (as applicable).  A urine pregnancy test for women of 
childbearing potential will be performed prior to each dose of MLN0002.
h Drug concentration may be determined as part of the HAHA testing.
i
A stool sample for culture, ova and parasite evaluation, and C. difficile assay will be obtained (if indicated) at any point during the study when a patient becomes 
symptomatic, including worsening or return of disease activity.
j
If the patient is transitioning from Study C13008 into the XAP study, complete the end-of-study eCRF page at their last dosing visit in C13008.  For all other 
patients, complete the end-of-study page at the Final Safety Visit.


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Schedule of Events:  Years 5 and Beyond, and the Final Safety Visit
Treatment: YEARS 5 and Beyond
Final Safety 
Visit a,b
Unscheduled Visit 
(Disease Exacerbation)
Study Procedures
Year 5
Weeks (1 week)
200
204
208
212
216
220
224
228
232
236
240
244
248
16 (2) wks
after last 
dose
Year 6
252
256
260
264
268
272
276
280
284
288
292
296
300
Year 7
304
308
312
316
320
324
328
332
336
340
344
348
352
Year 8
356
360
364
368
372
376
380
384
388
392
396
400
404
Physical examb
X
X
X
X
X
Neurological examb
X
X
X
X
Vital signsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weightc
X
X
X
X
12-lead ECG
X
PML checklist
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
X
Patient assessment of disease activity
Xd
Xd
Xd
Xd
Xd
Xd
Xd
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dosing
X
X
X
X
X
X
X
X
X
X
X
X
X
Partial Mayo scoree
Xd
Xd
Xd
Xd
Xd
Xd
Xd
X
HBIf
Xd
Xd
Xd
Xd
Xd
Xd
Xd
X
IBDQ
Xd
SF-36
Xd
EQ-5D
Xd
AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Samples for:  
Pregnancy testg
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xg
Clinical chemistry
Xd
Xd
Xd
X
X
Hematology
Xd
Xd
Xd
X
X


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Treatment: YEARS 5 and Beyond
Final Safety 
Visit a,b
Unscheduled Visit 
(Disease Exacerbation)
Study Procedures
Year 5
Weeks (1 week)
200
204
208
212
216
220
224
228
232
236
240
244
248
16 (2) wks
after last 
dose
Year 6
252
256
260
264
268
272
276
280
284
288
292
296
300
Year 7
304
308
312
316
320
324
328
332
336
340
344
348
352
Year 8
356
360
364
368
372
376
380
384
388
392
396
400
404
Coagulation
X
Urinalysis
X
HAHAh
Xd
Xd
X
X
Stool samplei
Xi
End-of-study eCRF
j
j
Abbreviations:  AEs = adverse events, CD = Crohn’s disease, EQ-5D = EuroQual, HAHA = human anti-human antibodies, IBDQ = Inflammatory 
Bowel Disease Questionnaire, HBI = Harvey-Bradshaw Index, PML = progressive multifocal leukoencephalopathy, SAEs = serious adverse events, 
SF-36 = Short Form-36, UC = ulcerative colitis.
a Patients will return 16 weeks after the last dose of MLN0002 for final safety assessments at the Final Safety visit.  This visit is not required for 
patients transitioning from Study C13008 into the XAP study.
b Clinically significant findings will be recorded as AEs.
c On dosing days, vital signs and weight (weight only at specified visits) will be obtained prior to dosing.
d To be performed prior to dosing.  
e For patients with UC. 
f
For patients with CD.  
g All female subjects of childbearing potential must have a serum pregnancy test at the Final Safety visit (as applicable). A urine pregnancy test will be 
performed for female subjects of childbearing potential prior to each dose of MLN0002.
h Drug concentration may be determined as part of the HAHA testing.
i
A stool sample for culture, ova and parasite evaluation, and C. difficile assay will be obtained (if indicated) at any point during the study when a 
patient becomes symptomatic, including worsening or return of disease activity.
j
If the patient is transitioning from Study C13008 into the XAP study, complete the end-of-study eCRF page at their last dosing visit in C13008.  For 
all other patients, complete the end-of-study page at the Final Safety Visit.


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TABLE OF CONTENTS
LIST OF ABBREVIATIONS.............................................................................................20
1. BACKGROUND AND STUDY RATIONALE..............................................................23
1.1 Scientific Background ..............................................................................................23
1.1.1 The Inflammatory Bowel Diseases:  Ulcerative Colitis and Crohn’s Disease......23
1.1.2 Study Drug:  Vedolizumab (MLN0002).............................................................25
1.2 Preclinical Experience ..............................................................................................25
1.3 Clinical Experience ..................................................................................................25
1.3.1 MLN0002 Efficacy............................................................................................26
1.3.2 MLN0002 Safety ...............................................................................................26
1.4 Study Rationale ........................................................................................................29
1.5 Potential Risks and Benefits .....................................................................................31
1.5.1 Identified Risk of MLN0002 Treatment:  Infusion-Related Reaction..................31
1.5.2 Potential Risk of MLN0002 Treatment:  Increased Rates of Infections...............32
1.5.3 Hypothetical Risks of MLN0002 Treatment (Not Observed to Date)..................32
1.5.4 Summary of Risks and Benefits .........................................................................33
2. STUDY OBJECTIVES ..................................................................................................35
2.1 Primary Objective.....................................................................................................35
2.2 Resource Utilization and Patient Reported Outcome Objectives ...............................35
2.3 Exploratory Objective...............................................................................................35
3. STUDY ENDPOINTS....................................................................................................36
3.1 Primary Endpoints....................................................................................................36
3.2 Resource Utilization and Patient Reported Outcome Endpoints ................................36
3.3 Exploratory Endpoint ...............................................................................................36
4. STUDY DESIGN...........................................................................................................36
4.1 Overview of Study Design........................................................................................36
4.2 Number of Patients...................................................................................................38
4.3 Duration of Study.....................................................................................................38
5. STUDY POPULATION.................................................................................................40
5.1 Inclusion Criteria for Rollover Patients.....................................................................40
5.2 Exclusion Criteria for Rollover Patients....................................................................42
5.3 Inclusion Criteria for De Novo Ulcerative Colitis Patients........................................42
5.4 Inclusion Criteria for De Novo Crohn’s Disease Patients..........................................45
5.5 Exclusion Criteria for Ulcerative Colitis and Crohn’s Disease De Novo Patients ......48
5.5.1 Gastrointestinal Exclusion Criteria for De Novo Patients ...................................49
5.5.2 Infectious Disease Exclusion Criteria for De Novo Patients ...............................49
5.5.3 General Exclusion Criteria for De Novo Patients ...............................................50
6. STUDY TREATMENT..................................................................................................52
6.1 Study Drug Administration.......................................................................................52
6.2 Concomitant Procedures and Medications ................................................................52
6.2.1 Permitted Medications for the Treatment of IBD................................................53
6.2.2 Excluded Medications........................................................................................53
6.2.3 Oral Corticosteroid Dosing and Tapering Regimen ............................................53
6.3 Precautions and Restrictions .....................................................................................54


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6.4 Management of Clinical Events................................................................................55
6.4.1 Adverse Event Collection Involving Medically Anticipated Clinical Events 
(IBD) ..........................................................................................................55
6.4.2 Infusion-Related Reactions ................................................................................55
6.4.3 Leukopenia or Lymphopenia..............................................................................56
6.4.4 Infection ............................................................................................................56
6.4.5 Malignancy........................................................................................................57
6.4.6 Hepatoxicity ......................................................................................................57
6.4.7 Management of Positive Subjective PML Checklist ...........................................57
6.4.8 Unscheduled Visits Due to Disease Exacerbation...............................................57
6.4.9 Need for Rescue Medications.............................................................................58
6.4.10 Long-term Treatment Failure ...........................................................................58
6.5 Blinding and Unblinding ..........................................................................................58
6.6 Description of Investigational Agents.......................................................................58
6.7 Preparation, Reconstitution, and Dispensation ..........................................................59
6.8 Packaging and Labeling............................................................................................59
6.9 Storage, Handling, and Accountability......................................................................59
6.10 Other Protocol-Specified Materials.........................................................................59
7. STUDY CONDUCT ......................................................................................................60
7.1 Study Personnel and Organizations...........................................................................60
7.2 Arrangements for Recruitment of Patients ................................................................60
7.3 Study Procedures......................................................................................................60
7.3.1 Informed Consent ..............................................................................................60
7.3.2 Wallet Card........................................................................................................61
7.3.3 Demographics....................................................................................................61
7.3.4 Tobacco Use......................................................................................................61
7.3.5 Medical History.................................................................................................61
7.3.6 Prior Therapies ..................................................................................................61
7.3.7 Disease History..................................................................................................61
7.3.8 Physical Examination.........................................................................................61
7.3.9 Neurological Examination..................................................................................62
7.3.10 Vital Signs and Weight ....................................................................................62
7.3.11 Progressive Multifocal Leukoencephalopathy (PML) Checklist .......................62
7.3.12 Patient Assessment of Disease Activity............................................................63
7.3.13 Concomitant Medications and Procedures........................................................63
7.3.14 Enrollment .......................................................................................................63
7.3.15 Dosing .............................................................................................................63
7.3.16 Partial Mayo Score...........................................................................................63
7.3.17 Harvey-Bradshaw Index (HBI) Score...............................................................63
7.3.18 Inflammatory Bowel Disease Questionnaire (IBDQ)........................................64
7.3.19 Short Form-36 (SF-36).....................................................................................64
7.3.20 EuroQual (EQ-5D)...........................................................................................64
7.3.21 12-Lead ECG...................................................................................................64
7.3.22 Tuberculosis Screening and Chest X-ray..........................................................64
7.3.23 Collection of Adverse Events and Serious Adverse Events...............................65
7.3.24 Sample Collection............................................................................................65


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7.4 Withdrawal of Patients From Study..........................................................................67
7.5 Study Compliance ....................................................................................................68
7.6 Post End of Study.....................................................................................................68
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................69
8.1 Determination of Sample Size ..................................................................................69
8.2 Randomization and Stratification..............................................................................69
8.3 Populations for Analysis...........................................................................................69
8.4 Procedures for Handling Missing, Unused, and Spurious Data..................................69
8.5 General Methodology...............................................................................................70
8.6 Baseline Comparisons ..............................................................................................70
8.7 Safety Analyses........................................................................................................70
8.8 Resource Utilization and Patient Reported Outcomes ...............................................71
8.9 Exploratory (Efficacy) Analyses...............................................................................72
8.10 Interim Analysis .....................................................................................................72
9. STUDY COMMITTEES................................................................................................73
9.1 Data Safety Monitoring Board..................................................................................73
9.2 Progressive Multifocal Leukoencephalopathy (PML) Independent Adjudication 
Committee ........................................................................................................73
9.3 Publications Committee............................................................................................73
10. ADVERSE EVENTS ...................................................................................................74
10.1 Definitions..............................................................................................................74
10.1.1 Adverse Event Definition.................................................................................74
10.1.2 Serious Adverse Event Definition ....................................................................74
10.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events.................................................................................................75
10.3 Monitoring of Adverse Events and Period of Observation.......................................77
10.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events........77
10.5 Risk Management...................................................................................................77
10.5.1 Specific Risk Assessment and Minimization Procedures for Identified Risk 
Associated With MLN0002 Treatment:  Infusion-Related Reaction.............78
10.5.2 Specific Risk Assessment and Minimization Procedures for Potential Risk 
of MLN0002 Treatment: Increased Rates of Infections................................78
10.5.3 Specific Risk Assessment and Minimization Procedures for Hypothetical 
Risks of MLN0002 Treatment (Not Observed to Date)................................78
10.5.4 Risk Assessment ..............................................................................................80
11. ADMINISTRATIVE REQUIREMENTS .....................................................................81
11.1 Good Clinical Practice............................................................................................81
11.2 Data Quality Assurance ..........................................................................................81
11.3 Electronic Case Report Form Completion...............................................................81
11.4 Study Monitoring ...................................................................................................82
11.5 Ethical Considerations............................................................................................82
11.6 Patient Information and Informed Consent..............................................................82
11.7 Patient Confidentiality............................................................................................82
11.8 Investigator Compliance.........................................................................................83
11.9 On-site Audits ........................................................................................................83
11.10 Investigator and Site Responsibility for Drug Accountability................................83


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11.11 Product Complaints ..............................................................................................84
11.12 Closure of the Study .............................................................................................84
11.13 Record Retention..................................................................................................85
12. USE OF INFORMATION............................................................................................86
13. INVESTIGATOR AGREEMENT................................................................................87
14. REFERENCES.............................................................................................................88
15. APPENDICES .............................................................................................................91
15.1 Partial Mayo Scoring System for the Assessment of Ulcerative Colitis Activity......91
15.2 Harvey-Bradshaw Scoring System for the Assessment of Crohn’s Disease 
Activity.............................................................................................................92
15.3 Purposes and Rationale for Amendment 1...............................................................93
15.4 Purposes and Rationale for Amendment 2...............................................................94
15.5 Purposes and Rationale for Amendment 3 (for use only outside of the US).............95
15.6 Purposes and Rationale for Amendment 4 (for use in Norway and the United 
Kingdom) .........................................................................................................96
15.7 Purposes and Rationale for Amendment 5 (for use in all countries except the 
US, Norway, and the United Kingdom).............................................................97
15.8 Purposes and Rationale for Amendment 6 (for use in the US only) .......................100
15.9 Purposes and Rationale for Amendment 7 (for use in Norway and the United 
Kingdom only)................................................................................................102
15.10 Purposes and Rationale for Amendment 8 (for use in all countries outside the 
US).................................................................................................................105
15.11 Purposes and Rationale for Amendment 9 (for use in the US only) .....................107
15.12 Purposes and Rationale for Amendment 10.........................................................109
15.13 Purposes and Rationale for Amendment 16.........................................................112
15.14 Amendment 20 Detailed Summary of Changes...................................................113


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LIST OF ABBREVIATIONS
Abbreviation
Term
5-ASAs
5-aminosalicylates
AEs
adverse events
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BUN
blood urea nitrogen
CD
Crohn’s disease
CFR
Code of Federal Regulations
CHO
Chinese hamster ovary
Cmin
minimum plasma concentration
CMV
cytomegalovirus
CNS
central nervous system
CRP
C-reactive protein
CV
coefficient of variation
DSMB
data safety monitoring board
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EQ-5D
EuroQual
ET
early termination
GCP
good clinical practice
GI
gastrointestinal
h
hours
HAHA
human anti-human antibody
HBI
Harvey-Bradshaw Index 
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HLT
high level term
IAC
Independent Adjudication Committee
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IFN
interferon
IL
interleukin
IRB
institutional review board
IV
intravenous
JCV
JC virus, a neurotropic DNA polyomavirus
IVRS
interactive voice response system


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Abbreviation
Term
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MLN0002
vedolizumab
NSAID
nonsteroidal anti-inflammatory drug
PD
pharmacodynamics
PK
pharmacokinetics
PML
progressive multifocal leukoencephalopathy
PVC
polyvinylchloride
QOL
quality of life
RAMP
Risk Assessment and Minimization for PML 
RBC
red blood cell(s)
SAEs
serious adverse events
SF-36
Short-Form 36
SOC
system organ class
TB
tuberculosis
TNF
tumor necrosis factor alpha
UC
ulcerative colitis
UCCS
Ulcerative Colitis Clinical Score
ULN
upper limit of normal
US
United States
WBC
white blood cell(s)
XAP
Extended Access Program


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Study Definitions
Pertaining to Patients With UC
Term
Definition
Clinical Remission
A partial Mayo score of ≤2 with no individual subscore > 1.
Clinical Response
A decrease in the partial Mayo Score of at least 2 points and 25from 
baseline, with an accompanying decrease in rectal bleeding subscore of 1 point 
from baseline or absolute rectal bleeding subscore of 1 point
Rescue Medication(s)
Any new medication to treat a new or unresolved luminal manifestation of 
ulcerative colitis (UC), with the following exceptions:  
oral and topical (rectal) 5-aminosalicylate (ASA) treatment
oral corticosteroids per the guidelines outlined in Section 6.2.3
topical (rectal) corticosteroid enemas/suppositories
azathioprine or 6-mercaptopurine; stable doses are recommended 
antibiotics
antidiarrheals for control of chronic diarrhea 
probiotics (eg, Culturelle, Saccharomyces boulardii)
Long-term Treatment 
Failure
Need for rescue medications, or major surgical intervention for treatment of UC, 
or a study drug-related adverse event leading to discontinuation from the study 
Pertaining to Patients With CD
Term
Definition
Clinical Remission
A Harvey-Bradshaw Index (HBI) score 4 points
Clinical Response
A 3-point decrease in HBI score from baseline
Rescue Medication(s)
Any new medication to treat a new or unresolved luminal manifestation of 
Crohn’s disease (CD), with the following exceptions:  
oral and topical (rectal) 5-ASA treatment
oral corticosteroids per the guidelines outlined in Section 6.2.3
topical (rectal) corticosteroid enemas/suppositories
azathioprine, 6-mercaptopurine, or methotrexate; stable doses are 
recommended 
antibiotics
antidiarrheals for control of chronic diarrhea 
probiotics (eg, Culturelle, S. boulardii)
Long-term Treatment 
Failure
Need for rescue medications, or major surgical intervention for treatment of CD, 
or a study drug-related adverse event leading to discontinuation from the study 


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1.   
BACKGROUND AND STUDY RATIONALE
1.1   Scientific Background
1.1.1   
The Inflammatory Bowel Diseases:  Ulcerative Colitis and Crohn’s Disease
Ulcerative colitis (UC) is a relapsing, remitting inflammatory disease of the colonic mucosa 
and submucosa.  The prevalence of UC is approximately 200/100,000 of population in the 
United States (US) and approximately 150/100,000 of population in Western Europe.(2, 3, 4)  
A genetic contribution to the disease is indicated by the increased incidence of UC (of 30 to 
100 times that of the general population) among first-degree relatives of patients with UC.  
The characteristic pathology is one of chronic inflammation characterized by large numbers 
of lymphocytes and histiocytes in the diseased mucosa and submucosa with an acute 
inflammatory infiltrate composed of neutrophils variably present.
Crohn’s disease (CD) is a relapsing, remitting inflammatory disease that may involve any 
portion of the length of the gastrointestinal tract from mouth to anus in a transmural fashion 
from mucosa to serosa.  The prevalence of CD is approximately 150/100,000 of population 
in the US and approximately 125/100,000 of population in Western Europe.(2, 3, 4)  The 
characteristic pathology involves a chronic inflammatory infiltrate consisting of neutrophils 
and macrophages.  Hallmarks of CD include granulomatous inflammation and aphthous 
ulceration.
Clinical manifestations of both diseases include diarrhea (typically bloody in patients with 
UC), as well as abdominal pain, fecal urgency, and incontinence.  Systemic features such as 
fever, weight loss, malaise, and fatigue are indicators of more extensive disease.  
Extra-intestinal manifestations such as uveitis, arthritis, ankylosis spondylitis, or primary 
sclerosing cholangitis may also be seen in conjunction with inflammatory bowel disease 
(IBD).  The diagnosis of UC or CD is usually made by histopathologic examination of 
endoscopic mucosal biopsy specimens obtained on ileocolonoscopy.
Current treatments have been effective for many patients with UC or CD but have numerous 
limitations for patients with moderate to severe disease.  5-Aminosalicylates (5-ASAs) are 
the mainstay of UC pharmacotherapy for induction and maintenance of remission for 
patients with mild to moderate disease, but are less effective in severe disease.  The National 
Cooperative Crohn’s Disease Study demonstrated a role for sulfasalazine (a 5-ASA 
containing molecule) in moderate to severe Crohn’s disease(5); however, the efficacy of 
5-ASAs in CD has been called into question by a recent meta analysis.(6)  Corticosteroids are 


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often required for the one-third of patients who fail to respond to 5-ASAs.  While highly 
effective for induction of remission, corticosteroids are not useful in either disease for 
maintenance of remission and carry significant undesirable side effects, including 
osteoporosis, glucose intolerance, and increased risk of infection.
Immunomodulatory agents, including 6-mercaptopurine and azathioprine, have a role in 
maintenance of remission in moderate to severe UC and moderate to severe CD.  Their 
relatively slow onset of action precludes their use during flares of disease, and the use of 
these agents has been reported to potentially increase the risk of lymphoma in patients with 
IBD.(7)  Intravenous cyclosporine has a role in the management of severe UC; however, it is 
impractical in nonhospitalized patients, requires intense monitoring, and may cause 
irreversible nephrotoxicity, all of which limit its use to severe cases.  Methotrexate, while 
ineffective in UC, has a role in the management of refractory CD; however, it also 
demonstrates a number of dose-limiting toxicities.  Antibiotics have marginal efficacy in 
maintenance of remission in CD and are not effective in UC.
Biologic agents, including monoclonal antibodies against tumor necrosis factor alpha 
(TNF), such as infliximab (Remicade®) and adalimumab (Humira®), have been studied and 
have proven useful for both induction and maintenance of remission in CD.  Infliximab is 
also useful for induction and maintenance of remission in UC.  However, only 
approximately one-third of patients have a sustained remission at 1 year following treatment 
with these agents.  In addition, treatment with TNFantagonists has been associated with a 
number of serious adverse events (SAEs) involving hypersensitivity and infection.  
Reactivations of latent tuberculosis (TB)(8) and disseminated histoplasmosis have been 
reported, and in some cases have been fatal.(9)  Induction of remission with infliximab 
occurs in only 31% to 39% of patients with UC(10) and durable clinical remission (at 1 year) 
occurs in only 26% of patients with UC.  Efficacy data for both infliximab and adalimumab 
in CD are quite similar to the infliximab data in UC with only a minority of patients having 
a durable response at 1 year.(11, 12)
Failure of medical therapy leads to colectomy in 9% to 35% of patients with UC within 
5 years.  Colectomy is considered to be an important adjunct treatment for refractory UC; 
however, colectomy with ileal pouch anal anastomosis (the standard surgical therapy) has 
many limitations and is associated with its own set of complications, including high stool 
frequency,(13) female infertility,(14) and a cumulative incidence of pouchitis of 50% at 
10 years.(15)  Surgical removal of highly diseased, strictured, or stenotic segments of bowel 


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in CD is not curative.  Relapse occurs in a majority of patients with CD who undergo 
segmental resections, and the need for reoperation is the rule rather than the exception.(16)
The limitations of current therapies for IBD indicate that there is a significant need for safer 
and more effective therapies.  MLN0002 (vedolizumab) is being developed to fulfill this 
important unmet medical need.
1.1.2   
Study Drug:  Vedolizumab (MLN0002)
MLN0002 is a humanized monoclonal antibody that binds to the 47 integrin, which is 
expressed on discrete populations of leukocytes involved in gut mucosal immunity.(17)  One 
of the adhesion ligands of 47, mucosal addressin cell adhesion molecule-1 (MAdCAM-1) 
is preferentially expressed on high endothelial venules at sites of lymphocyte extravasation 
in the gastrointestinal (GI) mucosa and associated lymphoid tissue.  Binding of MAdCAM-1 
by 47 mediates migration of leukocytes into GI mucosa and associated lymphoid tissue.(18, 
19, 20)  The 47 integrin has received particular attention in the context of mucosal immune 
responses given its unique role in mediating infiltration of the GI tract by leukocytes.  
MLN0002 antagonizes both the 47-MAdCAM-1 interaction, and the associated migration 
of leukocytes into GI mucosa.  This mechanism of action of MLN0002 reduces pathological 
bowel inflammation, thus providing a potential therapeutic option for patients with IBD.  A 
unique feature of MLN0002 is that it binds exclusively to an epitope that is unique to 47; 
it does not bind to 4 or 7 in association with other integrins, for example41 or E7.
1.2   Preclinical Experience
Detailed information regarding the nonclinical pharmacology and toxicology of MLN0002 
is found in the Investigator’s Brochure (IB).
1.3   Clinical Experience
More than 1800 people have participated or are participating in clinical trials with 
MLN0002.  In completed studies, nearly 600 men and women are known to have received at 
least 1 dose of MLN0002, which includes more than 300 people with UC or CD.  Further 
details are provided in the IB.


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1.3.1   
MLN0002 Efficacy
MLN0002 efficacy has been established in patients with UC and CD.  Specifically, in a 
phase 2 study in patients with moderately active UC (Study M200-022), MLN0002 
treatment (administered at doses of 0.5 and 2.0 mg/kg IV on Days 1 and 29) induced a 
statistically significant increase in rates of clinical remission compared with placebo.(21)
Clinical remission rates at Week 6 were 33%, 32%, and 14% for patients who received 
0.5 mg/kg MLN0002, 2.0 mg/kg MLN0002, and placebo, respectively (p = 0.017 for 
0.5 mg/kg dose group, p = 0.023 for 2.0 mg/kg dose group, and p = 0.009 for the combined 
MLN0002 groups vs placebo group).  Twenty-eight percent of patients receiving 0.5 mg/kg 
and 12% of those receiving 2.0 mg/kg had evidence of endoscopic remission compared to 
8% of patients receiving placebo (p = 0.007 for the combined MLN0002 groups vs placebo 
group).  Results from this study demonstrated proof-of-concept for the use of MLN0002 as a 
novel agent for the treatment of UC.(22)
Similarly, in a phase 2 study in patients with moderately active CD (Study L299-016), 
MLN0002 treatment (administered at doses of 0.5 and 2.0 mg/kg IV on Days 1 and 29), did 
not achieve its prospectively-defined primary endpoint of clinical response at 8 weeks (a 
70-point decline in Crohn’s Disease Activity Index [CDAI] from baseline), but did achieve 
the more rigorous secondary endpoints of clinical remission (CDAI 150 points) at 8 weeks 
and enhanced clinical response (CDAI decrease of 100 points) at 8 weeks for the 
2.0 mg/kg MLN0002 group versus placebo.(23)  Clinical remission rates were 30%, 37%, and 
21%, for patients who received 0.5 mg/kg MLN0002, 2.0 mg/kg MLN0002, and placebo, 
respectively (p = 0.044 for 2.0 mg/kg dose group vs placebo).  Other secondary endpoints 
also showed dose-dependent trends that achieved statistical significance in the 2.0 mg/kg 
MLN0002 dose group.  These include time to response, percentage of patients with 
normalization of C-reactive protein (CRP), and mean decline in CDAI score.  Together, 
these results suggest biologic activity of MLN0002 in CD.
1.3.2   
MLN0002 Safety 
Vedolizumab has shown an acceptable safety profile based on an integrated analysis of all 
adverse events and select safety laboratories for all completed phase 1 and phase 2 clinical 
studies. In addition, the blinded, aggregate safety data in the phase 3, placebo-controlled,
UC and CD studies has been similar to the safety experience in the open-label, phase 3,
safety extension study C13008. Of note, approximately 1800 patients have participated in 
Study C13008, the majority of whom have received multiple doses of vedolizumab.  The 


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integrated summary of safety for the completed studies, as well as a summary of safety from 
the ongoing phase 3 program (based on a data cutoff of 16 April 2010), are detailed in the 
current version of the IB.  The current experience with vedolizumab, based on review of 
data from the blinded safety data in Studies C13006, C13007, C13011, and from the 
open-label study C13008, is consistent with the findings as detailed in the IB.  The phase 3 
trials are also independently monitored for safety as described below. 
In the completed studies, overall, percentages of subjects who reported AEs and SAEs, or 
who discontinued due to an adverse event (AE), were similar between MLN0002- and 
placebo-treated groups.  Throughout the MLN0002 program, there has been no overt 
relationship between dose and specific AEs.
The safety profile of MLN0002 in the target patient populations is generally reflective of the 
indication under study.  That is, there are more reports of GI events in patients with IBD 
(UC, CD) compared with the experience in healthy subjects.  Baseline disease activity in 
patients with IBD did not influence the overall rate of AEs, although SAEs, severe AEs, and 
discontinuations due to AEs were reported more commonly in patients with more severe 
disease activity regardless of whether they received MLN0002 or placebo.
Patients in the completed and ongoing trials have been and are closely monitored for 
infection.
Additionally, in the completed studies, an analysis of concomitant use of 
immunosuppressants (ie, corticosteroids, azathioprine/6-mercaptopurine [6-MP], 
methotrexate, cyclosporine, or infliximab within 90 days of patients’ last dose of study drug) 
has not identified an acute, additive risk of infection attributable to MLN0002. 
Similarly, concomitant use of corticosteroids and/or conventional immunomodulators does 
not appear to be associated with a clinically meaningful increased rate of infections based on 
the comparative rates of infections in the blinded phase 3 trials among patients who have 
and have not received these medications.  
As shown in Table 1-1, overall rates of infection are relatively constant regardless of the use 
of these concomitant medications. Most infections (by preferred term) were reported by 
either 1 or 2 individuals, and no trends were observed when comparing the blinded 
aggregate data from C13006 and C13007 to the open-label experience (C13008). 
Concomitant use of these medications does not appear to be associated with any increased 
rate of specific infections.


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Table 1-1   
Overview of Subjects Reporting at Least 1 Infection According to 
Concomitant Medication Use
Study Population
C13006
n/N (%)
C13007
n/N (%)
C13008
n/N (%)
All patients
56/300  (19)
100/454 (22)
32/203  (16)
Neither steroids or immunomodulators
19/94 (20)
40/169 (24)
17/135 (13)
Steroids only
19/106 (18)
29/143 (20)
10/43 (23)
Immunomodulator only
5/30 (13)
16/76 (21)
2/13 (15)
Both steroids and immunomodulators
13/60 (22)
15/66 (23)
3/12 (25)
Either steroids, immunomodulators or both
37/206 (18)
60/285 (21)
15/68 (22)
Any steroids (with or without immunomodulators)
32/166 (19)
44/209 (21)
13/55 (24)
Any immunomodulator (with or without steroids)
18/100 (18)
31/142 (22)
5/25 (20)
In addition, all patients enrolled in the vedolizumab trials are actively monitored for 
progressive multifocal leukoencephalopathy (PML) through the Risk Assessment and 
Minimization for PML (RAMP) program. No cases of PML have been reported in any 
clinical trial. 
Deaths have occurred in patients participating in MLN0002 clinical trials, 2 of which were 
thought to be related to the study drug by the treating physicians.  However, the treating 
physicians do not know if these subjects received MLN0002 or placebo.
The phase 3 vedolizumab clinical program is overseen by an independent Data Safety 
Monitoring Board (DSMB) composed of 2 gastroenterologists, an infectious diseases 
physician, a physician with training in epidemiology, and a statistician. The DSMB reviews 
all SAEs monthly and unblinded safety data from all phase 3 trials every 6 months at a 
minimum. The DSMB convened on 13 December 2011, and after reviewing unblinded 
safety data, recommended that the trials proceed without modification.
In conclusion, substantial clinical exposures to vedolizumab have been accrued in patients
with moderate to severe IBD, and the clinical safety experience with vedolizumab has been
consistent with its mechanism of action as a selective integrin antagonist.  In consideration 
of the greater severity of disease of patients enrolled in the phase 3 studies, the overall safety 
profile of vedolizumab (MLN0002) remains consistent with the favorable safety experience 
in the phase 2 trials, and remains compatible with vedolizumab’s gut-selective 
anti-inflammatory effects. 


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Refer to Section 1.5 for the identified, potential, and hypothetical risks of MLN0002 based 
on clinical experience as of 16 April 2010.  Further details are provided in the current IB.
1.4   Study Rationale
Establishing the long-term safety and tolerability of MLN0002 is a key component of the 
pivotal development programs in both UC and CD.  From this long-term open-label study of 
active MLN0002 therapy, data regarding the occurrence of important clinical events 
resulting from chronic MLN0002 administration will be obtained.  Important clinical events 
including those related to safety (eg, opportunistic infections, malignancy, long-term 
immunogenicity profile) as well as efficacy (eg, maintenance of remission, quality of life, 
and various other health outcomes measures) will be collected.  The probability of 
experiencing uncommon safety events that occur at a frequency on the order of 
1/100-1/1500 that might not ordinarily be detected in year-long induction and maintenance 
studies may be estimated from this study data.  The probability of detecting at least 
1 uncommon adverse event with 2000 patients will be 0.9999, 0.9818, 0.8648, and 0.6322 
when the true rates are 1/100, 1/500, 1/1000, and 1/2000, respectively.
This study will allow patients with prior enrollment in a qualifying MLN0002 study 
(rollover patients, as detailed in Section 4.1) to receive long-term MLN0002 treatment. 
Although the study was due to complete in December 2016, Takeda has agreed to extend the 
treatment period until July 2017 to allow continued access for patients in countries where 
vedolizumab is either not commercially available or is not reimbursed, or for which the XAP 
study is not yet available at the site. For this reason, this amendment is being submitted in all 
countries currently following Amendment 16 except the following: Austria, France, 
Germany, Israel, Netherlands, Norway,  Spain, Sweden, Switzerland and the United 
Kingdom.  Current safety information is available in the latest version of the Investigator 
Brochure. 
A control group has not been included in this study based on the following considerations.  
First, since the observed rates of rare safety events such as those listed above can be 
estimated from an observational study, a controlled study is unnecessary.  Second, most of 
the patients participating in this long-term safety study will have participated in a previous 
MLN0002 study in which they may have been randomized to placebo therapy; therefore, the 
opportunity for these patients to receive active treatment should not be unnecessarily 
delayed.  Third, data from the study will be benchmarked with data from external databases 
(see Section 8.7 for further details on safety analyses that will be performed).  


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UC disease activity will be followed throughout this study using the partial Mayo score, a 
standardized measure for UC trials that includes 3 of the 4 components of the complete 
Mayo score.(10) CD disease activity will be followed throughout this study using the 
Harvey-Bradshaw Index (HBI), a standardized measure for CD trials that has previously 
been demonstrated to correlate highly with the Crohn’s Disease Activity Index (CDAI).(24)  
Exploratory efficacy outcomes such as clinical remission, clinical response, and decrease in 
corticosteroid use will be assessed in subgroups of patients to whom these endpoints are 
relevant.
Dose Selection Rationale
The strategy for dose selection in this phase 3 study was based on the following parameters:

Clinical efficacy and dose response in phase 2 

Suppression of human anti-human antibody (HAHA) formation

Serum concentration of MLN0002 at the efficacious doses in phase 2 trials 
(pharmacokinetic considerations)

Maintenance of 47 receptor saturation (pharmacodynamic considerations)
A dose of 300 mg MLN0002 (roughly equivalent to 4 mg/kg MLN0002 for a 75 kg patient) 
every 4 weeks has been selected for evaluation.  This selection is based on the phase 2 
findings that 2 mg/kg MLN0002 administered every 4 weeks as induction therapy was an 
efficacious dose for both UC and CD, but that maximal efficacy may not have been 
achieved.  Also, formation of HAHA following MLN0002 treatment has an inverse dose 
relationship, with higher doses within the tested range having a suppressive effect on 
immunogenicity (refer to the IB).  Therefore, doses higher than those that might ordinarily 
be acceptable short-term in the absence of HAHA are required to sustain remission 
throughout the dosing interval.  Therefore, as a strategy to maximally suppress HAHA 
formation with MLN0002, 300 mg MLN0002 will be administered every 4 weeks.  
MLN0002 treatment was generally well tolerated in 79 healthy subjects and patients with 
IBD that were treated with doses and/or dose regimens resulting in concentrations that 
exceed the median predicted steady-state MLN0002 peak and trough concentrations for the 
proposed dose (300 mg MLN0002 administered every 4 weeks).  The favorable safety 
profile of MLN0002 doses up to 10 mg/kg supports selection of this dose for evaluation in 
this study (for additional details, see Section 1.3.2).


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A dose of 300 mg MLN0002 every 4 weeks is expected to suppress immunogenicity during 
multiple dosing, thereby maintaining sufficient MLN0002 exposure and 47 receptor 
saturation throughout the dosing interval which, in previous efficacy studies, have been 
shown to result in clinical efficacy.  It is also one of the dose regimens currently being 
evaluated in the phase 3 induction and maintenance Studies C13006 and C13007 and the 
induction Study C13011.  This long-term safety study will provide additional supportive 
data for 300 mg MLN0002 administered every 4 weeks in patients with IBD and will ensure 
an adequate safety database for the eventual registration of MLN0002 in UC and CD.  
1.5   Potential Risks and Benefits
As described in Section 1.3, 2 well-powered, phase 2 studies have shown the benefit of 
MLN0002 treatment in inducing response and remission in UC and CD.  An integrated 
safety analysis was conducted using data from completed and unblinded clinical trials as of 
16 April 2010.  This analysis of 742 healthy subjects and patients with IBD, of whom 
560 received at least 1 dose of MLN0002, demonstrated an acceptable safety profile for 
MLN0002. Thus, MLN0002 has a favorable risk to benefit profile to date.  Section 10.5
describes the comprehensive risk management program for this study.
1.5.1   
Identified Risk of MLN0002 Treatment:  Infusion-Related Reaction
As of 16 April 2010, no anaphylactic or anaphylactoid reactions have been observed 
following initial dosing of MLN0002.  There is an identified risk of infusion-related reaction 
with vedolizumab, largely limited to individuals who develop clinically significant titers of 
HAHA.  Three (1%) of more than 300 subjects known to have received 2 or more 
infusions of MLN0002 developed an infusion-related reaction, 1 of which was reported as 
serious.  Following a second administration of the MLN0002 formulation used during earlier
development, 2 patients experienced signs and symptoms consistent with an acute 
infusion-related reaction either during or within minutes of administration.  These symptoms 
included rash, facial numbness, urticaria, pruritus, puffiness and pressure to the eye, 
angioedema of the lip, and throat tightness.  The third patient, who developed an acute 
infusion-related reaction after receiving a recent version of MLN0002, had been sensitized 
by exposure to an earlier version of MLN0002 in a previous study.  All of these 
infusion-related reactions were mild to moderate in intensity and were managed medically 
with either antihistamines alone or with the addition of steroids.  Please refer to the current 
IB for further information.


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Immunogenicity
Based on existing data from clinical studies with MLN0002, there is the possibility of 
developing HAHA to vedolizumab that may cause infusion-related reactions, other 
nonspecific AEs, and/or reduced efficacy.  The data from clinical studies with MLN0002 
demonstrate dose dependence in clinically relevant HAHA formation (HAHA associated 
with PK and/or pharmacodynamic changes).  Thus, the immunogenicity of vedolizumab 
may be substantially reduced at higher doses of MLN0002.
More data are required to fully characterize the immunogenicity profile of vedolizumab and 
the relationship between HAHA levels, efficacy, and AEs, including infusion-related 
reactions.  
1.5.2   
Potential Risk of MLN0002 Treatment:  Increased Rates of Infections
As observed in the phase 1 and 2 studies, patients with IBD receiving MLN0002 may have 
an increased rate of upper respiratory and mucosal infections.  Upper respiratory infections, 
Herpes labialis, and mucosal candidiasis were more common in subjects who received 
MLN0002 in the phase 1 and 2 studies.  Given the known distribution of the MAdCAM-1 
binding sites in the nasopharyngeal and oropharyngeal tissue and vagina, it is possible that 
upper respiratory tract, esophageal, and vaginal infections may be more common based on 
the mechanism of action of MLN0002.
1.5.3   
Hypothetical Risks of MLN0002 Treatment (Not Observed to Date)
Gastrointestinal Infections
There is a hypothetical risk that MLN0002 may increase GI infections, as well as systemic 
infections against which the gut constitutes a defensive barrier.  Examples of such infections 
include those caused by enteric pathogens (eg, Listeria, Salmonella, Campylobacter, 
Yersinia, C. difficile), viral infections such as CMV, and opportunistic infections (eg, 
cryptosporidiosis, Mycobacterium avium complex).
As of 16 April 2010, however, increased rates of GI infections or severe infections have not 
been observed among healthy subjects or patients administered MLN0002.  No systemic 
opportunistic infections with a portal of entry outside the GI tract have been reported.  In the 
subset of patients who received concomitant steroids and immunosuppressants while 
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Progressive Multifocal Leukoencephalopathy
The cases of progressive multifocal leukoencephalopathy (PML) reported in patients being 
treated with the pan-4 integrin antagonist natalizumab (Tysabri®) have focused safety 
concerns on integrin antagonists.  The gut-selective anti-inflammatory activity of MLN0002, 
as a specific 47 integrin antagonist, may not predispose patients to an increased risk of 
PML.  Nevertheless, all ongoing MLN0002 clinical studies use the Risk Assessment and 
Minimization for PML (RAMP) program as a Risk Minimization Action Plan for PML.  
Details of the RAMP program are provided in Section 10.5.3 and in the Study Manual.  
Malignancy
The incidence of certain malignancies, in particular lymphoma and colorectal cancer, may, 
in theory, increase in patients on long-term immunosuppressive therapies, particularly those 
which target cell-mediated immunity.
As of 16 April 2010, the percentages of MLN0002 and placebo subjects who have 
developed a malignancy during the long-term study follow-up are similar.  There have been 
4 cases of malignancies reported posttreatment in the completed studies:  2 cases of breast 
cancer, 1 case of cervical cancer, and 1 case of endometrial cancer, the latter of which was 
present before study entry.  No cases of lymphoma or neoplasia of another organ system 
were reported during the long-term follow-up periods (through 2 years from last dose of 
study drug) in any of the clinical studies for which these data are available.
A number of malignancies have occurred over the duration of the phase 3 program, which 
remains blinded at the time of the writing of this amendment. At the meeting in December 
2011, the DSMB for the phase 3 program reviewed unblinded data, and no modifications to 
the trial were requested. 
1.5.4   
Summary of Risks and Benefits
The safety analysis of all completed trials, as well as the current safety experience from the 
ongoing phase 3 trials, demonstrate that MLN0002 has an acceptable safety profile.  Phase 2 
studies have demonstrated efficacy in UC and CD.  These data support a favorable 
benefit-to-risk profile for MLN0002.  In addition, based on its targeted mechanism of action, 
MLN0002 may prove to have a superior benefit-to-risk profile compared with conventional 
systemic immunosuppressive therapies for IBD, such as corticosteroids and TNF


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antagonists.  On this basis, as well as the risk management procedures implemented in this 
study, further investigation of this novel compound for the treatment of IBD is warranted.


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2.   
STUDY OBJECTIVES
2.1   Primary Objective

To determine the safety profile of long-term MLN0002 treatment 
2.2   Resource Utilization and Patient Reported Outcome Objectives

To determine the effect of long-term MLN0002 treatment on time to major IBD-
related events (hospitalizations, surgeries, and procedures)

To examine the effect of long-term MLN0002 treatment on health-related quality of 
life (QOL) measurements
2.3   Exploratory Objective

To obtain data regarding the effect of long-term MLN0002 treatment on maintaining 
clinical response and remission 


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3.   
STUDY ENDPOINTS
3.1   Primary Endpoints

SAEs, AEs, vital signs, results of standard laboratory tests (clinical chemistry, 
hematology, coagulation, urinalysis, and HAHA), and results of electrocardiograms 
(ECGs)  
3.2   Resource Utilization and Patient Reported Outcome Endpoints

Time to major IBD-related events (hospitalizations, surgeries, or procedures)

Changes from baseline in IBDQ, SF-36, and EuroQual (EQ-5D) scores
3.3   Exploratory Endpoint

Partial Mayo scores and HBI scores will be used to monitor changes in IBD activity 
during long-term MLN0002 treatment
4.   
STUDY DESIGN 
4.1   Overview of Study Design
This is an open-label phase 3 study to determine the long-term safety and efficacy of 
vedolizumab (MLN0002) for the treatment of patients with moderate to severe UC or CD.  
All enrolled patients will receive 300 mg MLN0002 administered every 4 weeks.  
Most patients enrolling in this study will have participated in a previous qualifying 
MLN0002 study (rollover patients):

Patients with UC or CD who participated in the phase 2, open-label, 
long-term safety study (Study C13004), which includes up to 78 weeks of 
open-label treatment with MLN0002 

Patients who withdrew early from a phase 3 induction and maintenance study 
(Study C13006 [patients with UC] or Study C13007 [patients with CD]), 
which includes up to 50 weeks of blinded study treatment (MLN0002 or 
placebo).  These patients must have withdrawn due to sustained nonresponse, 
disease worsening, or the need for rescue medications

Patients who completed Study C13006, Study C13007, or Study C13011


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For rollover patients, the first dose of MLN0002 in this study (ie, Week 0) should occur no 
more than 9 weeks after the last dose of study drug in the previous study; the preferable 
period is within 3 to 5 weeks after the last dose in the previous study.  Patients will be 
consented and receive wallet cards prior to or at the Week 0 Visit.  Results of assessments 
from the last visit in the previous qualifying study will be used to determine their eligibility 
to participate in this study.  Baseline data will also be obtained from the previous study, 
including medical history, disease history, demographics, tobacco use, and prior therapies.  
In addition, up to 400 patients without previous treatment with vedolizumab may be enrolled 
directly into this study (de novo patients). Patients with UC or CD must meet the 
inclusion/exclusion criteria for de novo patients (Section 5). Baseline data will be obtained 
during the Screening period.
Enrollment in this study is defined as the time the patient is entered into the Interactive 
Voice Response System (IVRS) at Week 0.
Following enrollment all patients will be administered 300 mg vedolizumab every 4 weeks 
for the duration of the study. The total duration of MLN0002 treatment will vary by patient 
based on continued benefit until July 2017, or until the XAP study is available at the site, or 
until patient withdrawal, or until vedolizumab is available to the patient through commercial 
channels (including reimbursement) for the patient’s clinical scenario, or unless the study is 
terminated early by the sponsor, as described in Section 11.12, whichever is sooner. 
Patients may receive allowed concomitant medications for the treatment of IBD as detailed 
in Section 6.2.1, as determined by the principal investigator, at any time point during the 
study. Medications may be discontinued during the study, but if discontinuation is planned, 
it should be done prior to the first dose of vedolizumab. 
It is strongly recommended that patients receiving oral corticosteroids should begin an oral 
corticosteroid tapering regimen once they achieve clinical response or if, in the opinion of 
the investigator, they demonstrate sufficient improvement in clinical signs and symptoms.  
Patients will be withdrawn from the study for long-term treatment failure as described in the 
study definitions or if (in the opinion of the investigator or patient) they are not benefiting 
from therapy (see Section 6.2.3, Section 6.4.10, and Section 7.4).  Additionally, 
investigators should strongly consider withdrawing patients who require recurrent courses of 
corticosteroids with inability to taper.


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Patients who do not transition into the XAP study will return 16 weeks after their last dose 
of MLN0002 for the Final Safety visit. Patients who transition into the XAP study are not 
required to attend the Final Safety Visit.  The safety of these patients will be monitored as 
part of the XAP study.  The end-of-study eCRF page must be completed for all patients 
regardless of whether they transition into the XAP study or not.
Safety assessments and efficacy assessments using the partial Mayo Score (for patients with 
UC) or the HBI score (for patients with CD) will be made throughout the treatment period.  
Detailed visit-by-visit study procedures and assessments are provided in the Schedule of 
Events and Section 7.
This trial will be conducted in compliance with the protocol, good clinical practice (GCP), 
and the applicable regulatory requirements (including International Conference on 
Harmonisation [ICH] guidelines).
4.2   Number of Patients
Approximately 1800 rollover patients with UC or CD will enroll in this study from 
approximately 400 study centers worldwide following participation in other qualifying 
MLN0002 studies.  In addition, up to 400 de novo patients with UC or CD (not previously 
treated with vedolizumab) will enroll in this study.  These patients will be enrolled from 
approximately 150 of the 400 worldwide centers noted above.  Those sites selected to enroll 
de novo patients will be notified by the sponsor.
4.3   Duration of Study
It is anticipated that the duration of MLN0002 treatment will vary by patient based on 
continued benefit. Treatment duration may continue until July 2017, or until the XAP study
is available at the site, or until patient withdrawal, or until vedolizumab is available to the 
patient through commercial channels (including reimbursement) for the patient’s clinical 
scenario, or unless the study is terminated early by the sponsor, as described in Section 
11.12, whichever is sooner. After the final dose of MLN0002, patients who do not transition 
into the XAP study will complete the 16-week posttreatment observation and safety 
assessment period (not applicable to patients who transition to the XAP study). Concomitant 
vedolizumab (Entyvio) taken during the 16-week follow-up period will be recorded as a 
concomitant medication and will not be considered as a protocol deviation. 


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Additionally, upon completion of or termination from this study, patients will participate in 
a 2-year follow-up survey, as described in Section 7.6.


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5.   
STUDY POPULATION
5.1   Inclusion Criteria for Rollover Patients
Each rollover patient must meet all of the following inclusion criteria to be enrolled in the 
study:  
1. Voluntarily able to give informed consent.  
2. Previous treatment in Study C13004, Study C13006, Study C13007, or Study 
C13011 that, in the opinion of the investigator, was well tolerated.  Patients who 
participated in Study C13011 must have completed the Week 10 assessments in 
that study.  
Patients who withdrew early from C13006 or C13007 must have withdrawn due to 
one of the following:  

Sustained Nonresponse for patients with UC in C13006:  Failure to achieve a 
clinical response (2 point and 25% improvement in partial Mayo score) by 
Week 14 and a minimum partial Mayo score of 5 points 

Sustained Nonresponse for patients with CD in C13007:  Failure to achieve a 
clinical response (70 point improvement in CDAI score) by Week 14 and a 
minimum CDAI score of 220 points

Disease Worsening for patients with UC in C13006:  An increase in partial 
Mayo score of 3 points on 2 consecutive visits from the Week 6 value (or 
an increase to 9 points on 2 consecutive visits if the Week 6 value 6) and a 
minimum partial Mayo score of 5 points 

Disease Worsening for patients with CD in C13007:  A 100 point increase 
in CDAI score on 2 consecutive visits from the Week 6 value at any study 
visit and a minimum CDAI score of 220 points 

Required rescue medications for patients in C13006 and C13007 at Week 14 
or beyond.  Requirement for rescue medication is defined as the receipt of or 
need for any new medication or any increase in dose of a baseline medication 
required to treat new or unresolved UC or CD symptoms (other than 
antidiarrheals for control of chronic diarrhea). Patients who experienced 
treatment failure in Study C13006 or Study C13007 only as a result of 
receiving rescue medications (and without meeting the definition of Disease 


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Worsening) before Week 14 are not eligible for Study C13008.
3. The first dose of MLN0002 in this study (ie, Week 0) should occur no more than
9 weeks after the last dose of study drug in the previous study; the preferable 
period is within 3 to 5 weeks after the last dose in the previous study.
4.
Female patients who:

are postmenopausal for at least 1 year before enrollment, OR

are surgically sterile, OR

if they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed 
consent form through 18 weeks after the last dose of MLN0002, OR agree to
completely abstain from heterosexual intercourse.
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

agree to practice effective barrier contraception during the entire study 
treatment period and through 18 weeks after the last dose of MLN0002, OR

agree to completely abstain from heterosexual intercourse.
5. Patients with extensive colitis or pancolitis of > 8 years duration or limited colitis 
of > 12 years duration must have documented evidence that a surveillance 
colonoscopy was performed within 12 months of enrollment.
6. Patients with a family history of colorectal cancer, personal history of increased 
colorectal cancer risk, age 50 years, or other known risk factor must be 
up-to-date on colorectal cancer surveillance.  
7. May be receiving a therapeutic dose of the following drugs:  
a.
Oral 5-ASA compounds 
b. Oral corticosteroid therapy, as described in Section 6.2.3
c.
Topical (rectal) treatment with 5-ASA or corticosteroid enemas/suppositories
d. Probiotics (eg, Culturelle, Saccharomyces boulardii) 
e.
Antidiarrheals (eg, loperamide, diphenoxylate with atropine) for control of 
chronic diarrhea 
f.
Antibiotics used for the treatment of IBD (ie, ciprofloxacin, metronidazole)
g. Azathioprine, 6-mercaptopurine, or methotrexate (methotrexate for CD only)


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5.2   Exclusion Criteria for Rollover Patients
Rollover patients meeting any of the following exclusion criteria are not to be enrolled in the 
study:  
1. Female patients who are lactating or pregnant.  
2. Required major surgical intervention for IBD (eg, bowel resection) during or after 
participation in a prior MLN0002 study, currently requires major surgical 
intervention for IBD, or is anticipated to require major surgical intervention for 
IBD during this study; minor surgical procedures (eg, fistulotomy) are 
permissible. 
3. Any live vaccinations within 30 days prior to MLN0002 administration except for 
the influenza vaccine.
4. Development of any new, unstable, or uncontrolled cardiovascular, pulmonary, 
hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, 
immunological, endocrine/metabolic, neurologic, oncologic, or other medical 
disorder during or after participation in a prior MLN0002 study that, in the 
opinion of the investigator, would confound the study results or compromise 
patient safety.
5. Withdrawal from a previous MLN0002 study due to a study-drug related AE.   
6. Active psychiatric or substance abuse problems that, in the investigator’s opinion, 
may interfere with compliance with the study procedures.
7. Unable to attend all the study visits or comply with study procedures.
5.3   Inclusion Criteria for De Novo Ulcerative Colitis Patients
Each de novo UC patient must meet all of the following inclusion criteria to be enrolled in 
the study:  
1. Age 18 to 80.
2. Male or female patient who is voluntarily able to give informed consent.
3. Female patients who:


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
Are postmenopausal for at least 1 year before the Screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed 
consent form through 18 weeks after the last dose of study drug, OR agree to 
completely abstain from heterosexual intercourse.
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study 
treatment period and through 18 weeks after the last dose of study drug, OR

Agree to completely abstain from heterosexual intercourse.
4. Diagnosis of ulcerative colitis established at least 3 months prior to enrollment
by clinical and endoscopic evidence and corroborated by a histopathology 
report.
5. Moderately to severely active ulcerative colitis as determined by a partial 
Mayo score of 3 to 9 within 7 days prior to the first dose of study drug  (see 
Section 15.1).
6. Evidence of ulcerative colitis extending proximal to the rectum (15 cm of 
involved colon).
7. Patients with extensive colitis or pancolitis of > 8 years duration or left-sided 
colitis of > 12 years duration must have documented evidence that a 
surveillance colonoscopy with random and targeted biopsies was performed 
within 18 months of the initial Screening visit (may be performed during 
screening).
8. Patients with a family history of colorectal cancer, personal history of 
increased colorectal cancer risk, age > 50 years, or other known risk factor 
must be up-to-date on colorectal cancer surveillance (may be performed during 
screening).
9. Demonstrated, over the previous 5-year period, an inadequate response to, loss 
of response to, or intolerance of at least 1 of the following agents as defined 
below:


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
Corticosteroids
o
Signs and symptoms of persistently active disease despite a history of at 
least one 4-week induction regimen that included a dose equivalent to 
prednisone 30 mg daily orally for 2 weeks or intravenously for 1 week OR
o
Two failed attempts to taper corticosteroids to below a dose equivalent to 
prednisone 10 mg daily orally OR
o
History of intolerance of corticosteroids (including, but not limited to  
Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, 
infection)

Immunomodulators
o
Signs and symptoms of persistently active disease despite a history of at 
least one 8-week regimen of oral azathioprine (≥1.5 mg/kg) or 
6-mercaptopurine mg/kg (≥0.75 mg/kg) OR
o
History of intolerance of at least 1 immunomodulator (including, but not 
limited to nausea/vomiting, abdominal pain, pancreatitis, LFT 
abnormalities, lymphopenia, TPMT genetic mutation, infection)

TNFantagonists
o
Signs and symptoms of persistently active disease despite a history of at 
least one 4-week induction regimen of infliximab 5 mg/kg IV, 2 doses at 
least 2 weeks apart OR
o
Recurrence of symptoms during maintenance dosing following prior 
clinical benefit (discontinuation despite clinical benefit does not qualify) 
OR
o
History of intolerance of infliximab (including, but not limited to 
infusion-related reaction, demyelination, congestive heart failure, 
infection)
10. May be receiving a therapeutic dose of the following drugs: 
a.
Oral or topical (rectal) 5-ASA compounds provided that the dose has been 
stable for the 2 weeks immediately prior to enrollment


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b. Oral corticosteroid therapy (prednisone at a stable dose 30 mg/day, or 
equivalent steroid) provided that the dose has been stable for the 4 weeks 
immediately prior to enrollment if corticosteroids have just been initiated, 
or for the 2 weeks immediately prior to enrollment if corticosteroids are 
being tapered
c.
Topical (rectal) corticosteroid enemas/suppositories 
d. Azathioprine or 6-mercaptopurine provided that the dose has been stable 
for the 8 weeks immediately prior to enrollment
e.
Antibiotics used for the treatment of IBD (ie, ciprofloxacin, 
metronidazole)
f.
Antidiarrheals (eg, loperamide, diphenoxylate with atropine) for control of 
chronic diarrhea
g. Probiotics (eg, Culturelle, S. boulardii) provided that the dose has been 
stable for the 2 weeks immediately prior to enrollment
5.4   Inclusion Criteria for De Novo Crohn’s Disease Patients
Each de novo CD patient must meet all of the following inclusion criteria to be enrolled in 
the study:
1. Age 18 to 80.
2. Male or female patient who is voluntarily able to give informed consent.
3. Female patients who:

Are postmenopausal for at least 1 year before the Screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed 
consent form through 18 weeks after the last dose of study drug, OR agree to 
completely abstain from heterosexual intercourse.
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study 


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treatment period and through 18 weeks after the last dose of study drug, OR

Agree to completely abstain from heterosexual intercourse.
4. Diagnosis of Crohn’s disease established at least 3 months prior to enrollment by 
clinical and endoscopic evidence and corroborated by a histopathology report.  
Cases of Crohn’s disease established at least 6 months prior to enrollment for 
which a histopathology report is not available will be considered based on the 
weight of the evidence supporting the diagnosis and excluding other potential 
diagnoses, and must be discussed with the sponsor on a case-by-case basis prior to 
enrollment.
5. Moderately to severely active Crohn’s disease as determined by an HBI score of 
8 to 18 (see Section 15.2) within 7 days prior to the first dose of study drug and
1 of the following:
a.
CRP level > 2.87 mg/L during the Screening period OR
b. Ileocolonoscopy with photographic documentation of a minimum of 
3 nonanastomotic ulcerations (each > 0.5 cm in diameter) or 10 aphthous 
ulcerations (involving a minimum of 10 contiguous cm of intestine) consistent 
with CD, within 4 months prior to randomization OR
c.
Fecal calprotectin 250 mcg/g stool during the Screening period in 
conjunction with CT enterography, MR enterography, contrast-enhanced small 
bowel radiography, or wireless capsule endoscopy revealing Crohn’s 
ulcerations (aphthae not sufficient), within 4 months prior to screening 
(patients with evidence of fixed stenosis or small bowel stenosis with 
prestenotic dilation should not be included).
6. CD involvement of the ileum and/or colon, at a minimum.
7. Patients with extensive colitis or pancolitis of > 8 years duration or limited colitis 
of > 12 years duration must have documented evidence that a surveillance 
colonoscopy with random and targeted biopsies was performed within 18 months 
of enrollment (may be performed during screening).
8. Patients with a family history of colorectal cancer, personal history of increased 
colorectal cancer risk, age > 50 years, or other known risk factor must be 
up-to-date on colorectal cancer surveillance (may be performed during screening).
9. Demonstrated, over the previous 5 year period, an inadequate response to, loss of 


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response to, or intolerance of at least 1of the following agents as defined below:

Corticosteroids
o
Signs and symptoms of persistently active disease despite a history of at 
least one 4-week induction regimen that included a dose equivalent to 
prednisone 30 mg daily orally for 2 weeks or intravenously for 1 week OR
o
Two failed attempts to taper corticosteroids to below a dose equivalent to 
prednisone 10 mg daily orally on 2 separate occasions OR
o
History of intolerance of corticosteroids (including, but not limited to  
Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, 
infection)

Immunomodulators
o
Signs and symptoms of persistently active disease despite a history of at 
least one 8-week regimen of oral azathioprine (≥1.5 mg/kg) or 
6-mercaptopurine (≥0.75 mg/kg) OR
o
Signs and symptoms of persistently active disease despite a history of at 
least one 8-week regimen of methotrexate (≥12.5 mg/week) OR
o
History of intolerance of at least 1 immunomodulator (including, but not 
limited to nausea/vomiting, abdominal pain, pancreatitis, LFT 
abnormalities, lymphopenia, TPMT genetic mutation, infection)

TNFantagonists
o
Signs and symptoms of persistently active disease despite a history of at 
least one 4-week induction regimen of 1 of the following agents:
Infliximab: 5 mg/kg IV, 2 doses at least 2 weeks apart
Adalimumab: one 80-mg SC dose followed by one 40-mg dose at least 
2 weeks apart
Certolizumab pegol: 400 mg SC, 2 doses at least 2 weeks apart OR


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o
Recurrence of symptoms during scheduled maintenance dosing following 
prior clinical benefit (discontinuation despite clinical benefit does not 
qualify) OR
o
History of intolerance of at least 1 TNF antagonist (including, but not 
limited to infusion-related reaction, demyelination, congestive heart 
failure, infection)
10. May be receiving a therapeutic dose of the following drugs: 
a.
Oral or topical (rectal) 5-ASA compounds provided that the dose has been 
stable for the 2 weeks immediately prior to enrollment
b. Oral corticosteroid therapy (prednisone at a stable dose 30 mg/day,
budesonide at a dose 9 mg/day, or equivalent steroid) provided that the 
dose has been stable for the 4 weeks immediately prior to enrollment if 
corticosteroids have just been initiated, or for the 2 weeks immediately 
prior to enrollment if corticosteroids are being tapered
c.
Topical (rectal) corticosteroid enemas/suppositories 
d. Azathioprine or 6-mercaptopurine provided that the dose has been stable 
for the 8 weeks immediately prior to enrollment
e.
Methotrexate provided that the dose has been stable for the 8 weeks 
immediately prior to enrollment  
f.
Antibiotics used for the treatment of IBD (ie, ciprofloxacin, 
metronidazole)
g. Antidiarrheals (eg, loperamide, diphenoxylate with atropine) for control of 
chronic diarrhea
h. Probiotics (eg, Culturelle, S. boulardii) provided that the dose has been 
stable for the 2 weeks immediately prior to enrollment
5.5   Exclusion Criteria for Ulcerative Colitis and Crohn’s Disease De Novo Patients
The exclusion criteria are divided into 3 categories:  gastrointestinal exclusion criteria, 
infectious disease exclusion criteria, and general exclusion criteria.  Patients meeting any of 
the following exclusion criteria are not to be enrolled in the study.


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5.5.1   
Gastrointestinal Exclusion Criteria for De Novo Patients
1. Evidence of abdominal abscess at the initial Screening visit
2. Extensive colonic resection, subtotal or total colectomy
3. History of > 3 small bowel resections or diagnosis of short bowel syndrome
4. Have received tube feeding, defined formula diets, or parenteral alimentation 
within 21 days prior to the administration of the first dose of study drug
5. Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine
6. Within 30 days prior to enrollment, have received any of the following for the 
treatment of underlying disease:
a.
Any investigational or approved nonbiologic therapy for IBD (eg, 
cyclosporine, thalidomide) other than those specifically listed in Section 6.2.1.
b. Adalimumab
7. Within 60 days prior to enrollment, have received any of the following:
a.
Infliximab
b. Certolizumab pegol 
c.
Any other investigational or approved biological agent, other than  local 
injections for non IBD conditions (eg intra-ocular injections for the treatment 
of wet macular degeneration)
8. Any prior exposure to natalizumab, efalizumab, or rituximab
9. Evidence of or treatment for C. difficile infection or other intestinal pathogen 
within 28 days prior to enrollment
10. Currently require or are anticipated to require surgical intervention during the 
study
11. History or evidence of adenomatous colonic polyps that have not been removed
12. History or evidence of colonic mucosal dysplasia
5.5.2   
Infectious Disease Exclusion Criteria for De Novo Patients
1. Chronic hepatitis B or C infection 


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2. Active or latent tuberculosis, regardless of treatment history, as evidenced by any 
of the following:
a.
History of tuberculosis
b.
A diagnostic TB test performed within 1 month of enrollment that is 
positive, as defined by:
i.
a positive QuantiFERONtest or 2 successive indeterminate 
QuantiFERONtests OR
ii.
a tuberculin skin test reaction 10 mm (5 mm in patients receiving 
the equivalent of > 15 mg/day prednisone).  
c.
Chest X-ray within 3 months of enrollment in which active or latent 
pulmonary tuberculosis cannot be excluded
3. Any identified congenital or acquired immunodeficiency (eg, common variable 
immunodeficiency, human immunodeficiency virus [HIV] infection, organ 
transplantation)
4. Any live vaccinations within 30 days prior to study drug administration except for 
the influenza vaccine
5. Clinically significant extra-intestinal infection (eg, pneumonia, pyelonephritis) 
within 30 days of the initial Screening visit
5.5.3   
General Exclusion Criteria for De Novo Patients
1. Previous exposure to MLN0002
2. Female patients who are lactating or have a positive serum pregnancy test during 
the Screening period or a positive urine pregnancy test on Day 1 prior to study 
drug administration.  
3. Any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, 
gastrointestinal, genitourinary, hematological, coagulation, immunological, 
endocrine/metabolic, or other medical disorder that, in the opinion of the 
investigator, would confound the study results or compromise patient safety
4. Had any surgical procedure requiring general anesthesia within 30 prior to 
enrollment or is planning to undergo major surgery during the study period
5. Any history of malignancy, except for the following:  (a) adequately-treated 
nonmetastatic basal cell skin cancer; (b) squamous cell skin cancer that has been 


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adequately treated and that has not recurred for at least 1 year prior to enrollment; 
and (c) history of cervical carcinoma in situ that has been adequately treated and 
that has not recurred for at least 3 years prior to enrollment.  Patients with remote 
history of malignancy (eg, > 10 years since completion of curative therapy 
without recurrence) will be considered based on the nature of the malignancy and 
the therapy received and must be discussed with the sponsor on a case-by-case 
basis prior to enrollment.
6. History of any major neurological disorders, including but not limited to stroke, 
multiple sclerosis, brain tumor, or neurodegenerative disease
7. Positive PML subjective symptom checklist prior to the administration of the first 
dose of study drug
8. Any of the following laboratory abnormalities during the Screening period:
a.
Hemoglobin level 8 g/dL
b. White blood cell (WBC) count 3 109/L
c.
Lymphocyte count 0.5 109/L
d. Platelet count 100 109/L or 1200 109/L
e.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
3 the upper limit of normal (ULN)
f.
Alkaline phosphatase 3 ULN
g. Serum creatinine 2 ULN
h. Albumin < 2.0 g/dL (< 20 g/L)
9. Current or recent history (within 1 year prior to enrollment) of alcohol 
dependence or illicit drug use
10. Active psychiatric problems that, in the investigator’s opinion, may interfere with 
compliance with the study procedures
11. Unable to attend all the study visits or comply with study procedures


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6.   
STUDY TREATMENT
6.1   Study Drug Administration
Vedolizumab (MLN0002) will be administered only to eligible patients under the 
supervision of the investigator or identified designee(s).  Female patients of childbearing 
potential must have a negative urine pregnancy test prior to receiving each dose.
The study pharmacist will obtain study drug kit assignments through the IVRS.  Study 
medication will be prepared according to the procedures outlined in the Pharmacy Manual.  
Patients will receive a 300 mg dose of MLN0002 by intravenous (IV) infusion over 
approximately 30 minutes.  Longer infusion times of up to 60 minutes may be used based on 
study observations.  All patients will be observed at the clinical site for at least 1 hour after 
the completion of each dose in a room where appropriate treatment for infusion-related 
reactions is available. The patient should be considered clinically stable by the investigator 
or designee prior to discharge.
Please also refer to the Pharmacy Manual for additional details, and to the following related 
sections of this protocol:

Section 6.7, Preparation, Reconstitution, and Dispensation

Section 6.8, Packaging and Labeling
6.2   Concomitant Procedures and Medications
All medications that are administered and all procedures that are performed during the study 
must be recorded in the patient’s electronic case report form (eCRF) and in the source 
documents.  Concomitant medications for medical conditions other than UC or CD are 
permitted as clinically indicated, subject to specific protocol requirements outlined in 
Section 6.2.1 and Section 6.2.2.  The oral corticosteroid dosing and tapering schedule is 
described in Section 6.2.3.
The following should be taken into account with regard to concomitant procedures:

Patients should be encouraged to avoid major elective surgery while 
enrolled in this study.

Patients may not donate blood, sperm, or oocytes during the study and for 
18 weeks after the last dose of study drug.


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
Patients with extensive colitis or pancolitis of > 8 years duration or 
limited colitis of > 12 years duration must have a surveillance 
colonoscopy with random and targeted biopsies within 18 months of their 
most recent prior examination, and every 18 months thereafter.

Colorectal cancer screening should also be kept current during the study 
for patients with a family history of colorectal cancer, personal history of 
increased colorectal cancer risk, age 50 years, or other known risk 
factors.  
6.2.1   
Permitted Medications for the Treatment of IBD
The following concomitant medications for the treatment of IBD are permitted:  

Oral and topical (rectal) 5-ASA treatment.

Oral corticosteroids are permitted under the guidelines described in 
Section 6.2.3.  

Topical (rectal) corticosteroid enemas/suppositories.

Azathioprine, 6-mercaptopurine, or methotrexate (methotrexate for CD 
only); stable doses of these medications are encouraged.

Antibiotics.

Antidiarrheals for control of chronic diarrhea.

Probiotics (eg, Culturelle, S. boulardii).  

Vedolizumab (Entyvio) will be allowed during the 16-week follow-up 
where clinically indicated.
6.2.2   
Excluded Medications
The following medications are excluded from the study:

Treatments for UC or CD other than those listed in Section 6.2.1 (either 
approved or investigational)

All live vaccines during study treatment and for at least 6 months after the 
last dose of study drug (except for live influenza vaccine)

Either approved or investigational biological agents for the treatment of 
non-IBD conditions, other than localized injections (eg, intra-ocular 
injections for wet macular degeneration) 
6.2.3   
Oral Corticosteroid Dosing and Tapering Regimen
The maximum dose of oral corticosteroid for the treatment of IBD that may be 
co-administered with MLN0002 as a long-term regimen is 30 mg/day prednisone (or 
equivalent), or 9 mg/day budesonide.  Short-term use of higher doses, or corticosteroids that 
are required for pre-infusion medication (to be given only on the day of infusion), is


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acceptable.  However, patients who require consistent doses higher than 30 mg/day 
prednisone (or equivalent) should be withdrawn from the study.  Cases in which the 
investigator believes the patient should stay on study must be discussed with the Medical 
Advisor or the Takeda Medical Monitor.   
It is strongly recommended that patients receiving oral corticosteroids should begin an oral 
corticosteroid tapering regimen once they either achieve clinical response or if, in the 
opinion of the investigator, they have demonstrated sufficient improvement.
The recommended tapering schedule is as follows:

For prednisone at doses > 10 mg/day (or equivalent), the dose should be 
reduced at a rate of 5 mg per week until a 10 mg/day dose is reached.

For prednisone at doses 10 mg/day (or equivalent) or once a 10 mg/day 
dose (or equivalent) is achieved by tapering, the dose should be reduced 
at a rate of 2.5 mg/week until discontinuation.

For budesonide, the dose should be tapered at a rate of 3 mg every 
3 weeks.
Investigators should strongly consider withdrawing patients who require recurrent 
corticosteroid courses with an inability to taper.  
6.3   Precautions and Restrictions
Female patients participating in MLN0002 clinical studies should avoid becoming pregnant 
and male subjects should avoid impregnating a female partner.  
Female patients of childbearing potential must practice 2 effective methods of contraception, 
at the same time, during from the time of signing the informed consent form through 18 
weeks after the last dose of study drug.  It is strongly recommended that at least 1 of these 2 
methods be highly effective (eg, oral, implantable or injectable contraceptives, contraceptive 
patches, intrauterine devices).  Female patients are exempt from contraception requirements 
if they are postmenopausal for at least 1 year before enrollment, are surgically sterile (ie, 
status post effective tubal ligation, or bilateral oophorectomy, or hysterectomy), or 
completely abstain from heterosexual intercourse.
Male patients, even if surgically sterilized (ie, status postvasectomy), must practice effective 
barrier contraception during the entire study treatment period and continue contraception for 
18 weeks after their last dose of study drug, or completely abstain from heterosexual 
intercourse.


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6.4   Management of Clinical Events
6.4.1   
Adverse Event Collection Involving Medically Anticipated Clinical Events 
(IBD)
UC and CD are associated with certain characteristic signs and symptoms including 
diarrhea, rectal bleeding, and abdominal pain that may be present at baseline and persist or 
fluctuate based on the individual patient’s disease history during the course of the study.  
These signs and symptoms are considered medically anticipated clinical events for the 
condition under study and will not be collected as adverse events.  These characteristics of 
disease activity will be regularly captured in either the partial Mayo score or the HBI and 
will be reviewed by the DSMB.  
Exacerbations of disease activity for UC (eg, increase in the daily amount of rectal bleeding 
beyond the patient’s normal fluctuation) or CD (eg, increase in the daily amount of 
abdominal pain beyond the patient’s normal fluctuation) will be collected as adverse events 
(AEs) and reported according to regulatory reporting requirements.
Extra-intestinal manifestations of the patient’s disease (eg, arthralgias, arthritis, uveitis) that 
develop or worsen during the study are considered AEs.  
6.4.2   
Infusion-Related Reactions
Currently, there is no evidence to support the routine prophylactic administration of 
premedication (eg, antihistamines, corticosteroids) to patients receiving MLN0002; hence,
such premedications are unlikely to be necessary or beneficial.  At the discretion of the 
investigator, however, patients may be administered premedication prior to any study drug 
infusion.  Corticosteroids, if given as premedication, should be limited to the day of 
infusion.  
Patients will be monitored for acute infusion-related reactions during infusion and for at 
least 1 hour after the completion of each administration of MLN0002.  Epinephrine and 
parenteral diphenhydramine must be readily available for immediate use in case an 
infusion-related reaction occurs.  Site personnel must be able to detect and treat 
infusion-related reactions.
Patients should be instructed to report the development of rash, hives, pruritus, flushing, 
urticaria, etc. that may represent an infusion-related reaction to MLN0002.  If any signs or 
symptoms of infusion-related reactions are observed during the infusion, administration of 


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MLN0002 must be immediately discontinued and the patient treated as medically 
appropriate.  In the case of a mild reaction, MLN0002 infusion may be reinitiated (with 
appropriate premedication) at the discretion of the investigator.  Patients with a severe or 
serious infusion-related reaction (eg, stridor, angioedema, life-threatening change in vital 
signs) must be withdrawn from the study.
In all cases of infusion-related reactions, the medical monitor must be informed as soon as is 
practical (see the Study Manual for contact information).  The disposition of patients with 
less severe infusion-related reactions should be discussed with the medical monitor.  All 
cases of infusion-related reactions that do not meet SAE definitions as specified in 
Section 10.1.2 will be collected as AEs.  The intensity, relationship to study medication, 
action taken and outcome for all cases of infusion-related reactions, regardless of 
seriousness, will be recorded on the AE eCRF.
6.4.3   
Leukopenia or Lymphopenia
Total WBC and lymphocyte counts will be regularly monitored for all patients.  
Azathioprine, 6-mercaptopurine, or methotrexate, if applicable, must be discontinued and 
the dose of MLN0002 held for an absolute lymphocyte count < 0.5 109/L at any point 
during the study. The absolute lymphocyte count must be repeated at appropriate intervals 
as determined by the investigator. The next dose of MLN0002 can be administered only
if the absolute lymphocyte count is ≥0.5 109/L. If the absolute lymphocyte count remains 
< 0.5 109/L for greater than 9 weeks, permission for the patient to continue on study must 
be obtained from the Takeda Medical Monitor.
6.4.4   
Infection
Patients will be monitored for signs and symptoms of infection and for lymphopenia during 
the study.  Patients with signs and symptoms suggestive of infection, including GI 
infections, will be treated as clinically indicated; interventions may include antibiotic 
treatment, if appropriate, and/or discontinuation of concomitant immunomodulatory 
medications.  Blood, sputum, urine, and/or stool cultures will be obtained as appropriate for 
detection and diagnosis of infection.  Withholding or terminating MLN0002 administration 
may be considered as described in Section 7.4.  Failure to respond to standard therapies for 
infection will be recorded as part of AE collection.  


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6.4.5   
Malignancy
All cases of malignancies that are detected during the study will be reported as AEs or SAEs 
as defined in Section 10.1.  Local medical practices will apply.  Monitoring for colorectal 
mucosal dysplasia and cancer will be performed during the study as described in 
Section 6.2.
6.4.6   
Hepatoxicity
Patients will be monitored throughout the study for evidence of hepatotoxicity with regular 
liver function tests and routine clinical assessments.
6.4.7   
Management of Positive Subjective PML Checklist
All patients will be screened for new neurological signs and symptoms potentially consistent 
with PML at frequent and regular intervals and ad hoc as appropriate using the PML 
subjective symptom checklist.  De novo patients with a positive subjective PML checklist at 
screening will not be enrolled.  Any patient with a positive subjective PML checklist at any 
time after enrollment will be evaluated according to the PML case evaluation algorithm as 
described in the Study Manual.  The next dose of MLN0002 will be held until the evaluation 
is completed and results are available.  Subsequent doses of MLN0002 will be administered 
only if the possibility of PML is definitively excluded, as described in the RAMP program 
(see Section 10.5).
6.4.8   
Unscheduled Visits Due to Disease Exacerbation
Patients who are experiencing symptoms of possible disease exacerbation need not wait 
until their next scheduled visit to be seen; they should be evaluated as deemed appropriate 
by the treating physician. Patients who are seen by the investigator or site staff at a time 
point not required by the protocol (ie, an unscheduled visit) due to disease exacerbation 
should undergo the following:  

Symptom-directed physical examination

Vital signs assessment

Patient assessment of disease activity

Recording of concomitant medications and procedures

Collection of AEs and SAEs

Clinical chemistry and hematology as indicated


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!
Stool sample, if indicated, may be obtained for culture, ova and parasite
evaluation, and C. difficile assay
!
Partial Mayo score or HBI score
!
HAHA sample collection
There is no minimum time for repeat evaluation by unscheduled visit. 
6.4.9   
Need for Rescue Medications
Administration of a new medication to treat a new or unresolved luminal manifestation of 
UC or CD, with the exclusion of 5-ASA agents (oral and topical/rectal), oral corticosteroids 
as outlined in Section 6.2.3, topical (rectal) corticosteroids, azathioprine/
6-mercaptopurine/methotrexate (methotrexate for CD only), antibiotics, antidiarrheals for 
control of chronic diarrhea, and probiotics, is considered a rescue medication, and 
constitutes long-term treatment failure (Section 6.4.10).  
Medications should not be withheld if, in the opinion of the investigator, failure to prescribe 
them could compromise patient safety.  Based on the clinical pharmacology of MLN0002 
and the potential for additive toxicities with other immunosuppressive drugs, serious 
consideration should be given to the administration (as rescue medications) of biologic 
agents or other therapies with a prolonged pharmacodynamic effect.
6.4.10   
Long-term Treatment Failure
As defined in the Study Definitions, there are 3 types of long-term treatment failure:  
(1) patients who require rescue medications (see Section 6.4.9); (2) patients who require 
major surgical intervention for the treatment of IBD; and (3) patients who have a study 
drug-related AE leading to discontinuation from the study.  Patients who meet the definition 
of long-term treatment failure must be withdrawn from the study (Section 7.4).  
6.5   Blinding and Unblinding
This is an open-label study, there is no blinding.  
6.6   Description of Investigational Agents
MLN0002 drug product is a lyophilized solid formulation at 60 mg/mL in a solution 
containing 
 histidine, 
 arginine, 
 sucrose,
 polysorbate 80, 
CCI
CCI
CCI
CCI
CCI


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Each vial will be reconstituted with sterile water for injection according to the instructions in 
the Pharmacy Manual.
6.7   Preparation, Reconstitution, and Dispensation
The investigational pharmacist will prepare the study treatment under standard aseptic 
conditions.  Each vial will be reconstituted according to the Pharmacy Manual with 4.8 mL 
sterile water for injection.  A 300 mg dose (5.0 mL), will be removed from each vial and 
diluted into 0.9% sodium chloride to an approximate volume of 250 mL.  Additional details 
on the preparation of MLN0002 are provided in the Pharmacy Manual.
Because MLN0002 is a biological protein and therefore subject to denaturation upon 
shaking, reconstituted vials and IV solution bags should not be shaken.  Vials are for 
single use administration.
6.8   Packaging and Labeling
MLN0002 will be supplied in 20 mL 
 glass vials with 20 mm 
 
 rubber stoppers and aluminum crimp seals with 
flip-top covers.  
The injection vials will be packaged into kits containing one 20 mL vial of active 
MLN0002.  Both the primary and secondary label information will fulfill all requirements 
specified by local governing regulations.  Additional details are provided in the Pharmacy 
Manual.
6.9   Storage, Handling, and Accountability
MLN0002 will be stored in a secure facility with controlled access.  MLN0002 must be 
stored refrigerated at 2,C to 8,C.  Additional storage and handling instructions are provided 
in the Pharmacy Manual.
6.10   
Other Protocol-Specified Materials
The following supplies will also be required for study treatment administration and are to be 
provided by the clinical study center:
!
Bottled sterile water for injection (for MLN0002 reconstitution)
!
250 mL 0.9% sodium chloride for injection in polyvinyl chloride (PVC)
IV bag(s) or 250 mL 0.9% sodium chloride in alternative IV bags or
bottles listed in the Pharmacy Manual
CCI
CCI
CCI


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
Polyvinyl chloride (PVC) infusion line or alternative infusion line listed 
in the Pharmacy Manual
7.   
STUDY CONDUCT
7.1   Study Personnel and Organizations
The contact information for the Takeda medical monitor, the central and any additional 
clinical laboratories, the IVRS provider and other vendors, the coordinating investigator for 
each member state/country, and the contract research organization (CRO) team can be found 
in the Study Manual.  A full list of investigators is available in the sponsor’s investigator 
database.
7.2   Arrangements for Recruitment of Patients
Most patients enrolling in this study will have participated in a previous qualifying 
MLN0002 study (rollover patients) as detailed in Section 4.1. The remainder (de novo 
patients) will be recruited from a subset of the same sites.
7.3   Study Procedures 
The study procedures are described below.  After Week 0, dosing visits must occur within 
1 week of the specified time.  It is anticipated that the total duration of MLN0002 treatment 
will vary on a patient-by-patient basis, based on continued benefit.  Patients who do not 
transition into the XAP study will return 16 weeks after the last dose of MLN0002 for final 
safety assessments at the Final Safety visit.  All patients will also complete the 2-year 
follow-up survey (see Section 7.6).  Patients who transition into the XAP study are not 
required to attend the Final Safety Visit.  The safety of these patients will be monitored as 
part of the XAP study.  The end-of-study eCRF page must be completed for all patients 
regardless of whether they transition into the XAP study or not.
7.3.1   
Informed Consent
Rollover patients will be required to sign and date an informed consent form prior to 
enrollment (Week 0), and de novo patient will be required to sign and date an informed 
consent form prior to performance of any study-related procedures.  During the consent 
process, patients will be made aware of the known and potential risks of MLN0002 
treatment (including the hypothetical risk of PML and how to recognize symptoms of 


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possible PML), and what to report to their health care professional.  All patients will be 
given an opportunity to ask questions.  Patients will be given written information about PML 
to take home and read prior to their return at Week 0.
7.3.2   
Wallet Card
A wallet card specifically for this study that denotes key study information, including signs 
and symptoms of PML, will be distributed prior to Week 0.
7.3.3   
Demographics
Demographics information will be obtained from the MLN0002 study in which the patient 
previously participated (rollover patients) or during the Screening period (de novo patients).
7.3.4   
Tobacco Use
Tobacco use information will be obtained from the MLN0002 study in which the patient 
previously participated (rollover patients) or during the Screening period (de novo patients).
7.3.5   
Medical History
Medical history information will be obtained from the MLN0002 study in which the patient 
previously participated (rollover patients) or during the Screening period (de novo patients).
7.3.6   
Prior Therapies
Information regarding prior therapies for UC or CD will be obtained from the MLN0002 
study in which the patient previously participated (rollover patients) or during the Screening 
period (de novo patients).
7.3.7   
Disease History
UC or CD history information will be obtained from the MLN0002 study in which the 
patient previously participated (rollover patients) or during the Screening period (de novo 
patients).
7.3.8   
Physical Examination
A physical examination, which will include assessments of general appearance, skin, head 
(eyes, ears, nose, and throat), neck, lungs, heart, abdomen, back, lymph nodes, extremities, 


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and neurologic system, will be conducted at the study visits specified in the Schedule of 
Events.  A symptom-directed physical examination will be performed at any unscheduled 
visit(s) due to disease exacerbation.
Any clinically significant findings on the physical examination will be recorded as AEs.
7.3.9   
Neurological Examination
A neurological examination will be performed at the study visits specified in the Schedule of 
Events.  The neurological examination should be performed by the principal investigator or 
subinvestigator and will include assessments of cranial nerves, motor and sensory function, 
coordination, and mental status.
Any new clinically significant findings on the neurological examination will be recorded as 
AEs.  
7.3.10   
Vital Signs and Weight
Vital signs, including heart rate, respiratory rate, systolic and diastolic blood pressure, and 
temperature, will be obtained at screening (for de novo patients) and at every study visit, 
including any unscheduled visit(s) due to disease exacerbation.  On dosing days, vital signs 
will be obtained prior to dosing.  
Weight (in kg) will be recorded at screening (for de novo patients) as specified in the 
Schedule of Events.  On dosing days, weight will be recorded prior to dosing.
7.3.11   
Progressive Multifocal Leukoencephalopathy (PML) Checklist
The subjective PML symptom checklist will be administered at every study visit to probe for 
symptoms suggestive of PML.  On dosing days, the PML symptom checklist will be 
administered prior to dosing.  De novo patients with a positive subjective checklist during 
the Screening period will not be enrolled. Any patients reporting or exhibiting suspicious 
signs and/or symptoms of PML will undergo objective testing and may be referred to a 
neurologist for a full evaluation, as described in the RAMP algorithm.  The PML checklist
and the RAMP algorithm and tools are included in the Study Manual.  See Section 10.5 for 
additional details regarding RAMP program.


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7.3.12   
Patient Assessment of Disease Activity
The patient will be asked to report on components (ie, disease activity) of the partial Mayo 
score or HBI score at the study visits specified in the Schedule of Events.  On dosing days, 
these reports must be collected prior to dosing.  
7.3.13   
Concomitant Medications and Procedures
Any medications that are ongoing at the time of enrollment into the C13008 study will be 
recorded in the eCRF for Study C13008.  Concomitant medications and procedures must be 
reviewed at each study visit (including any unscheduled visit(s) due to disease exacerbation) 
and recorded in the eCRF.  For patients enrolling into the XAP study, concomitant 
medications will be collected until the patient is consented into the XAP study (this is 
expected to occur at the final C13008 dosing visit where possible).    
7.3.14   
Enrollment
Enrollment in this study is defined as the time the patient is entered into the IVRS at 
Week 0.
7.3.15   
Dosing
MLN0002 will be administered as described in Section 6.1 at the study visits specified in the 
Schedule of Events.  Female patients of childbearing potential must have a negative urine 
pregnancy test confirmed prior to receiving each dose of MLN0002.
7.3.16   
Partial Mayo Score 
A partial Mayo score will be evaluated for patients with UC at the study visits specified in 
the Schedule of Events.  On dosing days, the partial Mayo score will be evaluated prior to 
dosing.
7.3.17   
Harvey-Bradshaw Index (HBI) Score 
An HBI score will be evaluated for patients with CD at the study visits specified in the 
Schedule of Events.  On dosing days, data used to derive the HBI score (ie, clinical 
symptoms and physical exam findings) will be collected prior to dosing.  


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7.3.18   
Inflammatory Bowel Disease Questionnaire (IBDQ)
The IBDQ will be completed at the study visits specified in the Schedule of Events.
7.3.19   
Short Form-36 (SF-36)
The SF-36 will be completed at the study visits specified in the Schedule of Events.
7.3.20   
EuroQual (EQ-5D)
The EQ-5D will be completed at the study visits specified in the Schedule of Events.
7.3.21   
12-Lead ECG
A single 12-lead ECG will be obtained at screening for de novo patients and prior to dosing 
annually for the first 4 years of the study (as specified in the Schedule of Events) and at the 
Final Safety visit for all patients.
Patients will be supine and will have rested for 2 or more minutes before any ECG is 
recorded.  During the course of the study, ECGs will be reviewed by the investigational 
sites.  Any findings from ECGs collected after MLN0002 administration at Week 0 will be 
captured as AEs if, in the opinion of the investigator, there has been a clinically significant 
change from baseline.
7.3.22   
Tuberculosis Screening and Chest X-ray
All de novo patients will complete TB screening to determine eligibility.  All de novo 
patients who do not report a history of TB must complete a diagnostic TB test within 
1 month prior to enrollment and a chest X-ray within 3 months prior to enrollment.  Patients 
will be excluded from the study if they have active or latent TB, regardless of treatment 
history, as evidenced by any of the following:

History of TB

A diagnostic TB test within 1 month of enrollment that is positive, as defined by:
o
A positive QuantiFERON® test or 2 successive indeterminate 
QuantiFERON® tests OR


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o
A tuberculin skin test reaction 10 mm (5 mm in patients receiving the 
equivalent of > 15 mg/day prednisone)

Chest X-ray within 3 months of enrollment in which active or latent pulmonary 
TB cannot be excluded.  
7.3.23   
Collection of Adverse Events and Serious Adverse Events
For rollover patients, AEs and SAEs will be collected from the time the patient enrolls in the 
study through the Final Safety visit in Study C13008 (16 weeks after the last dose of 
MLN0002), as applicable.
For de novo patients, AEs will be collected from the time of enrollment, and SAEs will be 
collected from the time of signing informed consent; as with rollover patients, AEs and 
SAEs will be collected through the Final Safety visit (16 weeks after the last dose of 
MLN0002), as applicable.
For patients enrolling into the XAP study, AEs and SAEs will be collected until the patient 
is consented into the XAP study (this is expected to occur at the final C13008 dosing visit 
where possible).SAEs that occur after the end of study and are considered to be related to 
MLN0002 will be collected and forwarded to Takeda Pharmacovigilance (see Section 10.2).  
Definitions, documentation, and reporting of SAEs are described in detail in Section 10.  
7.3.24   
Sample Collection
Blood or urine samples will be obtained for the following assessments.  On dosing days, 
samples will be collected prior to dosing.  Any clinically relevant deterioration in laboratory 
assessments or other clinical finding is considered an adverse event and, if this AE leads to 
discontinuation of MLN0002, it must be recorded on the AE eCRF.
Pregnancy Testing
A serum pregnancy test will be performed at screening for all females enrolling de novo, 
and at the Final Safety visit for all females of childbearing potential.  A urine pregnancy test 
will be completed for all females of childbearing potential prior to each dose.


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Clinical Chemistry, Hematology, Coagulation, and Urinalysis
Clinical laboratory evaluations will be performed centrally.  Handling and shipment of 
clinical laboratory samples will be outlined in the Study Manual.  Clinical laboratory 
evaluations will be performed as outlined below:
Blood samples for clinical chemistry assessments, hematology assessments, and coagulation 
assessments, and urine samples for urinalysis will be collected at the study visits specified in 
the Schedule of Events.  
Blood samples for analysis of the following clinical chemistry, hematological, and 
coagulation parameters and urine samples for the following urinalysis tests will be obtained:
Clinical Chemistry

Albumin

Calcium

Phosphorus

Alkaline phosphatase 

Chloride

Potassium

ALT and AST

Creatinine

Sodium

Amylase 

Glucose

Total and direct bilirubin

Bicarbonate 

Lipase

Total protein

Blood urea nitrogen (BUN)

Magnesium

Uric acid
Hematology

Basophils 

Lymphocytes

Platelets

Eosinophils 

Monocytes

Red blood cells (RBCs)

Hemoglobin/hematocrit 

Neutrophils

WBCs 
Coagulation
PT

PTT
Urinalysis 
Bilirubin 

Leukocyte esterase 

Specific gravity 
Blood 

Nitrite

Microscopic (to be obtained in 
the event of positive leukocyte 
esterase or blood, will include 
WBCs, RBCs, and cast[s])
Glucose

pH 
Ketones

Protein 


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Hepatitis B, Hepatitis C, and HIV Screening
Screening for hepatitis B surface antigen, hepatitis C antibody, and human 
immunodeficiency virus (using an ELISA) will be performed during screening.
C-Reactive Protein Assessment
CRP levels will be measured at the study visits specified in the Schedule of Events.  The 
sample for CRP will be obtained from the blood drawn for the clinical chemistry 
assessments.
HAHA Assessment
Human anti-human antibody (HAHA) assessments will be performed at the study visits 
specified in the Schedule of Events.  Blood samples for HAHA assessments will be obtained 
prior to dosing, if applicable.  A blood sample for HAHA assessment will also be collected 
at any unscheduled visit(s) due to disease exacerbation, at any time during the visit. 
Neutralizing HAHA assessments may be performed for HAHA-positive samples.  Drug 
concentration may be determined as part of the HAHA testing.
Stool Sample
A stool sample for culture, ova and parasite evaluation, and C. difficile assay will be 
obtained (if indicated) at any point during the study when a patient becomes symptomatic, 
including worsening or return of disease activity.  
Fecal Calprotectin
For the de novo patients, a stool sample will be collected during screening for the analysis of 
fecal calprotectin, a biomarker of intestinal inflammatory activity.  Fecal calprotectin will 
only be analyzed if necessary for eligibility requirements.
7.4   Withdrawal of Patients From Study
Patients who meet the criteria for long-term treatment failure (Study Definitions) or who, in 
the opinion of the investigator or patient, are not benefiting from therapy must be withdrawn 
from the study. 
Investigators should strongly consider withdrawing patients who require recurrent 
corticosteroid courses with an inability to taper.  


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Patients who withdraw early will return 16 weeks after the last dose of MLN0002 for final 
safety assessments at the Final Safety visit.  The reason(s) for discontinuation from study 
treatment is/are listed below and is/are to be recorded in the source documents and on the 
eCRF.

Adverse event

Withdrawal by patient

Study terminated by sponsor

Protocol violation(s)

Lost to follow-up 

Lack of efficacy 
Patients who withdraw or are withdrawn from the study will participate in a 2-year 
follow-up survey, as discussed in Section 7.6.  Patients who withdraw or are withdrawn 
from the study will not be replaced.  
7.5   Study Compliance
A drug dispensing log, including records of drug received from the sponsor and drug 
dispensed to the patients, will be maintained at the study site.  A drug calculation and 
reconstitution worksheet, which details specific volumes used for MLN0002 reconstitution, 
will be completed for each MLN0002 administration and initialed by the pharmacy 
technician and/or investigational pharmacist or qualified site personnel.
7.6  Post End of Study
Upon completion of or early termination from this study, patients will participate in a 2-year 
follow-up survey.  A specific questionnaire will be administered via telephone at 6, 12, 18, 
and 24 months after the final dose of study drug.  The questionnaire will collect data on 
events such as pregnancy and infections resulting in hospitalization (6-month telephone call 
only), colorectal dysplasia or cancer, IBD-related surgeries, and the development of PML.  


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8.   
STATISTICAL AND QUANTITATIVE ANALYSES
8.1   Determination of Sample Size
This is a phase 3 study to determine the long-term safety of MLN0002 in patients with UC 
and CD.  Most patients enrolled in this study will have participated in a previous qualifying 
MLN0002 study as detailed in Section 4.1 (rollover patients).  Up to 400 additional patients 
who have not been previously treated with MLN0002 may be enrolled (de novo patients) to 
supplement the safety database. The current estimate is that approximately 2200 patients 
total will enter this study.
8.2   Randomization and Stratification
No randomization or stratification is planned for this study.
8.3   Populations for Analysis
There are 2 patient populations in this study for data analyses:  the efficacy population and 
the safety population.  
Efficacy Population
The efficacy population consists of all enrolled patients.  However, to be included in an 
analysis at any specific time point, the patient must have had a postbaseline measurement for 
the time point.  Additionally, to be included in a change from baseline analysis, the patient 
must have had a baseline measurement.
This population will be used for all exploratory efficacy analyses.  
Safety Population
The safety population for this study is defined as all patients who receive any amount of 
MLN0002 in this study.  The study safety population will be used for all safety analyses.  
8.4   Procedures for Handling Missing, Unused, and Spurious Data
All available safety and efficacy data will be included in data listings and tabulations.  No 
imputation of values for missing data will be performed.  Data that are potentially spurious 
or erroneous will be examined under the auspices of standard data management operating 
procedures.


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8.5   General Methodology
Summary tabulations will be presented and will display the number of observations, mean, 
standard deviation, median, minimum, and maximum for continuous variables, and the 
number and percent per category for categorical data.  Statistical analyses will be primarily 
descriptive in nature.  No formal statistical tests will be performed.
A formal statistical analysis plan will be developed and finalized prior to the completion of 
the study.  This plan will define the populations for analysis, outline the data handling 
conventions, and specify the statistical methods to be used for safety and exploratory 
efficacy analyses.
8.6   Baseline Comparisons
Demographic and baseline characteristics will be summarized using frequency distributions 
and summary statistics.  
8.7   Safety Analyses
Safety evaluations will be based on incidence, severity and type of AEs, PML checklist 
responses, vital signs, laboratory results and ECGs.  Descriptive statistics will be calculated.  
In addition to overall safety summary, subgroup analyses will be performed:  1) by UC 
patient population and CD patient population; and 2) by concomitant medication.  
Treatment emergent AEs (TEAEs) will be tabulated by primary system organ class (SOC), 
high level term (HLT), and preferred term.  The Medical Dictionary for Regulatory 
Activities (MedDRA) will be used for coding AEs.  To summarize the number of patients 
with AEs, patients reporting the same event more than once will have that event counted 
only once within each SOC, HLT, and preferred term.  Events that are considered related to 
treatment will also be tabulated.  AEs will also be summarized by intensity.  Death, patients 
with SAEs, and events resulting in study discontinuation, if present, will be presented in 
separate data listings.
The distribution of HAHA across time will be summarized.  Whether HAHA is neutralizing 
may be determined.  Furthermore, the results from HAHA and neutralizing HAHA may be 
used to evaluate the relationships among HAHA and efficacy and safety.


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Comprehensive Safety Assessment 
Safety data from this study will be reviewed using data including, but not limited to, the 
following:
a.
Data from both the active and the placebo arms of C13006, C13007 and C13011.
b. Data from the 2-year follow-up survey after the final dose of study drug in C13006, 
C13007, and C13011 (for patients who did not enroll in this Long-term Safety 
Study).
c.
Data from an external administrative database, which includes a broad representation 
of patients on various therapies for IBD (including biological agents).  This database 
will provide an understanding of the background rates of selected events, such as 
IBD-related surgeries and hospitalizations that may occur with current therapies for 
IBD.  Additionally, to allow comparison to Study C13008, a sub population of 
patients who have characteristics similar to those in Study C13008 will be selected 
from this database.  This will allow for some comparison to similar patients who may 
be on conventional treatment for IBD, including treatment with biological agents.  
Patients who previously participated in the phase 2, open-label, long-term safety study 
(Study C13004) will not be part of the integrated safety analysis for C13008.  Data from all 
patients who previously participated in Study C13004 will be analyzed separately.
Details for the condition and methods of comparison will be discussed in the statistical 
analysis plan.  
8.8   Resource Utilization and Patient Reported Outcomes
Changes in health-related quality of life over time will be assessed using IBDQ, SF-36 and 
EQ-5D scores.  Change from baseline in IBDQ, SF-36 and in EQ-5D will be calculated and 
95% confidence intervals will be provided.  For these quality of life assessments, the 
baseline value will be the last measurement from the previous study as applicable (ie, Study 
C13004, Study C13006, Study C13007, or Study C13011) or the measurement obtained 
during the Screening period for de novo patients.  The proportion of patients who fall into 
different categories in IBDQ, SF-36, and EQ-5D scores will be summarized and 95% 
confidence intervals will be provided.


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Time to major IBD-related events (hospitalizations, surgeries and procedures) will be 
analyzed and 95% confidence intervals will be provided.  
8.9   Exploratory (Efficacy) Analyses
This long-term safety study is not sized based on power considerations.  Thus, no formal 
statistical hypothesis testing is to be performed.  Furthermore, the lack of a true control arm 
for comparison purposes limits the use of any formal statistical comparisons that may be 
made.  Therefore, the primary statistical focus for the efficacy analyses will be on 
descriptive tabulation of efficacy endpoints rather than on formal analysis of the clinical 
data.  Descriptive statistics, including 95% confidence intervals, will be provided for all 
clinical efficacy variables of interest.  
Descriptive statistics will be used in analyses of partial Mayo score (patients with UC) or 
HBI score (patients with CD), IBDQ score, and SF-36 score.  
The change from baseline in CRP level, partial Mayo score or HBI score, and IBDQ score 
will be summarized by time point, and the means will be plotted over time.  The percentage
of patients with a clinical response and with clinical remission will be tabulated at each time 
point.  For patients who were not in clinical response or clinical remission at the beginning 
of the study, the percentage of patients who demonstrate an initial clinical response and go 
on to maintain a sustained clinical response or clinical remission will be tabulated at each 
time point.  
For definitions of clinical response and clinical remission, refer to the study definitions
Study Definitions.  Further details on the statistical analyses, including exploratory 
evaluations, any sensitivity analyses and data handling details regarding issues such as 
missing data, will be discussed in the statistical analysis plan.  
8.10   
Interim Analysis
Interim analyses and reports will be done periodically during the conduct of the study to 
support regulatory filings and updates.  


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9.   
STUDY COMMITTEES
9.1   Data Safety Monitoring Board
A data safety monitoring board (DSMB), independent from the sponsor, will be established 
to review safety data from this study including, but not limited to, AEs of special interest 
(eg, infusion-related reactions, infections) on a regular basis and to make appropriate 
recommendations.  With agreement of the DSMB and Takeda, the schedule may be 
modified based on the rate of patient accrual and findings from reviews.  A detailed charter 
outlines all activities of the DSMB (eg, type of data reviewed, frequency of meetings, 
location of meetings).  
The safety analyses will be generated for the DSMB by an independent statistician.  
New neurological signs and symptoms potentially consistent with PML will be reviewed 
and adjudicated by the IAC per the RAMP algorithm (see Section 9.2).
9.2   Progressive Multifocal Leukoencephalopathy (PML) Independent Adjudication 
Committee
Takeda’s RAMP program includes an independent adjudication committee (IAC) consisting 
of a panel of leading PML experts, including a neurologist, a neuroradiologist, and a 
virologist.  The RAMP PML evaluation algorithm describes the involvement of the IAC.  
Descriptions of the RAMP program and the IAC are in the Study Manual.  The processes for 
IAC case review are defined in the IAC Charter.  IAC proceedings and recommendations
will be promptly communicated to the DSMB.  
9.3   Publications Committee
A publications committee will be convened, details of which will be provided in a 
publications committee charter.  Additional details on the use of information are provided in 
Section 12.


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10.   
ADVERSE EVENTS
10.1   
Definitions
10.1.1   
Adverse Event Definition
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with the 
treatment.  An AE can be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the study 
drug, whether or not it is considered to be study drug related.  This includes any newly 
occurring event or previous condition that has increased in severity or frequency since the 
administration of study drug.
Refer to Section 6.4.1 for additional details regarding clinical events related to IBD.
10.1.2   
Serious Adverse Event Definition
A serious adverse event (SAE) is any AE, occurring at any dose and regardless of causality 
that:

Results in death

Is life-threatening.  Life-threatening means that the patient was at 
immediate risk of death from the reaction as it occurred, ie, it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more severe form.

Requires inpatient hospitalization or prolongation of existing 
hospitalization (see Section 10.2)

Results in persistent or significant disability/incapacity.  Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions.

Is a congenital anomaly/birth defect


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
Is an important medical event.  An important medical event is an event 
that may not result in death, be life-threatening, or require hospitalization 
but may be considered an SAE when, based upon appropriate medical 
judgment, it may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in the 
definitions for SAEs or involves suspected transmission via a medicinal 
product of an infectious agent.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug 
abuse; any organism, virus, or infectious particle (eg, prion protein 
transmitting Transmissible Spongiform Encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.

Additionally, in this study, any diagnosis of PML will be considered an 
SAE.
Clarification should be made between the terms “serious” and “severe” because they ARE 
NOT synonymous.  The term “severe” is often used to describe the intensity (severity) of a 
specific event (as in mild, moderate, or severe myocardial infarction); the event itself, 
however, may be of relatively minor medical significance (such as a severe headache).  This 
is NOT the same as “serious,” which is based on patient/event outcome or action criteria 
described above and are usually associated with events that pose a threat to a patient’s life or 
functioning.  A severe adverse event does not necessarily need to be considered serious.  For 
example, persistent nausea of several hours duration may be considered severe nausea but 
not an SAE.  On the other hand, a stroke resulting in only a minor degree of disability may 
be considered mild, but would be defined as an SAE based on the above noted criteria.  
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.
10.2   
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events 
All AEs spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination or other diagnostic 
procedures will be recorded on the appropriate page of the eCRF.  Any clinically relevant 
deterioration in laboratory assessments or other clinical finding is considered an adverse 
event and must be recorded on the appropriate pages of the eCRF.  When possible, signs and 
symptoms indicating a common underlying pathology should be noted as 1 comprehensive 
event.
All SAEs that occur during the course of the study, as defined in Section 10.1, must be 
reported by the investigator Takeda Pharmacovigilance, (contact information provided 
below) by faxing the SAE Form within 1 working day after becoming aware of the event.  


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All SAEs and deaths must be reported whether or not considered causally related to the 
study drug.  The SAE Form, created specifically by Takeda, will be provided to each clinical 
study site.  A sample of the SAE Form may be found in the Study Manual.  Follow-up 
information on the SAE may be requested by Takeda.  SAE report information must match 
the data provided on the eCRF.  
SAE Reporting Contact Information
Takeda Pharmacovigilance 
Fax:  +1 224-554-1052 (North and South America)
Email: TakedaEntyvioCases@cognizant.com (All countries)
Planned hospital admissions or surgical procedures for an illness or disease which existed 
before the patient was enrolled in the trial or before study drug was given are not to be 
considered AEs unless the condition deteriorated in an unexpected manner during the trial.
Hospital admissions related to a protocol-required procedure (eg, admissions for 
patient/clinic convenience prior to or following colonoscopy or infusion) will not be 
considered AEs.
Additionally, any diagnoses of PML will be reported as SAEs.
For both SAEs and AEs, the investigator must determine both the intensity of the event and 
the relationship of the event to MLN0002 administration.
Intensity for each AE, including any laboratory abnormality, will be defined according to the 
following criteria:
Mild
Awareness of sign or symptom, but easily tolerated
Moderate Discomfort enough to cause interference with normal daily activities
Severe
Inability to perform normal daily activities
Relationship to MLN0002 administration will be determined by the investigator responding 
yes or no to the question:  Is there a reasonable possibility that the AE was associated with 
the study drug?


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10.3   
Monitoring of Adverse Events and Period of Observation
All AEs and SAEs will be collected from the time of enrollment (for de novo patients, SAE 
collection will begin after the signing of informed consent) up to 16 weeks (112 days) after 
the last on-study dose of MLN0002 (as applicable).  For patients enrolling into the XAP 
study, AEs and SAEs will be collected until the patient is consented into the XAP study (this 
is expected to occur at the final C13008 dosing visit where possible).  All SAEs should be 
monitored until they are resolved or are clearly determined to be due to a patient’s stable or 
chronic condition or intercurrent illness(es).
Any SAE that occurs at any time after completion of the study period that the investigator 
considers to be related to study drug must be reported to Takeda Pharmacovigilance.
10.4   
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects she is pregnant while participating in this study, 
or within 18 weeks after the last dose of study drug, she must inform the investigator 
immediately and permanently discontinue study drug.  The sponsor must also be contacted 
immediately by faxing a completed Pregnancy Form to Takeda Pharmacovigilance (see 
Section 10.2).  The pregnancy must be followed through for the final pregnancy outcome.
If a female partner of a male study participant becomes pregnant during the male patient’s 
participation in this study, or within 18 weeks after the last dose of study drug, the sponsor 
must also be contacted immediately by faxing a completed Pregnancy Form to Takeda 
Pharmacovigilance.  Every effort should be made to follow the pregnancy for the final 
pregnancy outcome.
10.5   
Risk Management
Risk minimization, management, and assessment procedures have been implemented in the 
study to minimize and assess potential risks to patients who participate in clinical studies of 
MLN0002.  Components include:  (1) specific study entry and exclusion criteria to ensure 
that patients who have underlying characteristics that potentially increase their risk for an 
adverse outcome are excluded; (2) protocol-specific procedures for minimizing and 
managing certain AEs, such as infusion-related reactions and infections; (3) overview 
surveillance by 2 independent safety committees (DSMB and IAC; see Section 9.1 and 
Section 9.2, respectively); (4) a dedicated Risk Minimization Action Plan for PML (the 
RAMP, see Section 10.5.3) that educates staff and patients on PML and includes an 


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algorithm for early detection and evaluation of signs and symptoms suggestive of PML; and 
(5) long-term, poststudy follow-up (2 years) safety assessment.  Specific components are 
described below, in Section 6.4 and Section 7.6, and in the Study Manual.
10.5.1   
Specific Risk Assessment and Minimization Procedures for Identified Risk 
Associated With MLN0002 Treatment:  Infusion-Related Reaction
Site personnel will be trained in rapid detection and standard treatment of infusion-related 
reactions.  Management of infusion-related reactions is detailed in Section 6.4.2.  
Immunogenicity
Based on existing data from clinical studies with vedolizumab, there is the possibility of 
developing HAHA to vedolizumab that may cause infusion-related reactions, other 
nonspecific AEs, and/or reduced efficacy.  Patients will be monitored for AEs and treated as 
clinically appropriate.
10.5.2   
Specific Risk Assessment and Minimization Procedures for Potential Risk of 
MLN0002 Treatment: Increased Rates of Infections
Patients who have an increased risk of infection (eg, serious comorbidity, immune system 
dysfunction) will be excluded from the study.  Patients on study will be monitored for signs 
and symptoms of infection and for lymphopenia.  Patients with signs and symptoms 
suggestive of infection will be treated as clinically indicated; interventions may include 
antibiotic treatment, if appropriate, and/or discontinuation of concomitant 
immunomodulatory medications.  Blood, sputum, urine, and/or stool cultures will be 
obtained as appropriate for detection and diagnosis of infection.  Withholding or terminating 
study drug administration may be considered, as appropriate.  Management of infection is 
described in Section 6.4.4.
10.5.3   
Specific Risk Assessment and Minimization Procedures for Hypothetical 
Risks of MLN0002 Treatment (Not Observed to Date)
Gastrointestinal Infections
The hypothetical risk that MLN0002 may increase GI infections will be addressed as 
detailed above (Section 10.5.2) for the potential risk of increased rates of infections.


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Progressive Multifocal Leukoencephalopathy
The cases of PML reported in patients being treated with the pan-4 integrin antagonist 
natalizumab (Tysabri®) have focused safety concerns on integrin antagonists.  The 
immunomodulatory mechanism of vedolizumab, as a selective 47 integrin antagonist, may 
not predispose patients to an increased risk of PML.  Nevertheless, all ongoing vedolizumab 
clinical studies will use the RAMP program as a Risk Minimization Action Plan for PML.  
The RAMP program minimizes the risk of PML by focusing on early clinical detection and 
management of PML, including discontinuation of study drug, if applicable.  An 
independent adjudication committee (IAC) has been established as part of the RAMP 
program to review possible cases of PML and will provide input regarding patient 
evaluation and management as defined in the IAC charter.  Additional details of the RAMP 
program are in the Study Manual.  Plasmapheresis and mefloquine have been reported as 
potentially efficacious treatments for natalizumab-associated PML.(25, 26, 27, 28, 29, 30)
Patients are assessed for signs and symptoms of PML before the administration of each dose 
of study drug using a PML subjective symptom checklist.  Patients with a positive PML 
subjective symptom checklist at any time after enrollment in an MLN0002 clinical study 
will be evaluated according to a prespecified algorithm (the PML Case Evaluation 
Algorithm, provided in the Study Manual).  The next dose of study drug will be held until 
the evaluation is complete and results are available.  Subsequent doses of study drug will be 
administered only if the possibility of PML is definitively excluded, as described in the 
RAMP algorithm. The IAC will review new neurological signs and symptoms potentially 
consistent with PML and will provide input regarding patient evaluation and management as 
defined in the IAC charter.  
To ensure the success of the RAMP program, site personnel will be trained to recognize the 
features of PML, and patients will be trained to report specific neurological signs and 
symptoms without delay.  Educational materials for teaching site personnel and patients 
about PML and the RAMP procedures will be distributed to all sites.  Formal teaching and 
training will be performed for site personnel before the start of the study.  Patients will 
receive training and educational materials before enrollment.  The ICF will contain specific
information on the hypothetical risk of PML.
The PML IAC will be informed of all new neurological signs and symptoms potentially 
consistent with PML per the PML Case Evaluation Algorithm and will review the individual 
patient data.  The algorithm and tools are included in the Study Manual.


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All documented cases of PML will be reported as SAEs, regardless of whether 
hospitalization occurs.
Malignancy
Patients with a history of malignancy (except for specific cancers) or at increased risk for 
malignancy (eg, patients with identified established immunodeficiencies or colonic mucosal 
dysplasia) will be excluded from this study (see Section 5.2).  It is expected that patients 
enrolled in the study will be up-to-date on colorectal cancer screening. 
10.5.4   
Risk Assessment
For patients who do not enroll in Study C13008, the risk assessment part of this study will 
include a 2-year follow-up survey after the last dose of study drug, as described in 
Section 7.6, to determine if any patients have been diagnosed with PML or malignancy, or 
have had bowel surgeries.


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11.   
ADMINISTRATIVE REQUIREMENTS
11.1   
Good Clinical Practice
The study will be conducted in accordance with the ICH Guideline for GCP and the 
appropriate regulatory requirement(s).  The investigator will be thoroughly familiar with the 
appropriate use of MLN0002 as described in the protocol and the IB.
11.2   
Data Quality Assurance
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
patient.  Study data will be entered into an eCRF by site personnel using a secure, validated 
web-based electronic data capture (EDC) application.  Takeda will have access to all data 
upon entry in the EDC application.
Study monitors will discuss instances of missing or uninterpretable data with the 
investigator for resolution.  Any changes to study data will be made to the eCRF and 
documented via an electronic audit trail associated with the affected eCRF.
11.3   
Electronic Case Report Form Completion 
Takeda or designee will provide the study sites with secure access to and training on the 
EDC application, sufficient to permit site personnel to enter or correct information in the 
eCRFs for the patients for which they are responsible.
eCRFs will be completed for each study patient.  It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the 
patient’s eCRF.
The investigator, or designated representative, should complete the eCRF as soon as 
possible after information is collected.
The audit trail entry will show the user’s identification information, and the date and time of 
the correction.  The investigator must provide through the EDC application formal approval 
of all the information in the eCRFs and changes to the eCRFs to endorse the final submitted 
data for the patients for which he or she is responsible.


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Takeda, or a designee, will retain the eCRF data and corresponding audit trails.  A copy of 
the final archival eCRF in the form of a compact disk or other electronic media will be 
placed in the investigator’s study file.
11.4   
Study Monitoring
Monitoring and auditing procedures developed or approved by Takeda will be followed, in 
order to comply with GCP guidelines.
All information recorded on the eCRFs for this study must be consistent with the patient’s 
source documentation.  During the course of the study, the study monitor will make study 
site visits to review protocol compliance, verify eCRFs against source documentation, assess 
drug accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements.  The review of medical records will be performed in a manner to 
ensure that patient confidentiality is maintained.
11.5   
Ethical Considerations
The study will be conducted in accordance with ethical principles founded in the Declaration 
of Helsinki.  The IRB/IEC will review all appropriate study documentation in order to 
safeguard the rights, safety and well-being of the patients.  The study will only be conducted 
at sites where IRB/IEC approval has been obtained.  The protocol, IB, informed consent 
form, advertisements (if applicable), written information given to the patients (including 
diary cards and wallet cards, if applicable), safety updates, annual progress reports, and any 
revisions to these documents will be provided to the IRB/IEC by the investigator or the 
sponsor, as allowable by local regulations.
11.6   
Patient Information and Informed Consent
After the study has been fully explained, written informed consent will be obtained from 
either the patient or his/her guardian or legal representative prior to study participation.  The 
method of obtaining and documenting the informed consent and the contents of the consent 
is to comply with ICH-GCP and all applicable regulatory requirement(s).
11.7   
Patient Confidentiality
In order to maintain patient privacy, all eCRFs, MLN0002 accountability records, study 
reports and communications will identify the patient by initials where permitted and/or by 


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the assigned patient number.  The patient’s confidentiality will be maintained and will not be 
made publicly available to the extent permitted by the applicable laws and regulations.
11.8   
Investigator Compliance
The investigator will conduct the trial in compliance with the protocol provided by Takeda, 
and given approval/favorable opinion by the IRB/IEC and the appropriate regulatory 
authority(ies).  Modifications to the protocol are not to be made without agreement of both 
the investigator and Takeda.  Changes to the protocol will require written IRB/IEC 
approval/favorable opinion prior to implementation, except when the modification is needed 
to eliminate an immediate hazard(s) to patients.  Takeda, or a designee, will submit all 
protocol modifications to the appropriate regulatory authority(ies) in accordance with the 
governing regulations.
When immediate deviation from the protocol is required to eliminate an immediate 
hazard(s) to patients, the investigator will contact Takeda, or a designee, if circumstances 
permit, to discuss the planned course of action.  Any departures from the protocol must be 
documented.
11.9   
On-site Audits
Regulatory authorities, the IEC/IRB, and/or Takeda may request access to all source 
documents, eCRFs, and other study documentation for on-site audit or inspection.  Direct 
access to these documents must be guaranteed by the investigator, who must provide support 
at all times for these activities.
11.10   Investigator and Site Responsibility for Drug Accountability
Accountability for the MLN0002 at the trial site is the responsibility of the investigator.    
Drug accountability records indicating the drug’s delivery date to the site, inventory at the 
site, use by each patient, and amount returned to Takeda, or a designee, (or disposal of the 
drug, if approved by Takeda) will be maintained by the clinical site.  Takeda or its designee 
will review drug accountability at the site on an ongoing basis.
All material containing MLN0002 will be treated and disposed of in accordance with 
governing regulations.


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11.11   Product Complaints
A product complaint is a verbal, written or electronic expression which implies 
dissatisfaction regarding the identity, strength, purity, quality or stability of a drug product.  
Individuals who identify a potential product complaint situation should immediately contact 
the CRA or Takeda in accordance with the contact list provided in the Study Manual to
report the event.  Whenever possible, the associated product should be maintained in 
accordance with the label instructions pending further guidance from a Takeda quality 
representative.
11.12   Closure of the Study
Within 90 days of the end of the study, the sponsor will notify the competent authorities and 
ethics committees where the study is being carried out that the study has ended.
Within 1 year of the end of the study, a summary of the clinical trial results will be 
submitted to the competent authorities and IECs in all member states involved in the study.
Study participation by individual sites or the entire study may be prematurely terminated, if 
in the opinion of the investigator or Takeda, there is sufficient reasonable cause.  Written 
notification documenting the reason for study termination will be provided to the 
investigator or Takeda by the terminating party.
Circumstances that may warrant termination include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to patients

Failure to enter patients at an acceptable rate

Insufficient adherence to protocol requirements

Insufficient, incomplete, and/or unevaluable data

Determination of efficacy based on interim analysis

Plans to modify, suspend or discontinue the development of the study 
drug
Should the study be closed prematurely, the site will no longer be able to access the EDC 
application, will not have a right to use the EDC application, and will cease using the 
password or access materials once their participation in the study has concluded.  In the 
event that any access devices for the EDC application have been provided, these will be 
returned to Takeda once the site’s participation in the study has concluded.


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Within 15 days of premature closure, Takeda must notify the competent authorities and 
IECs of any member state where the study is being conducted, providing the reasons for 
study closure.
11.13   Record Retention
The investigator will maintain all study records according to ICH-GCP and applicable 
regulatory requirement(s).  Records will be retained for at least 2 years after the last 
marketing application approval or 2 years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory 
requirement(s).  If the investigator withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person willing to accept the responsibility and 
Takeda notified.


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12.   
USE OF INFORMATION
All information regarding MLN0002 supplied by Takeda to the investigator is privileged 
and confidential information.  The investigator agrees to use this information to accomplish 
the study and will not use it for other purposes without consent from Takeda.  It is 
understood that there is an obligation to provide Takeda with complete data obtained during 
the study.  The information obtained from the clinical study will be used towards the 
development of MLN0002 and may be disclosed to regulatory authority(ies), other 
investigators, corporate partners, or consultants as required.
Upon completion of the clinical study and evaluation of results by Takeda, the hospital or 
institution and/or investigator may publish or disclose the clinical trial results pursuant to the 
terms contained in the applicable Clinical Trial Agreement.
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer-reviewed scientific or medical journal.  A Publications Group, 
comprised of Takeda employees and study investigators will be formed to oversee the 
publication of the study results that will reflect the experience of all participating study 
centers.  Subsequently, individual investigators may publish results from the study in 
compliance with their agreements with Takeda.
A prepublication manuscript or abstract is to be provided to Takeda a minimum of 30 days 
prior to the intended submission date of the manuscript or abstract to a publisher.  Within 
30 days after receipt by Takeda of the notification, Takeda shall inform the study centers 
whether it has objections to the publication for reasons, including but not limited to, those 
defined below:
If patentable subject matter is disclosed, the publication shall be delayed for a period not to 
exceed 90 days from Takeda’s receipt of the proposed publication to allow time for the 
filing of patent applications covering patentable subject matter.
If confidential information is contained in any proposed publication or public disclosure, 
such confidential information will be removed at Takeda’s request.


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13.   
INVESTIGATOR AGREEMENT
I have read Protocol C13008 Amendment 20:  A Phase 3, Open-label Study to Determine 
the Long-Term Safety and Efficacy of Vedolizumab (MLN0002) in Patients With Ulcerative 
Colitis and Crohn’s Disease.
I agree to conduct the study as detailed herein and in compliance with ICH Guidelines for 
Good Clinical Practice and applicable regulatory requirements and to inform all who assist 
me in the conduct of this study of their responsibilities and obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)


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14.   
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Kandiel A, Fraser AG, Korelitz BI, Brensinger C, Lewis JD. Increased risk of 
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Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. 
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Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al. 
Adalimumab for maintenance of clinical response and remission in patients with 
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13.
McIntyre PB, Pemberton JH, Wolff BG, Beart RW, Dozois RR. Comparing 
functional results one year and ten years after ileal pouch-anal anastomosis for 
chronic ulcerative colitis. Diseases of the Colon and Rectum 1994;37(4):303-7.
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Ording Olsen K, Juul S, Berndtsson I, Oresland T, Laurberg S. Ulcerative colitis: 
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Penna C, Dozois R, Tremaine W, Sandborn W, LaRusso N, Schleck C, et al. 
Pouchitis after ileal pouch-anal anastomosis for ulcerative colitis occurs with 
increased frequency in patients with associated primary sclerosing cholangitis. Gut 
1996;38(2):234-9.
16.
Stenson WF. Inflammatory Bowel Disease. In: Yamada T, Alpers DH, Laine L, 
Owyang C, Powell DW, editors. Textbook of Gastroenterology. 3rd ed. Philadelphia, 
PA: Lippincott Williams & Wilkins; 1999. p. 1775-839.
17.
Butcher EC, Williams M, Youngman K, Rott L, Briskin M. Lymphocyte trafficking 
and regional immunity. Advances in Immunology 1999;72:209-53.
18.
Salmi M, Jalkanen S. Lymphocyte homing to the gut: attraction, adhesion, and 
commitment. Immunol Rev 2005;206:100-13.
19.
Briskin M, Winsor-Hines D, Shyjan A, Cochran N, Bloom S, Wilson J, et al. Human 
mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal 
tract and associated lymphoid tissue. American Journal of Pathology 
1997;151(1):97-110.
20.
Erle DJ, Briskin MJ, Butcher EC, Garcia-Pardo A, Lazarovits AI, Tidswell M. 
Expression and function of the MAdCAM-1 receptor, integrin alpha 4 beta 7, on 
human leukocytes. Journal of Immunology 1994;153(2):517-28.
21.
Feagan BG, Greenberg GR, Wild G, Fedorak RN, Pare P, McDonald JW, et al. 
Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 
integrin. New England Journal of Medicine 2005;352(24):2499-507.
22.
Markopoulos M. A Phase II, Randomized, Placebo-Controlled, Double-Blind, 
Parallel Group, Multicenter Study to Determine the Safety, Pharmacokinetics, and 
Effectiveness of LDP 02 in Patients with Mildly to Moderately Active Ulcerative 
Colitis. Final Clinical Study Report. Cambridge, MA: Millennium Pharmaceuticals, 
Inc.; 2005 03 February 2005. Report No.: CSR-M200-022.
23.
Feagan BG, Greenberg GR, Wild G, Fedorak RN, Paré P, McDonald JWD, et al. 
Treatment of Active Crohn’s Disease with MLN0002, a Humanized Antibody to the 
a4b7 Integrin: In Press. Clinical Gastroenterology and Hepatology 2008.
24.
Harvey RF, Bradshaw JM. A simple index of Crohn's-disease activity. Lancet 
1980;1(8167):514.


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25.
Nojima M, Yoshimoto T, Nakao A, Itahana R, Kyo M, Hashimoto M, et al. 
Sequential blood level monitoring of basiliximab during multisession plasmapheresis 
in a kidney transplant recipient. Transplantation Proceedings 2005;37(2):875-8.
26.
Okechukwu CN, Meier-Kriesche HU, Armstrong D, Campbell D, Gerbeau C, 
Kaplan B. Removal of basiliximab by plasmapheresis. American Journal of Kidney 
Diseases 2001;37(1):E11.
27.
Sharma A, Bumerts P, Gomez-Navarro J, Pavlov AR, D. . Clearance of monoclonal 
antibody (mAb) CP-675,206 by therapeutic plasma exchange (TPE) or 
plasmapheresis. Journal of Clinical Oncology 2007;25(18S (June 20 
Supplement)):Abstract No: 13515 
28.
Darabi K, Berg AH. Rituximab can be combined with daily plasma exchange to 
achieve effective B-cell depletion and clinical improvement in acute autoimmune 
TTP. American Journal of Clinical Pathology 2006;125(4):592-7.
29.
Khatri B, Fox R, Koo AP, Lynn F, Duda P, Jurgensen S, et al. Plasma Exchange 
Accelerates the Decline of Serum Natalizumab Concentration in Patients with 
Multiple Sclerosis: Results of the Natalizumab PLEX Study. In: 60th Annual 
Meeting of the American Academy of Neurology; 2008 Saint Paul, MN.
30.
Brickelmaier M, Lugovskoy A, Kartikeyan R, Reviriego-Mendoza MM, Allaire N, 
Simon K, et al. Identification and characterization of mefloquine efficacy against JC 
virus in vitro. Antimicrob Agents Chemother 2009;53(5):1840-9.
31.
Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy 
for mildly to moderately active ulcerative colitis. A randomized study. New England 
Journal of Medicine 1987;317(26):1625-9.


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15.   
APPENDICES
15.1   
Partial Mayo Scoring System for the Assessment of Ulcerative Colitis Activity
Category
Stool frequencyb
0 = Normal no. of stools for this patient
1 = 1 to 2 stools more than normal
2 = 3 to 4 stools more than normal
3 = 5 or more stools more than normal
Sub score, 0 to 3
Rectal bleedingc
0 = No blood seen 
1 = Streaks of blood with stool less than half the time 
2 = Obvious blood with stool most of the time 
3 = Blood alone passes 
Sub score, 0 to 3
Physician’s global assessmentd
0 = Normal
1 = Mild disease
2 = Moderate disease
3 = Severe disease
Sub score, 0 to 3
Partial Mayo score ranges from 09 with higher scores indicating more severe disease.(31)
b Each patient serves as his or her own control to establish the degree of abnormality of the stool frequency.
c
The daily bleeding score represents the most severe bleeding of the day.
d The physician’s global assessment acknowledges the 3 other criteria, the patient’s daily recollection of 
abdominal discomfort and general sense of well-being, and other observations, such as physical findings 
and the patient’s performance status.
Adapted from:  Schroeder KW, Tremaine WJ, Ilstrup DM.  Coated oral 5-aminosalicylic 
acid therapy for mildly to moderately active ulcerative colitis.  A randomized study.  N Engl 
J Med 1987; 317 (26):1625-9 


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15.2   Harvey-Bradshaw Scoring System for the Assessment of Crohn’s Disease 
Activity
Category
Total
General Wellbeing
0 = Very Well
1 = Slightly Below Par
2 = Poor
3 = Very Poor
4 = Terrible
Abdominal Pain
0 = None
1 = Mild
2 = Moderate
3 = Severe
Number of Liquid Stools Per Day
Abdominal Mass
0 = None
1 = Dubious
2 = Definite
3 = Definite and Tender
Complications (score 1 per item)
  Arthralgia/Arthritis
  Uveitis/Iritis
  Erythema nodosum
  Apthous ulcers
  Pyoderma gangrenosum
  Anal fissure
  Draining fistula (eg, perianal, enterocutaneous, rectovaginal)
  Perianal Abscess
Final Score (add totals)             
Adapted from:  Harvey RF, Bradshaw JM.  A simple index of Crohn's-disease activity.  
Lancet 1980; 1 (8167):514.


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15.3    Purposes and Rationale for Amendment 1
Rationale for Amendment 1
Since the previous version of the protocol a generic name for MLN0002, vedolizumab, was 
approved by USAN and has hence been included in key sections of the protocol for 
reference.
As planned in the original protocol, blood samples collected at regular intervals throughout 
the study will be assessed for HAHA as a safety endpoint.  The decision of whether or not to 
assess any HAHA-positive samples for neutralizing HAHA will be determined as HAHA 
and pharmacodynamic data from all ongoing MLN0002 studies are reviewed.  A 
neutralizing HAHA assay will be performed only if the results will contribute to a better 
understanding of the immunogenicity of MLN0002.  
Other changes are corrections of primarily typographical, grammatical, contextual and 
punctuation errors.
Purposes for Amendment 1
The purposes of this amendment are to:

Cross-reference the USAN-approved generic name, vedolizumab, which is 
synonymous with the MLN0002 drug product being investigated in this study

Clarify that neutralizing HAHA assessment may be performed if necessary to better 
understand the immunogenicity of MLN0002

Clarify that recommendations regarding pregnancy begin at the time of signing the  
informed consent form

Clarify that the RAMP (Risk Assessment and Minimization for PML) is a RiskMAP

Clarify in Section 7.3.23 that hematology is not being performed at Week 0 

Clarify in Section 7.6 that all patients will participate in a 2 year follow-up survey

Correct the value for absolute lymphocyte count in Section 6.4.3

Clarify that concomitant procedures will be recorded starting at time of enrollment 
(concomitant procedures from a previous study will not be recorded in the eCRFs for 
Study C13008)

Expand the definition of serious adverse event (SAE) to include any event that involves 
suspected transmission of an infectious agent via a medicinal product 

Correct typographical, grammatical, contextual, and punctuation errors


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15.4   
Purposes and Rationale for Amendment 2
Rationale for Amendment 2
Revisions and corrections have been made to clarify the initial intent of this protocol as 
listed below in the purposes.  Also, the window for patients to enroll in this study after the 
last dose of MLN0002 in Study C13004 has been extended from 5 to 9 weeks.  This window 
is consistent with the dosing intervals in Study C13004 and is not expected to affect the 
patients’ clinical progress or the planned statistical analyses.  The enrollment window for 
patients entering this study after Study C13006 or Study C13007 is unchanged.
Purposes for Amendment 2
The purposes of this amendment are to:

Revise the definition of rescue medications with all applicable exceptions.

Clarify that data for pre-enrollment quality of life assessments will be obtained from the 
previous study as applicable.

Clarify that patients who withdrew from Study C13006 or Study C13007 only as a result 
of receiving rescue medications before Week 14 are not eligible for Study C13008.

Extend the window for patients to enroll in this study after the last dose of MLN0002 in 
Study C13004 from 5 to 9 weeks.

Revise inclusion criteria by removing the requirement of "stable dose" for patients on 
corticosteroids at the time of enrollment.  

Clarify the length of required observation at the clinical site based on the completion of 
dosing.

Revise the advice regarding prophylactic administration of premedication for better 
clarity.

Add language to Section 6.4.8 to clarify the timing of an unscheduled visit as it relates to
the criteria for defining disease worsening.

Remove language in Section 7.3.22 regarding the transfer of AE and SAE information 
from the previous study to the C13008 eCRFs.  

Clarify that data from patients who previously participated in Study C13004 will not be 
part of the integrated safety analysis, but will be analyzed separately.

Correct an incorrect crossreference in Section 10.5.3 and remove an unnecessary 
statement regarding the reporting of malignancies.  Reporting of malignancies is covered 
in Section 6.4.5 and governed by the definitions and reporting requirements of adverse 
events (AEs) and serious adverse events (SAEs) as detailed in Section 10.

Remove statements in the rationale for Amendment 1 (see Section 15.3) regarding 
pharmacodynamic sampling and objectives.  These statements were incorrect because 
there were no pharmacodynamic objectives or pharmacodynamic samples to be 
collected in this study at any time.

Correct typographical, grammatical, contextual, and punctuation errors, as necessary.


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15.5   
Purposes and Rationale for Amendment 3 (for use only outside of the US)
Rationale for Amendment 3
Recently published data suggest incremental efficacy, acceptable safety, and the potential 
for decreased long-term immunogenicity with concomitant immunomodulator therapy; 
therefore, it may be beneficial for patients enrolled in this study to receive concomitant 
immunomodulators.  If deemed appropriate by the investigator, patients will now be allowed 
to continue azathioprine, 6-mercaptopurine, or methotrexate if they were receiving these 
medications during prior participation in Study C13006 or Study C13007.  
This amendment also allows patients who are unable to complete the corticosteroid taper 
within the first 6 months of the study to continue in the study, provided they do not exceed a 
daily oral corticosteroid dose of the equivalent of 5 mg/day of prednisone or 3 mg/day of 
budesonide.  After 6 months, given the long duration of this study, a one-time oral 
corticosteroid course of up to the equivalent of 30 mg/day of prednisone or 9 mg/day of 
budesonide is permitted for documented disease flare; however, the dose must be tapered to 
the equivalent of 5 mg/day of prednisone or 3 mg/day of budesonide within 3 months.  
Patients who fail to meet these corticosteroid tapering requirements will be withdrawn.
Purposes for Amendment 3

Allow patients who received azathioprine, 6-mercaptopurine, or methotrexate during 
prior participation in Study C13006 or Study C13007 to continue these medications in 
this study

Allow patients who are unable to complete the corticosteroid taper within the first 
6 months of the study to continue in the study  

Correct typographical, grammatical, contextual, and punctuation errors, as necessary.


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15.6   
Purposes and Rationale for Amendment 4 (for use in Norway and the United 
Kingdom)
Rationale for Amendment 4
This amendment, which is for use only in Norway and in the United Kingdom (UK), 
incorporates changes requested by the Norwegian Medicines Agency (NMA) and the 
Medicines and Healthcare products Regulatory Agency (MHRA).  
Purposes for Amendment 4

Change the study length for patients enrolled in Norway and in the UK, based on a 
request by the NMA and MHRA, to a maximum of 100 weeks irrespective of 
marketing authorization.

Add a requirement, based on a request by the MHRA, that patients enrolling in this 
study in the UK must have negative hepatitis B virus (HBV), hepatitis C virus (HCV), 
and human immunodeficiency virus (HIV) tests within 4 months before enrollment.

Correct typographical, grammatical, contextual, and punctuation errors, as necessary


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15.7   
Purposes and Rationale for Amendment 5 (for use in all countries except the 
US, Norway, and the United Kingdom)
Rationale for Amendment 5
With this amendment, the maximum duration of study treatment with MLN0002 is being 
increased from 100 weeks to 196 weeks (approximately 46 months).  This increase accounts 
for the maximum estimated time from enrollment of the first patient in the trial until 
approval for MLN0002.  Extension of the maximum treatment duration is supported by the 
accumulated safety data to date, including data from this open-label study.  This extension 
serves the dual purposes of providing patients who are deriving clinical benefit continued 
access to MLN0002 and increasing our understanding of the long-term safety profile of this 
compound.  Safety assessments, including the predose progressive multifocal 
leukoencephalopathy (PML) checklists and the Risk Assessment and Minimization for PML 
(RAMP), will continue during the entire course of the trial.  It should be noted that the total 
duration of study treatment is a maximum duration; if approval is obtained and MLN0002 
becomes available in a specific country while the study is still ongoing, the study may be 
terminated in that country.  
This amendment also will allow patients who participated in Study C13011 to continue 
MLN0002 treatment in this study (C13008).  Study C13011, a pivotal phase 3 induction 
study in patients with Crohn’s disease, has been added to the GEMINI program 
(Millennium’s phase 3 pivotal program for vedolizumab [MLN0002] in Crohn’s disease and 
ulcerative colitis).  Patients who complete induction therapy and follow-up through Week 10 
in Study C13011 may be eligible to enroll in this study.  
Additionally, the maximum time allowed from last dose of study drug in the prior qualifying 
MLN0002 study to first dose of MLN0002 in this study (C13008) has been increased from 
5 weeks to 9 weeks to allow more flexibility for patients to enroll in this study.  This 
extension is based on cumulative clinical pharmacology data in the entire vedolizumab 
program to date, as well as data from a recently completed study (C13004) that showed that 
patients tolerated an interruption in dosing longer than 5 weeks and were also able to derive 
therapeutic benefit from subsequent dosing. 
Several other modifications have been made to the protocol in light of the increased duration 
of the study.  The observation time after first infusion has been modified from 2 hours to 
1 hour.  This modification is acceptable based on the considerable increase in accumulated 
safety experience to date involving first and subsequent doses of MLN0002, since the prior 
version of this protocol.
Given the long duration of the trial, it is likely that patients may require antibiotics, either 
for control of symptoms for IBD or for infections, or may undergo surgery during the course 
of the trial.  Antibiotic use (both for IBD and for other conditions) and surgery 
(non-IBD-related) are now allowed during the course of the study.  Similarly, if a patient is 
otherwise demonstrating benefit from MLN0002, short-term courses of corticosteroids to 
control occasional and intermittent exacerbations of disease are allowed (up to a maximum 
daily dose of 30 mg of prednisone or its equivalent) for documented disease exacerbations 
after 6 months on study (previously, only a single course was allowed after 6 months).  This 


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modification allows for the treatment of modest disease fluctuations, allowing patients the 
opportunity to continue receiving long-term MLN0002 treatment. 
Patients who undergo or may need to undergo minor surgical procedures in Studies C13006, 
C13007, or C13011 as a result of their IBD (eg, fistulotomy) are now permitted to enroll.  
Patients who require or who have undergone major surgery for control of IBD during or 
after participation in a prior MLN0002 study continue to be excluded.
Finally, the definition of rescue medication in the context of this trial was clarified so that 
common medications taken for symptoms of disease that are not intestinal anti-inflammatory 
therapies (such as probiotics) are allowed during the course of the study.
Purposes for Amendment 5
The purposes of this amendment are to:

Increase maximum on-study MLN0002 treatment from 100 weeks to 46 months or 
until MLN0002 becomes available in the patient’s country, whichever is sooner 

Allow patients who participated in Study C13011 to enroll in this study 
(Study C13008)

Increase maximum time allowed from last dose of study drug in the prior qualifying 
MLN0002 study to first dose of MLN0002 in this study (C13008) from 5 weeks to 
9 weeks 

Clarify that the number of study centers is approximately 400 (rather than 550 as 
originally projected)

Clarify timing of and requirement for rescue medication in prior study (Study C13006 
or Study C13007) as it relates to eligibility for this study (Study C13008) 

Correct reference in inclusion criterion #5 from “left-sided colitis” to the more 
appropriate term of “limited colitis”

Permit use of antibiotics and methotrexate for all patients (ie, patients with UC as well 
as patients with CD)

Clarify that patients who undergo or may need to undergo minor surgical procedures in 
Studies C13006, C13007, or C13011 as a result of their IBD (eg, fistulotomy) are 
permitted to enroll

Allow for minor IBD-related surgery (eg, fistulotomy) to occur during the study

Allow for non-IBD-related surgery to occur during the study

Clarify excluded medications description

Allow occasional short-term courses of corticosteroids for disease exacerbations 
throughout the study (previously, only a single course was allowed after 6 months) 

Clarify the definition of rescue medications as those that are used to treat luminal 
disease

Update information on clinical experience

Update information on potential risks

Revise the term “Long-Term Population” to “Efficacy Population” to be consistent 


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with the statistical analysis plan terminology 

Update contact information for serious adverse event (SAE) reporting

Clarify that drug concentration may be determined as part of the HAHA testing

Change the post-infusion observation time requirement to at least 1 hour for all 
infusions, including Week 0 (previously this was approximately 2 hours at Week 0)

Correct typographical, grammatical, contextual, and punctuation errors, as necessary


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15.8   
Purposes and Rationale for Amendment 6 (for use in the US only)
Rationale for Amendment 6
With this amendment, the maximum duration of study treatment with MLN0002 is being 
increased from 100 weeks to 196 weeks (approximately 46 months).  This increase accounts 
for the maximum estimated time from enrollment of the first patient in the trial until 
approval for MLN0002.  Extension of the maximum treatment duration is supported by the 
accumulated safety data to date, including data from this open-label study.  This extension 
serves the dual purposes of providing patients who are deriving clinical benefit continued 
access to MLN0002 and increasing our understanding of the long-term safety profile of this 
compound.  Safety assessments, including the predose progressive multifocal 
leukoencephalopathy (PML) checklists and the Risk Assessment and Minimization for PML 
(RAMP), will continue during the entire course of the trial.  It should be noted that the total 
duration of study treatment is a maximum duration; if approval is obtained and MLN0002 
becomes available in the United States (US) while the study is still ongoing, the study may 
be terminated in the US.  
This amendment also will allow patients who participated in Study C13011 to continue 
MLN0002 treatment in this study (C13008).  Study C13011, a pivotal phase 3 induction 
study in patients with Crohn’s disease, has been added to the GEMINI program 
(Millennium’s phase 3 pivotal program for vedolizumab [MLN0002] in Crohn’s disease and 
ulcerative colitis).  Patients who complete induction therapy and follow-up through Week 10 
in Study C13011 may be eligible to enroll in this study.  
Additionally, the maximum time allowed from last dose of study drug in the prior qualifying 
MLN0002 study to first dose of MLN0002 in this study (C13008) has been increased from 
5 weeks to 9 weeks to allow more flexibility for patients to enroll in this study.  This 
extension is based on cumulative clinical pharmacology data in the entire vedolizumab 
program to date, as well as data from a recently completed study (C13004) that showed that 
patients tolerated an interruption in dosing longer than 5 weeks and were also able to derive 
therapeutic benefit from subsequent dosing. 
Several other modifications have been made to the protocol in light of the increased duration 
of the study.  The observation time after first infusion has been modified from 2 hours to 
1 hour.  This modification is acceptable based on the considerable increase in accumulated 
safety experience to date involving first and subsequent doses of MLN0002, since the prior 
version of this protocol.
Given the long duration of the trial, it is likely that patients may require antibiotics, either 
for control of symptoms for IBD or for infections, or may undergo surgery during the course 
of the trial.  Antibiotic use (both for IBD and for other conditions) and surgery 
(non-IBD-related) are now allowed during the course of the study.
Patients who undergo or may need to undergo minor surgical procedures in Studies C13006, 
C13007, or C13011 as a result of their IBD (eg, fistulotomy) are now permitted to enroll.  
Patients who require or who have undergone major surgery for control of IBD during or 
after participation in a prior MLN0002 study continue to be excluded.
Finally, the definition of rescue medication in the context of this trial was clarified so that 


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common medications taken for symptoms of disease that are not intestinal anti-inflammatory 
therapies (such as probiotics) are allowed during the course of the study.
Purposes for Amendment 6
The purposes of this amendment are to:

Increase maximum on-study MLN0002 treatment from 100 weeks to 46 months or 
until MLN0002 becomes available in the US, whichever is sooner

Allow patients who participated in Study C13011 to enroll in this study 
(Study C13008)

Increase maximum time allowed from last dose of study drug in the prior qualifying 
MLN0002 study to first dose of MLN0002 in this study (C13008) from 5 weeks to 
9 weeks 

Clarify that the number of study centers is approximately 400 (rather than 550 as 
originally projected)

Clarify timing of and requirement for rescue medication in prior study (Study C13006 
or Study C13007) as it relates to eligibility for this study (Study C13008) 

Correct reference in inclusion criterion #5 from “left-sided colitis” to the more 
appropriate term of “limited colitis”

Permit use of antibiotics for all patients (ie, patients with UC as well as patients with 
CD)

Clarify that patients who undergo or may need to undergo minor surgical procedures in 
Studies C13006, C13007, or C13011 as a result of their IBD (eg, fistulotomy) are 
permitted to enroll

Allow for minor IBD-related surgery (eg, fistulotomy) to occur during the study

Allow for non-IBD-related surgery to occur during the study

Clarify excluded medications description

Clarify the definition of rescue medications as those that are used to treat luminal 
disease

Update information on clinical experience

Update information on potential risks

Revise the term “Long-Term Population” to “Efficacy Population” to be consistent 
with the statistical analysis plan terminology 

Update contact information for serious adverse event (SAE) reporting

Clarify that drug concentration may be determined as part of the HAHA testing

Change the post-infusion observation time requirement to at least 1 hour for all 
infusions, including Week 0 (previously this was approximately 2 hours at Week 0)

Correct typographical, grammatical, contextual, and punctuation errors, as necessary


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15.9   
Purposes and Rationale for Amendment 7 (for use in Norway and the United 
Kingdom only)
Rationale for Amendment 7
With this amendment, the maximum duration of study treatment with MLN0002 is being 
increased from 100 weeks to 196 weeks (approximately 46 months).  This increase accounts 
for the maximum estimated time from enrollment of the first patient in the trial until 
approval for MLN0002.  Extension of the maximum treatment duration is supported by the 
accumulated safety data to date, including data from this open-label study.  This extension 
serves the dual purposes of providing patients who are deriving clinical benefit continued 
access to MLN0002 and increasing our understanding of the long-term safety profile of this 
compound.  Safety assessments, including the predose progressive multifocal 
leukoencephalopathy (PML) checklists and the Risk Assessment and Minimization for PML 
(RAMP), will continue during the entire course of the trial.
This amendment also will allow patients who participated in Study C13011 to continue 
MLN0002 treatment in this study (C13008).  Study C13011, a pivotal phase 3 induction 
study in patients with Crohn’s disease, has been added to the GEMINI program 
(Millennium’s phase 3 pivotal program for vedolizumab [MLN0002] in Crohn’s disease and 
ulcerative colitis).  Patients who complete induction therapy and follow-up through Week 10 
in Study C13011 may be eligible to enroll in this study.  
Additionally, the maximum time allowed from last dose of study drug in the prior qualifying 
MLN0002 study to first dose of MLN0002 in this study (C13008) has been increased from 
5 weeks to 9 weeks to allow more flexibility for patients to enroll in this study.  This 
extension is based on cumulative clinical pharmacology data in the entire vedolizumab 
program to date, as well as data from a recently completed study (C13004) that showed that 
patients tolerated an interruption in dosing longer than 5 weeks and were also able to derive 
therapeutic benefit from subsequent dosing. 
Several other modifications have been made to the protocol in light of the increased duration 
of the study.  The observation time after first infusion has been modified from 2 hours to 
1 hour.  This modification is acceptable based on the considerable increase in accumulated 
safety experience to date involving first and subsequent doses of MLN0002, since the prior 
version of this protocol.
Given the long duration of the trial, it is likely that patients may require antibiotics, either 
for control of symptoms for IBD or for infections, or may undergo surgery during the course 
of the trial.  Antibiotic use (both for IBD and for other conditions) and surgery 
(non-IBD-related) are now allowed during the course of the study.  Similarly, if a patient is 
otherwise demonstrating benefit from MLN0002, short-term courses of corticosteroids to 
control occasional and intermittent exacerbations of disease are allowed (up to a maximum 
daily dose of 30 mg of prednisone or its equivalent) for documented disease exacerbations 
after 6 months on study (previously, only a single course was allowed after 6 months).  This 
modification allows for the treatment of modest disease fluctuations, allowing patients the 
opportunity to continue receiving long-term MLN0002 treatment. 


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Patients who undergo or may need to undergo minor surgical procedures in Studies C13006, 
C13007, or C13011 as a result of their IBD (eg, fistulotomy) are now permitted to enroll.  
Patients who require or who have undergone major surgery for control of IBD during or 
after participation in a prior MLN0002 study continue to be excluded.
Finally, the definition of rescue medication in the context of this trial was clarified so that 
common medications taken for symptoms of disease that are not intestinal anti-inflammatory 
therapies (such as probiotics) are allowed during the course of the study.
Purposes for Amendment 7
The purposes of this amendment are to:

Increase maximum on-study MLN0002 treatment from 100 weeks to 46 months 

Allow patients who participated in Study C13011 to enroll in this study 
(Study C13008)

Increase maximum time allowed from last dose of study drug in the prior qualifying 
MLN0002 study to first dose of MLN0002 in this study (C13008) from 5 weeks to 
9 weeks 

Clarify that the number of study centers is approximately 400 (rather than 550 as 
originally projected)

Clarify timing of and requirement for rescue medication in prior study (Study C13006 
or Study C13007) as it relates to eligibility for this study (Study C13008) 

Correct reference in inclusion criterion #5 from “left-sided colitis” to the more 
appropriate term of “limited colitis”

Permit use of antibiotics and methotrexate for all patients (ie, patients with UC as well 
as patients with CD)

Clarify that patients who undergo or may need to undergo minor surgical procedures in 
Studies C13006, C13007, or C13011 as a result of their IBD (eg, fistulotomy) are 
permitted to enroll

Allow for minor IBD-related surgery (eg, fistulotomy) to occur during the study

Allow for non-IBD-related surgery to occur during the study

Clarify excluded medications description

Allow occasional short-term courses of corticosteroids for disease exacerbations 
throughout the study (previously, only a single course was allowed after 6 months) 

Clarify the definition of rescue medications as those that are used to treat luminal 
disease

Update information on clinical experience

Update information on potential risks

Revise the term “Long-Term Population” to “Efficacy Population” to be consistent 
with the statistical analysis plan terminology 

Update contact information for serious adverse event (SAE) reporting


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
Clarify that drug concentration may be determined as part of the HAHA testing

Change the post-infusion observation time requirement to at least 1 hour for all 
infusions, including Week 0 (previously this was approximately 2 hours at Week 0)

Correct typographical, grammatical, contextual, and punctuation errors, as necessary


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15.10   Purposes and Rationale for Amendment 8 (for use in all countries outside the 
US)
Rationale for Amendment 8
Amendment 8 is an update to Amendment 5 and Amendment 7 of the C13008 protocol.  
With this amendment, patients participating in Study C13008 will have access to 
vedolizumab until March 2016, or until vedolizumab is available in the country in which the 
patient resides, or until patient withdrawal, whichever comes first (unless the study is 
terminated early by the sponsor, as described in Section 11.12).  Changes in this amendment 
incorporate or supersede the United Kingdom (UK)/Norway-specific language in 
Amendment 7.
Another change to the protocol includes removal of JC virus DNA testing.  When the 
vedolizumab pivotal studies were planned in 2008, it was unclear if JC virus DNA testing in 
the blood might be predictive of progressive multifocal leukoencephalopathy (PML) risk.  
More recently, controlled studies of natalizumab (which has a proven risk of PML) have 
conclusively demonstrated that detection of JC virus DNA in the blood is of no clinical 
utility in minimizing risk of PML.(1)  Therefore, monitoring for JC virus DNA in the blood is 
discontinued with this amendment.  
Other changes to the protocol allow for the use of conventional, nonbiological concomitant 
medications for inflammatory bowel disease (IBD) to be more consistent with standard 
clinical practice.  Thus, patients will now be allowed to start azathioprine, 6-mercaptopurine, 
methotrexate (methotrexate for Crohn’s disease only), or corticosteroids during the course of 
the study, even if they were not on these medications when enrolled in the study.  In 
addition, oral corticosteroid regimens have been modified to be more consistent with 
individual patient needs, and the corticosteroid tapering requirement has been changed to a 
recommendation. 
The definition of treatment failure that mandates withdrawal from the study has been 
modified to “long-term treatment failure” to more accurately reflect true treatment failure 
that occurs in clinical practice.  Given the fluctuating natural history of IBD, patients may be 
treated for short-term disease worsening with conventional therapies for IBD, as allowed per 
protocol, without being required to withdraw from the study.  Accordingly, one of the 
criteria for the protocol-defined treatment failure, “disease worsening,” that was based on 
disease activity indices (Harvey-Bradshaw Index and partial Mayo score), has been removed 


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from the definition of long-term treatment failure.  Importantly, patients are still required to 
be withdrawn if they require rescue medication or major surgery for the treatment of IBD.
Purposes for Amendment 8
The purposes of this amendment are to:

Extend the duration of this study to allow all patients access to vedolizumab until 
March 2016, or until vedolizumab is available in the country in which the patient 
resides, or until patient withdrawal, whichever comes first (unless the study is 
terminated early by the sponsor, as described in Section 11.12)

Increase the maximum number of subjects to 2200

Discontinue JC virus DNA testing

Incorporate text from Amendment 7 that required HBV, HCV, and HIV testing for patients 
in the UK prior to enrolling in Study C13008

Revise the concomitant medication criteria to make them consistent with the changes 
allowed in concomitant medications

Change the requirement for corticosteroid tapering to a recommendation, and clarify 
the recommended tapering process

Replace the term “treatment failure” with the term “long-term treatment failure” to be 
more consistent with clinical practice

Update the recommendations for unscheduled visits

Remove the term “disease worsening” from the study definitions and from the 
definition of “long-term treatment failure”

Clarify that enrollment for all patients is the time the patient is entered into the IVRS at 
Week 0.

Update Inclusion Criterion 7

Provide updated safety information

Clarify and update the actions to be taken if a patient experiences leukopenia or 
lymphopenia

Align the study withdrawal criteria with the new definition of long-term treatment 
failure and the changes to the corticosteroid tapering recommendations

Clarify the inclusion of weight in patient assessments

Update requirements for 12-lead ECG

Correct typographical, grammatical, contextual, punctuation, and formatting errors, as 
necessary


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15.11   Purposes and Rationale for Amendment 9 (for use in the US only)
Rationale for Amendment 9
Amendment 9 is an update to Amendment 6 of the C13008 protocol.  The primary reason 
for this amendment is to allow enrollment of up to 400 additional patients with either 
ulcerative colitis or Crohn’s disease who have not been previously treated with vedolizumab 
(“de novo patients”).  The additional patients will increase the number of patients with 
exposure to vedolizumab and supplement the safety database to detect adverse events 
resulting from long-term vedolizumab administration that may not be detected in the year-
long induction and maintenance studies.  The addition of 400 patients will allow for the 
detection of adverse events that occur at a prevalence of 0.1% to be detected with more than 
85% likelihood, and events that occur at a prevalence of 1% to be detected with 99.99% 
likelihood.  Importantly, the inclusion and exclusion criteria for the de novo patients are 
nearly identical to the criteria for patients who enrolled in Studies C13006, C13007, and 
C13011; study treatment and assessments will be the same for these de novo patients as for 
rollover patients (those patients who enrolled in C13008 following participation in C13004, 
C13006, C13007, or C13011).  The additional patients will be enrolled at a subset of 
existing sites in select countries, including the United States (US).
In addition, with this amendment, both rollover and de novo patients participating in C13008 
will have access to vedolizumab until March 2016, or until vedolizumab is available in the 
US, or until patient withdrawal, whichever comes first (unless the study is terminated early 
by the sponsor, as described in Section 11.12).
Another change to the protocol includes removal of JC virus DNA testing.  When the 
vedolizumab pivotal studies were planned in 2008, it was unclear if JC virus DNA testing in 
the blood might be predictive of progressive multifocal leukoencephalopathy (PML) risk.  
More recently, controlled studies of natalizumab (which has a proven risk of PML) have 
conclusively demonstrated that detection of JC virus DNA in the blood is of no clinical 
utility in minimizing risk of PML.(1)  Therefore, monitoring for JC virus DNA in the blood is 
discontinued with this amendment.  
The definition of treatment failure that mandates withdrawal from the study has been 
modified to “long-term treatment failure” to more accurately reflect true treatment failure 
that occurs in clinical practice.  Given the fluctuating natural history of inflammatory bowel 
disease (IBD), patients may be treated for short-term disease worsening with conventional 
therapies for IBD, as allowed per protocol, without being required to withdraw from the 


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study.  Accordingly, one of the criteria for the protocol-defined treatment failure, “disease 
worsening,” that was based on disease activity indices (Harvey-Bradshaw Index and partial 
Mayo score), has been removed from the definition of long-term treatment failure.  
Importantly, patients are still required to be withdrawn if they require rescue medication or 
major surgery for the treatment of IBD.
Purposes for Amendment 9
The purposes of this amendment are to:
Allow up to 400 patients without previous treatment with vedolizumab (de novo 
patients) to enroll directly into this study
Extend the duration of this study to allow patients access to vedolizumab until March 
2016, or until vedolizumab is available in the US, or until patient withdrawal, 
whichever comes first (unless the study is terminated early by the sponsor, as described 
in Section 11.12)
Discontinue JC virus DNA testing
Clarify requirements for concomitant medications
Replace the term “treatment failure” with the term “long-term treatment failure” to 
be more consistent with clinical practice
Update the recommendations for unscheduled visits
Remove the term “disease worsening” from the study definitions and from the 
definition of “long-term treatment failure”
Clarify that enrollment for all patients is the time the patient is entered into the IVRS 
at Week 0.
Update Inclusion Criterion 7
Provide updated safety information
Clarify and update the actions to be taken if a patient experiences leukopenia or 
lymphopenia
Align the study withdrawal criteria with the new definition of long-term treatment 
failure and the changes to the corticosteroid tapering recommendations
Specify PML checklist requirements for de novo patients at screening
Clarify the inclusion of weight in patient assessments
Update requirements for 12-lead ECG
Correct typographical, grammatical, contextual, punctuation, and formatting errors, 
as necessary


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15.12
Purposes and Rationale for Amendment 10
Rationale for Amendment 10
Amendment 10 is an update to Amendment 5 of the C13008 protocol.  The primary reason 
for this amendment is to allow enrollment of up to 400 additional patients with either 
ulcerative colitis or Crohn’s disease (CD) who have not been previously treated with 
vedolizumab (“de novo patients”).  The additional patients will increase the number of 
patients with exposure to vedolizumab and supplement the safety database to detect adverse 
events resulting from long-term vedolizumab administration that may not be detected in the 
year-long induction and maintenance studies.  The addition of 400 patients will allow for the 
detection of adverse events that occur at a prevalence of 0.1% to be detected with more than 
85% likelihood, and events that occur at a prevalence of 1% to be detected with 99.99% 
likelihood.  Importantly, the inclusion and exclusion criteria for the de novo patients are 
nearly identical to the criteria for patients who enrolled in Studies C13006, C13007, and 
C13011; study treatment and assessments will be the same for these de novo patients as for 
rollover patients (those patients who enrolled in C13008 following participation in C13004, 
C13006, C13007, or C13011).  The additional patients will be enrolled at a subset of 
existing sites in select countries.
In addition, with this amendment, both rollover and de novo patients participating in Study 
C13008 will have access to vedolizumab until March 2016, or until vedolizumab is available 
in the country in which the patient resides, or until patient withdrawal, whichever comes 
first (unless the study is terminated early by the sponsor, as described in Section 11.12).
Another change to the protocol includes removal of JC virus DNA testing.  When the 
vedolizumab pivotal studies were planned in 2008, it was unclear if JC virus DNA testing in 
the blood might be predictive of progressive multifocal leukoencephalopathy (PML) risk.  
More recently, controlled studies of natalizumab (which has a proven risk of PML) have 
conclusively demonstrated that detection of JC virus DNA in the blood is of no clinical 
utility in minimizing risk of PML.(1)  Therefore, monitoring for JC virus DNA in the blood is 
discontinued with this amendment.  
Other changes to the protocol allow for the use of conventional, nonbiological concomitant 
medications for IBD to be more consistent with standard clinical practice.  Thus, patients 
will now be allowed to start azathioprine, 6-mercaptopurine, methotrexate (methotrexate for 
CD only), or corticosteroids during the course of the study, even if they were not on these 
medications when enrolled in the study.  In addition, oral corticosteroid regimens have been 


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modified to be more consistent with individual patient needs, and the corticosteroid tapering 
requirement has been changed to a recommendation. 
The definition of treatment failure that mandates withdrawal from the study has been 
modified to “long-term treatment failure” to more accurately reflect true treatment failure 
that occurs in clinical practice.  Given the fluctuating natural history of inflammatory bowel 
disease (IBD), patients may be treated for short-term disease worsening with conventional 
therapies for IBD, as allowed per protocol, without being required to withdraw from the 
study.  Accordingly, one of the criteria for the protocol-defined treatment failure, “disease 
worsening,” that was based on disease activity indices (Harvey-Bradshaw Index and partial 
Mayo score), has been removed from the definition of long-term treatment failure.  
Importantly, patients are still required to be withdrawn if they require rescue medication or 
major surgery for the treatment of IBD.
Purposes for Amendment 10
The purposes of this amendment are to:

Allow up to 400 patients without previous treatment with vedolizumab (de novo 
patients) to enroll directly into this study

Extend the duration of this study to allow patients access to vedolizumab until March 
2016, or until vedolizumab is available in the country in which the patient resides, or 
until patient withdrawal, whichever comes first (unless the study is terminated early by 
the sponsor, as described in Section 11.12)

Discontinue JC virus DNA testing

Revise the concomitant medication criteria to make them consistent with the changes 
allowed in concomitant medications

Change the requirement for corticosteroid tapering to a recommendation, and clarify 
the recommended tapering process

Replace the term “treatment failure” with the term “long-term treatment failure” to be 
more consistent with clinical practice

Update the recommendations for unscheduled visits

Remove the term “disease worsening” from the study definitions and from the 
definition of “long-term treatment failure”

Clarify that enrollment for all patients is the time the patient is entered into the IVRS at 
Week 0.

Update Inclusion Criterion 7

Provide updated safety information

Clarify and update the actions to be taken if a patient experiences leukopenia or 
lymphopenia

Align the study withdrawal criteria with the new definition of long-term treatment 


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failure and the changes to the corticosteroid tapering recommendations

Specify PML checklist requirements for de novo patients at screening

Clarify the inclusion of weight in patient assessments

Update requirements for 12-lead ECG

Correct typographical, grammatical, contextual, punctuation, and formatting errors, as 
necessary


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15.13
   Purposes and Rationale for Amendment 16
Rationale for Amendment 16
Amendment 16 is an update to Amendment 10 of the C13008 protocol to be implemented in 
countries where vedolizumab is either not commercially available or is not reimbursed. With 
this amendment, patients participating in these countries will have access to vedolizumab in 
Study C13008 either until December 2016 (at which time patients will be able to transition 
into an Extended Access Program) or until patient withdrawal, whichever comes first, unless 
the study is terminated early by the sponsor, as described in Section 11.12. Patients may be 
transitioned from the C13008 study to an Extended Access Program prior to December 
2016, if available.
Purposes for Amendment 16
The purpose of this amendment is to:

Extend the duration of this study to allow all patients in countries where vedolizumab 
is either not commercially available or is not reimbursed access to vedolizumab until 
December 2016 (at which time patients will be able to transition into an Extended 
Access Program) or until patient withdrawal, whichever comes first, unless the study is 
terminated early by the sponsor, as described in Section 11.12. Patients may be 
transitioned from the C13008 study to an Extended Access Program prior to December 
2016, if available.

Remove requirement for women who are not of childbearing potential to perform 
pregnancy tests prior to each dose of vedolizumab and at the Final Safety Visit as it is 
not possible for these women to become pregnant. 

Clarify in the Schedule of Events the requirement for sites to obtain a 12-lead ECG 
from patients at their Final Safety Visit.

Update the sponsor name and contact details from Millennium to Takeda. 

Update SAE reporting details contact information. 

Clarify that concomitant vedolizumab (Entyvio) taken during the 16-week follow-up 
period will be recorded as a concomitant medication and will not be considered as a 
protocol deviation


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15.14
Amendment 20 Detailed Summary of Changes
THE PRIMARY SECTIONS OF THE PROTOCOL AFFECTED BY THE CHANGES 
FROM AMENDMENT 16 ARE INDICATED.  THE CORRESPONDING TEXT HAS 
BEEN REVISED THROUGHOUT THE PROTOCOL.
Purpose:  Extend the duration of this study in countries where vedolizumab is not 
commercially available or is not reimbursed until July 2017, or until an Extended Access 
Program is available at the site, or until patient withdrawal, or unless the study is 
terminated early by the sponsor (as described in Section 11.12), whichever comes first. 
The primary changes occur in the following sections: Schedule of Events, 1.3.2
(MLN0002 Safety), 1.4 (Study Rationale), 1.5.3 (Hypothetical Risks of MLN0002 
Treatment), 4.1 (Overview of Study Design), 4.3 (Duration of Study), 5.1 (Inclusion 
Criteria for Rollover Patients), 5.3 (Inclusion Criteria for De Novo Ulcerative Patients), 
5.4 (Inclusion Criteria for De Novo Crohn’s Disease Patients), 6.2 (Concomitant 
Procedures and Medications), 6.3 (Precautions and Restrictions), 7.3 (Study Procedures),
7.3.13 (Concomitant Medications and Procedures), 7.3.23 (Collection of AEs and SAEs), 
10.3 (Monitoring of AEs and Period of Observation), and 10.4 (Procedures for Reporting 
Drug Exposure During Pregnancy and Birth Events).
Schedule of 
Events Pre-
enrollment 
Through 
Year 2 
formerly 
read:
Note: All patients will return 16 weeks after the last dose of MLN0002 for final safety 
assessments at the Final Safety visit, as described in the Schedule of Events for Years 5 
and beyond.
Now reads:
Note: Patients will return 16 weeks after the last dose of MLN0002 for final safety 
assessments at the Final Safety visit, as described in the Schedule of Events for Years 
5 and beyond.  This visit is not required for patients transitioning from Study 
C13008 into the XAP study.
p If the patient is transitioning from Study C13008 into the XAP study, complete the 
end-of-study eCRF page at their last dosing visit in C13008.  For all other patients, 
complete the end-of-study page at the Final Safety Visit.
Schedule of 
Events 
Year 3 and 
4 formerly 
read:
a All patients will return 16 weeks after the last dose of MLN0002 for final safety 
assessments at the Final Safety visit, as described in the Schedule of Events for Years 5 
and beyond.
Now reads:
a Patients will return 16 weeks after the last dose of MLN0002 for final safety 
assessments at the Final Safety visit.  This visit is not required for patients 
transitioning from Study C13008 into the XAP study.
g All female subjects of childbearing potential must have a serum pregnancy test at the 
Final Safety visit (as applicable). A urine pregnancy test will be performed for 


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female subjects of childbearing potential prior to each dose of MLN0002.
j
If the patient is transitioning from Study C13008 into the XAP study, complete the 
end-of-study eCRF page at their last dosing visit in C13008.  For all other patients, 
complete the end-of-study page at the Final Safety Visit.
Schedule of 
Events 
Years 5 
and 
Beyond 
formerly 
read:
a All patients will return 16 weeks after the last dose of MLN0002 for final safety 
assessments at the Final Safety visit.
g All female subjects of childbearing potential must have a serum pregnancy test at the 
Final Safety visit. A urine pregnancy test will be performed for female subjects of 
childbearing potential prior to each dose of MLN0002.
Now reads:
a Patients will return 16 weeks after the last dose of MLN0002 for final safety 
assessments at the Final Safety visit.  This visit is not required for patients 
transitioning from Study C13008 into the XAP study.
g All female subjects of childbearing potential must have a serum pregnancy test at the 
Final Safety visit (as applicable). A urine pregnancy test will be performed for 
female subjects of childbearing potential prior to each dose of MLN0002.
j
If the patient is transitioning from Study C13008 into the XAP study, complete the 
end-of-study eCRF page at their last dosing visit in C13008.  For all other patients, 
complete the end-of-study page at the Final Safety Visit.
Section 
1.3.2 
formerly 
read:
The phase 3 vedolizumab clinical program is overseen by an independent 
Data Safety Monitoring Board (DSMB) composed of 2 gastroenterologists, 
an infectious diseases physician, a physician with training in epidemiology, 
and a statistician.  The DSMB reviews all SAEs monthly and unblinded 
safety data from all phase 3 trials every 6 months at a minimum.  The DSMB 
last convened on 13 December 2011, and after reviewing unblinded safety 
data, recommended that the trials proceed without modification.
Now reads:
The phase 3 vedolizumab clinical program is overseen by an independent 
Data Safety Monitoring Board (DSMB) composed of 2 
gastroenterologists, an infectious diseases physician, a physician with 
training in epidemiology, and a statistician.  The DSMB reviews all SAEs 
monthly and unblinded safety data from all phase 3 trials every 6 
months at a minimum.  The DSMB convened on 13 December 2011, and 
after reviewing unblinded safety data, recommended that the trials 
proceed without modification.
Section 1.4 
formerly 
read
Although the study was due to complete in March 2016, Takeda has agreed 
to extend the treatment period until December 2016 to allow access for 
patients in countries where vedolizumab is either not commercially available 
or is not reimbursed. For this reason, this amendment is being submitted in 
all countries currently following Amendment 10 except the following: 
Austria, France, Germany, Israel, Netherlands, Norway, Serbia, Spain, 
Sweden, Switzerland and the United Kingdom.  Patients may be transitioned 
from the C13008 study to an Extended Access Program prior to December 


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2016, if available. Current safety information is available in the latest version 
of the Investigator Brochure. 
Now reads
Although the study was due to complete in December 2016, Takeda has 
agreed to extend the treatment period until July 2017 to allow continued 
access for patients in countries where vedolizumab is either not 
commercially available or is not reimbursed. For this reason, this 
amendment is being submitted in all countries currently following 
Amendment 16 except the following: Austria, France, Germany, Israel, 
Netherlands, Norway,  Spain, Sweden, Switzerland and the United 
Kingdom.  Current safety information is available in the latest version of 
the Investigator Brochure. 
Section 
1.5.3 
formerly 
read:
A number of malignancies have occurred over the duration of the phase 3 
program, which remains blinded at the time of the writing of this amendment.  
At its most recent meeting in December 2011, the DSMB for the phase 3 
program reviewed unblinded data, and no modifications to the trial were 
requested.
Now reads:
A number of malignancies have occurred over the duration of the phase 
3 program, which remains blinded at the time of the writing of this 
amendment.  At the meeting in December 2011, the DSMB for the phase 
3 program reviewed unblinded data, and no modifications to the trial 
were requested.
Section 4.1 
formerly 
read:
Following enrollment all patients will be administered 300 mg vedolizomab 
every 4 weeks for the duration of the study, followed by a 16-week 
posttreatment observation and safety assessment period. The total duration of 
MLN0002 treatment will vary by patient based on continued benefit until 
December 2016 (at which time patients will be able to transition into an 
Extended Access Program) or until patient withdrawal, whichever is sooner 
(unless the study is terminated early by the sponsor, as described in Section 
11.12). Patients may be transitioned from the C13008 study to an Extended 
Access Program prior to December 2016, if available.
Now reads:
Following enrollment all patients will be administered 300 mg 
vedolizumab every 4 weeks for the duration of the study. The total 
duration of MLN0002 treatment will vary by patient based on continued 
benefit until July 2017, or until the XAP study is available at the site, or 
until patient withdrawal, or until vedolizumab is available to the patient 
through commercial channels (including reimbursement) for the 
patient’s clinical scenario, or unless the study is terminated early by the 
sponsor, as described in Section 11.12, whichever is sooner. 


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Section 4.1
formerly 
read:
All patients will return 16 weeks after their last dose of MLN0002 for the 
Final Safety visit.  
Now reads:
Patients who do not transition into the XAP study will return 16 weeks 
after their last dose of MLN0002 for the Final Safety visit. Patients who 
transition into the XAP study are not required to attend the Final Safety 
Visit.  The safety of these patients will be monitored as part of the XAP 
study.  The end-of-study eCRF page must be completed for all patients 
regardless of whether they transition into the XAP study or not.
Section 4.3
formerly 
read:
It is anticipated that the duration of MLN0002 treatment will vary by patient 
based on continued benefit.  Treatment duration may continue until 
December 2016 (at which time patients will be able to transition into an 
Extended Access Program) or until patient withdrawal, whichever is sooner 
(unless the study is terminated early by the sponsor, as described in Section 
11.12). Patients may be transitioned from the C13008 study to an Extended 
Access Program prior to December 2016, if available. After the final dose of 
MLN0002, patients will complete the 16-week posttreatment observation and 
safety assessment period. Concomitant vedolizumab (Entyvio) taken during 
the 16-week follow-up period will be recorded as a concomitant medication 
and will not be considered as a protocol deviation. 
Now reads: 
It is anticipated that the duration of MLN0002 treatment will vary by 
patient based on continued benefit.  Treatment duration may continue 
until July 2017, or until the XAP study is available at the site, or until 
patient withdrawal, or until vedolizumab is available to the patient 
through commercial channels (including reimbursement) for the 
patient’s clinical scenario, or unless the study is terminated early by the 
sponsor, as described in Section 11.12, whichever is sooner. After the 
final dose of MLN0002, patients who do not transition into the XAP 
study will complete the 16-week posttreatment observation and safety 
assessment period (not applicable to patients who transition to the XAP 
study). Concomitant vedolizumab (Entyvio) taken during the 16-week 
follow-up period will be recorded as a concomitant medication and will 
not be considered as a protocol deviation.
Section 5.1
formerly 
read:
4.
Female patients who:

are postmenopausal for at least 1 year before enrollment, OR

are surgically sterile, OR

if they are of childbearing potential, agree to practice 2 
effective methods of contraception, at the same time, from the 
time of signing the informed consent form through 6 months 
after the last dose of MLN0002, OR agree to completely 
abstain from heterosexual intercourse.


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Male patients, even if surgically sterilized (ie, status 
postvasectomy), who:

agree to practice effective barrier contraception during the 
entire study treatment period and through 6 months after the
last dose of MLN0002, OR

agree to completely abstain from heterosexual intercourse.
Now reads:
4.
Female patients who:

are postmenopausal for at least 1 year before enrollment, 
OR

are surgically sterile, OR

if they are of childbearing potential, agree to practice 2 
effective methods of contraception, at the same time, from 
the time of signing the informed consent form through 18 
weeks abstain from heterosexual intercourse.
Male patients, even if surgically sterilized (ie, status 
postvasectomy), who:

agree to practice effective barrier contraception during 
the entire study treatment period and through 18 weeks
after the last dose of MLN0002, OR

agree to completely abstain from heterosexual 
intercourse.
Section 5.3 
formerly 
read:
3.
Female patients who:

Are postmenopausal for at least 1 year before the Screening 
visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 2 
effective methods of contraception, at the same time, from the 
time of signing the informed consent form through 6 months
after the last dose of study drug, OR agree to completely 
abstain from heterosexual intercourse.
Male patients, even if surgically sterilized (ie, status 
postvasectomy), who:

Agree to practice effective barrier contraception during the 
entire study treatment period and through 6 months after the 
last dose of study drug, OR

Agree to completely abstain from heterosexual intercourse.
Now reads:
3.
Female patients who:

Are postmenopausal for at least 1 year before the 
Screening visit, OR

Are surgically sterile, OR


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
If they are of childbearing potential, agree to practice 2 
effective methods of contraception, at the same time, from 
the time of signing the informed consent form through 18 
weeks after the last dose of study drug, OR agree to 
completely abstain from heterosexual intercourse.
Male patients, even if surgically sterilized (ie, status 
postvasectomy), who:

Agree to practice effective barrier contraception during 
the entire study treatment period and through 18 weeks 
after the last dose of study drug, OR

Agree to completely abstain from heterosexual 
intercourse.
Section 5.4
formerly 
read:
3.
Female patients who:

Are postmenopausal for at least 1 year before the Screening 
visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 2 
effective methods of contraception, at the same time, from the 
time of signing the informed consent form through 6 months
after the last dose of study drug, OR agree to completely 
abstain from heterosexual intercourse.
Male patients, even if surgically sterilized (ie, status 
postvasectomy), who:

Agree to practice effective barrier contraception during the 
entire study treatment period and through 6 months after the 
last dose of study drug, OR

Agree to completely abstain from heterosexual intercourse.
Now reads:
3.
Female patients who:

Are postmenopausal for at least 1 year before the 
Screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 2 
effective methods of contraception, at the same time, from 
the time of signing the informed consent form through 18 
weeks after the last dose of study drug, OR agree to 
completely abstain from heterosexual intercourse.
Male patients, even if surgically sterilized (ie, status 
postvasectomy), who:

Agree to practice effective barrier contraception during 
the entire study treatment period and through 18 weeks 
after the last dose of study drug, OR


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
Agree to completely abstain from heterosexual 
intercourse.
Section 6.2
formerly 
read:

Patients may not donate blood, sperm, or oocytes during 
the study and for 6 months after the last dose of study 
drug.
Now reads:

Patients may not donate blood, sperm, or oocytes 
during the study and for 18 weeks after the last dose of 
study drug.
Section 6.3
formerly 
read:
Female patients of childbearing potential must practice 2 effective methods 
of contraception, at the same time, during from the time of signing the 
informed consent form through 6 months after the last dose of study drug.  It 
is strongly recommended that at least 1 of these 2 methods be highly 
effective (eg, oral, implantable or injectable contraceptives, contraceptive 
patches, intrauterine devices).  Female patients are exempt from 
contraception requirements if they are postmenopausal for at least 1 year 
before enrollment, are surgically sterile (ie, status post effective tubal 
ligation, or bilateral oophorectomy, or hysterectomy), or completely abstain 
from heterosexual intercourse.
Male patients, even if surgically sterilized (ie, status postvasectomy), must 
practice effective barrier contraception during the entire study treatment 
period and continue contraception for 6 months after their last dose of study 
drug, or completely abstain from heterosexual intercourse.
Now reads:
Female patients of childbearing potential must practice 2 effective 
methods of contraception, at the same time, during from the time of 
signing the informed consent form through 18 weeks after the last dose 
of study drug.  It is strongly recommended that at least 1 of these 2 
methods be highly effective (eg, oral, implantable or injectable 
contraceptives, contraceptive patches, intrauterine devices).  Female 
patients are exempt from contraception requirements if they are 
postmenopausal for at least 1 year before enrollment, are surgically 
sterile (ie, status post effective tubal ligation, or bilateral oophorectomy, 
or hysterectomy), or completely abstain from heterosexual intercourse.
Male patients, even if surgically sterilized (ie, status postvasectomy), 
must practice effective barrier contraception during the entire study 
treatment period and continue contraception for 18 weeks after their last 
dose of study drug, or completely abstain from heterosexual intercourse.
Section 7.3 
formerly 
read:
The study procedures are described below.  After Week 0, dosing visits must 
occur within 1 week of the specified time.  It is anticipated that the total 
duration of MLN0002 treatment will vary on a patient-by-patient basis, based 
on continued benefit.  All patients will return 16 weeks after the last dose of 
MLN0002 for final safety assessments at the Final Safety visit.  All patients 


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will also complete the 2-year follow-up survey (see Section 7.6).
Now reads:
The study procedures are described below.  After Week 0, dosing visits 
must occur within 1 week of the specified time.  It is anticipated that 
the total duration of MLN0002 treatment will vary on a patient-by-
patient basis, based on continued benefit.  Patients who do not transition 
into the XAP study will return 16 weeks after the last dose of MLN0002 
for final safety assessments at the Final Safety visit.  All patients will also 
complete the 2-year follow-up survey (see Section 7.6).  Patients who 
transition into the XAP study are not required to attend the Final Safety 
Visit.  The safety of these patients will be monitored as part of the XAP 
study.  The end-of-study eCRF page must be completed for all patients 
regardless of whether they transition into the XAP study or not.
Section 
7.3.13 
formerly 
read:
Any medications that are ongoing at the time of enrollment into the C13008 
study will be recorded in the eCRF for Study C13008.  Concomitant 
medications and procedures must be reviewed at each study visit (including 
any unscheduled visit(s) due to disease exacerbation) and recorded in the 
eCRF.
Now reads
Any medications that are ongoing at the time of enrollment into the 
C13008 study will be recorded in the eCRF for Study C13008.  
Concomitant medications and procedures must be reviewed at each 
study visit (including any unscheduled visit(s) due to disease 
exacerbation) and recorded in the eCRF.  For patients enrolling into the 
XAP study, concomitant medications will be collected until the patient is 
consented into the XAP study (this is expected to occur at the final 
C13008 dosing visit where possible).
Section 
7.3.23 
formerly 
read:
For rollover patients, AEs and SAEs will be collected from the time the 
patient enrolls in the study through the Final Safety visit in Study C13008 
(16 weeks after the last dose of MLN0002).
For de novo patients, AEs will be collected from the time of enrollment, and 
SAEs will be collected from the time of signing informed consent; as with 
rollover patients, AEs and SAEs will be collected through the Final Safety 
visit (16 weeks after the last dose of MLN0002).
Now reads
For rollover patients, AEs and SAEs will be collected from the time the 
patient enrolls in the study through the Final Safety visit in Study 
C13008 (16 weeks after the last dose of MLN0002), as applicable.
For de novo patients, AEs will be collected from the time of enrollment, 
and SAEs will be collected from the time of signing informed consent; as 
with rollover patients, AEs and SAEs will be collected through the Final 
Safety visit (16 weeks after the last dose of MLN0002), as applicable.
For patients enrolling into the XAP study, AEs and SAEs will be 


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collected until the patient is consented into the XAP study (this is 
expected to occur at the final C13008 dosing visit where possible).
Section 
10.3 
formerly 
read:
All AEs and SAEs will be collected from the time of enrollment (for de novo 
patients, SAE collection will begin after the signing of informed consent) up 
to 16 weeks (112 days) after the last on-study dose of MLN0002.  All SAEs 
should be monitored until they are resolved or are clearly determined to be 
due to a patient’s stable or chronic condition or intercurrent illness(es).
Now reads:
All AEs and SAEs will be collected from the time of enrollment (for de 
novo patients, SAE collection will begin after the signing of informed 
consent) up to 16 weeks (112 days) after the last on-study dose of 
MLN0002 (as applicable).  For patients enrolling into the XAP study, 
AEs and SAEs will be collected until the patient is consented into the 
XAP study (this is expected to occur at the final C13008 dosing visit 
where possible).  All SAEs should be monitored until they are resolved 
or are clearly determined to be due to a patient’s stable or chronic 
condition or intercurrent illness(es).
Section 
10.4 
formerly 
read:
If a woman becomes pregnant or suspects she is pregnant while participating 
in this study, or within 6 months after the last dose of study drug, she must 
inform the investigator immediately and permanently discontinue study drug.  
The sponsor must also be contacted immediately by faxing a completed 
Pregnancy Form to Takeda Pharmacovigilance (see Section 10.2).  The 
pregnancy must be followed through for the final pregnancy outcome.
If a female partner of a male study participant becomes pregnant during the 
male patient’s participation in this study, or within 6 months after the last 
dose of study drug, the sponsor must also be contacted immediately by faxing 
a completed Pregnancy Form to Takeda Pharmacovigilance.  Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
Now reads
If a woman becomes pregnant or suspects she is pregnant while 
participating in this study, or within 18 weeks after the last dose of study 
drug, she must inform the investigator immediately and permanently 
discontinue study drug.  The sponsor must also be contacted 
immediately by faxing a completed Pregnancy Form to Takeda 
Pharmacovigilance (see Section 10.2).  The pregnancy must be followed 
through for the final pregnancy outcome.
If a female partner of a male study participant becomes pregnant during 
the male patient’s participation in this study, or within 18 weeks after 
the last dose of study drug, the sponsor must also be contacted 
immediately by faxing a completed Pregnancy Form to Takeda 
Pharmacovigilance.  Every effort should be made to follow the 
pregnancy for the final pregnancy outcome.


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PPD
PPD
PPD

SAP_000.pdf: 
This may include, but is not limited to, redaction of the following: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 3, Open-label Study to Determine the Long-term Safety and Efficacy of 
Vedolizumab (MLN0002) in Patients With Ulcerative Colitis and Crohn’s Disease
NCT Number: NCT00790933
SAP Approve Date: January 7, 2013
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content 
is masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


PPD


Vedolizumab
Statistical Analysis Plan, Study C13008
Confidential
2
TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...........................................4
1. INTRODUCTION ................................................................................................................8
1.1 Study Design...................................................................................................................8
1.2 Study Objectives...........................................................................................................10
1.2.1 Primary Objective..................................................................................................10
1.2.2 Resource Utilization and Patient Reported Outcome Objectives ..........................10
1.2.3 Exploratory Objective............................................................................................10
2. POPULATIONS FOR ANALYSIS....................................................................................10
2.1 Safety Population..........................................................................................................10
2.2 Efficacy Population.......................................................................................................12
3. HYPOTHESES AND DECISION RULES........................................................................13
4. INTERIM ANALYSIS .......................................................................................................13
4.1 Interim Analysis............................................................................................................13
4.2 Data Safety Monitoring Board......................................................................................13
5. STUDY DEFINITIONS AND CONVENTIONS ..............................................................13
5.1 Study Definitions..........................................................................................................13
5.2 Definition of Baseline Values.......................................................................................15
5.2.1 Change and Percent Change From Baseline..........................................................15
5.3 Visit Assignments.........................................................................................................16
5.3.1 Study Start and End Dates .....................................................................................16
5.3.2 Visit Assignments for Efficacy Variables..............................................................17
5.3.3 Visit Assignments for Safety Variables.................................................................20
5.3.4 Conventions for Missing Adverse Event Dates.....................................................25
5.3.5 Conventions for Missing Concomitant Medication Dates.....................................27
5.3.6 Conventions for Missing Previous Medication Dates ...........................................27
5.4 Calculation of Body Mass Index ..................................................................................27
6. STATISTICAL METHODOLOGY ...................................................................................28
6.1 Determination of Sample Size for the Long-term Safety Study...................................28
6.2 Randomization and Stratification.................................................................................28
6.3 Unblinding....................................................................................................................28
6.4 Methods for Handling Missing Data ............................................................................28
6.5 Patient Disposition........................................................................................................28
6.6 Demographics and Baseline Disease Characteristics ...................................................29
6.6.1 Demographics ........................................................................................................29
6.7 Treatments and Medications.........................................................................................31
6.7.1 Concomitant Medications and Procedures ............................................................31
6.7.2 Study Drug Administration....................................................................................32
6.8 Safety Analyses.............................................................................................................35
6.8.1 Safety Data Summary Grouping for Long-term Safety Study...............................36
6.8.2 Adverse Events ......................................................................................................36
6.8.3 Laboratory Data .....................................................................................................41
6.8.4 ECG .......................................................................................................................43


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Statistical Analysis Plan, Study C13008
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6.8.5 Vital Signs..............................................................................................................44
6.8.6 Immunogenicity Analysis ......................................................................................44
6.9 Exploratory Efficacy Analyses .....................................................................................45
6.9.1 General Methods....................................................................................................45
6.9.2 Exploratory Efficacy Endpoints.............................................................................46
6.9.3 Exploratory Efficacy Analysis ...............................................................................46
6.10 Resource Utilization Outcomes..................................................................................47
6.11 Patient-Reported Outcomes (PROs)...........................................................................48
7. CHANGES TO PLANNED ANALYSES FROM PROTOCOL .......................................49
8. REFERENCES ...................................................................................................................49


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Statistical Analysis Plan, Study C13008
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
5-ASAs
5-aminosalicylates
AEs
adverse events
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BUN
blood urea nitrogen
CD
Crohn’s disease
CFR
Code of Federal Regulations
CHO
Chinese hamster ovary
Cmin
minimum plasma concentration
CMV
cytomegalovirus
CNS
central nervous system
CRP
C-reactive protein
CV
coefficient of variation
DSMB
data safety monitoring board
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EQ-5D
EuroQual
ET
early termination
GCP
good clinical practice
GI
gastrointestinal
h
hours
HAHA
human anti-human antibody
HBI
Harvey-Bradshaw Index 
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HLT
high level term
IAC
Independent Adjudication Committee
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IFN
interferon
IL
interleukin
IRB
institutional review board
IV
intravenous
JCV
JC virus, a neurotropic DNA polyomavirus
IVRS
interactive voice response system


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Statistical Analysis Plan, Study C13008
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Abbreviation
Term
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MCS
mental component score
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc.  or its affiliates
MLN0002
Vedolizumab
NSAID
nonsteroidal anti-inflammatory drug
PCS
physical component score
PD
pharmacodynamics
PK
pharmacokinetics
PML
progressive multifocal leukoencephalopathy
PT
Preferred Term
PVC
polyvinylchloride
QOL
quality of life
RAMP
Risk Assessment and Minimization for PML 
RBC
red blood cell(s)
SAEs
serious adverse events
SF-36
Short-Form 36
SOC
System Organ Class
TB
tuberculosis
TNF
tumor necrosis factor alpha
UC
ulcerative colitis
UCCS
Ulcerative Colitis Clinical Score
ULN
upper limit of normal
US
United States
VAS
visual analogue scale
WBC
white blood cell(s)


Vedolizumab
Statistical Analysis Plan, Study C13008
Confidential
6
Rationale for SAP amendment 2
The  protocol was changed to include up to 400 additional patients with either ulcerative 
colitis or Crohn’s disease who had not been previously treated with vedolizumab (“de novo 
patients”). The additional patients will increase the number of patients with exposure to 
vedolizumab and supplement the safety database to detect adverse events resulting from 
long-term vedolizumab administration that may not be detected in the year-long induction 
and maintenance studies. The addition of 400 patients allows for the detection of adverse 
events that occur at a prevalence of 0.1% to be detected with more than 85% likelihood, and 
events that occur at a prevalence of 1% to be detected with 99.99% likelihood. Importantly, 
the inclusion and exclusion criteria for the de novo patients are nearly identical to the criteria 
for patients who enrolled in Studies C13006, C13007, and C13011; study treatment and 
assessments  are the same for these de novo patients as for rollover patients (those patients 
who enrolled in C13008 following participation in C13004, C13006, C13007, or C13011). 
The additional patients  are enrolled at a subset of existing sites in select countries, including 
the United States (US).
In addition, with this protocol amendment, both rollover and de novo patients participating 
in C13008 will have access to vedolizumab until March 2016, or until vedolizumab is 
available in the country in which the patient resides , or until patient withdrawal, whichever 
comes first (unless the study is terminated early by the sponsor, as described in Section 
11.12 of study protocol).
Another change to the protocol includes removal of JC virus DNA testing. When the
vedolizumab pivotal studies were planned in 2008, it was unclear if JC virus DNA testing in
the blood might be predictive of progressive multifocal leukoencephalopathy (PML) risk.
More recently, controlled studies of natalizumab (which has a proven risk of PML) have
conclusively demonstrated that detection of JC virus DNA in the blood is of no clinical
utility in minimizing risk of PML. Therefore, monitoring for JC virus DNA in the blood  has 
been discontinued.
Other changes to the protocol allow for the use of conventional, non-biological concomitant
medications for IBD to be more consistent with standard clinical practice. Thus, patients
are now  allowed to start azathioprine, 6-mercaptopurine, methotrexate (methotrexate for
CD only), or corticosteroids during the course of the study, even if they were not on these


Vedolizumab
Statistical Analysis Plan, Study C13008
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7
medications when enrolled in the study. In addition, oral corticosteroid regimens have been 
modified to be more consistent with individual patient needs, and the corticosteroid tapering
requirement has been changed to a recommendation.
The definition of treatment failure that mandates withdrawal from the study has been
modified to “long-term treatment failure” to more accurately reflect true treatment failure
that occurs in clinical practice. Given the fluctuating natural history of inflammatory bowel
disease (IBD), patients may be treated for short-term disease worsening with conventional
therapies for IBD, as allowed per protocol, without being required to withdraw from the
study. Accordingly, one of the criteria for the protocol-defined treatment failure, “disease
worsening,” that was based on disease activity indices (Harvey-Bradshaw Index and partial
Mayo score), has been removed from the definition of long-term treatment failure.
Importantly, patients are still required to be withdrawn if they require rescue medication or
major surgery for the treatment of IBD.


Vedolizumab
Statistical Analysis Plan, Study C13008
Confidential
8
1.   
INTRODUCTION
This Statistical Analysis Plan (SAP) presents a detailed plan for the analyses of the long-
term safety and efficacy study C13008.  The analysis is designed to evaluate the safety 
profile of long-term vedolizumab treatment.  
The objectives of this analysis are stated in Section 1.2, and a discussion of the analyses to 
be performed is provided in Section 6.8 through Section 6.11.
Reference materials for this SAP include Clinical Study Protocol C13008 (Amendment 10 
of the protocol, dated 15 February 2012) and the accompanying data collection documents 
(Annotated Case Report Form [CRF], final version, dated 07 May 2012).
1.1   
Study Design
This is an open-label, phase 3 study to support the long-term safety and efficacy of 
vedolizumab for the treatment of patients with moderate to severe ulcerative colitis (UC) or 
Crohn’s disease (CD).  All enrolled patients  receive 300 mg vedolizumab administered 
every 4 weeks. 
Most patients enrolling in this study  have participated in a previous vedolizumab study 
(rollover patient).

Patients with UC or CD who participated in the phase 2, open-label, long-term safety 
study (Study C13004), which includes up to 78 weeks of open-label treatment with 
vedolizumab.

Patients who withdrew early from a phase 3 induction and maintenance study (Study 
C13006 [patients with UC] or Study C13007 [patients with CD]), which includes up 
to 50 weeks of blinded study treatment (vedolizumab or placebo).  These patients 
must have withdrawn due to sustained non-response, disease worsening, or the need 
for rescue medications 

Patients who completed Study C13006 or Study C13007

Patients who completed (through Week 10) Study C13011

Waiver patient(s)


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Statistical Analysis Plan, Study C13008
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For rollover patients, the first dose of vedolizumab in this study (Week 0) should occur no 
more than 9 weeks after the last dose of study drug in the previous study; the preferable 
period is within 3 to 5 weeks after the last dose in the previous study. Results of assessments 
from the last visit in the previous vedolizumab study are used to determine their eligibility to 
participate in this study. Baseline data are also obtained from the previous study, including 
medical history, disease history, demographics, tobacco use, and prior therapies.
In addition, up to 400 patients without previous treatment with vedolizumab are enrolled 
directly into this study (de novo patients). Patients with UC or CD must meet the 
inclusion/exclusion criteria for de novo patients (Section 5 of study protocol).  
Baseline data for these patients is obtained during the Screening period.
Following enrollment, all patients are administered 300 mg vedolizomab every 4 weeks for 
the duration of the study, followed by a 16-week post-treatment observation and safety
assessment period. The total duration of MLN0002 treatment varies by patient based on
continued benefit until March 2016, or until vedolizumab is available in the country in 
which the patient resides , or until patient withdrawal, whichever is sooner (unless the study 
is terminated early by the sponsor, as described in Section 11.12 of study protocol).
Patients may receive allowed concomitant medications for the treatment of IBD as detailed
in Section 6.2.1 of study protocol, as determined by the principal investigator, at any time 
point during the study. Medications may be discontinued during the study, but if 
discontinuation is planned, it should be done prior to the first dose of vedolizumab.
It is strongly recommended that patients receiving oral corticosteroids  begin an oral
corticosteroid tapering regimen once they achieve clinical response or if, in the opinion of
the investigator, they demonstrate sufficient improvement in clinical signs and symptoms.
Patients are withdrawn from the study for long-term treatment failure as described in the
study definitions, or if they are not benefiting from therapy (see Section 6.2.3, Section 
6.4.10, and Section 7.4 of study protocol).
All patients  return 16 weeks after their last dose of MLN0002 for the Final Safety visit.
Safety assessments and efficacy assessments using the partial Mayo Score (for patients with
UC) or the HBI score (for patients with CD) will be made throughout the treatment period.


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Statistical Analysis Plan, Study C13008
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10
Detailed visit-by-visit study procedures and assessments are provided in the Schedule of
Events and Section 7 of study protocol.
This trial is conducted in compliance with the protocol, good clinical practice (GCP),
and the applicable regulatory requirements (including International Conference on
Harmonisation [ICH] guidelines).
1.2   
Study Objectives
1.2.1   
Primary Objective

To determine the safety profile of long-term vedolizumab treatment 
1.2.2   
Resource Utilization and Patient Reported Outcome Objectives

To determine the effect of long-term vedolizumab treatment on time to major 
inflammatory bowel disease (IBD)-related events (hospitalizations, surgeries, and 
procedures) 

To examine the effect of long-term vedolizumab treatment on health-related quality 
of life (QOL) measurements 
1.2.3   
Exploratory Objective

To obtain data regarding the effect of long-term vedolizumab treatment on 
maintaining clinical response and remission based on partial Mayo score (for patients 
with UC) and Harvey-Bradshaw Index (HBI) (for patients with CD)
2.   
POPULATIONS FOR ANALYSIS
There will be 2 analysis populations: the safety population and the efficacy population.  
2.1   
Safety Population
The safety population for this study is defined as all patients who receive any amount of


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Statistical Analysis Plan, Study C13008
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vedolizumab in this study. Waiver patient(s) are excluded.  The study safety population is 
used for all safety analyses.
Exposure for patients who first participated in Study C13004, C13006, C13007, or C13011 
and who are now participating in the C13008 study, is evaluated from the first dose of  
vedolizumab in Studies C13004, C13006, C13007, and C13011.  
For de novo patients, exposure  is calculated from the first dose of vedolizumab in Study 
C13008. 
Adverse events (AEs) are also evaluated from the first dose of vedolizumab in Studies 
C13004, C13006, C13007, and C13011 for the patients who received vedolizumab in Study
C13004, C13006, C13007, or C13011.  AEs are counted only during the time of  
vedolizumab administration, as follows:

For patients who received placebo in Studies C13006, C13007, and C13011, AEs are 
counted from first dose of vedolizumab in the C13008 study.

For patients who received vedolizumab in the induction phase and placebo in the
maintenance phase, AEs are counted if the AE occurred between the first dose of 
vedolizumab and the last dose of vedolizumab  in the induction phase.

For patients who were in the placebo group in Study C13002, AEs are counted from 
the first dose of vedolizumab in the C13004 study.

For patients who were in the vedolizumab group in Study C13002, AEs are counted 
from the first dose of vedolizumab in the C13002 study.

For de novo patients, AEs are counted from the first dose of  vedolizumab in the 
C13008 study. 
Concomitant medications for patients who participated in Study C13004 and continue 
participating in Study C13008 are evaluated only for the C13008 experience, while the 
concomitant medications for patients who were in Studies C13006, C13007, and C13011  
are evaluated following the administration of the first dose of vedolizumab in Studies 
C13006, C13007 and C13011.


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Concomitant medications for de novo patients are evaluated from first dose onwards of 
vedolizumab in C13008 Study.
Other safety data, such as laboratory parameters, vital signs, and electrocardiograms (ECGs),
are evaluated only for the C13008 experience.
The safety data from patients who participate in Study C13008 as waiver patient(s) will be 
included in the listings but will not be represented in the summary tables and figures.  
2.2   
Efficacy Population
The efficacy population consists of all enrolled patients. However, to be included in an
analysis at any specific time point, the patient must have had a post-baseline measurement 
for the time point. Additionally, to be included in a change from baseline analysis, the 
patient must have had a baseline measurement. Waiver patient(s) who receive any amount of 
vedolizumab in this study are excluded from the efficacy population.
The efficacy data for patients who were in Study C13006 or C13007 and continue 
participating in C13008 is analyzed from the first efficacy assessment in C13006 or C13007
for the maintenance intent-to-treat (ITT) population and non-ITT population.  The 
maintenance ITT population has 3 treatment groups : placebo, vedolizumab every 4 weeks 
(Q4 wks) dosing, and vedolizumab every 8 weeks (Q8 wks) dosing.  The non-ITT 
population has 2 treatment groups: placebo and vedolizumab every 4 weeks (Q4 wks).
The efficacy data for patients who were in Study C13011 and continue participating in Study 
C13008 is analyzed from the first efficacy assessment in C13011 by vedolizumab and 
placebo treatment groups.
The efficacy data for de novo patients is analyzed for the C13008 experience. 
All efficacy analyses is performed for patients who completed the previous Study C13006 or
C13007 (52 weeks completers) or C13011 (10 weeks completers) and those who terminated 
early (early termination) from C13006 and C13007.  
The efficacy data for patients who participated in Study C13004 and continue participating 
in C13008 is not analyzed.


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The efficacy data from waiver patient(s) who participate in C13008 is included in the listings 
but is not included in the summary tables and figures.  
The efficacy population is also used for all exploratory efficacy, resource utilization and 
patient reported outcome analyses.  
3.   
HYPOTHESES AND DECISION RULES
The analyses are primarily descriptive in nature.  Point estimations along with 95% 
confidence intervals are presented for important safety and efficacy parameters.  No formal 
statistical hypothesis tests are performed.  
4.   
INTERIM ANALYSIS
4.1   
Interim Analysis
Two interim analyses will be conducted for safety at the time of BLA/MAA filing.  
Additional interim analyses on long-term safety data will be conducted for the Day 120 
safety update(s).  
4.2   
Data Safety Monitoring Board
An independent data safety monitoring board (DSMB)  reviews safety data from this study 
including, but not limited to, incidence of AEs and AEs of special interest (eg, infusion-
related reactions, infections) on a regular basis and makes appropriate recommendations to 
Millennium.  A statistical reporting organization has been designated by Millennium to 
provide the DSMB with essential safety data during the study.  The DSMB does not review 
the efficacy data.  The DSMB responsibilities, authorities, and procedures are documented in 
a DSMB charter.  
5.   
STUDY DEFINITIONS AND CONVENTIONS
5.1   
Study Definitions
Study terms and definitions are provided below.


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Pertaining to Patients with UC
Term
Definition
Clinical Remission
A partial Mayo score of ≤2 with no individual subscore > 1.
Clinical Response
A decrease in the partial Mayo Score of at least 2 points and 25
from baseline, with an accompanying decrease in rectal bleeding 
subscore of 1 point from baseline or absolute rectal bleeding 
subscore of 1 point
Rescue 
Medication(s)
Any new medication to treat a new or unresolved luminal 
manifestation of ulcerative colitis (UC), with the following 
exceptions:
 oral and topical (rectal) 5-aminosalicylate (ASA) treatment
 oral corticosteroids per the guidelines outlined in Section 6.2.3
 topical (rectal) corticosteroid enemas/suppositories
 azathioprine or 6-mercaptopurine; stable doses are recommended
 antibiotics
 antidiarrheals for control of chronic diarrhea

 probiotics (eg, Culturelle, Saccharomyces boulardii)
Long-term 
Treatment Failure
Need for rescue medications, or major surgical intervention for 
treatment of UC, or a study drug-related adverse event leading to 
discontinuation from the study
Pertaining to Patients with CD
Term
Definition
Clinical Remission
A HBI score 4 points
Clinical Response
A 3-point decrease in HBI score from baseline
Rescue 
Medication(s)
Any new medication to treat a new or unresolved luminal 
manifestation of Crohn’s disease (CD), with the following 
exceptions:

oral and topical (rectal) 5-ASA treatment


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Term
Definition

oral corticosteroids per the guidelines outlined in Section 
6.2.3

topical (rectal) corticosteroid enemas/suppositories

azathioprine, 6-mercaptopurine, or methotrexate; stable 
doses are recommended

antibiotics

antidiarrheals for control of chronic diarrhea

probiotics (eg, Culturelle, S. boulardii)
Long-term 
Treatment Failure
Need for rescue medications, or major surgical intervention for 
treatment of CD, or a study drug-related adverse event leading to 
discontinuation from the study
5.2   
Definition of Baseline Values
For partial Mayo score, HBI, and QOL variables, the baseline value is defined as the last 
assessments before the first dose of study drug administration from each previous study in 
Studies C13006, C13007, and C13011.  For medical history, UC/CD disease history, 
tobacco use, and prior therapies, the baseline value is also obtained from the previous 
studies.  For demographics, the baseline value is defined as the last assessment before the 
first induction dose in Study C13006, C13007, or C13011 (see Section 6.6).  For the 
analyses of UC or CD, overall phase 3 clinical response, changes in partial Mayo score, and 
changes in HBI are based on the baseline calculated in Study C13006, C13007, or C13011.  
For safety analyses, such as laboratory values, vital sign measurements, and ECGs, baseline 
is defined as the value collected at the last visit before the first dose of vedolizumab in Study
C13008.  For human anti-human antibody (HAHA) and C-reactive protein (CRP) data, 
baseline values are also obtained from the previous studies.
For de novo patients, the baseline value is defined as the last assessment before the first dose 
of vedolizumab in Study C13008.
5.2.1   
Change and Percent Change From Baseline
Change from baseline to any  treatment study Week t is defined as follows:


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C t = M t – M Baseline
where:

C t is the change from baseline at Week t

M t is the measurement at Week t

M Baseline is the measurement at baseline
Percent change from baseline to any maintenance treatment study Week t is defined as 
follows:
P t = 100 (M t – M Baseline) / M Baseline.
The “Week t” to which the measurement belongs is determined using the conventions 
described in Section 5.3.
5.3   
Visit Assignments
5.3.1   
Study Start and End Dates
Enrollment is defined as the time at which the patient is entered into the Interactive Voice 
Response System (IVRS) for this study.  Long-term safety study (C13008) treatment begins 
on the date of the first dose of study drug as recorded on the CRF.
Following enrollment, all patients are administered 300 mg vedolizumab every 4 weeks for 
the duration of the study , followed by a 16-week, post-treatment observation and safety 
assessment period.  The total duration of vedolizumab treatment varies by patient based on 
continued benefit until March 2016, or until vedolizumab is available in the country in 
which the patient resides, or until patient withdrawal, whichever is sooner (unless the study 
is terminated early by the sponsor). The end of long-term treatment for patients who
complete the study or who terminate early is defined as the date of the last known dose of 
vedolizumab during the C13008 study plus 16 weeks.    


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5.3.2 Visit Assignments for Efficacy Variables
Week assignment:  Patients may not adhere strictly to the visit timing in the protocol.  
Therefore the designation of visits during the long-term safety is based on the day of 
evaluation relative to the start of the study rather than the nominal visit recorded in the CRF.  
Accordingly, the study is divided into continuous, mutually exclusive, analysis windows 
(Table 5-1), for the following efficacy measurements.  
For efficacy parameters (partial Mayo score and HBI), if a patient has more than 1 score 
within a window, the assessment closest to the target day is used.  In case of ties between 
observations located on different sides of the target day, the later assessment is used.  If more
than 1 score is available on the same day, the mean of the values is used.  
Table 5-1   
Day Windows: Partial Mayo Score and HBI Score for the Patients Who 
Were in Studies C13006 and C13007, and C13008 de novo patients
Visit in C13006/7
Target Day
Day Range
Week 2
15
2 - 21
Week 4
29
22 - 35
Week 6
43
36 - 56
Week 10
71
57 – 84
Week 14
99
85 – 112
Week 18
127
113 – 140
Week 22
155
141 – 168
Week 26
183
169 – 196
Week 30
211
197 – 224
Week 34
239
225 – 252
Week 38
267
253 – 280
Week 42
295
281 – 308
Week 46
323
309 – 336
Week 50
351
337 - 357
Week 52
365
358 - 392
Visit in C13008
Target Day
Day Range
Screening*
Week 0*
1
-14
Week 4
29
15-42
Week 8
57
43-70
Week 12
85
71 – 112
Week 20
141
113 – 168
Week 28
197
169 – 224


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Table 5-1   
Day Windows: Partial Mayo Score and HBI Score for the Patients Who 
Were in Studies C13006 and C13007, and C13008 de novo patients
Week 36
253
225 – 280
Week 44
309
281 – 336
Week 52
365
337 – 392
Week 60
421
393 – 448
Week 68
477
449 – 504
Week 76
533
505 – 560
Week 84
589
561 – 616
Week 92
645
617 – 672
Week 100
701
673 - 728
Week 108
757
729-784
Week 116
813
785-840
Week 124
869
841 – 896
Week 132
925
897 – 952
Week 140
981
953 – 1008
Week 148
1037
1009 – 1064
Week 156
1093
1065 – 1120
Week 164
1149
1121 – 1176
Week 172
1205
1177 – 1232
Week 180
1261
1233 – 1288
Week 188
1317
1289 – 1344
Week 196
1373
1345 – 1400
Week 204
1429
1401-1456
Week 212
1485
1457-1512
Week 220
1541
1513-1568
Week 228
1597
1569-1624
Week 236
1653
1625-1680
Week 244
1709
1681-1722
Week 248
1737
1723-1764
Week 256
1793
1765-1820
Week 264
1849
1821-1876
Week 272
1905
1877-1932
Week 280
1961
1933-1988
Week 288
2017
1989-2044
Week 296
2073
2045-2086
Week 300
2101
2087-2128
Week 308
2157
2129-2184


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Table 5-1   
Day Windows: Partial Mayo Score and HBI Score for the Patients Who 
Were in Studies C13006 and C13007, and C13008 de novo patients
Week 316
2213
2185-2240
Week 324
2269
2241-2296
Week 332
2325
2297-2352
Week 340
2381
2353-2408
Week 348
2437
2409-2450
Week 352
2465
2451-2492

For de novo patients, screening and week 0 are from nominal visit.
Table 5-2   
Day Windows: HBI Score for the Patients Who Were in Study C13011
Visit in C13011
Target Day
Day Range
Week 2
15
2 - 28
Week 6
43
29-56
Week 10
71
57-84
Visit in C13008
Target Day
Day Range
Screening*
Week 0*
1
-14
Week 4
29
15-42
Week 8
57
43-70
Week 12
85
71 – 112
Week 20
141
113 – 168
Week 28
197
169 – 224
Week 36
253
225 – 280
Week 44
309
281 – 336
Week 52
365
337 – 392
Week 60
421
393 – 448
Week 68
477
449 – 504
Week 76
533
505 – 560
Week 84
589
561 – 616
Week 92
645
617 – 672
Week 100
701
673 - 728
Week 108
757
729-784
Week 116
813
785-840
Week 124
869
841 – 896
Week 132
925
897 – 952
Week 140
981
953 – 1008
Week 148
1037
1009 – 1064


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Table 5-2   
Day Windows: HBI Score for the Patients Who Were in Study C13011
Week 156
1093
1065 – 1120
Week 164
1149
1121 – 1176
Week 172
1205
1177 – 1232
Week 180
1261
1233 – 1288
Week 188
1317
1289 – 1344
Week 196
1373
1345 – 1400
Week 204
1429
1401-1456
Week 212
1485
1457-1512
Week 220
1541
1513-1568
Week 228
1597
1569-1624
Week 236
1653
1625-1680
Week 244
1709
1681-1722
Week 248
1737
1723-1764
Week 256
1793
1765-1820
Week 264
1849
1821-1876
Week 272
1905
1877-1932
Week 280
1961
1933-1988
Week 288
2017
1989-2044
Week 296
2073
2045-2086
Week 300
2101
2087-2128
Week 308
2157
2129-2184
Week 316
2213
2185-2240
Week 324
2269
2241-2296
Week 332
2325
2297-2352
Week 340
2381
2353-2408
Week 348
2437
2409-2450
Week 352
2465
2451-2492
* For de novo patients, screening and week 0 are from nominal visit.   
5.3.3Visit Assignments for Safety Variables 
Table 5-3   
Day Windows: JCV, Clinical Chemistry, and Hematology*
Visit in C13008
Target Day
Day Range
Screening**
Week 4
29
2 – 56
Week 12
85
57 – 112


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Table 5-3   
Day Windows: JCV, Clinical Chemistry, and Hematology*
Visit in C13008
Target Day
Day Range
Week 20
141
113 – 168
Week 28
197
169 – 224
Week 36a
253
225 – 280
Week 44
309
281 – 336
Week 52b
365
337 – 392
Week 60
421
393 – 448
Week 68a
477
449 – 504
Week 76
533
505 – 560
Week 84
589
561 – 616
Week 92
645
617 – 672
Week 100a
701
673 – 728 (673 -- 756)c
Week 108
757
729-784
Week 116
813
785-840 (757-868)
Week 124
869
841 – 896
Week 132
925
897 – 952 (869 – 980)
Week 140
981
953 – 1008
Week 148
1037
1009 – 1064 (981- 1092)
Week 156
1093
1065 – 1120
Week 164
1149
1121 – 1176 (1093 -1204)
Week 172
1205
1177 – 1232
Week 180
1261
1233 – 1288 (1205 -1316)
Week 188
1317
1289 – 1344
Week 196
1373
1345 – 1421 (1317 -1428)
Week 212
1485
1429-1540
Week 228
1597
1541-1666
Week 248
1737
1667-1792
Week 264
1849
1793-1904
Week 280
1961
1905-2030
Week 300
2101
2031-2156
Week 316
2213
2157-2268
Week 332
2325
2269-2394
Week 352
2465
2395-2535
* JCV assessment, clinical chemistry and hematology are not conducted at Day 0.  For baseline, the last 
measurement from the previous study (eg, C13004, C13006, C13007, or C13011) is used.
** For de novo patients, screening and week 0 are from nominal visit.
a Schedule for CRP follows Weeks 36, 68,  100, 132, 164, and 196 visits window above.
b Schedule for coagulation follows Week 52, 104, and 152 visit window above.
c Windows in the brackets are for clinical chemistry and hematology in Years 3 and 4 only. . JCV testing 


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Table 5-3   
Day Windows: JCV, Clinical Chemistry, and Hematology*
Visit in C13008
Target Day
Day Range
was discontinued per protocol amendment 8.  No JCV testing beyond Week 196.
Duplicate laboratory assessments:  If the same parameter is reported more than once on the 
same date, the mean of that parameter is used in the analyses.  If a patient has more than 1 
measure within a visit but on different dates, the assessment closest to the target day is used.  
In case of ties between observations located on different sides of the target day, the later 
assessment is used.  In case of ties located on the same side of the target day (ie, more than 1 
value for the same day), the mean of the values is used.  For HAHA and CRP, if a patient 
has more than 1 measurement within the same study day, the highest value is used.
For JCV, if a patient has more than 1 measurement within an analysis window, the positive 
assessment value is chosen over a negative JCV value regardless of the target date.  If more
than 2 negative JCVs are within the same window, the 1 closest to the target date is used.  If 
more than 2 positive JCVs are within the same window, the 1 with the higher titer value is 
chosen over the 1 with lower titer value.  For duplicate vital sign parameters, the same rule 
as above is followed.
Table 5-4   
Study Visit Windows: Vital Signs
Visit in C13008
Target Day
Day Range
Screening*
Week 0*
Week 4
29
2 – 42
Week 8
57
43 – 70
Week 12
85
71 – 98
Week 16
113
99 – 126
Week 20
141
127 – 154
Week 24
169
155 – 182
Week 28
197
183 – 210
Week 32
225
211 – 238
Week 36
253
239 – 266
Week 40
281
267 – 294
Week 44
309
295 – 322
Week 48
337
323 – 350
Week 52
365
351 – 378
Week 56
393
379 – 406


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Table 5-4   
Study Visit Windows: Vital Signs
Visit in C13008
Target Day
Day Range
Week 60
421
407 – 434
Week 64
449
435 – 462
Week 68
477
463 – 490
Week 72
505
491 – 518
Week 76
533
519 – 546
Week 80
561
547 – 574
Week 84
589
575 – 602
Week 88
617
603 – 630
Week 92
645
631 – 658
Week 96
673
659 – 686
Week 100
701
687 – 714
Week 104
729
715 – 742
Week 108
757
743 – 770
Week 112
785
771 – 798
Week 116
813
799 – 826
Week 120
841
827 – 854
Week 124
869
855 – 882
Week 128
897
883 – 910
Week 132
925
911 – 938
Week 136
953
939 – 966
Week 140
981
967 – 994
Week 144
1009
995 – 1022
Week 148
1037
1023 – 1050
Week 152
1065
1051 – 1078
Week 156
1093
1079 – 1106
Week 160
1121
1107 – 1134
Week 164
1149
1135 – 1162
Week 168
1177
1163 – 1190
Week 172
1205
1191 – 1218
Week 176
1233
1219 – 1246
Week 180
1261
1247 – 1274
Week 184
1289
1275 – 1302
Week 188
1317
1303 – 1330
Week 192
1345
1331 – 1358
Week 196
1373
1359 – 1386
Week 200
1401
1387-1414
Week 204
1429
1415-1442


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Table 5-4   
Study Visit Windows: Vital Signs
Visit in C13008
Target Day
Day Range
Week 208
1457
1443-1470
Week 212
1485
1471-1498
Week 216
1513
1499-1526
Week 220
1541
1527-1554
Week 224
1569
1555-1582
Week 228
1597
1583-1610
Week 232
1625
1611-1638
Week 236
1653
1639-1666
Week 240
1681
1667-1694
Week 244
1709
1695-1722
Week 248
1737
1723-1750
Week 252
1765
1751-1778
Week 256
1793
1779-1806
Week 260
1821
1807-1834
Week 264
1849
1835-1862
Week 268
1877
1863-1890
Week 272
1905
1891-1918
Week 276
1933
1919--1946
Week 280
1961
1947-1974
Week 284
1989
1975-2002
Week 288
2017
2003-2030
Week 292
2045
2031-2058
Week 296
2073
2059-2086
Week 300
2101
2087-2114
Week 304
2129
2115-2142
Week 308
2157
2143-2170
Week 312
2185
2171-2198
Week 316
2213
2199-2226
Week 320
2241
2227-2254
Week 324
2269
2255-2282
Week 328
2297
2283-2310
Week 332
2325
2311-2338
Week 336
2353
2339-2366
Week 340
2381
2367-2394
Week 344
2409
2395-2422
Week 348
2437
2423-2450
Week 352
2465
2451-2478


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*For de novo patients, screening and week 0 are from nominal visit.
For parameters that are not listed in the above tables, data collected from scheduled visits are 
analyzed by the nominal visit week as labeled in the CRF.  Data collected from unscheduled 
visits are presented in the listings, but not  summarized in the pre-planned analysis.  For 
example, IBDQ, SF-36, EQ-5D, and HAHA data are analyzed by the nominal visit week as 
labeled in the CRF.    
Duplicates in Quality of Life Parameters:  For handling partial and complete questionnaire 
data, when multiple records of the same type are present for a visit, the following 
conventions are used:

If 1 complete score (all components and total [where applicable]) and 1 partial score 
(at least 1 missing component) are available for the same visit, the complete score is 
used—regardless of proximity to target date.

If 2 partial scores are available, for overlapping components, the score from the date 
closest to the target date is given precedence for the given component.  Components 
can be mixed from the 2 dates (if available components differ) and a new total 
calculated.

If more than 1 complete score is available for the same visit, the data from the date 
closest to the target date is used.

If partial scores are on separate dates but are the same proximity to the target date,
the latest partial date is used.
5.3.4   
Conventions for Missing Adverse Event Dates
Every effort is made to determine the actual onset date for the event or to obtain a reliable 
estimate for the onset date from the investigator.
For AEs or SAEs, a missing or incomplete onset date is imputed according to the following 
conventions:
1. If an onset date is missing, the derived onset date  is calculated as the first non-
missing valid date from the following list (in order of precedence):


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
First  vedolizumab dose date 

Consent date (for SAEs only)
2. If an onset date is incomplete, the derived onset date  is calculated by the following:

Missing day, but month and year present: the day is imputed as the 15th of the 
month.  If the month and year are equal to the month and year of the first 
vedolizumab dose and the first  vedolizumab dose occurs after the imputed date, 
the derived onset date is set equal to the first vedolizumab date.  If the AE end 
date occurs before the imputed date, the derived onset date is set equal to the AE 
end date.

Missing day and month, but year present: the day and month is imputed as the 
30th June of the year.  If the year is equal to the year of the first vedolizumab dose 
and the first vedolizumab dose occurs after the imputed date, the derived onset 
date  is set equal to the first vedolizumab  date.  If the AE end date occurs before
the imputed date, the derived onset date is set equal to the AE end date.

If the imputed AE onset date occurs after the database lock date, the imputed AE 
onset date is imputed as the database lock date.  
For AEs or SAEs, a missing or incomplete end date is imputed according to the following 
conventions:
1. If an end date is missing, the derived end date is imputed as the last assessment date, 
assuming that the last assessment occurs after the AE start.  If the last assessment 
occurs before the AE start date, the derived end date is imputed as the AE start date.  
2. If an end date is incomplete, the derived end date  is calculated by the following:

Missing day, but month and year present: the day is imputed as the last date (for 
example February 2009 is imputed as 28 February 2009) of the month.  

Missing day and month, but year present: the day and month is imputed as the 
31st December of the year.  

If the imputed AE end date occurs after the database lock date, the imputed AE 
end date is imputed as the database lock date.  


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Missing dates for hospitalizations for UC or CD, colectomies (UC) or bowel surgeries (CD),
and UC or CD procedures follow the same rules as previously defined.
5.3.5   
Conventions for Missing Concomitant Medication Dates
Start and stop dates for all concomitant medications are collected on the CRF.  However, in
the case of missing or partial information in these dates, the following rules are used:
If the start date is missing or partial:

If the day is missing, the start day is the first day of the month.

If the month is missing, the start month is the month corresponding to 90 days before
the first study medication date.

If the year is missing, the start year is the year of the entry visit (or consent date, for 
those missing entry visit).

If the entire date is missing, the start date is the date of first vedolizumab 
administration.
If the stop date is missing, partial, or “continuing:”

If the day is missing, the stop day is the last day of the month reported.

If the month is missing, the stop month is the month during which the last assessment 
occurred.

If the year or the entire date is missing or if the medication is “continuing”, the stop 
year is the year in which the last assessment occurred.
5.3.6   
Conventions for Missing Previous Medication Dates
No dates are imputed for previous medications.
5.4   
Calculation of Body Mass Index
Millennium  calculates BMI as the ratio of patient’s weight (in kilograms) to the square of 
the patient’s height (in meters): BMI = kg/m2.  


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6.   
STATISTICAL METHODOLOGY
6.1   
Determination of Sample Size for the Long-term Safety Study
This is a phase 3 study to determine the long-term safety of vedolizumab (MLN0002) in 
patients with UC and CD. Most patients enrolled in this study  have participated in a 
previous qualifying MLN0002 study as detailed in Section 4.1 (rollover patients). Up to 400 
additional patients who have not been previously treated with vedolizumab may be enrolled 
(de novo patients) to supplement the safety database. The current estimate is that 
approximately 2200 patients in total will enter this study.
6.2   
Randomization and Stratification
No randomization or stratification is planned for this study.
6.3   
Unblinding
This is an open-label study; there is no blinding.  
6.4   
Methods for Handling Missing Data
All available safety and efficacy data are included in data listings and tabulations.  No 
imputation of values for missing data are performed, except as described within this 
statistical analysis plan.    
All patients who prematurely discontinue for any reason are considered censored for time to 
event type of analyses and endpoints.
6.5   
Patient Disposition
Patient disposition is summarized by  study: 

Patients who were in C13004 study,

Patients who were in C13006 study,

Patients who were in C13007 study

Patients who were in C13011 study


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
De novo patients in C13008 study
In addition to the above 5 groups, safety data  is also  summarized by the following 
subgroups:

By indication: UC and CD

By prior TNF-α failures (Yes/No)
Data for waiver patients are not presented in the summary tables, but are displayed in the 
listings.  
The disposition table displays the number of patients in:

Safety Population

Efficacy Population

Prior TNF failure population 

Early termination from prior study

Completed prior study

Ongoing Patients 

Completed Long-term Safety Study 

Not Completing Long-term Safety Study, Primary Reasons
Patients who discontinued from the C13008 study are listed.  This listing uses the safety 
population.  
6.6   
Demographics and Baseline Disease Characteristics
6.6.1   
Demographics
For demographic characteristics, the baseline value is defined as the last assessment before
the first induction dose of blinded study drug (C13006, C13007, or C13011) and the first 
dose of vedolizumab (C13004) or the assessment at screening for de novo patients.  


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Demographic baseline data, such as age, gender, race, and ethnicity (Hispanic/Latino and 
non-Hispanic/Latino), body weight, BMI, and geographic region (as defined in Appendix 3) 
are summarized overall and by the 3 categories as defined in Section 6.5, using the safety 
population.  Patient baseline age and BMI are summarized as continuous variables.  
For baseline disease characteristics, UC- or CD-related medical and disease history and QOL 
baseline variables, the values are defined as the last assessments before the first dose of 
study drug administration in previous Studies C13004, C13006, C13007, and C13011.  For 
de novo patients, the values at screening are used. 
Disease-specific baseline disease characteristics are summarized by UC and CD indication, 
and by the categories as defined in Section 6.5.
Table 6-1   
Summaries of UC/CD-Related Baseline Characteristics
Characteristic
Summarized as
Categories
Duration of Crohn’s Disease 
(CD only)
Continuous 
Duration of Ulcerative Colitis 
(UC only)
Continuous 
Categorical Duration of 
Ulcerative Colitis (UC only)
Categorical
< 1 year, 1- < 3 years, 3- < 7 years
Categorical Duration of Crohn’s 
Disease ( CD only)
Categorical
< 1 year, 1- < 3 years, 3-7 years, 
missing
Patients with prior TNF α use
Categorical
Yes/No
Patients with  prior TNFα 
failure
Categorical 
Yes/No
Patients with TNF α and 
immunomodulator  failure
Categorical 
Yes/No
Patients with corticosteroid or  
immunomodulator 
Categorical 
Yes/No
Patients with only concomitant 
corticosteroid 
Categorical
Yes/No
Patients with only concomitant 
immunomodulator 
Categorical 
Yes/No
Patients with concomitant 
corticosteroid and 
Immunomodulator 
Categorical 
Yes/No
Patients with concomitant 
corticosteroid
Categorical 
Yes/No
Patients with concomitant 
immunomodulator
Categorical 
Yes/No
HBI (CD only)
Continuous


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Table 6-1   
Summaries of UC/CD-Related Baseline Characteristics
Characteristic
Summarized as
Categories
CRP (CD only)
Continuous
Fistulizing Disease (CD only)
Categorical 
Yes/No
Smoking Status
Categorical 
Current Smoker
Nonsmoker
Former Smoker
Partial Mayo Score (UC only)
Continuous
Baseline of Extraintestinal 
Manifestations(UC only)
Categorical
Yes/No
Baseline of Extraintestinal 
Manifestations(CD only)
Categorical
Yes/No
For categorical characteristics, percent is calculated out of the total number of patients in the 
data set, overall and by subcohorts.  
Duration of UC or CD is calculated as below:
(1 + C13008 first dose date – diagnosis date from C13004/006/007/011)/ 365.25.
For de novo patients, duration of UC or CD is calculated as (1 + C13008 first dose date –
diagnosis date)/ 365.25.
Demographics are presented in listings for each patient in the safety population.
6.7   
Treatments and Medications
6.7.1   
Concomitant Medications and Procedures
Concomitant medication is defined as medication, any amount of which is taken between the 
first and last day (inclusive) of vedolizumab administration.  Concomitant procedures are 
similarly defined.  
Concomitant medications are summarized for the safety population by drug class (ATC 
Pharmacological subgroup), generic drug name, and patient categories as defined in Section 
6.5.  Concomitant medication use is also presented in listings.  
Concomitant procedures are not coded, but presented in listings for each patient in the safety 
population.  


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6.7.2   
Study Drug Administration
Patients  receive open-label vedolizumab by intravenous (IV) infusion.   
6.7.2.1   Extent of Exposure
Extent of exposure is defined as the number of complete infusions a patient receives.  A 
patient must receive at least 75% of an infusion for it to be considered complete.  
Exposure to study drug is defined as the number of days the patient received study drug 
based on the first and last doses regardless of in which study the beginning or end of dosing 
occurred.  Given Q8 week dosing schedule, exposure  also includes an additional 56 days 
after the last dose:   
Exposure = (date of last infusion – date of first infusion) + 56
The cumulative distribution of the number of months on study drug (categorized by ≥1
month, ≥6 months, ≥ 12 months, ≥ 18 months, ≥ 24 months, ≥ 30 months, and ≥36 months) 
is provided as well as the cumulative distribution of the infusions.  
The exposure presentations are provided for overall (CD and UC combined) and by 
indication.  The overall vedolizumab experience includes the exposure to vedolizumab in all 
the  trials (double-blind: C13006, C13007, and C13011 and open-label: C13002-C13004 
and C13008).
The following rules are set up as referenced by the Request for Information FDA Advisory 
Committee April 2011.  
General Rules:

Last Dose Date in Induction is defined as the latest dose date entered into Inform, 
before the maintenance randomization date.

Last Dose Date on Study is defined as the latest dose date entered into Inform.

Methods are heavily reliant on data being entered into InForm.


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Exposure Calculation Rules for Incorporating Up to 16 Week PK/PD Effect 
C13006/7 Patients

Calculate exposure for C13006/7 and C13008 separately and sum.  

For C13006/7:
o
If on placebo in Induction in C13006/7, then C13006/7 EXPOSURE = 0
o
If on drug in Induction only (and not on drug in Maintenance):

Calculate C13006/7 End Exposure Date as min((Last Dose in Induction + 16 
weeks), C13008 Start Date)

C13006/7 EXPOSURE = (C13006/7 End Exposure Date – First Dose in 
Induction + 1)
o
If on drug in Induction & Maintenance:

Calculate C13006/7 End Exposure Date as min (Last Dose in Maintenance + 
16 weeks, C13008 Start Date)

C13006/7 EXPOSURE = (C13006/7 End Exposure Date – First Dose in 
Induction + 1)

For C13008:
o
End exposure date = min((Last Dose Date on C13008 + 16 weeks), Data Cutoff 
Date)
o
C13008 EXPOSURE = (End Exposure Date-First Dose Date in C13008 + 1)

TOTAL EXPOSURE = C13006/7 EXPOSURE + C13008 EXPOSURE
C13011 Patients

Calculate exposure for C13011 and C13008 separately and sum.  

For C13011:


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o
If placebo in C13011, then C13011 EXPOSURE = 0
o
Calculate C13011 End Exposure Date as min ((Last Dose in Induction in C13011 
+ 16 weeks), C13008 Start Date)
o
C13011 EXPOSURE = (C13011 End Exposure Date – First Dose in Induction 
+ 1)

For C13008:
o
End exposure date = min((Last Dose Date on C13008 + 16 weeks), Data Cutoff 
Date)
o
C13008 EXPOSURE = (End Exposure Date-First Dose Date in C13008 + 1)

TOTAL EXPOSURE = C13011 EXPOSURE + C13008 EXPOSURE
C13002/4 Patients
For patients who have rolled over into C13008:

For C13002/4:
o
Calculate C13002 End Exposure Date as min ((Last Dose in C13002 + 16 
weeks), C13004 Start Date)
o
Calculate C13004 End Exposure Date as min ((Last Dose in C13004 + 16 
weeks), C13008 Start Date)
o
If not in C13002 or on placebo in C13002, C13002/4 EXPOSURE = C13004 
End Exposure Date - First Dose Date in C13004 + 1
o
If on drug in C13002, C13002/4 EXPOSURE = (C13004 End Exposure Date -
First Dose Date in C13004 + 1) + (C13002 End Exposure Date – First Dose Date 
in C13002 + 1)

For C13008:
o
Calculate C13008 End Exposure Date as min((Last Dose in C13008 + 16 weeks), 
C13008 Data Cutoff Date)


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o
C13008 EXPOSURE = (C13008 End Exposure Date-First Dose Date in C13008 
+ 1)
TOTAL EXPOSURE = C13002/4 EXPOSURE + C13008 EXPOSURE  
Exposure is also calculated  incorporating up to 8 weeks (56 days).  The same rules as above 
are applied but by adding 8 weeks instead of 16 weeks in the calculations.  
Exposure Calculation Rules Without Incorporating Up to 16 Week PK/PD Effect 
In addition, exposure without incorporating up to 16 week PK/PD effect post last dose is
calculated as below.
Use the exposure calculation rules above with the following modifications: 
1. Do not add 16 weeks at any point in the calculations.
2. For patients C13006/7/11 on drug in induction only, calculate the end of exposure 
date as min (last dose date in induction + 4 weeks, C13008 start date).  
3. For patients C13006/7 on drug in induction and maintenance, calculate the end of 
exposure date as min (last dose date in maintenance + 2 weeks, C13008 start date).  
For de novo patients, the following rule is used to calculate exposure (in days):
o
End exposure date = min((Last Dose Date on C13008 + 16 weeks), Data Cutoff 
Date)
o
C13008 EXPOSURE = (End Exposure Date-First Dose Date in C13008 + 1)
Extent of exposure for the long-term safety treatment is listed by patient.
6.8  
Safety Analyses
Summaries of safety data such as Lab, JCV, RAMP, vital, PML checklist responses, and 
ECG are provided for data collected on patients during Study C13008 up to the final safety 
visit.  These analyses are performed using the safety population.
Summary of AEs, SAE, and infections are based on the safety population as described in 
Section 2.1.  In addition to incidence rates, rates of certain AEs, such as infections, are 
expressed in terms of time adjusted incidence rates (eg, events/person-year) to accommodate 
variable patient follow-up time and recurrent AEs within the same patient.


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No statistical tests are performed.
6.8.1   
Safety Data Summary Grouping for Long-term Safety Study
AE incidence rates and other safety parameters are summarized for all C13002/4/6/7/8/11 
patients, and by the patient groups defined in Section 6.5.  In addition, incidence rates are 
summarized by CD and UC.  
The comprehensive safety assessment as described in Section 8.7 of the C13008 Protocol 
Amendment 10 will be covered by the integrated safety summary that will have a separate 
analysis plan.
6.8.2   
Adverse Events
The Medical Dictionary for Regulatory Activities (MedDRA) is used for coding AEs.  To 
summarize the number of patients with AEs, patients reporting the same event more than 
once has that event counted only once within each system organ class (SOC), high-level 
term (HLT), and preferred term (PT).  
Key guidelines for the selection of AE incident rates for counting are as follows:
1. Where a patient has the same AE, based on preferred terminology, reported multiple 
times in a single analysis period, the patient  is counted only once in the preferred 
terminology level in AE tables.
2. When a patient has the same AE, based on preferred terminology, reported multiple 
times in a single analysis phase, the following criteria, in order of precedence, are 
used to select the event to be included in summary tables.

Relationship to study medication

Intensity of event

Onset date and time (the earlier onset date and time are selected for the incident 
rates)
3. When reporting AE incident rates by intensity, the most intense event during the 
analysis phase is summarized, independent of relationship to study medication.  For 


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these tables, the following criteria, in order of precedence, are used to select the event
to be included in summary tables.  

Intensity of event

Onset date and time (the earlier onset date and time are  selected for the incident 
rates)
For any AE (serious or not), onset of the AE is determined using the Conventions outlined in 
Section 5.3.4.
In summaries by SOC, HLT, and PT, AEs are sorted by decreasing frequency of each PT, 
HLT, and SOC according to the incident rates.  In summaries by PT, AEs are sorted by 
decreasing frequency within PT according to the incident rates.
6.8.2.1   Treatment-Emergent Adverse Events  
A treatment-emergent AE (TEAE) is defined as any new medical event/finding that occurs 
after the first vedolizumab administration in C13002/4/6/7/8/11  as recorded on the CRF.
6.8.2.2   Time Adjusted Incidence Rates 
To provide a benchmark for evaluation of AEs reported in the long-term safety study, a 
cohort study was performed on data from an external administrative database (HealthCore 
Integrated Research Database, HIRDTM), which includes a broad representation of patients 
on various therapies for IBD including biological agents.  These analyses will provide 
estimates of the background rates of AEs of special interest.  
For the analysis of the HIRD and Study C13008, the time adjusted incidence rate is defined 
as the number of patients experiencing an AE of interest divided by the person-time at risk.  
The amount of person-time will be truncated after a patient experiences an adverse event of 
special interest, although that patient will continue to contribute person-time for unrelated 
adverse events of special interest.  
AE of special interest can be found in Appendix 8.  The final list for AEs of special interest 
will depend on the results of Study C13008.


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6.8.2.3   All Adverse Events  
AE incidence rates are summarized by SOC, HLT, PT, and by the groups defined in Section 
6.5.  
All reported AEs during the long-term safety study are listed by the groups defined in 
Section 6.5.
6.8.2.4   Serious Adverse Events
Serious adverse event (SAE) incident rates are presented by SOC, HLT, PT, and by the 
groups defined in Section 6.5.  In addition, related SAE incident rates are presented by SOC, 
HLT, PT, and by the groups defined in Section 6.5.
All SAEs are listed by the groups defined in Section 6.5.
6.8.2.5   Deaths
All on-study deaths recorded on the AE page (outcome), or death page (with a death date
and cause of death) of the CRF are considered in the analyses.  All deaths are summarized by 
PT for the total patient group.  All deaths are listed.
6.8.2.6   Adverse Events Resulting in Discontinuation of Study Drug
AEs reported with an action taken of “discontinuation of study drug” are summarized by 
SOC, HLT, PT, and the groups defined in Section 6.5.  Adverse events resulting in 
discontinuation of study are also summarized by SOC, HLT, PT, and CD/UC subgroups as 
defined in Section 6.5.
In addition, all AEs leading to discontinuation of study drug are listed.
6.8.2.7   Adverse Events of Special Interest
Based on the mechanism of action of vedolizumab, certain adverse events and safety 
laboratories are of special interest.  AEs of special interest include unusual or opportunistic 
infections, serious infections, and neoplasms.  AEs of special interest are summarized by 
MedDRA SOC, HLT, and PT according to the groups defined in Section 6.5.  Separately, 


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some AEs of special interest are also summarized by SOC, HLT, PT, and CD/UC subgroups 
as defined in Section 6.5.  
The categories of adverse events of special interest and other planned analyses are as 
follows:
Infections
Summary tables of all serious infections and infections leading to discontinuation of study 
drug are presented .  As vedolizumab is a local immunomodulator of the gastrointestinal 
tract, mucosal and gastrointestinal infections are also summarized separately.  TEAE 
infections are also listed.  Incidence of infections are summarized by the groups defined in 
Section 6.5.  Infection rates are summarized by SOC, HLT, PT, and CD/UC subgroups as 
defined in Section 6.5.  
Infections are also presented by time adjusted incidence rate (eg, events/person years).
Comparative rates of infection in patients who have not received concomitant 
immunomodulators or concomitant corticosteroids (monotherapy) , patients who have 
received concomitant immunomodulators  (eg, azathioprine, 6-mercaptopurine), and patients 
who have received concomitant corticosteroids (eg, prednisone, prednisolone),  are reported.
Gastrointestinal Adverse Events
Subset analyses of all gastrointestinal AEs include all serious AEs and gastrointestinal AEs 
leading to discontinuations.  Gastrointestinal AE incident rates are summarized by the 
patient groups defined in Section 6.5.  
Infusion-Related Reactions/Immunogenicity
Infusion-related AEs are summarized by PT and the patient groups defined in Section 6.5.  
In addition, all AEs beginning on or 1 calendar day after the dates of study drug infusions are 
similarly analyzed.  Comparative rates of infusion-related AEs are reported in HAHA-
negative and HAHA- positive patients (see Section 6.8.6.3).  Comparative rates of infusion-
related AEs are also reported by CD/UC subgroups as defined in Section 6.5.  Infusion-
related AEs (investigator defined) are presented by preferred term.


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Safety Related to Risk Management (RAMP Algorithm, JC Viremia, and Long-term Follow-
up Data) 
The protocol incorporates an active screening program to identify and manage any case of 
progressive multifocal leukencephalopathy (Protocol Section 10.5.3).  This program is 
known as the Risk Assessment and Minimization for PML (or RAMP).  In addition to the 
RAMP, plasma specimens were collected during the study and assayed for JC virus (JCV).  
However, JCV testing was discontinued per protocol amendment 8.
The results of the RAMP screening program are summarized for the patient groups defined 
in Section 6.5.  Results of JCV testing are also summarized for the overall patient group.  
The RAMP algorithm findings are also listed.  
Summary tables for long-term follow-up data are summarized.  
Neoplasms (Benign, Malignant, and Unspecified) 
All neoplasms are summarized overall, by patient groups, and by CD/UC subgroups as 
defined in Section 6.5.
Liver Function Tests
Descriptive statistics and shift tables for all liver function test results are reported, and all 
liver function abnormalities reported as AEs are summarized by the patient cohorts 
described in Section 6.5.  In addition, the percentage of subjects who develop categorical 
increases (≤1, > 1 x ULN to ≤ 2 x ULN; > 2 x ULN to ≤ 3 X ULN, > 3 x ULN to ≤5 x ULN 
and > 5) in ALT, AST, or bilirubin are summarized.  Individual narratives are written for 
patients with evidence of significant liver dysfunction.  
Hematology
Descriptive statistics and shift tables for each subtype of white blood cell (ie, neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils) are summarized by the patient groups 
defined in Section 6.5.
6.8.2.8   Adverse Events in Special Groups
AEs by preferred term are presented separately based on the special groups listed below:


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
Age (< 65, 65 years) 

Race (White, Black, Asian, and Other)

Sex (Male, Female)

Baseline disease activity (moderate [UC: Baseline Partial Mayo Score < 6, CD:  
CDAI < 330], severe [UC: Baseline Partial Mayo Score ≥6, CD:  CDAI ≥330])

Body Weight (< 70 kg, 70-90 kg, > 90 kg)
6.8.3   
Laboratory Data
Unless otherwise specified, laboratory data obtained on and after Week 4 in the long-term 
safety study are included in the summary tables.  Additionally, since laboratory tests will not 
be restricted to scheduled visits, Section 0 provides uniform visit windows to link each 
laboratory test to a scheduled visit.  Assignment of patient treatment to a laboratory 
measurement is described in Section 0.
For the purposes of summarization in both the tables and listings, all laboratory values are 
converted to standardized units.  If a lab value is reported using a non-numeric qualifier (eg, 
less than (<) a certain value, or greater than (>) a certain value), the given numeric value is
used in the summary statistics, ignoring the non-numeric qualifier.  All laboratory data are
summarized by the patient groups defined in Section 6.5.  
6.8.3.1   Marked Laboratory Abnormalities 
Laboratory abnormalities are evaluated based on marked abnormality (MA) criteria.  
Appendix 2 (Laboratory Abnormality Criteria) lists the predefined criteria for MAs.  If both 
the baseline and on-treatment values of a parameter are beyond the same MA limit for that 
parameter, then the on-treatment value is considered an MA only if it is more extreme 
(farther from the limit) than the baseline value.  If the baseline value is beyond the low MA 
limit and the on-treatment value is beyond the high MA limit (or vice versa), then the on-
treatment value is considered a MA.
Laboratory MAs occurring during the long-term safety study are summarized.  The 
directions of changes (high or low) in MAs are indicated in the tables.  Additionally, for 


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each patient with an MA for a parameter, all the patient’s values of that parameter over the 
long-term safety study are listed.  
6.8.3.2   Changes from Baseline Values for Selected Laboratory Parameters over
Time
The following hematology parameters and their changes from baseline values are  
summarized over all scheduled times of assessment, presenting n, means, medians, standard 
deviations and 95% CIs.  

hematocrit (changes from baseline)

hemoglobin (changes from baseline)

platelet count (changes from baseline)

red blood cell (RBC) count (changes from baseline)

white blood cell (WBC) count (changes from baseline)

absolute neutrophil count (ANC) (changes from baseline)

absolute lymphocyte count (changes and percent changes from baseline)

absolute monocyte counts (changes and percent changes from baseline)

absolute eosinophil counts (changes and percent changes from baseline)

absolute basophil counts (changes and percent changes from baseline)
The following serum chemistry parameters and their change from baseline values are 
summarized over all scheduled times of assessment, presenting n, means, medians, standard 
deviations, and 95% CIs:  

total and direct bilirubin (changes from baseline)

alanine aminotransferase (ALT) (changes from baseline)

alkaline phosphatase (changes from baseline)


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
aspartate aminotransferase (AST) (changes from baseline)

amylase (changes from baseline)

bicarbonate (changes from baseline)

blood urea nitrogen (BUN) (changes from baseline).  

creatinine, serum (Scr) (changes from baseline)

calcium (changes from baseline)

glucose (changes from baseline)

lipase (changes from baseline)

magnesium (changes from baseline)

phosphorus (changes from baseline)

electrolytes - sodium, potassium, chloride, (changes from baseline)

total protein and albumin (changes from baseline)

coagulation (changes from baseline)
Baseline is defined as the value collected at the last visit prior to the first dose of 
vedolizumab administration in C13008 study. The baseline and the visit window defined in 
Section 0  is followed for this calculation.  For patients who were in C13004, the last 
measurement from C13004 is used for the baseline. For de novo patients, the assessments at 
screening are used for the baseline.    
6.8.4     ECG
Percent of subjects with abnormal ECGs are summarized by study visits.  ECG 
abnormalities reported as AEs are summarized in the AE analysis as specified in 
Section 6.8.2.


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6.8.5   
Vital Signs
The values and changes from baseline for heart rate, temperature, respiratory rate, and 
systolic and diastolic blood pressure are summarized by the patient groups defined in Section
6.5 at each scheduled time of assessment using the safety population.  Vital sign 
abnormalities reported as AEs are summarized in the AE analysis as specified in Section 
6.8.2.
6.8.6   
Immunogenicity Analysis
6.8.6.1   Data Set Analyzed
HAHA baseline data is taken from the last measurements of the previous study (eg, C13004, 
C13006, C13007, or C13011) since HAHA is not measure on Day 0 of Study C13008. For 
de novo patients, the HAHA at screening is used for the baseline. Vedolizumab serum 
concentrations and HAHA data are summarized by study visits and by the patient groups 
defined in Section 6.5 using the safety population. Listings of vedolizumab and HAHA are 
also included.  Serum concentration below limit of quantification is set to zero. No 
imputation is performed.
6.8.6.2   HAHA Definitions
Negative HAHA
A sample that has been evaluated as negative in the HAHA screening assay is considered 
negative.  Samples that are determined to be positive in the HAHA screening assay, but the 
result is not confirmed in the HAHA confirmatory assay is considered negative.  
Positive HAHA 
A sample that has been evaluated as positive in both the HAHA screening and confirmatory 
assays is considered positive.
Positive Neutralizing HAHA 
A sample that has been evaluated as positive in the neutralizing HAHA assay is considered 
positive.


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6.8.6.3   Patient Status
Baseline Positive 
All patients who are HAHA positive from measurements from the previous study (eg,
C13004, C13006, C13007, or C13011) are defined as baseline positive.
Patient HAHA status is further categorized and summarized as follows:
Negative 
All patients who have no positive HAHA sample.
Positive 
All patients who have at least 1 positive HAHA sample.
Persistent Positive 
All patients who have 2 or more consecutive positive HAHA samples.
The maximum HAHA titer and percentage of subjects with each HAHA status are presented 
overall and by the patient groups defined in Section 6.5.  Additional HAHA titer categories 
(eg, titer ≥ 5, ≥ 15, ≥ 45, ≥ 125, ≥625, and ≥3125) are summarized if deemed appropriate.  
6.8.6.4   Effects of HAHA on Safety
Summary of overall AEs by HAHA status is presented.  Summary of infusion-related AEs 
by HAHA status is also reported.
6.9   
Exploratory Efficacy Analyses
This section describes the analyses conducted on the exploratory efficacy, resource 
utilization, and patient-reported outcome endpoints.
6.9.1   
General Methods
The primary statistical focus for the exploratory efficacy analyses is on descriptive summary 
of efficacy endpoints rather than on formal analysis of the clinical data.  Descriptive 
statistics, including 95% CIs, are provided for all clinical efficacy variables of interest.  


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The exploratory efficacy summaries are carried out using the baseline defined in Section 5.2.  
The exploratory efficacy analyses use the C13008 efficacy population.
6.9.2   
Exploratory Efficacy Endpoints 
The following exploratory efficacy variables are summarized by study visits:

HBI score (CD only)

Proportions of HBI score ≤4, 4 < HBI score ≤7 and HBI score > 7 

Partial Mayo score (UC only )

Proportions of Partial Mayo score ≤2, 3 ≤partial Mayo score ≤5 and partial Mayo 
score ≥6  

CRP levels (CD only) 
6.9.3   
Exploratory Efficacy Analysis
The descriptive statistics for observed values and change from baseline in CRP level, partial 
Mayo score (UC only) or HBI score (CD only), IBDQ score, SF-36 score, and EQ-5D score 
are summarized.  The means of CRP level, partial Mayo score, and HBI score are plotted 
over time.  
Table 6-2 describes the analyses for the exploratory efficacy objective.
Table 6-2   
Summary of Analyses for Exploratory Objectives
Variable
Subpopulation
Analysis Type
CRP level
CD
Tabulate descriptive statistics for observed values and 
change from baseline
Partial Mayo Score
UC
Tabulate descriptive statistics for observed values and 
change from baseline
Partial Mayo Score
UC
Proportions of Partial Mayo score ≤2, 3 ≤partial Mayo 
score ≤5 and partial Mayo score ≥6 over time
HBI Score
CD
Tabulate descriptive statistics for observed values and 
change from baseline
HBI Score
CD
Proportions of  HBI score ≤4, 4 < HBI score ≤7 and 
HBI score > 7


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Table 6-2   
Summary of Analyses for Exploratory Objectives
Variable
Subpopulation
Analysis Type
CRP level
CD
Plot of mean observed values with 95% CI at each time 
point
Partial Mayo Score
UC
Plot of mean observed values with 95% CI at each time 
point
HBI Score
CD
Plot of mean observed values and with 95% CI  at each 
time point
Abbreviations:  CD = Crohn’s disease; CI = confidence interval; CRP = C-reactive protein; HBI = Harvey-
Bradshaw Index; UC = ulcerative colitis.
A comprehensive efficacy assessment for long-term clinical response and clinical remission 
as measured by partial Mayo score for UC and by HBI for CD will be covered by the 
integrated summary of efficacy that will have a separate analysis plan.
6.10   Resource Utilization Outcomes
Resources Utilization Outcomes collected in this study are as follows and are analyzed by 
CD or UC indication:

Proportion of patients with CD-related hospitalization, bowel resection, or CD-
related procedures(for CD patients)

Proportion of patients with UC-related hospitalization, colectomies, or UC-related 
procedures (for UC patients)

Time to CD-related hospitalization, bowel surgeries, or CD-related procedures (for 
CD patients)

Proportion of patients with UC-related hospitalization, colectomies, or UC-related 
procedures (for CD patients)
For time-to-event analyses, Kaplan-Meier method is used for summarizing combined events.  
Table 6-3   
Summary of Analyses for Resource Utilization Objectives
Variable
Population
Analysis Type
Time to combined CD-
related events 
Efficacy population 
CD patients
Kaplan Meier estimates along with 95% CI at 52, 100, 
148,196 weeks and continued at weeks by 
approximately 1 year until  the final safety visit  


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Table 6-3   
Summary of Analyses for Resource Utilization Objectives
Variable
Population
Analysis Type
Time to combined UC-
related events 
Efficacy population 
UC patients
Kaplan Meier estimates along with 95% CI at 52, 100, 
148, 196 weeks and continued at weeks by 
approximately 1 year until  the final safety visit 
Abbreviations:  CD = Crohn’s disease; CI = confidence interval; UC = ulcerative colitis.
6.11   Patient-Reported Outcomes (PROs)
Patient-reported outcomes on quality of life collected in this study are as follows: 

Inflammatory Bowel Disease Questionnaire (IBDQ)

Short Form-36 (SF-36)

EuroQol (EQ-5D)
Patient-reported outcomes are analyzed using the efficacy population.  The baseline value is 
the last measurement before the first dose of vedolizumab from the previous study (C13006, 
C13007 or C13011) as defined in Section 5.2.
Summary tables for patient-reported outcomes such as IBDQ  include baseline and each 
scheduled visit for the endpoint under consideration.  
Inflammatory Bowel Disease Questionnaire (IBDQ), SF-36, and EQ-5D are assessed at each 
scheduled visit.  The mean changes from baseline in IBDQ total and subscale scores are 
presented  along with 95% two-sided CIs for the differences in mean changes from baseline.  
In a similar manner, summaries of the changes from baseline in SF-36 summary scores 
physical component score (PCS) and mental component score (MCS), subscale scores, and 
EQ-5D utility and visual analogue scale (VAS) scores are provided.
Table 6-4 describes the tables and figures generated for the patient-reported outcomes 
objectives.  


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Table 6-4   
Summary of Analyses for Patient-Reported Outcomes Objectives
Variable
Imputation
Analysis Type
IBDQ (total)
Efficacy 
Population
Changes from baseline at each scheduled visit, including mean and 
mean changes from baseline and 95% CI
IBDQ (subscales)
Efficacy 
Population
Changes from baseline at each scheduled visits, including mean and 
mean changes from baseline and 95% CI
SF-36 (PCS and 
MCS)
Efficacy 
Population
Changes from baseline at each scheduled visits, including mean and 
mean changes from baseline and 95% CI
SF-36 (subscales)
Efficacy 
Population
Changes from baseline at each scheduled visits, including mean and 
mean changes from baseline and 95% CI
EQ-5D Utility
Efficacy 
Population
Changes from baseline at each scheduled visits, including mean and 
mean changes from baseline and 95% CI
EQ-5D VAS
Efficacy 
Population
Changes from baseline at each scheduled visits, including mean and 
mean changes from baseline and 95% CI
7.   
CHANGES TO PLANNED ANALYSES FROM PROTOCOL
Patients who previously participated in the phase 2, open-label, long-term safety study 
(Study C13004) are part of the integrated safety analysis for Study C13008.  Exposure, AE,
and concomitant medication data from all patients who previously participated in Study 
C13004 are analyzed in Study C13008.
8.   
REFERENCES
1. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events.  December, 2004
2. Lachin, J.M., Biostatistical Methods, The Assessment of Relative Risks,  2000, Wiley 
Serious in Probability and Statistics


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APPENDICES
APPENDIX 1
TABLES AND FIGURES
Tables and Figures will be provided upon request.


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APPENDIX 2
LABORATORY ABNORMALITY CRITERIA
Table A2.1 provides the criteria for assessing marked abnormalities in safety laboratory 
parameters with thresholds based on grade 2 moderate intensity levels from the Division of 
AIDS table for grading the severity of adult and pediatric adverse events (December, 2004).  
As stated in Section 6.11.2.1, if both the baseline and on-treatment values of a parameter are 
beyond the same MA limit for that parameter, then the on-treatment value is considered a 
MA only if it is more extreme (farther from the limit) than was the baseline value.
Table A2.1:
Marked Abnormality Criteria for Safety Laboratory Parameters
Parameter
Test Code
Units
Direction of 
Change
Marked Abnormalities
HEMATOLOGY
Hemoglobin
HB
g/L
Low Only
≤ 70 g/L
Absolute Lymphocyte 
Count
LYMPH
10E9
Low Only
<0.5 X10E9 
Leukocytes
WBC
10E9
Low Only
Absolute Value < 2.0X10E9
Platelets
PLT
10E9
Low Only
<75.0X10E9
Absolute Neutrophil Count
ANC
10E9
Low Only
<1.0X10E9 
Prothrombin Time
PT
%
High Only
>1.25 x ULN
CHEMISTRIES
SGPT
ALT
ULN
High Only
>3.0 x ULN
SGOT
AST
ULN
High Only
>3.0 x ULN
Bilirubin
BILI
ULN
High Only
>2.0 x ULN
Amylase
AMYL
ULN
High Only
>2.0 x ULN
Lipase
LIP
ULN
High Only
>2.0 x ULN
Serum Creatinine
CREAT
ULN
High Only
>2.0 x ULN


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APPENDIX 3
GEOGRAPHIC REGIONS
Region
Countries
North America
Canada 
Puerto Rico
United States
Western/ Northern Europe
Austria
France
Ireland
Norway
Sweden 
Belgium
Germany
Italy
Portugal
Switzerland
Denmark
Iceland
Netherlands
Spain
United Kingdom
Central Europe
Czech Republic
Poland 
Slovak Republic 
Greece
Romania
Hungary
Serbia
Eastern Europe
Bulgaria
Latvia
Turkey
Estonia
Malta
Ukraine
Israel
Russia
Africa/Asia / Australia
Australia
New Zealand
Taiwan
South Africa
Hong Kong
South Korea
China
India
Malaysia
Singapore


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APPENDIX 4
MAYO SCORE CALCULATION WORKSHEET
Complete and Partial Mayo Scoring “Points to Remember”
The Mayo Score is widely used in clinical trials to assess Ulcerative Colitis disease activity.  It is a combination of two 
patient-reported and two physician-determined components.  The Partial Mayo Score includes only the Stool Frequency, 
Rectal Bleeding, and PGA subscores. (Does not include endoscopy) 
Sub Scores
Stool Frequency                 
(Patient)
0 = Normal number of 
stools for this patient
1 = 1 to 2 stools more 
than normal
2 = 3 to 4 stools more 
than normal
3 = 5 or more stools more 
than normal
Stool frequency WILL:

Be 
derived from patient reported diary data in IVRS and will be the average of 3 
days prior to visit

Be variable from patient to patient.  Instruct patients to set the baseline of “normal” 
to whatever is “normal” for them.  (eg, A patient normally has 1 stool per day and 
today has had 4 stools.  Therefore the patient has had 3 more than “normal”, which 
yields a value of 2 for that day)

Be defined as the passage of solid or liquid fecal material. Episodes of incontinence 
count.  A non-productive trip to the bathroom or the simple passage of gas DO NOT 
COUNT as a stool.
Rectal Bleeding                   
(Patient)
0 = No blood seen 
1 = Streaks of blood with 
stool less than half the 
time 
2 = Obvious blood with 
stool most of the time 
3 = Blood alone passes
Rectal bleeding WILL:

Be derived from patient reported diary data in IVRS and will be the average of 3 
days prior to visit

Represent the most severe bleeding of the day.  Hemorrhoidal bleeding DOES NOT 
COUNT.
Findings on Endoscopy       
(Physician)
0 = Normal or inactive 
disease 
1 = Mild disease 
(erythema, decreased 
vascular pattern, 
mild friability)
2 = Moderate disease 
(marked erythema, 
lack of vascular 
pattern, friability, 
erosions)
3 = Severe disease 
(spontaneous 
bleeding, ulceration)
Findings on Endoscopy WILL:

Be documented by photographic evidence

Be classified by the worst affected segment if mucosal appearance varies

Be characterized as follows
Moderate: Bleeds to touch (forceps applied to colonic mucosa for 1 second)
Severe: Bleeds spontaneously 

Endoscopy should be performed by the same endoscopist for any given patient
Physician’s Global 
Assessment                          
(Physician)
0 = Normal
Physician’s Global Assessment WILL:

Be based on  the patient’s overall status on the day of visit

Reflect how the patient is doing at present.  Assessment SHOULD NOT reflect past 
disease severity or complexity or the number/kinds of medications the patient is 


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1 = Mild disease
2 = Moderate disease
3 = Severe disease
receiving.

Be based on the
Other 3 components of the Mayo score
Patient’s recollection of abdominal discomfort and general sense of well-being
Patient’s performance status, fecal incontinence, and mood
Physician's observations and physical exam findings

Reflect disease activity, NOT disease severity (eg. Do not automatically give a high 
PGA to patients with pancolitis or severe/complicated disease, or patients requiring 
multiple medications.)

Subscores representing the average of 3 days of patient diary data can be obtained from the IVRS subscore report. If 
calculated manually, subscores should be rounded to the nearest integer.

The Mayo score is equal to the sum of the subscores.


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APPENDIX 5
AES OF SPECIAL INTEREST

Gastrointestinal Events 

Use SOC of GASTROINTESTINAL DISORDERS to flag

Malignancies 

Use SOC of NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED 
(INCL CYSTS AND POLYPS) to flag

Infections 

Use SOC of INFECTIONS AND INFESTATIONS to flag

Infusion Related Reactions

Analysis for these AEs will occur on two levels:

Investigator defined Infusion Related Reactions (as indicated on the 
AE CRF)

All AEs that occur on or one calendar day after the infusion date.


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APPENDIX 6
PRIOR THERAPIES
Systemic 
Corticosteroids
Immunomodulators
Anti TNF
CRF Label
Systemic 
Corticosteroids
Azathioprine/
6-Mercaptopurine
Infliximab
Methotrexate
Adalimumab
Certolizumab


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APPENDIX 7
PATIENT REPORTED OUTCOMES 
Table A7.1:
Patient Reported Outcomes – IBDQ, SF-36 and EQ-5D
Variable
SF-36
Sub-score
Calculation
Physical Functioning (raw 
score)
Sum of (Q3a, Q3b,Q3c,Q3d,Q3e,Q3f,Q3g,Q3h, 
Q3i, Q3J)
Role Physical (raw score)
Sum of (Q4a, Q4b, Q4c, Q4d)
Bodily Pain (raw score)
Sum of (Q7,Q8)
General Health (raw 
score)
Sum of (Q1, Q11a, Q11b, Q11c, Q11d)
Vitality (raw score)
Sum of (Q9a, Q9e, Q9g, Q9i)
Social Functioning (raw 
score)
Sum of (Q6, Q10)
Role-Emotional (raw 
score)
Sum of (Q5a, Q5b, Q5c)
Mental Health (raw score) Sum of (Q9b,Q9c,Q9d,Q9f,Q9h)
Note
For each component score above, if 50% or less of the component score is 
missing at a visit, the MEAN of the remaining component score will be 
imputed as the value for the missing component score. If more than 50% of 
the component score is missing for the item, the imputed value will be set to 
missing.
Physical Functioning (S-
score)
(PF score -10)/20*100
Role Physical (S- score)
(RP score -4)/16*100 
Bodily Pain (S- score)
(BP score-2)/10*100 
General Health (S- score)
(GH  score -5)/20*100
Vitality (S- score)
(VT score -4)/16*100
Social Functioning (S-
score)
(SF score -2)/8*100
Role-Emotional (S- score) (RE score -3)/12*100 
Mental Health (S- score)
(MH score -5)/20*100
Physical Functioning (Z-
score*)
(PF – 83.29094)/23.75883
Role Physical (Z-score)
(RP-82.50964)/25.52028
Bodily Pain (Z-score)
(BP-71.32527)/23.66224
General Health (Z-score)
(GH-70.84570)/20.97821
Vitality (Z-score)
(VT-58.31411)/20.01923
Social Functioning (Z-
score)
(SF-84.30250)/22.91921
Role-Emotional (Z-score)
(RE-87.39733)/21.43778


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Table A7.1:
Patient Reported Outcomes – IBDQ, SF-36 and EQ-5D
Variable
Mental Health (Z-score)
(MH-74.98685)/17.75604
Aggregated physical score PHYS = (PF_Z*0.42402) + (RP_Z*0.35119) +( 
BP_Z*0.31754)+(GH_Z*0.24954)+( 
VT_Z*0.02877) +( SF_Z*0.00753*(-1))+( 
RE_Z* 0.19206*(-1)) + (MH_Z*0.22069*(-1))
Aggregated Mental score
MENT = (PF_Z*0.22999*(-1)) + 
(RP_Z*0.12329*
(-1)) +( BP_Z*0.09731*(-
1))+(GH_Z*0.01571*(-1))+ ( VT_Z*0.23534) +( 
SF_Z*0.26876)+( RE_Z* 0.43407) + 
(MH_Z*0.48581)
Note 
If less than or equal to 4 Z-scores are missing, the average of the remaining Z 
scores will be used to compute the value for the missing component score.  If 
more than 4 Z scores are missing, the aggregate mental or physical will be set 
to missing.
IBDQ
Sub-score
Calculation
IBDQ Bowel symptoms 
score
Sum of (Q1, Q5, Q9, Q13, Q17, Q20, Q22, Q24, 
Q26, Q29), Ranging from 10 to 70, 10 questions
IBDQ Emotional function 
score
Sum of (Q3, Q7, Q11, Q15, Q19, Q21, Q23, 
Q25, Q27, Q30, Q31, Q32), Ranging from 12 to 
84, 12 questions
IBDQ Social function 
score
Sum of (Q4, Q8, Q12, Q16,Q28), Ranging from 
5 to 35, 5 questions
IBDQ Systemic symptoms 
score
Sum of (Q2, Q6, Q10, Q14,Q18), Ranging from 
5 to 35, 5 questions
Note
For each component score above, if 50% or less of the component score is 
missing at a visit, the MEAN of the remaining component score will be 
imputed as the value for the missing component score. If more than 50% of 
the component score is missing for the item, the imputed value will be set to 
missing. 
IBDQ score
Sum of (bowel, emotion, social, system)
Note
If any of the component score is missing at a visit, the imputed value will be 
set to missing..
EQ-5D
Sub-score
Calculation
EQ5D Mobility 
component score
Ranging from 1 to 3
EQ5D self-care 
component score
Ranging from 1 to 3
EQ5D usual activities 
component score
Ranging from 1 to 3
EQ5D Pain/discomfort 
Ranging from 1 to 3


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Table A7.1:
Patient Reported Outcomes – IBDQ, SF-36 and EQ-5D
Variable
component score
EQ5D anxiety/depression 
component score
Ranging from 1 to 3
Note
If 2 or less out of 5 of the components are missing at a visit, the MEAN of 
the remaining component score will be imputed as the value for the missing 
component score.  If 3 or more components are missing, the imputed value 
will be set to missing.
EQ5D VAS
On a scale of 0 to 100, where 0 is the worst imaginable health state and 100 
is the best imaginable health state.
* Z-scores formula are described in the SC-36 Manual


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APPENDIX 8
AES OF SPECIAL INTEREST
Infections
Bacterial pneumonia
Bacteremia
Sepsis
Pneumocystis jiroveci (carinii) pneumonia
Pyelonephritis
Herpes zoster
Progressive multifocal leukoencephalopathy
Tuberculosis
Histoplasmosis
Listeria meningitis
Mycobacteria avium complex
Candidiasis
Herpes simplex
Dental abscesses/periodontitis
Rectal or peritoneal abscesses
Salmonella septicemia
Cryptosporidiosis
C. difficile diarrhea/colitis
CMV colitis
Urinary tract infection
Giardiasis
Cellulitis
Viral meningitis
Cancer
All primary solid tumors 
Lymphatic and hematopoietic malignancies
Lymphosarcoma and reticulosarcoma
Marginal zone lymphoma
Hodgkin’s disease
Other malignant neoplasms of lymphoid and histiocytic tissue
Peripheral t-cell lymphoma
Multiple myeloma and immunoproliferative neoplasms
Lymphoid leukemia
Myeloid leukemia
Monocytic leukemia
Other leukemia
Digestive tract 
Oropharyngeal


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Esophagus
Stomach
Small intestine
Colon
Rectum, anus
Intrahepatic bile ducts
Gall bladder
Pancreas
Retroperitoneum and peritoneum
Other
Cervical carcinoma
Melanoma
B-cell lymphoma
Cervical dysplasia
Gastrointestinal 
Intestinal obstruction/stenosis
Abdominal abscesses
Abscess of anal and rectal regions
Campylobacter gastroenteritis
Salmonella gastroenteritis
Viral gastroenteritis
Intestinal/gastric perforation
Miscellaneous
Deep venous thrombophlebitis
Pulmonary embolus
Stroke
Congestive heart failure and/or Stevens-Johnson syndrome/toxic epidermal necrolysis
Erythema multiforme
Stevens-Johnson syndrome/Toxic epidermal necrolysis
Acute myocardial infarction
Kidney stones
Acute renal failure/renal insufficiency (excluding chronic)
Angioedema