Conditions: Ulcerative Colitis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1822
Healthy volunteers: no

Brief summary:
This two-part, part 1: open-label extension (OLE) and part 2: safety monitoring (SM) study will examine the efficacy and safety of continued etrolizumab treatment in moderate to severe ulcerative colitis (UC) participants previously enrolled in etrolizumab Phase II/III studies. Participants with moderate to severe UC who were enrolled in the Phase II OLE study (GA27927 \[NCT01461317\]) or the Phase III studies (GA28948 \[NCT02163759\], GA28949 \[NCT02171429\], GA28950 \[NCT02100696\], GA29102 \[NCT02165215\], and GA29103 \[NCT02136069\]) were included. Participants from the Phase II OLE study or the Phase III studies who are not eligible or willing to receive etrolizumab in the OLE-SM study, and who have completed the 12-week safety follow-up period will be enrolled in Part 2. Part 1 of OLE-SM will continue for up to 9 years after the first participant is enrolled into the study. Following Part 1, participants will enter Part 2 for a period of 92 weeks.

Detailed description:

Arms:
arm 1: Participants with moderate to severe UC who were enrolled in the Phase II OLE study or the Phase III studies, and who meet the eligibility criteria for enrollment will receive open-label etrolizumab in Part 1 (OLE). arm 2: All participants from Part 1 (OLE), participants whose PML follow-up is not completed within the Phase II OLE study, and participants transferring from the Phase III double-blind studies after the 12-week safety follow-up will be monitored for PML (92 weeks).

Interventions: intervention 1: Etrolizumab
Intervention descriptions: intervention 1: Participants will receive etrolizumab 105 milligrams (mg), administered subcutaneously (SC) every 4 weeks for up to 9 years or until either commercial availability or the Sponsor's decision to terminate the study.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
An Open-Label Extension and Safety Monitoring Study of Moderate 
to Severe Ulcerative Colitis Patients Previously Enrolled in 
Etrolizumab Phase II/III Studies 
NCT Number: 
NCT02118584 
Document Date: 
Protocol Version 9: 12-Feb-2019 
 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Etrolizumab—F. Hoffmann-La Roche Ltd
Protocol GA28951, Version 9
PROTOCOL
TITLE:
AN OPEN-LABEL EXTENSION AND SAFETY
MONITORING STUDY OF MODERATE TO SEVERE 
ULCERATIVE COLITIS PATIENTS PREVIOUSLY 
ENROLLED IN ETROLIZUMAB PHASE II/III
STUDIES
PROTOCOL NUMBER:
GA28951
VERSION NUMBER:
9
EUDRACT NUMBER:
2013-004435-72
IND NUMBER:
100366
TEST PRODUCT:
Etrolizumab (PRO145223, RO5490261)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  27 November 2013
DATES AMENDED:
Version 2:  24 January 2014
Version 3:  30 March 2014
Version 4:  4 July 2014
Version 5:  1 August 2014
Version 6:  22 October 2015
Version 7 (VHP):  7 December 2015
Version 8:  5 September 2017
Version 9:  See electronic date stamp below.
 
12-Feb-2019 21:05:10
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Etrolizumab—F. Hoffmann-La Roche Ltd
2/Protocol GA28951, Version 9
PROTOCOL AMENDMENT, VERSION 9:
RATIONALE
Protocol GA28951 has been amended to align with changes implemented in the parent 
studies GA29102, GA29103, GA28948, GA28949, and GA28950, as follows:

Language in the Background section has been amended to align with the other 
ulcerative colitis studies in the Etrolizumab Phase III Program (Sections 1.2 
and 1.3.2).

The duration of Part 1open-label extension has been updated to approximately 
9 years (Sections 3.1.1.1, 3.1.1.3, and 4.4.3.2 and Figure 1).

Consistent with the reduction in sample size of some of the parent studies, the 
maximum number of patients potentially enrolling in this study has been updated to 
approximately 2100 (Sections 3.1.1.1, 4.1, and 6.1).

Janus kinase inhibitors have been added to the list of rescue therapies prohibited at 
any time during the study (Sections 3.1.1.1, 4.1.2, 4.2.2, and 5.1.2). 

References to "Latvia/Lithuania" have been changed to "VHP" to reflect inclusion of
all countries participating in the Voluntary Harmonisation Procedure (Section 4.1.1 
and Table 1). 

Clarification regarding the reporting of adverse events related to medical device 
complaints in individuals other than the study patient has been added in 
Section 4.3.3.3.

Language in Section 5.4.6.7 has been amended to indicate that a death occurring 
during Part 2safety monitoring should be reported directly to the Sponsor, 
regardless of causality.

Procedures for adverse event reporting have been updated to clarify that sites are 
not expected to review patient-reported outcome data for adverse events 
(Section 5.4.6.12).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Etrolizumab—F. Hoffmann-La Roche Ltd
3/Protocol GA28951, Version 9
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................ 9
PROTOCOL SYNOPSIS .................................................................................... 10
1.
BACKGROUND .......................................................................................... 18
1.1
Background Ulcerative Colitis................................................ 18
1.2
Background on Etrolizumab................................................... 20
1.3
Study Rationale and Benefit-Risk Assessment...................... 21
1.3.1
Study Rationale ..................................................................... 21
1.3.2
Benefit-Risk Assessment....................................................... 22
1.3.3
Rationale for Test Product Dosage........................................ 23
2.
OBJECTIVES.............................................................................................. 24
2.1
Objectives of the Study.......................................................... 24
2.2
Other Safety Objectives......................................................... 24
2.3
Exploratory Objective............................................................. 24
3.
STUDY DESIGN......................................................................................... 24
3.1
Description of Study .............................................................. 24
3.1.1
Overview of Study Design ..................................................... 24
3.1.1.1
Open-Label Extension (Part 1) .............................................. 25
3.1.1.2
Extended PML Safety Follow-Up (Part 2).............................. 31
3.1.1.3
Study Duration....................................................................... 31
3.2
End of Study.......................................................................... 34
3.3
Outcome Measures ............................................................... 34
3.3.1
Efficacy Outcome Measures (Part 1; OLE)............................ 34
3.3.2
Safety Outcome Measures (Part 1; OLE) .............................. 34
3.3.3
Safety Outcome Measure (Part 2; SM).................................. 34
3.3.4
Exploratory Outcome Measure.............................................. 34
4.
MATERIALS AND METHODS .................................................................... 35
4.1
Patients.................................................................................. 35
4.1.1
Inclusion Criteria.................................................................... 35
4.1.2
Exclusion Criteria................................................................... 37


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4.2
Concomitant Medication and Treatment 
Assignment............................................................................ 38
4.2.1
Concomitant Therapy ............................................................ 39
4.2.1.1
Permitted Concomitant Therapy............................................ 39
4.2.1.2
Requirements Regarding Concomitant Therapy 
for Ulcerative Colitis............................................................... 39
4.2.2
Prohibited Therapy ................................................................ 40
4.3
Study Treatment.................................................................... 40
4.3.1
Formulation, Packaging, and Handling.................................. 40
4.3.1.1
Etrolizumab............................................................................ 40
4.3.1.2
Concomitant Therapy and Treatments .................................. 41
4.3.2
Dosage, Administration, and Compliance.............................. 41
4.3.2.1
Etrolizumab............................................................................ 41
4.3.3
Investigational Medicinal Product Accountability ................... 43
4.3.3.1
Assessment of Compliance ................................................... 44
4.3.3.2
Destruction of the Investigational Medicinal 
Product .................................................................................. 45
4.3.3.3
Reporting of Prefilled Syringe Complaints/Events ................. 45
4.4
Study Assessments ............................................................... 46
4.4.1
Description of Study Assessments in Part 1 (OLE)................ 46
4.4.1.1
Physical Examinations........................................................... 46
4.4.1.2
Vital Signs.............................................................................. 46
4.4.1.3
Ulcerative Colitis Disease Activity Assessments ................... 46
4.4.1.4
Laboratory Assessments ....................................................... 49
4.4.1.5
Electrocardiograms................................................................ 50
4.4.1.6
Medication Use and Compliance........................................... 50
4.4.1.7
Samples for Roche Clinical Repository.................................. 50
4.4.2
Description of Study Assessments in Part 2 (SM) ................. 53
4.4.3
Timing of Study Assessments ............................................... 54
4.4.3.1
Assessments during Treatment............................................. 54
4.4.3.2
Assessments at Study Completion/Early 
Withdrawal from Treatment Visit/Early 
Withdrawal............................................................................. 55


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4.4.3.3
Assessments at Unscheduled Visits in OLE 
(Part 1) and in 12-Week Safety Follow-Up ............................ 55
4.5
Patient, Study, and Site Discontinuation................................ 56
4.5.1
Patient Discontinuation.......................................................... 56
4.5.1.1
Discontinuation from Study Drug........................................... 56
4.5.1.2
Withdrawal from Study........................................................... 57
4.5.1.3
Study and Site Discontinuation.............................................. 57
5.
ASSESSMENT OF SAFETY....................................................................... 58
5.1
Safety Plan (Part 1 Open-Label Extension)........................... 58
5.1.1
Potential Risks for Etrolizumab.............................................. 58
5.1.1.1
Serious Infections.................................................................. 58
5.1.1.2
Hypersensitivity Reactions..................................................... 61
5.1.1.3
Local Injection-Site Reactions ............................................... 62
5.1.1.4
Hepatic Effects ...................................................................... 62
5.1.1.5
Malignancies.......................................................................... 63
5.1.1.6
Immunogenicity ..................................................................... 63
5.1.1.7
Decreased Effectiveness of Immunizations........................... 63
5.1.2
Risks Associated with Worsening of Ulcerative 
Colitis..................................................................................... 64
5.2
Safety Plan (Part 2 Safety Monitoring)................................... 64
5.3
Safety Parameters and Definitions ........................................ 65
5.3.1
Adverse Events ..................................................................... 65
5.3.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 66
5.3.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 66
5.4
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 67
5.4.1
Adverse Event Reporting Period for Part 1 (OLE) ................. 67
5.4.2
Adverse Event Reporting Period for Part 2 (SM)................... 68
5.4.3
Eliciting Adverse Event Information in Part 1 
(OLE)..................................................................................... 69
5.4.4
Assessment of Severity of Adverse Events ........................... 69
5.4.5
Assessment of Causality of Adverse Events ......................... 70


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5.4.6
Procedures for Recording Adverse Events............................ 70
5.4.6.1
Diagnosis versus Signs and Symptoms................................. 71
5.4.6.2
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 71
5.4.6.3
Persistent or Recurrent Adverse Events................................ 72
5.4.6.4
Abnormal Laboratory Values ................................................. 72
5.4.6.5
Abnormal Vital Sign Values ................................................... 73
5.4.6.6
Abnormal Liver Function Tests.............................................. 73
5.4.6.7
Deaths ................................................................................... 74
5.4.6.8
Preexisting Medical Conditions.............................................. 74
5.4.6.9
Lack of Efficacy or Worsening of Ulcerative 
Colitis..................................................................................... 75
5.4.6.10
Hospitalization or Prolonged Hospitalization.......................... 75
5.4.6.11
Adverse Event Associated with Overdose or 
Error in Drug Administration .................................................. 75
5.4.6.12
Patient-Reported Outcome Data ........................................... 76
5.5
Immediate Reporting Requirements from 
Investigator to Sponsor during Part 1 and Part 2................... 76
5.5.1
Emergency Medical Contacts................................................ 77
5.5.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 77
5.5.3
Reporting Requirements for Pregnancies.............................. 78
5.5.3.1
Pregnancies in Female Patients............................................ 78
5.5.3.2
Pregnancies in Female Partners of Male Patients................. 78
5.5.3.3
Abortions ............................................................................... 78
5.5.3.4
Congenital Anomalies/Birth Defects ...................................... 79
5.5.4
Reporting Requirements for Medical Device 
Complaints............................................................................. 79
5.6
Follow-Up of Patients after Adverse Events .......................... 79
5.6.1
Investigator Follow-Up........................................................... 79
5.6.2
Sponsor Follow-Up ................................................................ 79
5.7
Post-Study Adverse Events................................................... 79
5.7.1
Post-Study Adverse Events Part 1 (OLE).............................. 79
5.7.2
Post-Study Adverse Events Part 2 (SM)................................ 80


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5.8
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 80
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 81
6.1
Number of Patients................................................................ 81
6.2
Summaries of Conduct of Study............................................ 81
6.3
Safety Analyses for Part 1 (OLE)........................................... 81
6.3.1
Adverse Events ..................................................................... 82
6.3.2
Laboratory Tests.................................................................... 82
6.4
Safety Analyses for Part 2 (SM) ............................................ 82
7.
DATA COLLECTION AND MANAGEMENT ............................................... 82
7.1
Data Quality Assurance......................................................... 82
7.2
Electronic Case Report Forms............................................... 83
7.3
Electronic Patient-Reported Outcome Data........................... 83
7.4
Source Data Documentation.................................................. 84
7.5
Use of Computerized Systems .............................................. 84
7.6
Retention of Records............................................................. 84
8.
ETHICAL CONSIDERATIONS.................................................................... 85
8.1
Compliance with Laws and Regulations ................................ 85
8.2
Informed Consent.................................................................. 85
8.3
Institutional Review Board or Ethics Committee.................... 86
8.4
Confidentiality........................................................................ 86
8.5
Financial Disclosure .............................................................. 87
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 87
9.1
Study Documentation ............................................................ 87
9.2
Protocol Deviations................................................................ 87
9.3
Site Inspections ..................................................................... 88
9.4
Administrative Structure......................................................... 88
9.5
Publication of Data and Protection of Trade 
Secrets .................................................................................. 88
9.6
Protocol Amendments ........................................................... 89
10. REFERENCES ........................................................................................... 90


Etrolizumab—F. Hoffmann-La Roche Ltd
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LIST OF TABLES
Table 1
Eligibility Criteria for Enrollment into Part 1 of Open-Label 
Extension and Safety Monitoring Study GA28951 ...................... 27
Table 2
Efficacy Outcome Definitions ...................................................... 31
Table 3
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 69
Table 4
Causal Attribution Guidance ....................................................... 70
LIST OF FIGURES
Figure 1
Study Schema for Part 1 (OLE) of the OLE-SM Study................ 32
Figure 2
Study Schema for Part 2 (SM) of the OLE-SM Study ................. 33
LIST OF APPENDICES
Appendix 1
Open-Label Extension (Part 1, OLE) Schedule of 
Assessments............................................................................... 92
Appendix 2
12-Week Safety Follow-Up (Part 1, OLE)  Schedule of 
Assessments............................................................................... 96
Appendix 3
Extended Progressive Multifocal Leukoencephalopathy 
Safety Monitoring (Part 2, SM) Schedule of Assessments.......... 97
Appendix 4
Childbearing Potential, Pregnancy Testing, and 
Contraception.............................................................................. 98
Appendix 5
Mayo Clinic Score Measurement .............................................. 100
Appendix 6
Worksheet for the PML Neurologic Examination....................... 104
Appendix 7
Algorithm for the Evaluation of Progressive Multifocal 
Leukoencephalopathy............................................................... 111
Appendix 8
Patient Daily Diary .................................................................... 112
Appendix 9
Clinical Criteria for Diagnosing Anaphylaxis.............................. 113


Etrolizumab—F. Hoffmann-La Roche Ltd
9/Protocol GA28951, Version 9
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
AN OPEN-LABEL EXTENSION AND SAFETY 
MONITORING STUDY OF MODERATE TO SEVERE 
ULCERATIVE COLITIS PATIENTS PREVIOUSLY 
ENROLLED IN ETROLIZUMAB PHASE II/III
STUDIES
PROTOCOL NUMBER:
GA28951
VERSION NUMBER:
9
EUDRACT NUMBER:
2013-004435-72
IND NUMBER:
100366
TEST PRODUCT:
Etrolizumab (PRO145223, RO5490261)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please return the signed original of this form to a Sponsor representative.  Please retain 
a copy for your study files.


Etrolizumab—F. Hoffmann-La Roche Ltd
10/Protocol GA28951, Version 9
PROTOCOL SYNOPSIS
TITLE:
AN OPEN-LABEL EXTENSION AND SAFETY MONITORING 
STUDY OF MODERATE TO SEVERE ULCERATIVE COLITIS 
PATIENTS PREVIOUSLY ENROLLED IN ETROLIZUMAB 
PHASE II/III STUDIES
PROTOCOL NUMBER:
GA28951
VERSION NUMBER:
9
EUDRACT NUMBER:
2013-004435-72
IND NUMBER:
100366
TEST PRODUCT:
Etrolizumab (PRO145223, RO5490261)
PHASE:
III
INDICATION:
Ulcerative colitis
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
The objectives of this open-label extensionsafety monitoring (OLE-SM) study are as follows:
Part 1 (Open-Label Extension; OLE)

To assess the long-term safety and efficacy of etrolizumab in patients eligible for 
Part 1 (OLE)
Part 2 (Safety Monitoring; SM)

Progressive multifocal leukoencephalopathy (PML) safety monitoring
Safety Objectives
The other safety objectives for this study are as follows:
Part 1 (OLE)

To evaluate the incidence and severity of infection-related adverse events

To evaluate the incidence of malignancies

To evaluate the incidence and severity of hypersensitivity reactions

To evaluate the incidence and the clinical significance of anti-therapeutic antibodies (ATAs)
Exploratory Objective
The exploratory objective for this study is as follows:
Part 1 (OLE)

To evaluate histology at Week 108


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Study Design
Description of Study
This OLE-SM study is composed of two parts:

Part 1 is the OLE for eligible patients, during which active etrolizumab, 105 mg
subcutaneous (SC), will be administered every 4 weeks followed by a 12-week safety 
follow-up.

Part 2 is the 92-week PML SM for all patients, during which no etrolizumab will be 
administered.
Patients who are enrolled in Part 1 (OLE) should participate in Part 1 (OLE) and Part 2 (SM).
There may be patients who are ineligible for or choose not to participate in Part 1 (OLE) who will 
directly enroll in Part 2 (SM) only.
Number of Patients
The OLE-SM study will be conducted in centers that have participated in the Phase II OLE 
Study GA27927 and/or the double-blinded Phase III Studies GA28948, GA28949, GA28950, 
GA29102, and GA29103.  The maximum number of patients potentially enrolling in this study 
will be all patients from the studies; approximately 2100 patients.  Patients will be allocated the 
same subject number they had in the initial Phase II OLE study or Phase III study.
Target Population
Patients must meet the following criteria for study entry:
Part 1 (OLE)

Patients who were previously enrolled in the Phase II OLE study or a Phase III controlled 
study and meet the eligibility criteria for treatment with open-label etrolizumab as described 
in the protocol may enroll in Part 1 (OLE) of the study.  These patients must provide written 
informed consent and comply with the requirements of the OLE-SM protocol.
Patients not in safety follow-up or PML follow-up within Study GA27927 and whose last 
dose of etrolizumab is by July 2016 may enroll in Part 1 (OLE) of Study GA28951, if 
eligible, and receive their first dose in this study 4 weeks after their last dose in Study 
GA27927.  On occasions where this first dose of etrolizumab cannot be administered 
in accordance with these requirements, the first dose of etrolizumab is to be 
administered with a maximum delay of 2 weeks (i.e., up to 6 weeks after their last dose 
of etrolizumab in Study GA27927).
Eligible patients who exit from Study GA28948 or GA28949 at Week 10 because either 
they did not achieve clinical remission or they required the use of rescue medication 
prior to the Week 10 timepoint should not receive their first dose of open-label 
etrolizumab in Study GA28951 until 2 weeks after the Week 10 timepoint in the Phase 
III controlled study to allow for adalimumab washout.  The first dose of etrolizumab 
given to these patients entering Study GA28951 should not exceed 4 weeks following 
the Week 10 timepoint from the Phase III controlled study.
With the exception of VHP countries participating in GA28949 and Estonia
(participating in GA28948):  Patients who remain in Study GA28948 or Study 
GA28949 through Week 14 because they have achieved clinical remission may enroll 
in Part 1 (OLE) of Study GA28951 at Week 14.  The first dose of open-label 
etrolizumab will be given on Day 1 upon enrollment into Part 1 (OLE) of Study 
GA28951.  The first dose of etrolizumab given to the patients entering Study GA28951 
should not exceed 2 weeks following the Week 14 timepoint from the Phase III 
controlled study.
With the exception of VHP countries participating in GA28949 and Estonia
(participating in GA28948):  Eligible patients who receive rescue medication between 
Weeks 10 and 14 may enroll in Part 1 (OLE) of Study GA28951 at Week 14.


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For VHP countries participating in GA28949 and Estonia (participating in 
GA28948):  Patients who remain in Study GA28948 or GA28949 through Week 14 
because they have achieved clinical remission at Week 10 may enroll in Part 1 (OLE) 
of Study GA28951 at Week 16.  The first dose of open-label etrolizumab will be given 
on Day 1 upon enrollment into Part 1 (OLE) of Study GA28951 (4 weeks after their last 
etrolizumab/etrolizumab placebo dose or 8 weeks after their last 
adalimumab/adalimumab placebo dose in Study GA28948 or GA28949).  On 
occasions where the first OLE dose of etrolizumab cannot be administered in 
accordance with these requirements, the first dose may be delayed by a maximum of 
2 weeks (i.e., first OLE dose up to 6 weeks after their last etrolizumab/etrolizumab 
placebo dose or 10 weeks after their last adalimumab/adalimumab placebo dose in
Study GA28948 or GA28949).
For VHP countries participating in GA28949 and Estonia (participating in 
GA28948):  Eligible patients who receive rescue medication between Weeks 10 and 
16 may enroll in Part 1 (OLE) of Study GA28951 at Week 16.

For women who are not postmenopausal (at least 12 months of non-therapy-induced 
amenorrhea) or surgically sterile (i.e., absence of ovaries and/or uterus):  agreement to 
remain abstinent or use a highly effective method of contraception during the treatment 
period and for at least 24 weeks after the last dose of study drug.  
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 
24 weeks after the last dose of study drug to avoid exposing the embryo to study drug.  
Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.
Part 2 (SM)

Patients whose safety follow-up or PML follow-up is not completed within Study GA27927 
and patients who had their last dose of etrolizumab in July 2016 in Study GA27927 and are 
not eligible or choose not to enroll in Part 1 (OLE)

Patients who participated in one of the etrolizumab Phase III studies (GA28948, GA28949, 
GA28950, GA29102, and GA29103) and are not eligible or chose not to enroll in 
Part 1 (OLE) 

Patients who transfer from Part 1 (OLE) of this protocol

Ability and willingness to provide written informed consent and comply with the 
requirements of Part 2 (SM) of the OLE-SM protocol.
All patients must have completed the 12-week safety follow-up prior to entering Part 2 (SM).
Patients who meet any of the following criteria will be excluded from study entry:
Part 1 (OLE)

Withdrawal of consent from the Phase II OLE study or any of the Phase III studies 

Patients who discontinued etrolizumab/etrolizumab placebo prior to Week 10 or did not 
perform the Week 10 visit of the Phase III Studies GA28948, GA28949, GA29102, and 
GA29103

Patients who discontinued etrolizumab/etrolizumab placebo prior to Week 14 or did not 
perform the Week 14 visit of the Phase III Study GA28950


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
Inability to comply with the study protocol, in the opinion of the investigator

Patients not compliant in the Phase II OLE or Phase III studies or did not complete the 
required washout period for an active comparator in Studies GA28948, GA28949, and 
GA29103

Pregnancy or lactation
Exclusion due to Safety Reasons

Patients who developed an anaphylactic/anaphylactoid or severe allergic reaction to study 
medication during the Phase II OLE or Phase III studies

Patients who experienced or have an ongoing serious infection event (except for those 
listed below) should not receive study drug until the event has completely resolved and 
treatment with anti-infective medications has been completed

Patients who experienced a specific de novo or reactivated serious viral infection such as 
hepatitis B virus (HBV), hepatitis C virus (HCV), or HIV during the Phase II OLE or 
Phase III studies

Patients who develop cytomegalovirus (CMV) colitis leading to early treatment 
discontinuation in the Phase II OLE or Phase III studies 

Patients who develop life-threatening infections during the Phase II OLE or Phase III 
studies

Patients who developed a malignancy (with the exception of local and resected basal or 
squamous cell carcinoma of the skin), or who develop adenocarcinoma in situ (AIS), high-
grade squamous intraepithelial lesions (HSIL), or cervical intraepithelial neoplasia (CIN) of 
Grade 1 on cervical Pap smear, or who develop colonic dysplasia during the 
Phase II OLE or Phase III studies

Receipt of the following since commencement of the Phase II OLE or Phase III controlled 
studies:
Any investigational treatment, including investigational vaccines
Use of agents that deplete B or T cells (e.g., alemtuzumab or visilizumab), except AZA 
and 6-MP
Use of anti-adhesion molecules
Use of Janus kinase (JAK) inhibitors
Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF)
Patients who have previously received rituximab, natalizumab, vedolizumab, or 
efalizumab may not enter the study
Immunization with a live/attenuated vaccine

In the opinion of the investigator, any new (since enrolling in the Phase II OLE or Phase III 
controlled studies), significant, uncontrolled comorbidity, such as neurological, cardiac 
(e.g., moderate to severe heart failure New York Heart Association [NYHA] Class III/IV),
pulmonary, renal, hepatic, endocrine, or gastrointestinal (GI) disorders (excluding 
ulcerative colitis [UC])

Any patient who developed PML in the Phase II OLE or Phase III studies

Any patient with neurological symptoms where suspected PML has not been ruled out
Part 2 (SM)

No exclusion criteria
Length of Study
Patients will be enrolled into this study from the Phase II OLE study and the Phase III controlled 
studies.  Part 1 (OLE) will continue for up to approximately 9 years after the first patient is
enrolled into the study, until commercial availability, or until the Sponsor’s decision to terminate 
the study, whichever is earlier.  Following Part 1, patients will enter Part 2 for a period of 
92 weeks.


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End of Study
The end of the study is defined as the date when the last patient completes the 92-week PML 
safety-monitoring period.
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:

To describe the long-term efficacy of etrolizumab (105 mg SC every 4 weeks) by pMCS 
clinical remission for patients with UC in Part 1 (OLE)

To evaluate remission by MCS at Week 108 in Part 1 (OLE)

To evaluate endoscopic remission by MCS at Week 108 in Part 1 (OLE)
Safety Outcome Measures
The safety outcome measures for this study are as follows:
Part 1 (OLE)

Incidence and severity of adverse events

Incidence of serious adverse events

Incidence and severity of infection-related adverse events

Incidence of serious infection-related adverse events

Incidence and severity of injection-site reactions

Incidence of adverse events leading to etrolizumab discontinuation

Incidence of laboratory abnormalities

Incidence of malignancies

Incidence of ATAs to etrolizumab

Incidence and severity of hypersensitivity reaction events
Part 2 (SM)

Incidence of suspected or confirmed PML events
Exploratory Outcome Measure
The exploratory outcome measure for this study is as follows:

Histologic appearance of mucosa at Week 108
Investigational Medicinal Products
Test Product
Etrolizumab prefilled syringe (PFS):  containing SC formulation, 105 mg given as 0.7 mL of a 
150-mg/mL solution will be administered by SC injection every 4 weeks.
Non-Investigational Medicinal Products
None
Statistical Methods
Primary Analysis
Because of the non-comparative character of the study, no statistical tests are planned.  
Efficacy in Part 1 will be assessed by change from baseline in pMCS and proportion of patients 
achieving pMCS remission.  Additionally, remission and endoscopic remission by MCS at 
Week 108 will be summarized.  All efficacy parameters will be summarized descriptively.  
Demographic and baseline characteristics such as age, sex, race, region, use of corticosteroids 
and immunosuppressants, duration of disease, and pMCS will be summarized by use of 
descriptive statistics. 
Further analysis details for Part 1 and Part 2 of the study will be provided in the Statistical 
Analysis Plan.


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Determination of Sample Size  
The maximum number of patients enrolled in the OLE-SM study is approximately 2100 
(i.e., all patients enrolled in the Phase II OLE protocol and the five UC Phase III protocols).  
No formal sample size calculations were performed.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
5-ASA
5-aminosalicylates
6-MP
6-mercaptopurine
AIS
adenocarcinoma in situ
ATA
anti-therapeutic antibody
AZA
azathioprine
CD
Crohn’s disease
CHO
Chinese hamster ovary
CIN
cervical intraepithelial neoplasia
CMV
cytomegalovirus 
CNS
central nervous system
CRO
contract research organization
CRP
C-reactive protein
CSF
cerebrospinal fluid 
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
ePRO
electronic patient-reported outcome
FDA
U.S. Food and Drug Administration
GI
gastrointestinal
HBV
hepatitis B virus
HCP
health care professional
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HSIL
high-grade squamous intraepithelial lesions
IBD
inflammatory bowel disease
ICH
International Council for Harmonisation
IMP
investigational medicinal product
IND
Investigational New Drug
IRB
Institutional Review Board
JAK
Janus kinase 
JCV
John Cunningham virus
IxRS
interactive voice/Web-based response system
mAb
monoclonal antibody
MAdCAMFc
mucosal addressin cell adhesion molecule-
fragment crystallizable region


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Abbreviation
Definition
MCS
Mayo Clinic Score
MMF
mycophenolate mofetil
MRI
magnetic resonance imaging
MTX
methotrexate
NCI CTCAE
National Cancer Institute Common Terminology 
Criteria for Adverse Events
NYHA
New York Heart Association
OLE
open-label extension
OLE-SM
open-label extension and safety monitoring
QOL
quality of life
PCR
polymerase chain reaction
PD
pharmacodynamic
PFS
prefilled syringe
PGA
Physician’s Global Assessment
PK
pharmacokinetic
pMCS
partial Mayo Clinic Score
PML
progressive multifocal leukoencephalopathy
PRO
patient-reported outcome
RCR
Roche Clinical Repository 
SC
subcutaneous
SM
Safety Monitoring
SUSAR
Suspected Unexpected Serious Adverse Reaction
TNF
tumor necrosis factor
UC
ulcerative colitis
ULN
upper limit of normal


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1.
BACKGROUND
1.1
BACKGROUND ULCERATIVE COLITIS 
Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease (IBD) that affects the 
colon in a diffuse, continuous, and superficial pattern.  Approximately 40%50% of 
patients have disease limited to the rectum and rectosigmoid colon, 30%40% have 
disease extending beyond the sigmoid but not involving the whole colon, and 20% have 
a total colitis.  Proximal spread occurs in continuity without areas of uninvolved mucosa.  
When the whole colon is involved, the inflammation extends 23 cm into the terminal 
ileum in 10%20% of patients.
UC is characterized by mucosal ulceration, rectal bleeding, diarrhea, and abdominal pain 
and may be complicated by severe bloody diarrhea and toxic megacolon, requiring 
major and sometimes urgent surgery.  UC represents dysregulation of the mucosal 
immune system in genetically susceptible individuals in response to commensal 
microbiota and other environmental triggers.  The overall incidence of UC ranges from 
6.3 to 24.3 cases per 100,000 persons per year, and prevalence ranges from 
4.9 to 505.0 cases per 100,000 persons, with the highest estimates in European and 
Northern American populations (Molodecky et al. 2012).  Although the incidence and 
prevalence vary between regions of the world, both have been increasing in some 
regions, which may be due in part to better detection and diagnosis, as well as 
environmental factors such as improved hygiene and Western diet.  The disease can 
affect any age group, but occurrence peaks between the ages of 15 and 35 years.
The goals of treatment are to induce and maintain remission, decrease corticosteroid 
use (as measured by steroid-free remission), induce mucosal healing, reduce 
hospitalization and surgery, improve quality of life (QOL), and avoid disability.  For mildly 
to moderately active UC, oral and rectal preparations of 5-aminosalicylate (5-ASA) 
medications are used either alone or together and result in remission in approximately 
50% of patients.  Patients whose UC fails to respond to 5-ASA drugs or who have 
moderately to severely active UC often receive conventional therapy, including 
corticosteroids and immunomodulator therapy (e.g., azathioprine [AZA], 
6-mercaptopurine [6-MP], and methotrexate [MTX]).  Corticosteroids achieve remission 
in about 70% of patients, but approximately 20% become steroid dependent and only 
half maintain steroid-free remission (Faubion et al. 2001).  Corticosteroids are also 
associated with significant side effects, such as infections, osteopenia, glucose 
intolerance, and adrenal suppression.  Immunomodulators, such as 6-MP, AZA, and 
MTX, have also been used to achieve steroid-free remission, but efficacy in maintaining 
steroid-free remission is modest (Lobel et al. 2004; Chebli et al. 2010; 
Mañosa et al. 2011; Khan et al. 2013).  In addition, these medications are associated 
with significant side effects, including hepatotoxicity, pancreatitis, and bone marrow 
suppression.


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Monoclonal antibodies (mAbs) targeting tumor necrosis factoralpha (TNF-), such as 
infliximab and adalimumab, have been used to induce and maintain remission in patients 
whose immunomodulatory therapy fails, are steroid dependent or refractory, and have 
moderately to severely active UC.  These biologic agents induce remission in up to 40% 
of patients, but sustained remission is seen in only 10%20% of patients over 1 year 
(Rutgeerts et al. 2005; Sandborn et al. 2013).  Importantly, TNF inhibitor therapies are 
associated with serious adverse events, such as bacterial infection, including 
tuberculosis (TB), disseminated fungal infections, lymphoma, and demyelination 
(Chang and Lichtenstein 2006).  In fulminant steroid-unresponsive colitis, infliximab and 
(less commonly) cyclosporine are utilized as bridging agents to avoid urgent colectomy.  
With either therapy, however, treatment failure occurs in approximately 55%60% of 
patients (Laharie et al. 2012).
In short, a large proportion of patients with moderately to severely active UC do not 
maintain a durable response to therapy.  Available therapies are associated with 
significant adverse events and at best achieve sustained remission in only 10%30% of 
patients with IBD who have chronic disease (Hanauer et al. 2002; Sandborn et al. 2005).  
Patients whose disease fails to respond to medical therapy may be treated with total 
proctocolectomy with an ileal pouch-anal anastomosis.  Although surgical intervention 
may be curative, complications such as chronic pouchitis, fecal incontinence, or 
decreased female fertility can occur (Bradley and Oliva-Hemker 2012).  The current 
treatments are associated with significant adverse events, resulting in low rates of 
sustained remission, or are highly invasive.
Consequently, there continues to be a high unmet medical need in moderately to 
severely active UC.  Targeted therapy with an improved safety profile and ability to 
sustain remission and prevent long-term complications would provide a valuable 
therapeutic option for these patients.
Part 1 of this study (open-label extension; OLE) investigates the long-term safety of 
patients with UC who were initially treated in the Phase II OLE (GA27927) or Phase III 
UC studies (GA28948, GA28949, GA28950, GA29102, and GA29103) and are enrolled 
into this open-label study for long-term treatment with etrolizumab and safety monitoring.
Part 2 of this study (safety monitoring; SM) includes long-term monitoring for progressive 
multifocal leukoencephalopathy (PML) for all patients following the last dose of their 
study medication and the 12-week safety follow-up.  Patients who discontinue therapy in 
this OLE study, OR patients whose safety follow-up or PML follow-up is not completed 
within the Phase II OLE study, OR patients from the Phase III UC studies who 
discontinue therapy, or are not eligible for, or choose not to receive open-label 
etrolizumab, will be monitored for PML within Part 2 (SM) of this protocol.


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1.2
BACKGROUND ON ETROLIZUMAB
A new class of molecules targeting the integrin receptors that regulate leukocyte 
trafficking to specific tissues in the body has been developed for treatment of IBD.  
Clinical studies have shown evidence of efficacy for these agents, including natalizumab 
(anti-4) for Crohn’s disease (CD) (Sandborn et al. 2005) and vedolizumab (anti-47) 
for UC and CD (Feagan et al. 2005, 2008); both agents have been approved for their 
respective indications.  Natalizumab and vedolizumab require IV administration, but 
only vedolizumab is gut-selective.  Natalizumab is not gut-selective and is associated 
with the risk of progressive multifocal leukoencephalopathy (PML).   Etrolizumab 
distinguishes itself from these molecules by specifically binding the integrin 7 subunit, 
found in both 47 (Holzmann et al. 1989; Hu et al. 1992) and E7 (Cepek et al. 1993), 
which regulate trafficking and retention of leukocyte/lymphocyte subsets, respectively, in 
the intestinal mucosa.
It is important to note that etrolizumab does not bind to 41 (target for natalizumab), 
which regulates trafficking to both mucosal and non-mucosal tissues, including the CNS.  
Etrolizumab, therefore, represents a novel gut mucosalselective anti-trafficking agent 
whose selectivity may enhance efficacy in UC and eliminate generalized 
immunosuppression by preferentially targeting trafficking to the gut rather than to other 
organs and tissues.  Data from multiple nonclinical toxicology studies of up to 6 months’ 
duration in adult animals demonstrated no adverse effects in any organ system 
(including the CNS and hematologic and cardiovascular systems).  No adverse events 
were observed in the embryo-fetal developmental toxicity studies.
Etrolizumab is a humanized mAb based on the human IgG1 subgroup-III VH, 
subgroup-1 VL consensus sequences and was constructed using standard 
recombinant DNA techniques.  This recombinant antibody consists of two heavy chains 
(446 residues) and two light chains (214 residues) and is produced in Chinese hamster 
ovary (CHO) cells that have been genetically engineered to synthesize the antibody.  
The protein is manufactured in bioreactors and purified using a series of harvest, 
purification, and formulation steps.  The potency of etrolizumab is determined by an 
in vitro assay that measures the inhibition of adhesion of 47-expressing cells to 
mucosal addressin cell adhesion moleculefragment crystallizable region (MAdCAM-Fc).
Safety assessments for etrolizumab have been completed in the adult Phase I, Phase II, 
and Phase II open-label extension (OLE) studies without significant safety concerns.
The following is a summary of the etrolizumab safety experience to date:

There were no observed significant adverse effects in multiple nonclinical toxicity 
studies of up to 6 months’ duration in adult animals or in embryo-fetal 
developmental toxicity studies.  No adverse effects were seen in any organ system 
(including the CNS and hematologic and cardiovascular systems), no effects were 
seen in embryo-fetal development, and there was no evidence of increased rates of 
infection.


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
No significant adverse safety signal, including any evidence of increased rates of 
serious or opportunistic infections, was associated with etrolizumab treatment in the 
Phase I or Phase II trials in adult patients with moderately to severely active UC who 
received either single or multiple doses of intravenous (IV) or subcutaneous (SC) 
etrolizumab.

No events of PML have been reported in etrolizumab-treated patients.
See the most recent Etrolizumab Investigator's Brochure for details on nonclinical and 
clinical studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
1.3.1
Study Rationale
This open-label extension and safety monitoring (OLE-SM) study consists of two parts.
Part 1 (Open-Label Extension or “OLE”) 
Part 1 (OLE) of this study is designed to assess the long-term safety and tolerability of 
105 mg SC etrolizumab every 4 weeks with regard to adverse events and laboratory 
abnormalities and to obtain long-term data on the efficacy, immunogenicity, and 
exposure of etrolizumab.  Patients may enroll in this study from:
a)
Phase II OLE Study GA27927
b)
Phase III controlled studiesnamely, Studies GA28948, GA28949, GA28950, 
GA29102, and GA29103
Patients who complete the last dose of etrolizumab within Study GA27927 by July 2016 
will be given the option to continue open-label etrolizumab within Part 1 (OLE) of this
study, if eligible. 
Eligible patients receiving etrolizumab, placebo, or active comparator (following blinded 
washout) in the Phase III controlled studies may receive active etrolizumab in 
Part 1 (OLE) of this study.  Eligibility criteria and the timepoints for enrollment into the 
Part 1 (OLE) of this study are described in Section 4.1.1 for the Phase II OLE study and 
for each of the Phase III controlled studies, respectively, and summarized in Table 1 in 
this protocol.


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Part 2 (Safety Monitoring or “SM”)
Part 2 (SM) is designed to monitor for PML in patients who have stopped taking 
etrolizumab.
a)
For patients in Phase II OLE Study GA27927, if the 12-week safety follow-up and 
92-week PML follow-up cannot be completed before July 2016, safety follow-up 
and/or PML follow-up will take place entirely within this study (GA28951) if all health 
authority/Institutional Review Board (IRB)/Ethics Committee (EC) approvals in the 
respective country for this study (GA28951) are in place by the time follow-up is 
scheduled to begin.  Otherwise, safety follow-up and/or PML follow-up will first start 
within Study GA27927 then will be completed within this study (GA28951) once all 
HA/EC/IRB approvals for this study (GA28951) are obtained.  
b)
Patients who exit Part 1 (OLE) of this study will then enter Part 2 (SM) for 
monitoring for events of PML.  In addition, given that it is desirable to capture all 
long-term PML follow-up under a single protocol, all patients from the Phase III 
studies who do not enroll in Part 1 (OLE) for continued etrolizumab treatment will 
enroll directly into Part 2 (SM) of this study for extended PML safety monitoring 
(following completion of the 12-week safety follow-up in the Phase III studies).
1.3.2
Benefit-Risk Assessment
Although effective therapeutic options including TNF inhibitors are available to help 
patients with moderate to severe ulcerative colitis to reduce the acute symptomatic flares 
in disease activity, no currently available therapy, including approved anti-integrins 
(natalizumab for CD and vedolizumab for UC and CD), achieves sustained remission 
in more than 10%30% of patients with IBD (Hanauer et al. 2002; Sandborn et al. 2005; 
Feagan et al. 2013).  
Furthermore, TNF inhibitors are associated with elevated rates of serious bacterial 
infection, including tuberculosis, and (more rarely) lymphoma and demyelination 
(Chang and Lichtenstein 2006); commonly associated with neutropenia, anemia, 
depression, allergic respiratory symptoms, arthralgias, myalgias, tachycardia, and 
vascular disorders; and very commonly associated with infusion-related reactions, 
abdominal pain, and nausea (REMICADE Summary of Product Characteristics).  
Consequently, patients and investigators carefully weigh these benefit-risk tradeoffs both 
before embarking and while managing long-term treatment with TNF inhibitors. 
The recent availability of the gut-selective anti-integrin class of monoclonal antibody 
treatments may provide potential treatment alternatives to TNF inhibitors and may 
exhibit a more tolerable safety profile.  To establish more effective care standards and 
understand long-term benefit-risk of etrolizumab, acquisition of robust, long-term data 
is required.


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Etrolizumab distinguishes itself from other anti-integrins on the basis of gut selectivity 
combined with a dual mechanism of action.  It binds E7 in addition to 47 and so 
regulates retention as well as trafficking of leukocytes/lymphocytes in the intestinal 
mucosa.
No clinically significant safety signals have been detected on administration of 
etrolizumab to patients with moderate to severe UC across a dose range of 
0.310.0 mg/kg IV/SC in the single ascending dose stage and of 0.53.0 mg/kg SC and 
4 mg/kg IV monthly for 3 doses in the multidose stage of the Phase I study.
The Phase II Study ABS4986g (EUCALYPTUS) and the corresponding OLE study 
(SPRUCE; Study GA27927) illustrated that a compelling efficacy is achieved with 
etrolizumab treatment in patients with moderate to severe UC.  There was no evidence 
of increased rates of serious or opportunistic infections and the overall safety profile of 
etrolizumab was similar to that of placebo.  In Phase III, etrolizumab is being assessed 
for induction and long-term maintenance therapy.  Therefore, this study is being 
conducted to treat patients with etrolizumab in an open-label fashion in order to assess 
its long-term safety and efficacy.
The nongut-selective anti-integrin natalizumab has been associated with an increased 
risk of PML.  No events of PML to date have been reported for etrolizumab during the 
2-year PML extensive monitoring in the Phase II study, EUCALYPTUS, and the OLE 
SPRUCE study.  Nevertheless, because etrolizumab is also an anti-integrin, albeit with a 
different subunit target, careful monitoring for possible PML events will be conducted in 
all studies with an extended period of PML safety monitoring within this protocol.
In summary, there is no known safety risk identified for etrolizumab at this time, but as 
an investigational medicinal product with limited Phase II data, the full safety profile for 
etrolizumab will be further characterized as Phase III clinical development progresses.  
A safety plan is provided in Section 5.1, describing potential risks for etrolizumab and the 
risk-mitigation strategies to minimize risks for the patients in this trial.  
Refer to the most recent Etrolizumab Investigator’s Brochure for additional details on 
clinical and non-clinical studies.
1.3.3
Rationale for Test Product Dosage
Patients enrolling in Part 1 (OLE) of this OLE-SM study from the Phase III etrolizumab 
studies will receive a dose of etrolizumab that remains unaltered from those studies.  
Patients enrolling from Phase II OLE Study GA27927 who were receiving a nominal 
100-mg dose of etrolizumab (0.7 mL of 150 mg/mL solution via vial and syringe) will 
receive an actual dose of 105 mg in this study (formulation is a prefilled syringe [PFS]
containing 0.7 mL of 150 mg/mL etrolizumab solution, corresponding to delivering a 
dose of 105 mg etrolizumab per injection). This dose regimen has been demonstrated 


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to reach full receptor occupancy in the Eucalyptus Phase II clinical study.  Of note, no
etrolizumab will be administered during Part 2 (SM).
2.
OBJECTIVES
2.1
OBJECTIVES OF THE STUDY
The objectives of this OLE-SM study are as follows:
Part 1 (OLE)

To assess the long-term safety and efficacy of etrolizumab in patients eligible for 
Part 1 (OLE)
Part 2 (SM)

PML safety monitoring
2.2
OTHER SAFETY OBJECTIVES
The other safety objectives for this study are as follows:
Part 1 (OLE)

To evaluate the incidence and severity of infection-related adverse events

To evaluate the incidence of malignancies

To evaluate the incidence and severity of hypersensitivity reactions

To evaluate the incidence and the clinical significance of anti-therapeutic 
antibodies (ATAs)
2.3
EXPLORATORY OBJECTIVE
The exploratory objective for this study is as follows:
Part 1 (OLE)

To evaluate histology at Week 108
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
3.1.1
Overview of Study Design
This OLE-SM study is composed of two parts:

Part 1 is the OLE for eligible patients, during which active etrolizumab, 105 mg SC,
will be administered every 4 weeks followed by a 12-week safety follow-up.

Part 2 is the 92-week PML SM for all patients, during which no etrolizumab will be 
administered.
Patients who are enrolled in Part 1 (OLE) should participate in Part 1 (OLE) and 
Part 2 (SM).
There may be patients who are ineligible for or choose not to participate in Part 1 (OLE) 
who will directly enroll in Part 2 (SM) only.


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3.1.1.1
Open-Label Extension (Part 1)
Part 1 (OLE) of this study is an open-label, multicenter study to evaluate the long-term 
efficacy and safety of etrolizumab in patients with moderate to severe UC who were 
enrolled in the Phase II OLE study (GA27927) or the Phase III studies (GA28948, 
GA28949, GA28950, GA29102, and GA29103) and who meet the eligibility criteria for 
enrollment into Part 1 (OLE) (see Table 1).  All patients will receive open-label 
etrolizumab in Part 1 (OLE).
Throughout Part 1 (OLE), patients will be monitored for safety by collection of adverse 
events (both serious and non-serious) and will be monitored for symptoms of PML by 
administration of the neurologic examination.  Efficacy data will consist of Mayo Clinic 
Score (MCS) at Week 108 and partial Mayo Clinic Score (pMCS) every 4 weeks for the 
first 3 months and then every 12 weeks thereafter until safety follow-up. Patients will 
undergo flexible sigmoidoscopy/colonoscopy performed and read by local endoscopist 
at Week 108 for the assessment of MCS. The local endoscopist will evaluate the 
endoscopic MCS subscore. In addition, a single paired colonic biopsy sample will be 
obtained during the procedure to evaluate histology.  The paired biopsy sample should 
be taken from the worst affected segment visualized (up to and including the descending 
colon).  For patients without inflammation on endoscopy, the paired biopsy sample 
should be taken from the worst affected area visualized in the last endoscopy (up to and 
including the descending colon).
Patients will have in-clinic visits at Weeks 0, 4, 8, and 12 and every 12 weeks thereafter 
(see Figure 1 and Appendix 1) and may continue to receive open-label etrolizumab in 
Part 1 (OLE) until commercial availability in their country, up to approximately 9 years
after the first patient is enrolled (see Section 3.2), or until the Sponsor’s decision to 
terminate the study, whichever is earlier.  Upon the completion of Part 1 (OLE) or early 
withdrawal from Part 1 (OLE), all patients will enter a 12-week safety follow-up, which 
consists of a telephone visit at Week 6 and an in-clinic visit at Week 12 (see 
Appendix 2).
The study population for Study GA27927 consists of patients who are naive to TNF 
inhibitors and patients who have been previously exposed to TNF inhibitors.  
Studies GA28948, GA28949, GA29102, and GA29103 enroll patients who are naive to
TNF inhibitors. Study GA28950 enrolls patients who have been previously exposed to 
TNF inhibitors.  Protocol design and comparators are provided in Table 1.
Study Drug Administration
Part 1 (OLE)
Patients enrolling from the Phase II OLE or Phase III controlled studies were previously 
treated with placebo, etrolizumab, infliximab, or adalimumab depending on the study and 
the group to which the patients were randomized.  Patients may also have been 
receiving concomitant background medication for UC including corticosteroids and/or 
immunosuppressants.


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All patients in Part 1 (OLE) will receive 105 mg etrolizumab every 4 weeks by the SC 
route.  Because a substantial proportion of patients enrolling in this study may be 
receiving etrolizumab for the first time, all patients will be required to receive their first 
four doses (Week 0, Day 1Week 12) of etrolizumab in the clinic setting and to be 
monitored for 60 minutes following each dose.  These in-clinic doses may be 
administered by the patient if he or she is competent at self-administration following the 
Phase III controlled study.  Patients enrolling from Studies GA27927, GA28948, and 
GA28949 in which self-administration was not permitted (study medication administered 
by health care professional [HCP]) may be trained on self-administration of etrolizumab 
in this study.  If patients from Studies GA28950, GA29102, or GA29103 who did not 
previously self-administer drug at home wish to switch to self-administration, these 
patients should be trained on self-administration during the first four etrolizumab 
administrations in this study.  Patients may self-administer or have their caregivers 
administer study treatment in the home setting starting at Week 16, if considered 
competent to do so by the HCP.  Clinic visits during OLE (Part 1) will be every 4 weeks 
for the first 12 weeks, then every 12 weeks until the patient enters SM (Part 2).  If 
necessary, patients or their HCP may choose to continue administration of study 
medication in the clinic.


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Table 1
Eligibility Criteria for Enrollment into Part 1 of Open-Label Extension and Safety Monitoring Study 
GA28951
Protocol 
Number(s)
Title
Eligibility and Timing for Enrollment a
GA27927
Phase II open-label extension study to evaluate 
the long-term safety of etrolizumab in patients 
with moderate to severe ulcerative colitis
Patients who meet the following criteria:

Patients not in safety follow-up or PML follow-up within Study GA27927 and 
whose last dose of etrolizumab was during the month of July 2016 may enroll in 
Part 1 (OLE) of Study GA28951, if eligible, and receive their first dose in this 
study 4 weeks after their last dose in Study GA27927
GA28948 
and 
GA28949
Phase III, randomized, double-blind, controlled, 
multicenter study to evaluate the efficacy of 
(induction of remission) and safety of etrolizumab 
compared with adalimumab and placebo in 
patients with moderate to severe active ulcerative 
colitis who are naive to TNF inhibitors
Treatment Arms:  etrolizumab, adalimumab, 
placebo
Patients who performed the Week 10 visit who:

Have not achieved clinical remission at Week 10; may receive their first dose of 
etrolizumab upon enrollment into Part 1 (OLE) of the OLE-SM study 2 weeks 
after the Week 10 timepoint in Study GA28948/GA28949

With the exception of VHP countries participating in GA28949 and Estonia 
(participating in GA28948):  achieved clinical remission e at Week 10 and 
performed the Week 14 visit; may receive their first dose of etrolizumab upon 
enrollment into Part 1 (OLE) of the OLE-SM study at Week 14 in Study 
GA28948/GA28949

With the exception of VHP countries participating in GA28949 and Estonia 
(participating in GA28948):  received rescue medication between Week 0 and 
Week 10, as defined in the GA28948 or GA28949 protocol; patients receiving 
rescue medication between Weeks 10 and 14 may enroll in Part 1 (OLE) of the 
OLE-SM study at Week 14

For VHP countries participating in GA28949 and Estonia (participating in 
GA28948) only: achieved clinical remission at Week 10 and performed the 
Week 14 visit; may receive their first dose of etrolizumab upon enrollment into 
Part 1 (OLE) of the OLE-SM study at Week 16 (4 weeks after the last 
etrolizumab/etrolizumab placebo dose in Study GA28948/GA28949)


Table 1
Eligibility Criteria for Enrollment into PART 1 of Open-Label Extension and Safety Monitoring Study 
(GA28951) (cont.)
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Protocol 
Number(s)
Title
Eligibility and Timing for Enrollment a
GA28948 
and 
GA28949
(cont.)

For VHP countries participating in GA28949 and Estonia (participating in 
GA28948) only:  received rescue medication between Week 0 and Week 10, as 
defined in the GA28948 or GA28949 protocol; patients receiving rescue 
medication between Weeks 10 and 16 may enroll in Part 1 (OLE) of the OLE-
SM study at Week 16
GA28950
Phase III, randomized, double-blind, 
placebo-controlled, multicenter study of the 
efficacy and safety of etrolizumab during induction 
and maintenance in patients with moderate to 
severe active ulcerative colitis who have been 
previously exposed to TNF inhibitors
Treatment Arms:  etrolizumab, placebo
At end of Induction Phase:

Patients who performed the Week 14 visit who did not meet the criteria for 
clinical response b
During the Maintenance Phase

Patients who met the criteria for clinical relapse c

Patients receiving rescue medications, as defined in the Study GA28950 
protocol
All remaining patients at the end of Week 66 visit (completion of Maintenance Phase)
GA29102
Phase III, randomized, double-blind, 
placebo-controlled, multicenter study to evaluate 
the efficacy (maintenance of remission) and 
safety of etrolizumab compared with placebo in 
patients with moderate to severe active ulcerative 
colitis who are naive to TNF inhibitors
Treatment Arms:  etrolizumab, placebo
At the end of the Induction Phase:

Patients who performed the Week 10 visit and who have not achieved clinical 
response b at Week 10

Patients receiving rescue medications during the Induction Phase, as defined in the 
GA29102 protocol
During the Maintenance Phase:

Patients who met the criteria for clinical relapse c

Patients receiving rescue medications, as defined in the GA29102 protocol
All remaining patients at the end of Week 62 visit (completion of Maintenance Phase)


Table 1
Eligibility Criteria for Enrollment into PART 1 of Open-Label Extension and Safety Monitoring Study 
(GA28951) (cont.)
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Protocol 
Number(s)
Title
Eligibility and Timing for Enrollment a
GA29103
Phase III, randomized, double-blind,
double-dummy multicenter study to evaluate 
the efficacy and safety of etrolizumab compared 
with infliximab in patients with moderate to severe 
active ulcerative colitis who are naive to TNF 
inhibitors
Treatment Arms:  etrolizumab, infliximab
Patients who met criteria for disease worsening d at any time between Week 10 and 
Week 54 may enter OLE-SM after an infliximab washout period within Study GA29103 
Patients receiving rescue medications, as defined in the GA29103 protocol
All remaining patients at the end of Week 54 visit (completion of Maintenance Phase)
MCSMayo Clinic Score; OLEopen-label extension; OLE-SMopen-label extensionsafety monitoring; pMCSpartial Mayo Clinic Score; SMsafety 
monitoring; TNFtumor necrosis factor.
a Patients are to receive their first dose of etrolizumab in this protocol 4 weeks after their last dose of study medication in Studies GA27927, GA28950 and 
GA29102; as specified above for Studies GA28948 and GA28949, and as described in the washout schedule for Study GA29103.  On occasions where 
this first dose of etrolizumab cannot be administered in accordance with these requirements, the first dose of etrolizumab is to be administered with a 
maximum delay of 2 weeks.
b Definition of Clinical Response:  MCS with 3-point decrease and 30% reduction from baseline as well as 1-point decrease in rectal bleeding 
subscore or an absolute rectal bleeding score of 0 or 1.
c
Definition of Clinical Relapse:  Clinical relapse is defined as an increase in pMCS 3 points compared with induction timepoint (Week 10 or 14) AND 
absolute pMCS of 5 AND an endoscopy subscore of 2.
d Definition of Disease Worsening:  Disease worsening is defined as an increase in pMCS 3 points from the induction timepoint AND absolute pMCS of 
5 AND an endoscopy subscore of 2.
e Definition of Clinical Remission:  MCS 2 with individual subscores 1.


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Number of Patients
The OLE-SM study will be conducted in centers that have participated in the Phase II 
OLE Study GA27927 and/or the double-blinded Phase III Studies GA28948, GA28949, 
GA28950, GA29102, and GA29103.  The maximum number of patients potentially 
enrolling in this study will be all patients from the studies; approximately 2100 patients.  
Patients will be allocated the same subject number they had in the initial Phase II OLE 
study or Phase III study.
Rescue Therapy That Can Be Given with Study Medication
At any time during the study, patients who have worsening UC may receive concomitant 
therapy with corticosteroids (IV, oral, or topical).  Addition of or increases in doses of 
5-ASA (oral or topical) and/or initiation of immunosuppressant treatment (i.e., AZA, 6-MP, 
or MTX), including patients from Study GA27927, is also permitted during this study at 
the discretion of the investigator.
Patients who are taking immunosuppressants (i.e., AZA, 6-MP, or MTX) as part of their 
concomitant treatment in the Phase II OLE and Phase III controlled studies may 
continue to receive immunosuppressants in OLE-SM study with dose adjustments at the 
discretion of the investigator. Generally accepted criteria for discontinuation of 
immunosuppressants due to toxicity include, but are not limited to, acute pancreatitis, 
severe leukopenia, severe thrombocytopenia, or clinically significant elevations of the 
liver-associated enzymes from baseline, especially in the presence of an elevated total 
bilirubin.  The ultimate decision to reduce dose or discontinue immunosuppressants due 
to toxicity or any other reason remains at the discretion of the investigator. 
Rescue Therapy That CANNOT Be Given with Study Medication
At ANY time during the conduct of the study, use of other immunosuppressive agents 
including, but not limited to, other anti-integrins, T or B cell depleters (except AZA and 
6-MP), TNF inhibitors (including TNF inhibitor biosimilars), anti-adhesion molecules,
cyclosporine, tacrolimus, Janus kinase (JAK) inhibitors, or investigational agents are 
prohibited.  Patients who do receive such rescue therapies are not allowed to receive 
further etrolizumab treatment and are to be withdrawn into the 12-week safety follow-up.  
These patients will then enter Part 2 (SM) of the OLE-SM study for 92 weeks of 
extended PML monitoring.
Moving from Part 1 (Open-Label Extension) to Part 2 (Safety Monitoring) 
in this Study
Patients who discontinue treatment with open-label etrolizumab will be requested to 
enter a post-treatment 12-week safety follow-up, and then be requested to enter 
Part 2 (SM) of this study.  Part 2 (SM) will consist of an additional 92 weeks of extended 
PML monitoring following the initial 12-week safety follow-up period.  See Figure 1 and 
Figure 2 for schemas of the study and see Section 3.1.1.2.


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3.1.1.2
Extended PML Safety Follow-Up (Part 2)
Patients may enroll into Part 2 (SM) of this study for 92 weeks of PML monitoring via 
three routes:

Patients exiting Part 1 (OLE)

Patients from the Phase II OLE study or the Phase III controlled studies who are 
not eligible or willing to receive etrolizumab in this study (e.g., due to receipt of 
prohibited medication)

Patients whose safety follow-up or PML follow-up is not completed within 
Study GA27927 by July 2016
Regardless of route of entry, patients will enroll following completion of the 12-week 
safety follow-up period, which will occur within Part 1 of this study (OLE; for those 
entering from OLE) or within the Phase III controlled studies (for those enrolling directly 
from the Phase III studies).  Patients from the Phase II OLE study whose safety 
follow-up is not completed within Study GA27927 by July 2016 will complete their safety 
follow-up period in this study (GA28951).
3.1.1.3
Study Duration
Part 1 (OLE)
Part 1 (OLE) will continue for up to approximately 9 years after the first patient is 
enrolled into the study, until commercial availability, or until the Sponsor’s decision to 
terminate the study, whichever is earlier.  Patients who withdraw from Part 1 (OLE) 
should complete the 12-week safety follow-up and then enter Part 2 (SM) for PML 
monitoring.
Part 2 (SM)
For patients who enter Part 2 (SM), either from Part 1 (OLE) or enroll directly from the 
Phase II OLE study or any of the Phase III studies, the study will last 92 weeks.
Schedules of Assessments are provided in Appendix 1, Appendix 2, and Appendix 3.  
The efficacy outcome definitions are given in Table 2.
Table 2
Efficacy Outcome Definitions
Outcome Term
Definition
Endoscopic remission
Endoscopic subscore0
MCS
MCS is a composite of 4 assessments, each rated from 0 to 3:  stool 
frequency, rectal bleeding, endoscopy, and physician’s global 
assessment
MCS Remission
MCS2, a rectal bleeding score of 0, physician’s global assessment of 
01, stool frequency subscore of 01, endoscopy score of 01
pMCS
pMCS is a composite of 3 assessments, each rated from 0 to 3:  stool
frequency, rectal bleeding, and physician’s global assessment
pMCS Clinical 
Remission
pMCS2, a rectal bleeding score of 01, physician’s global assessment 
of 01, stool frequency subscore of 01
MCSMayo Clinic Score; pMCSpartial Mayo Clinic Score.




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Figure 2
Study Schema for Part 2 (SM) of the OLE-SM Study 
OLEopen-label extension; OLE-SMopen-label extensionsafety monitoring study; PMLprogressive multifocal leukoencephalopathy; 
SMsafety monitoring.
a Study GA27927.
b Studies GA28948, GA28949, GA28950, GA29102, and GA29103.


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3.2
END OF STUDY
The end of the study is defined as the date when the last patient completes the 92-week 
PML safetymonitoring period.
3.3
OUTCOME MEASURES 
3.3.1
Efficacy Outcome Measures (Part 1; OLE)
The efficacy outcome measures for this study are as follows:  

To describe the long-term efficacy of etrolizumab (105 mg SC every 4 weeks) 
by pMCS clinical remission for patients with UC in Part 1 (OLE)

To evaluate remission by MCS at Week 108 in Part 1 (OLE)

To evaluate endoscopic remission by MCS at Week 108 in Part 1 (OLE)
3.3.2
Safety Outcome Measures (Part 1; OLE)
The safety outcome measures for Part 1 of this study are as follows:

Incidence and severity of adverse events

Incidence of serious adverse events

Incidence and severity of infection-related adverse events

Incidence of serious infection-related adverse events

Incidence and severity of injection-site reactions

Incidence of adverse events leading to etrolizumab discontinuation

Incidence of laboratory abnormalities

Incidence of malignancies

Incidence of ATAs to etrolizumab

Incidence and severity of hypersensitivity reaction events
3.3.3
Safety Outcome Measure (Part 2; SM)
The safety outcome measure for Part 2 of this study is as follows:  

Incidence of suspected or confirmed PML events
3.3.4
Exploratory Outcome Measure
The exploratory outcome measure for this study is as follows:

Histologic appearance of mucosa at Week 108


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4.
MATERIALS AND METHODS
4.1
PATIENTS
Part 1 (OLE)
Approximately 2100 patients enrolled in the Phase II OLE study (GA27927) and the
Phase III studies (GA28948, GA28949, GA28950, GA29102, and GA29103) will be 
potentially eligible for Part 1 (OLE) of this OLE-SM study.  There will be no 
randomization in this OLE-SM study; all patients entering Part 1 (OLE) will receive 
open-label etrolizumab.
Part 2 (SM)
Approximately 2100 patients enrolled in the Phase II OLE study and the Phase III 
controlled studies who provide consent are eligible for Part 2 (SM) of this OLE-SM study.
4.1.1
Inclusion Criteria
Part 1 (OLE)

Patients who were previously enrolled in the Phase II OLE study or a Phase III 
controlled study and meet the eligibility criteria for treatment with open-label 
etrolizumab as described in Table 1 (see Section 3.1.1.1) may enroll in Part 1 (OLE) 
of the study.  These patients must provide written informed consent and comply with 
the requirements of the OLE-SM protocol.
Patients not in safety follow-up or PML follow-up within Study GA27927 and 
whose last dose of etrolizumab is by July 2016 may enroll in Part 1 (OLE) of 
Study GA28951, if eligible, and receive their first dose in this study 4 weeks
after their last dose in Study GA27927.  On occasions where this first dose of 
etrolizumab cannot be administered in accordance with these requirements, 
the first dose of etrolizumab is to be administered with a maximum delay of 
2 weeks (i.e., up to 6 weeks after their last dose of etrolizumab in 
Study GA27927).
Eligible patients who exit from Study GA28948 or GA28949 at Week 10 
because either they did not achieve clinical remission or they required the use 
of rescue medication prior to the Week 10 timepoint should not receive their 
first dose of open-label etrolizumab in Study GA28951 until 2 weeks after the 
Week 10 timepoint in the Phase III controlled study to allow for adalimumab 
washout. The first dose of etrolizumab given to these patients entering 
Study GA28951 should not exceed 4 weeks following the Week 10 timepoint 
from the Phase III controlled study.
With the exception of VHP countries participating in GA28949 and Estonia
(participating in GA28948):  Patients who remain in Study GA28948 or Study 
GA28949 through Week 14 because they have achieved clinical remission 
may enroll in Part 1 (OLE) of Study GA28951 at Week 14.  The first dose of 
open-label etrolizumab will be given on Day 1 upon enrollment into Part 1 (OLE) 
of Study GA28951.  The first dose of etrolizumab given to the patients entering 


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Study GA28951 should not exceed 2 weeks following the Week 14 timepoint 
from the Phase III controlled study.
With the exception of VHP countries participating in GA28949 and Estonia
(participating in GA28948):  Eligible patients who receive rescue medication 
between Weeks 10 and 14 may enroll in Part 1 (OLE) of Study GA28951 at 
Week 14.
For VHP countries participating in GA28949 and Estonia (participating in 
GA28948):  Patients who remain in Study GA28948 or GA28949 through 
Week 14 because they have achieved clinical remission at Week 10 may enroll 
in Part 1 (OLE) of Study GA28951 at Week 16.  The first dose of open-label 
etrolizumab will be given on Day 1 upon enrollment into Part 1 (OLE) of Study 
GA28951 (4 weeks after their last etrolizumab/etrolizumab placebo dose or 8 
weeks after their last adalimumab/adalimumab placebo dose in Study 
GA28948 or GA28949). On occasions where the first OLE dose of etrolizumab 
cannot be administered in accordance with these requirements, the first dose 
may be delayed by a maximum of 2 weeks (i.e., first OLE dose up to 6 weeks 
after their last etrolizumab/etrolizumab placebo dose or 10 weeks after their 
last adalimumab/adalimumab placebo dose in Study GA28948 or GA28949).
For VHP countries participating in GA28949 and Estonia (participating in 
GA28948):  Eligible patients who receive rescue medication between Weeks 
10 and 16 may enroll in Part 1 (OLE) of Study GA28951 at Week 16.

For women who are not postmenopausal (at least 12 months of 
nontherapy-induced amenorrhea) or surgically sterile (i.e., absence of ovaries 
and/or uterus):  agreement to remain abstinent or use a highly effective method of 
contraception during the treatment period and for at least 24 weeks after the last 
dose of study drug (see Appendix 4).
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below: 
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at 
least 24 weeks after the last dose of study drug to avoid exposing the embryo 
to study drug.  Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception.


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Part 2 (SM)

Patients whose safety follow-up or PML follow-up is not completed within 
Study GA27927 and patients who had their last dose of etrolizumab by July 2016 in 
Study GA27927 and are not eligible or choose not to enroll in Part 1 (OLE) 

Patients who participated in one of the etrolizumab Phase III studies ( GA28948, 
GA28949, GA28950, GA29102, and GA29103) and are not eligible or chose not to 
enroll in Part 1 (OLE) 

Patients who transfer from Part 1 (OLE) of this protocol

Ability and willingness to provide written informed consent and comply with the 
requirements of Part 2 (SM) of the OLE-SM protocol
All patients must have completed the 12-week safety follow-up prior to entering 
Part 2 (SM).
4.1.2
Exclusion Criteria
Part 1 (OLE)

Withdrawal of consent from the Phase II OLE study or any of the Phase III studies 

Patients who discontinued etrolizumab/etrolizumab placebo prior to Week 10 or did 
not perform the Week 10 visit of the Phase III Studies GA28948, GA28949, 
GA29102, and GA29103

Patients who discontinued etrolizumab/etrolizumab placebo prior to Week 14 or did 
not perform the Week 14 visit of the Phase III Study GA28950

Inability to comply with the study protocol, in the opinion of the investigator

Patients not compliant in the Phase II OLE or Phase III studies or did not complete 
the required washout period for an active comparator in Studies GA28948, 
GA28949, and GA29103

Pregnancy or lactation
Exclusion Due to Safety Reasons

Patients who developed an anaphylactic/anaphylactoid or severe allergic reaction to 
study medication during the Phase II OLE or Phase III studies

Patients who experienced or have an ongoing serious infection event (except for 
those listed below) should not receive study drug until the event has completely 
resolved and treatment with anti-infective medications has been completed

Patients who experienced a specific de novo or reactivated serious viral infection 
such as hepatitis B virus (HBV), hepatitis C virus (HCV), or HIV during the 
Phase II OLE or Phase III studies

Patients who develop cytomegalovirus (CMV) colitis leading to early treatment 
discontinuation in the Phase II OLE or Phase III studies

Patients who develop life-threatening infections during the Phase II OLE or 
Phase III studies


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
Patients who developed a malignancy (with the exception of local and resected
basal or squamous cell carcinoma of the skin), or who develop adenocarcinoma in 
situ (AIS), high-grade squamous intraepithelial lesions (HSIL), or cervical 
intraepithelial neoplasia (CIN) of Grade 1 on cervical Pap smear, or who develop 
colonic dysplasia during the Phase II OLE or Phase III studies

Receipt of the following since commencement of the Phase II OLE or 
Phase III controlled studies:
Any investigational treatment, including investigational vaccines
Use of agents that deplete B or T cells (e.g., alemtuzumab or visilizumab), 
except AZA and 6-MP
Use of anti-adhesion molecules
Use of JAK inhibitors
Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF)
Patients who have previously received rituximab, natalizumab, vedolizumab, or 
efalizumab may not enter the study
Immunization with a live/attenuated vaccine

In the opinion of the investigator, any new (since enrolling in the Phase II OLE or 
Phase III controlled studies), significant, uncontrolled comorbidity, such as 
neurological, cardiac (e.g., moderate to severe heart failure New York Heart 
Association [NYHA] Class III/IV), pulmonary, renal, hepatic, endocrine, or 
gastrointestinal (GI) disorders (excluding UC)

Any patient who developed PML in the Phase II OLE or Phase III studies

Any patient with neurological symptoms where suspected PML has not been 
ruled out
Part 2 (SM)

No exclusion criteria
4.2
CONCOMITANT MEDICATION AND TREATMENT ASSIGNMENT
Part 1 (OLE)
In Part 1 (OLE), all patients will receive 105 mg etrolizumab every 4 weeks by the SC 
route.  Because a substantial proportion of patients enrolling in this study may be 
receiving etrolizumab for the first time, all patients will be required to receive their first 
four doses of etrolizumab (i.e., Week 0, Day 1Week 12) in the clinic setting and to be 
monitored for 60 minutes following each dose.  These in-clinic doses may be 
administered by the patient if he or she is competent at self-administration following the 
Phase III controlled study. 
Patients enrolling in this study from Studies GA27927, GA28948, and GA28949 (study 
medication administered by HCP) may be trained on self-administration of etrolizumab in 
this study.  If patients from the Phase II OLE study or any Phase III study who did not 
previously self-administer drug at home wish to switch to self-administration, these 


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patients are to be trained during the first four administrations.  Starting at Week 16, 
patients may self-administer or have their caregivers administer study treatment in the 
home setting, if considered competent to do so by the HCP.  Clinic visits during OLE 
(Part 1) will be every 4 weeks for the first 12 weeks, then every 12 weeks until the 
patient enters SM (Part 2).  If necessary, patients or their HCP may choose to continue 
administration of study medication in the clinic.
Part 2 (SM)
In Part 2 (SM), no study drug will be administered.
4.2.1
Concomitant Therapy 
4.2.1.1
Permitted Concomitant Therapy
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal/homeopathic remedies, preventative vaccines, vitamins, nutritional 
supplements) used by a patient from the start of the study to completion/early withdrawal 
from treatment. During Part 1 (OLE), all concomitant medications should be reported to 
the investigator and recorded on the Concomitant Medications electronic Case Report 
Form (eCRF).  During Part 2 (SM), the use of concomitant therapies will not be required 
to be documented in the eCRF.
Patients who use oral contraceptives or maintenance therapy for comorbidities should 
continue their use.
4.2.1.2
Requirements Regarding Concomitant Therapy for Ulcerative 
Colitis
Part 1 (OLE)

Patients who are taking immunosuppressants as part of their concomitant treatment 
in the Phase II OLE or Phase III controlled studies may continue to receive 
immunosuppressants in the OLE-SM study with dose adjustments at the discretion 
of the investigator.  Generally accepted criteria for discontinuation of 
immunosuppressants due to toxicity include, but are not limited to, acute 
pancreatitis, severe leukopenia, severe thrombocytopenia, or clinically significant 
elevations of the liver-associated enzymes from baseline, especially in the presence 
of an elevated total bilirubin.  The ultimate decision to reduce dose or discontinue 
immunosuppressants due to toxicity or any other reason remains at the discretion of 
the investigator.

All sites, including U.S. sites in Phase II OLE study, may initiate 
immunosuppressant treatment (i.e., AZA, 6-MP, or MTX) in their patients during this 
study at the discretion of the investigator.
At any time during the study, patients may receive concomitant therapy with 
corticosteroids (IV, oral, or topical) or 5-ASA (oral or topical).


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Part 2 (SM)
There are no requirements regarding concomitant therapies during Part 2 (SM) of this 
study.  During Part 2 (SM), investigators should follow standard practice and 
prescribe the local standard of care or treatments that, in their opinion, meet the needs 
of the patient.
4.2.2
Prohibited Therapy
Part 1 (OLE)
Use of the following therapies is prohibited during Part 1 (OLE) of this study.  Any patient 
taking the following therapies is to be withdrawn into Part 2 (SM) following 12-week 
safety follow-up.

Any investigational treatment including investigational vaccines

Use of lymphocyte-depleting agents (e.g., alemtuzumab or visilizumab), except AZA 
and 6-MP

Use of cyclosporine, tacrolimus, sirolimus, or MMF

Use of natalizumab, vedolizumab, efalizumab, or rituximab 

Use of TNF inhibitors (including TNF inhibitor biosimilars)

Use of anti-adhesion molecules (e.g., anti-MAdCAM-1)

Use of JAK inhibitors
Part 2 (SM)
There are no prohibited therapies in Part 2 (SM).
4.3
STUDY TREATMENT
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Etrolizumab
Part 1 (OLE)
Etrolizumab will be supplied by the Sponsor as a liquid formulation in PFSs and is 
administered as a SC injection.  Each 1mL PFS will contain 150 mg/mL of etrolizumab 
(0.7 mL nominal volume).  Etrolizumab is formulated as 150 mg/mL in 20 mM histidine, 
0.2 M arginine succinate, and 0.04% polysorbate 20, pH 5.8.  Each syringe is for 
single-dose parenteral administration and contains no preservatives.
Study drug packaging will be overseen by the Sponsor’s Clinical Trial Supplies 
Department and will be a labeled with the identification required by local law, the 
protocol number, drug identification, and dosage.  The packaging and labeling of the 
study medication will be in accordance with Sponsor’s standards and local regulations.
Upon arrival of investigational products at the site, the pharmacist or medication nurse 
should check them for damage and verify proper identity, quantity, integrity of seals, and 
temperature conditions and report any deviations or product complaints to the monitor 
upon discovery.


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The study drug must be stored according to the details on the product label.  The 
drug label indicates the storage temperature.  PFSs of study medication should be 
refrigerated at 2°C8°C and protected from excessive light and heat.  PFSs should not 
be frozen, shaken, or stored at room temperature.
The PFS containing study drug is stable for no longer than 8 hours at room temperature 
(up to 30C).  If a PFS is left at room temperature for longer than this time, it should not 
be used.  In the home setting, patients should be instructed to contact the study site staff 
for a replacement.
Used PFSs with study drug will be stored at room temperature in designated sharps 
containers and returned to the site for disposal per local schedule.
Under no circumstances is the investigator to allow study medication to be used other 
than as directed by the protocol.
Details about the packaging and labeling of the study drug will be provided in the 
protocol-supporting documents.
For further details, see the current Etrolizumab Investigator's Brochure.
4.3.1.2
Concomitant Therapy and Treatments
Please refer to product label, local prescribing dosage, administration, and compliance 
information for the formulation, packaging, and handling details of agents prescribed as 
concomitant therapy for UC.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Etrolizumab
Part 1 (OLE)
All patients will receive one 0.7-mL injection with use of a PFS device once every 
4 weeks.  The device is a 1-mL long glass syringe with a staked-in stainless steel needle. 
The needle is a 27G ½" thin-wall design.  The needle-safety device is a standard design
(SSI X100L), and the device is fitted with a custom-designed plunger rod and an 
extended finger flange.
A part of the needle cap of the PFS may contain natural rubber latex that may cause 
allergic reactions in latex-sensitive individuals.
Study site HCPs will be trained on the use of the PFS device and SC administration of 
study medication into the thigh, abdomen, or upper arm.


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Patients Self-Administering for the First Time in this Protocol
As mentioned in Section 4.2, in order to monitor for any possible hypersensitivity 
reactions in patients who would receive their first active etrolizumab dose upon enrolling 
in the OLE-SM study, etrolizumab administration is to be conducted in the clinic setting 
for the first four drug administrations. Patients who are to self-administer for the first 
time in this study will be trained in the use of the device by an HCP and be given an 
“Information for Use” leaflet.  In the event that a caregiver will ultimately administer study 
drug to the patient in the home setting, the caregiver is to be trained.  The upper arm,
abdomen, or thigh site may be used by the caregiver. Note: The upper arm site is not to 
be used for patient administration of study treatment.
For the initial 4 dose administrations, study medication is to be administered under close 
supervision of the HCP in a setting where medications and resuscitation facilities are 
available.  The first two treatments (each 0.7 mL delivered via PFS; Week 0 [Day 1] and 
Week 4) will be administered by the HCP and observed by the patient (and/or caregiver).  
The following two treatments (Week 8 and Week 12) will be administered by the patient 
(or caregiver) and observed by the HCP in the clinic setting.  Following the first four 
study treatment administrations, patients will be monitored for acute hypersensitivity 
reactions for at least 1 hour after the end of the injection.
Epinephrine must be readily available for immediate use if required to treat anaphylaxis.  
Adjunctive medications such as parenteral diphenhydramine and inhaled bronchodilators 
can also be used IN ADDITION to epinephrine if necessary.   Resuscitation equipment 
should also be available.  Site personnel must be able to detect and treat such reactions.
Patients with severe hypersensitivity reactions (e.g., stridor, angioedema, life-threatening 
change in vital signs) must be withdrawn from study treatment.  These patients are to 
enter the 12-week safety follow-up in this study followed by PML monitoring in 
Part 2 (SM) of this study.
All adverse events of systemic hypersensitivity reactions or anaphylactoid or anaphylaxis 
reactions must be reported within 24 hours to the Sponsor and the Medical Monitor must 
be informed as soon as is practical (see the Study Manual for contact information).
Following the first four drug administrations (typically expected at 12 weeks), study drug 
administration will be continued in the home setting by the patient or a caregiver, if 
considered appropriate by the investigator.  Study medication will be administered in the 
patient’s home after return from the clinic visit on days when drug administration is to 
take place on the same day as a clinic visit day.  Patients and/or the caregiver will be
provided with contact information for questions related to self-administration between
visits.  Competence of the patient or caregiver to administer at home will be documented 
in source documents.  Compliance in the home setting is to be monitored by use of an
e-diary to record drug administration and return of used and unused medication syringes
(see Appendix 8).  Patients and/or the caregiver will be provided with alert cards for 


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themselves and a partner/caregiver, which they will be requested to carry at all times.  
These will include guidance on recognizing allergic/anaphylactic/anaphylactoid reactions
and how to obtain emergency care in the event such a reaction occurs and information 
regarding recognition of symptoms of PML.
If the HCP/patient cannot administer study medication on the scheduled dosing day, 
study medication is to be administered within a window of +3 days from the scheduled 
dosing date.  If the patient experiences a minor illness (e.g., minor infection), at the 
discretion of the investigator, study medication may be delayed for a maximum period of 
2 weeks.  Study medication dosing is to be resumed in accordance with the original 
dosing schedule.  Any potential deviation from this window is to be discussed with the 
Medical Monitor for the study.
If necessary, patients or their HCP may choose to continue administration of study 
medication in the clinic.
The recommended injection sites are the front of the middle thighs and the lower part of 
the abdomen below the navel except for the 2-inch area directly around the navel.  
Patients should place themselves in a comfortable position before self-administering
study drug. As previously recommended, caregivers responsible for administering the 
injection should utilize the outer area of the upper arm, abdomen, or thigh. Injections 
should never be given into areas where the skin is not intact or is tender, bruised, red, 
or hard.  The injection sites will be inspected by the site personnel at each clinic visit.  
Any injection-site reactions (see Section 5.1.1.3) should be documented on the 
appropriate Adverse Event eCRF page.  Patients administering at home should be
taught to report any injection-site reactions as adverse events (e.g., redness and/or
swelling).
For dosage and administration of concomitant therapy for UC see Section 4.2.1.2 and 
for compliance see Section 4.3.3.1.
Guidelines for treatment interruption or discontinuation are provided in Section 4.5.
Part 2 (SM)
No study drug will be administered during Part 2 (SM) of this protocol.
4.3.3
Investigational Medicinal Product Accountability
Part 1 (OLE)
All investigational medicinal products (IMPs) required for completion of this study, 
namely, etrolizumab, will be provided by the Sponsor.  The investigator is responsible for 
the control of the drugs under investigation.  The investigational site will acknowledge 
receipt of IMP (e.g., drug receipt record) and disposition (e.g., drug dispensing log).  
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records.  Interactive voice/Web-based response system (IxRS) will be used to confirm 
the shipment condition and content.  Any damaged shipments will be replaced.
Accurate records must be kept for all study drug provided by the Sponsor.
These records must contain the following:

Documentation of drug shipments received from the Sponsor (date received and 
quantity)

Disposition of unused study drug not dispensed to patients

Drug Dispensing Log must be kept current and should contain the following 
information:
Identification of the patient to whom the study medication was dispensed
Date(s) and quantity of the study medication dispensed to the patient
Date(s) and quantity of the unused study medication returned by the patient
All records and drug supplies must be available for inspection by the study monitor.
4.3.3.1
Assessment of Compliance
Part 1 (OLE)
Patient compliance will be assessed by maintaining adequate drug dispensing logs, the 
patient e-diary, and return records.
Home injection:  An e-diary will be provided to patients to record home injections.  
Patients will be asked to return all unused PFS in the provided boxes at each visit as a 
measure of drug accountability and patient compliance.  Site personnel will monitor the 
medication records from the e-diary via an online portal.  However, patients should bring 
the e-diary to the clinic during each visit.
Sharps containers for any used PFS will be provided to patients for home usage.  After 
home injections, the used syringes must be placed into the sharps containers 
immediately.  The sharps containers should be returned to sites.  Sharps containers will 
be discarded by the site staff at the frequency per local schedule.
A Drug Dispensing Log must be kept as described in Section 4.3.3.  The investigator is 
responsible for ensuring that dosing is administered in compliance with the protocol.  
Delegation of this task must be clearly documented and approved by the investigator.  
When the study is completed, the investigator will return all completed Drug Dispensing 
Logs to the Monitors.
Any unused study drug and Drug Return Records should be returned to the Monitor, 
unless alternate destruction has been authorized by Roche or required by local or 
institutional regulations (Section 4.3.3.2). The investigator's copy of the Drug Return 
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4.3.3.2
Destruction of the Investigational Medicinal Product
Part 1 (OLE)
Any used PFS will be placed into the sharps containers immediately after SC injections 
either at site or at home.  The sharps containers should be discarded at the study site by 
the site staff per local schedule.  Written documentation of destruction of unused study 
drug must contain the following:

Identity (batch numbers or subject numbers) of IMP(s) destroyed

Quantity of IMP(s) destroyed

Date of destruction

Method of destruction

Name and signature of responsible person who destroyed investigational product(s)
In case of device failure or if there are any issues with the drug, the PFS should not be 
destroyed, and instead should be returned to the study site in the packaging provided for 
this purpose. The device is to be sent from the investigator site to the appropriate 
Roche Clinical Trial Supplies Department for further assessment (see Section 4.3.3.3).
4.3.3.3
Reporting of Prefilled Syringe Complaints/Events
Part 1 (OLE)
The investigator should report all medical device complaints to the Sponsor.  The 
investigator must document as much information as possible on the PD103 IMP 
deviation form, including product batch number and expiration date, and forward the 
complaint form to the Sponsor within 24 hours of the investigator becoming aware of the 
event. PD103 IMP deviation form, together with pictures of the defective PFS, should be 
sent to kaiseraugst.global_impcomplaint_management@roche.com.  
Where possible, the investigator will retrieve the PFS unit(s) involved in the complaint 
and attempt to return it to the Sponsor for further assessment.
If the medical device complaint results in an adverse event, an Adverse Event eCRF 
must be completed and submitted through the electronic data capture (EDC) system 
immediately (i.e., no more than 24 hours after learning of the event).  If the event is 
serious, the Adverse Event eCRF must be completed and submitted through the EDC 
immediately (i.e., no more than 24 hours after learning of the event), as outlined in 
Section 5.4.1. If the medical device complaint results in an adverse event to an 
individual other than the study patient (e.g. nurse at the site or relative/caregiver during 
a home administration), the device complaint must be reported on the PD103 IMP 
deviation form. The adverse event must be reported to the Sponsor as a spontaneous 
adverse event (see Section 5.4.6).


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4.4
STUDY ASSESSMENTS
The schedules of assessments are provided in the Study Flowcharts in Appendix 1,
Appendix 2, and Appendix 3.  Study assessments are detailed below and will be 
undertaken at study visits as indicated in the Schedule of Assessments.  Assessments 
will be performed only after informed consent has been obtained.
4.4.1
Description of Study Assessments in Part 1 (OLE)
On the final visit of the Phase II OLE or Phase III controlled study, patients should have 
had procedures and laboratory assessments performed as part of their withdrawal visit.  
Therefore, to minimize burden on the patient, results from the single set of procedures 
and laboratory assessments from the final visit of the Phase II OLE or Phase III 
controlled study will be used for analysis and data sets for the first visit of the OLE-SM 
study, with the exception of ATA samples, which must be collected at Week 0 if the 
Week 0 visit occurs 7 days after the final visit of the Phase II OLE or Phase III 
controlled study.  Only if any procedure and assessment was missed at the time of the 
final visit, it should be performed for the first visit of the OLE-SM study.
4.4.1.1
Physical Examinations
A partial physical examination will be performed at Day 1 of the OLE-SM study and 
recorded as “normal” or “abnormal” at the times indicated in the Schedule of 
Assessments.  New or worsened clinically significant abnormalities should be recorded 
as adverse events on the Adverse Event eCRF.  Past resolved adverse events will be 
recorded in the medical history according to their medical relevance.  Adverse events 
reported as ongoing at the end of the parent study (i.e., the Phase II OLE study or a
Phase III controlled study) will be stated as unresolved in those studies and reopened in 
Study GA28951.  The adverse event will be reported in Study GA28951 with the start 
date and adverse event term identical to those in the Phase II OLE study or the 
Phase III controlled study.  The adverse event severity (National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] grade) should be 
evaluated by the investigator at the start of Part I (OLE) and recorded in the "AE initial 
NCI CTCAE grade" field of the Adverse Event eCRF for Study GA28951.  The most 
extreme NCI CTCAE grade for the event should also be recorded, taking into account 
the severity of the event since it was first reported during the parent study.
4.4.1.2
Vital Signs
Vital signs will include measurements of heart rate and systolic and diastolic blood 
pressure, after the patient has been in a seated position for 5 minutes, and are to be 
recorded at the indicated timepoints in the Schedule of Assessments (see Appendix 1) 
before study drug administration at clinic visit only.
4.4.1.3
Ulcerative Colitis Disease Activity Assessments
Efficacy will be assessed with use of the MCS (at Week 108) and pMCS at the indicated 
timepoints in the Schedule of Assessments (see Appendix 1).  The MCS has a range of 
012, whereas the pMCS has a range of 09, with higher scores indicating more severe 


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disease. The MCS is a composite of four assessments, each rated from 03:  stool 
frequency, rectal bleeding, endoscopy, and physician’s global assessment (PGA).  The 
pMCS is a composite of three assessments, each rated from 03:  stool frequency, 
rectal bleeding, and PGA (see Appendix 5).  
One of the components of the MCS is the endoscopic subscore.  At Week 108, for the 
assessment of the MCS (i.e., that requires endoscopy), every effort should be made to 
schedule the endoscopy on the same day as the study visit.  If this is not possible, 
endoscopy should be performed within 2 weeks prior to the day of the visit.  The 
endoscopy score should be considered when determining the PGA (as applicable), a 
component of the MCS.
The symptoms of UC must be recorded in the e-diary at specified timepoints throughout
the study.  To help characterize the clinical profile of etrolizumab, the stool frequency 
and rectal bleeding components of the pMCS will be collected daily during the initial 
12 weeks. After the Week 12 visit, the stool frequency and rectal bleeding components 
of the pMCS (performed every 12 weeks) and MCS (for the Week 108 assessment) will 
be collected daily for 4 weeks prior to clinic visit and the PGA component of the 
MCS/pMCS will be determined at study visits.  The format of the MCS/pMCS questions 
may change when they are converted to electronic format.  The questions will be 
translated as required in the local language.
In order to ensure instrument validity and that data standards meet health authority 
requirements, the stool frequency and rectal bleeding components of the MCS/pMCS, 
when completed at the sites, should be administered at the investigational site prior to 
the completion of other assessments and before the patient receives any disease-status 
information or study drug during that visit.
The e-diary entries will be reviewed by site personnel during study visits, including early 
withdrawal from treatment visit and any unscheduled visit(s) due to disease exacerbation.  
Because the colonoscopy/flexible sigmoidoscopy and bowel cleansing preparations may
interfere with the assessment of patient-reported symptoms, e-diary entries used to 
calculate the complete MCS should not correspond to days of bowel preparation or 
endoscopy or the day following the endoscopy.  Further details and examples of stool 
frequency and rectal bleeding subscore derivation are provided in Appendix 5.  
Appendix 5 also outlines procedures to follow in the event of e-diary malfunction or loss.
Flexible Sigmoidoscopy/Colonoscopy with Colonic Biopsies
Patients are to prepare their bowel prior to the flexible sigmoidoscopy 
colonoscopy/procedures.  Medications used for bowel preparation should be recorded 
on concomitant medications pages of the eCRF. 
Flexible sigmoidoscopy (or full colonoscopy, if required) will be performed on all patients 
at Week 108 in Part 1(OLE) of the study and/or at withdrawal from the study if the 


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withdrawal visit is prior to the Week 108 visit (see Appendix 1).  The endoscopic 
procedure will be performed by local endoscopist who will evaluate the endoscopic MCS 
subscore.  
Each patient entered into the study will have one paired colonic biopsy sample taken 
during this flexible sigmoidoscopy/full colonoscopy.  The paired biopsy sample should be 
taken from the worst affected segment visualized (up to and including the descending 
colon).  For patients without inflammation on endoscopy, the paired biopsy sample 
should be taken from the worst affected area visualized in the last endoscopy (up to and 
including the descending colon). This paired biopsy sample will be placed in formalin at 
the sites.
Necrotic areas of ulcerated mucosa should be avoided during biopsy.  Original location 
(colonic segment and endoscopic depth) of biopsy specimen should be clearly indicated.  
Progressive Multifocal Leukoencephalopathy Assessment
Study site personnel and patients will be educated regarding the signs and symptoms 
of PML.  Close monitoring during the course of the study for any new symptoms or signs 
suggestive of PML will be performed, with regular neurologic examinations (including 
evaluation of cranial nerves, motor and sensory function, coordination, and mental status) 
as per the Schedule of Assessments (see Appendix 1).  The PML Subjective Checklist 
(symptom assessment) and the PML Objective Checklist (neurologic evaluation) will be 
administered by a qualified HCP and will be performed as indicated on the Schedule of 
Assessments (see Appendix 6).  
During the in-clinic visits, patients will undergo PML monitoring assessments.
If a patient has a positive finding on the PML Subjective Checklist that is accompanied 
by a positive finding on the PML Objective Checklist or if there is strong clinical suspicion 
for PML the event should be expeditiously reported as an adverse event of special 
interest within 24 hours (see Section 5.3 and Appendix 7 for the Algorithm for Evaluation 
of Progressive Multifocal Leukoencephalopathy).  If PML is suspected, dosing with 
etrolizumab for that patient will be suspended and the patient should be promptly 
referred to a neurologist.  Following formal evaluation by a neurologist, if PML cannot be 
ruled out, the case will be referred to an expert PML adjudication committee for further 
work-up, which may include brain magnetic resonance imaging (MRI) performed with 
and without contrast.  If there remains any suspicion for PML, the PML adjudication 
committee may recommend performing a lumbar puncture with cerebrospinal fluid (CSF) 
analysis for John Cunningham virus (JCV) by PCR.  If JCV is detected, the patient 
should be treated as a PML case, permanently discontinue study drug, and transfer to 
safety follow-up. 


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Dosing with etrolizumab can only be resumed in patients where PML has been ruled out.  
See Appendix 7 for the Algorithm for Evaluation of Progressive Multifocal 
Leukoencephalopathy.
After completing Part 1 (OLE), patients will enter the 12-week safety follow-up 
(see Appendix 2).  The PML neurologic examination is to be performed at Week 12 of 
this safety follow-up.
Following the 12-week safety follow-up, all patients (i.e., patients entering from Part 1
[OLE] and those enrolling directly from Phase II OLE or blinded Phase III studies) will be 
requested to continue to be monitored for PML for an additional 92 weeks by enrolling in 
the Part 2 (SM) portion of the this study; thus, providing a total of 2 years PML follow-up 
after the last dose of study medication (see Section 4.4.1.6 for details of assessments in 
Part 2 [SM]).  
4.4.1.4
Laboratory Assessments
Laboratory assessments will be performed as indicated on the Schedule of Assessments 
(see the Study Flowchart in Appendix 1 and Appendix 2).  With the exception of urine 
pregnancy tests, all laboratory investigations will be performed by a central laboratory.  
Urine pregnancy tests will be performed at specified subsequent visits or in the patient’s 
home.  If a urine pregnancy test result is positive, it must be confirmed by a serum 
pregnancy test.
On days of etrolizumab administration, indicated laboratory samples should be drawn
prior to study drug administration.  Laboratory assessments will include the following:

Hematology (hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
absolute count [neutrophils, eosinophils, lymphocytes, monocytes, basophils, other 
cells], mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, and red cell distribution width)

Serum chemistries, including liver function tests (sodium, potassium, chloride, 
bicarbonate, glucose, blood urea nitrogen, creatinine, calcium, phosphorus, 
magnesium, total and direct bilirubin, total protein, albumin, alanine 
aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline 
phosphatase, creatine phosphokinase, and uric acid)

C-reactive protein (CRP)

Pregnancy test:  All women of childbearing potential (including those who have had 
a tubal ligation) will have a urine pregnancy test performed at monthly intervals.  
Pregnancy tests are to be conducted at home on a monthly basis when drug 
administration is in the home setting and the outcome of the pregnancy test should 
be recorded on an e-diary. If a urine pregnancy test result is positive, it must be 
confirmed by a serum pregnancy test.


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
Serum samples will be collected for the detection and characterization of ATAs.  
ATA samples will be analyzed using validated assays.  ATA samples may also be 
utilized for exploratory PD biomarker assessments or assessment of etrolizumab
concentrations.

Serum samples will be collected for monitoring the etrolizumab concentration (PK) 
during the long-term dosing period. PK samples will be analyzed using validated 
assays.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.4.1.7), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Serum samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization and PK and immunogenicity assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed.

Colon biopsy samples (formalin and RNA later) will be destroyed no later than 
5 years after the final Clinical Study Report has been completed.
4.4.1.5
Electrocardiograms
A 12-lead electrocardiogram (ECG) with formal readings will be taken at the end of each 
year of treatment as indicated on the Schedule of Assessments.  The patient should be 
supine for 10 minutes before the measurement is taken.
4.4.1.6
Medication Use and Compliance
Following each home administration of study medication, the patient is to record the 
location of each injection and whether the injection was successfully administered.  The 
e-diary will automatically collect date and time information for when the patient 
completes the study medication administration report.  Note that details of the study 
medication administration are to be entered directly into the eCRF following clinic 
administrations.
4.4.1.7
Samples for Roche Clinical Repository
Overview of the Roche Clinical Repository
The Roche Clinical Repository (RCR) is a centrally administered group of facilities for 
the long-term storage of human biologic specimens, including body fluids, solid tissues, 
and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future.


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Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  Any residual colonic biopsy sample will be 
transferred to the RCR in consenting patients.  RCR specimens will be used to achieve 
the following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
Approval by the Institutional Review Board or Ethics Committee
Sampling for the RCR is contingent upon the review and approval of the exploratory 
research and the RCR portion of the Informed Consent Form by each site's IRB/EC and, 
if applicable, an appropriate regulatory body.  If a site has not been granted approval for 
RCR sampling, this section of the protocol will not be applicable at that site.
Sample Collection
For patients who have consented to donate samples to the RCR, any residual or not 
entirely consumed colonic biopsy sample obtained at Week 108 and residual serum 
samples (see Appendix 1 for specific collection timepoints) will be stored in the RCR and 
will be destroyed no later than 15 years after the date of final closure of the associated 
clinical database.
Potential applications of RCR samples include these samples being assayed for mRNA 
expression, genetic variation, and other biomarker(s) that predict response or toxicity to 
etrolizumab.
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the Reference Manual or Laboratory Manual.
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.


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Confidentiality
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable.
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.
Patient medical information associated with RCR specimens is confidential and may only 
be disclosed to third parties permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise.
Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF.


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In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes using the RCR Subject Withdrawal Form and, if 
the trial is ongoing, must enter the date of withdrawal on the RCR Research Sample 
Withdrawal of Informed Consent eCRF.  The patient will be provided with instructions on 
how to withdraw consent after the trial is closed.  A patient's withdrawal from 
Study GA28951 does not, by itself, constitute withdrawal of specimens from the RCR.  
Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
Study GA28951.
Monitoring and Oversight
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples.
4.4.2
Description of Study Assessments in Part 2 (SM)
During the SM portion of the OLE-SM study, patients will not be administered study 
drug.
The PML safety monitoring portion of the OLE-SM study will consist of telephone calls
approximately every 6 months (see Appendix 3) with administration of the PML 
Subjective Checklist.  If there are any signs or symptoms suggestive of PML identified 
on this subjective checklist during the telephone call, the patient will be asked to come 
into the clinic for a neurologic examination, including administration of the PML Objective 
Checklist (see Appendix 6). The PML Algorithm (see Appendix 7) will be followed for 
any suspected case of PML, and any confirmed case of PML will be reported as a 
serious adverse event (see Section 5.1.1.1.1).


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4.4.3
Timing of Study Assessments
4.4.3.1
Assessments during Treatment
Part 1 (OLE)
Written informed consent for participation in the study must be obtained before 
performing any study-specific tests or evaluations.  For patients enrolling into Part 1, the 
informed consent for enrollment into Part 1(OLE) also includes informed consent for 
Part 2 (SM) of the study. Note that patients enrolling only in Part 2 (SM) from the 
Phase II OLE or Phase III studies will be required to sign a separate informed consent. 
Eligibility criteria will be reviewed prior to the initial administration of etrolizumab in this 
study.  Patients must meet all inclusion and exclusion criteria for study entry 
(see Sections 4.1.1 and 4.1.2).  Informed Consent Forms for enrolled patients and for 
patients who are not subsequently enrolled will be maintained at the study site.
All assessments will be performed during the specified visit week, except where a time 
window is specified.  Assessments scheduled on the day of etrolizumab administration 
should be performed prior to dosing, unless otherwise noted.  When etrolizumab 
administration in the home is required on the same day as a clinic visit, drug is to be 
administered at home AFTER the clinic visit.
All patients would have received hands-on training in use of the e-diary and tablet in the 
Phase III controlled studies and will continue to document compliance for etrolizumab 
administration.  Patients enrolling in Part 1 (OLE) are to record their stool frequency and 
rectal bleeding in the e-diary daily during the initial 12 weeks for the pMCS. After the 
Week 12 visit, the stool frequency and rectal bleeding components of the pMCS 
(performed every 12 weeks) and MCS (for the Week 108 assessment) will be collected 
by the patient daily for 4 weeks prior to clinic visit assessment.  Patients will also be 
instructed to contact the site promptly if they have any questions about the use of the 
device at any time during the study.
See the Study Flowcharts provided in Appendix 1 and Appendix 2 for the Schedule of 
Assessments to be performed during the treatment period.
Part 2 (SM)
For patients enrolling directly into Part 2 (SM) of this study, written informed consent for 
participation in Part 2 (SM) of the study must be obtained prior to entry.  Note that for 
patients enrolling only into Part 2 (SM), a separate informed consent form detailing only 
Part 2 assessments will be available. 
See the Study Flowchart provided in Appendix 3 for the assessments to be performed 
during the safety monitoring period.


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4.4.3.2
Assessments at Study Completion/Early Withdrawal from 
Treatment Visit/Early Withdrawal
Part 1 (OLE)
Part 1 (OLE) of OLE-SM study (during which patients receive treatment with open-label 
etrolizumab) will continue for up to approximately 9 years after the first patient is enrolled 
into the study, until commercial availability, or until the Sponsor’s decision to terminate 
the study, whichever is earlier.
After completion of Part 1 of the study and availability of commercial etrolizumab, 
patients who do not go on to receive commercial etrolizumab (via a prescription) should 
enter the 12-week safety follow-up in Part 1 (OLE) and then enter Part 2 (SM) for 
PML follow-up.
Discontinuation during the OLE (Part 1)
Patients who discontinue treatment for any reason will be asked to complete the early 
withdrawal from treatment visit for the OLE (Part 1; see Appendix 1).  The early 
withdrawal from treatment visit will be followed by a 12-week safety follow-up consisting 
of one telephone call at Week 6 and one clinic visit at Week 12 (see Appendix 2).  The 
patient should then enter the extended PML monitoring in Part 2 (SM; see Appendix 3).  
Patients who discontinue before entering safety follow-up will be asked to return to the 
clinic for an early withdrawal visit (see Appendix 2).
Discontinuation during the 12-Week Safety Follow-Up Period of OLE 
(Part 1)
Patients who discontinue the study during the 12-week safety follow-up will be asked to 
complete the early withdrawal visit from the 12-week safety follow-up (see Appendix 2) 
and then enter the extended PML monitoring in Part 2 (SM).
Part 2 (SM)
Discontinuation during the Extended PML Monitoring Period of SM (Part 2)
Patients who discontinue from Part 2 (SM) of this study prior to completion of the 
extended PML monitoring period will be asked to complete the early termination visit 
from the extended PML monitoring period (see Appendix 3).
After the study completion/early termination visit, adverse events should be followed as 
outlined in Section 5.7.
See Appendix 3 for specified follow-up assessments.
4.4.3.3
Assessments at Unscheduled Visits in OLE (Part 1) and in 
12-Week Safety Follow-Up
An unscheduled visit may occur at any time during the treatment period in Part 1, 
including during the 12-week safety follow-up period (e.g., due to relapse of disease, 
disease worsening, or an adverse event). Patients who are seen by the investigator or 
site staff at a timepoint not required by the protocol due to assessment of potential 


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relapse or disease worsening will undergo assessments consistent with the purpose of 
the unscheduled visit.  Such assessments may include:

Review of e-diary and assessment of pMCS if e-diary data is available

Recording of concomitant medications and procedures

Collection of adverse events and serious adverse events

Clinical chemistry and hematology and CRP, if indicated

Collection of ATA sample, if indicated
For unscheduled visits for reasons other than possible disease worsening or an adverse 
event, assessments will be done at the discretion of the investigator.
4.5
PATIENT, STUDY, AND SITE DISCONTINUATION
4.5.1
Patient Discontinuation
Part 1 (OLE) and Part 2 (SM)
The investigator has the right to discontinue a patient from study drug or withdraw a 
patient from the study at any time.  In addition, patients have the right to voluntarily 
discontinue study drug or withdraw from the study at any time for any reason.  Reasons 
for discontinuation of study drug or withdrawal from the study may include, but are not 
limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance, specifically defined as missing scheduled visits
4.5.1.1
Discontinuation from Study Drug
Part 1 (OLE)
Patients must discontinue study drug if they experience any of the following:

Pregnancy

Anaphylaxis or other severe hypersensitivity reaction

PML

Develop colonic mucosal dysplasia

Malignancy (with the exception of local and resected basal or squamous cell 
carcinoma of the skin) or who develop AIS, HSIL, or CIN of Grade 1 on cervical 
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
Specific serious infection (see Section 5.1.1.1 for details on serious infection):
Any patient who experiences a specific de novo or reactivated serious viral 
infection, such as HBV, HCV, HIV, should discontinue study drug.
Patients who develop life-threatening infections during the study should 
discontinue study drug.

Use of any prohibited medication as a concomitant therapy (see Section 4.2.2)
Every effort should be made to obtain information about patients who discontinue early 
from the study.  Patients who discontinue study drug prematurely for the reasons listed 
above will be asked to return to the clinic for an early withdrawal from treatment visit 
(see Section 4.4.3.2) and will undergo follow-up assessments for 12 weeks within 
Part 1 (OLE) of this study.  Patients should then enter Part 2 (SM) for 92 weeks of 
monitoring for PML (see Section 4.4.1.6).  The primary reason for premature study drug 
discontinuation should be documented on the appropriate eCRF.
4.5.1.2
Withdrawal from Study
Part 1 (OLE) and Part 2 (SM)
Every effort should be made to obtain information about patients who withdraw consent 
or are withdrawn from the study.  The primary reason for withdrawal from the study 
should be documented on the appropriate eCRF.  Patients will not be followed for any 
reason after consent has been withdrawn.  Patients who withdraw from the study will not 
be replaced.
4.5.1.3
Study and Site Discontinuation
Part 1 (OLE)
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.
The Sponsor will notify the investigator if the study is placed on hold or if the Sponsor 
decides to discontinue the study or development program.
The Sponsor has the right to replace a site at any time.  Reasons for replacing a site 
may include, but are not limited to, the following:

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice
Part 2 (SM)

In the event of discontinuation of Part 1 (OLE), Part 2 (SM) may continue depending 
on the reason for study or site discontinuation.


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5.
ASSESSMENT OF SAFETY
The safety plan for Part 1 (OLE) and the 12-week safety follow-up is provided first, 
followed by the safety plan for Part 2 (SM) that focuses on PML safety monitoring in 
patients off etrolizumab.
5.1
SAFETY PLAN (PART 1 OPEN-LABEL EXTENSION)
The safety plan for this study is designed to ensure patient safety and mitigate potential 
risks. The principles of the safety plan include education of investigators and patients 
regarding all identified and potential safety risks, specific eligibility criteria to screen out 
at-risk patients, monitoring to ensure timely identification and management of a safety 
event, and management strategy such as guidelines for treating an event and for 
withholding or discontinuing study treatment, as appropriate.  These principles are to be 
applied for all safety risks in the clinical program. 
5.1.1
Potential Risks for Etrolizumab
Etrolizumab is an investigational drug that demonstrated a safety profile similar to 
placebo in the Phase II study, EUCALYPTUS.  Given the relatively limited size of 
Phase II studies, the full safety profile will be further characterized during the 
Etrolizumab Phase III program.  The safety plan for this study is designed to ensure 
patient safety and mitigate potential risks, including specific eligibility criteria, monitoring,
and management strategy as described below.
The potential and/or hypothetical risks for etrolizumab are based on its mechanism of 
action, available nonclinical and clinical data, data from other anti-integrin drugs, and 
general risks associated with biologic agents.
Investigators should refer to the Etrolizumab Investigator's Brochure (see Section 6) for 
a complete summary of safety information.
5.1.1.1
Serious Infections
5.1.1.1.1
Progressive Multifocal Leukoencephalopathy 
Background
PML is a potentially fatal neurological condition linked to reactivation of a polyomavirus 
(JCV) and active viral replication in the brain. Cases of PML have been reported in 
patients with CD and multiple sclerosis who received concomitant treatment with the 
anti-4 integrin natalizumab and immunosuppressives. 
Integrin 41, which is inhibited by natalizumab, is a pleiotropic integrin that is believed 
to facilitate T cell migration into the CNS.  Inhibition of integrin 41 is thought to reduce 
(CNS) immune surveillance and facilitate development of PML.


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PML has not been attributed to vedolizumab, which selectively impedes lymphocyte 
trafficking into gut tissue by specifically blocking only the 47 integrin and not the 41 
integrin, despite extensive treatment exposure (Dotan 2017).
Etrolizumab targets cells expressing the 7 integrin (47 and E7 cells) and not 
41 cells.  Despite the lack of theoretical or experimental evidence for a specific role 
of 7 integrins in leukocyte homing to the CNS and given the observation of PML risk 
with natalizumab, the Sponsor will continue to conduct extensive risk-monitoring 
procedures during the Phase III trials.  There have been no cases of PML in patients 
treated with etrolizumab.
Patient Selection and PML Education
No known interventions can reliably prevent PML or adequately treat PML if it occurs;
therefore, it is important to exclude patients with a perceived higher baseline risk for 
PML, such as patients who have received natalizumab, efalizumab, vedolizumab, 
rituximab, B- or T-celldepleting agents (e.g., alemtuzumab or visilizumab), 
cyclosporine, anti-adhesion molecules, tacrolimus, sirolimus, or MMF.  Patients with a 
history of PML or neurological symptoms where suspected PML has not been ruled out 
should also be excluded.
Study site personnel and patient participants should be educated regarding the signs 
and symptoms of PML.  Patients and partners/caregivers should be issued with alert 
cards to remind them of these and to advise them to contact the investigator right away if 
they notice any new or worsening neurological abnormalities.  
See Appendix 1 for details of assessments regarding PML.  
PML Monitoring
During the study, patients should be closely monitored for any signs and symptoms of 
PML via regular (approximately once every 12 weeks) subjective and objective tests 
employing the use of checklists to assess the patient’s mental and neurological status.  
These will comprise regular neurologic examinations (including evaluation of cranial 
nerves, motor and sensory function, coordination, and mental status) as per the 
Schedule of Assessments (see Appendix 1). The PML Subjective Checklist (symptom 
assessment) and the PML Objective Checklist (neurologic evaluation) will be 
administered (see Appendix 6; Worksheet for the PML Neurologic Examination) by a 
qualified HCP and will be performed as indicated on the Schedule of Assessments 
(see Appendix 1).
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If a patient has a positive finding on the PML Subjective Checklist that is accompanied 
by a positive finding on the PML Objective Checklist or if there is strong clinical suspicion 
for PML, the event should be expeditiously reported to the Sponsor as an adverse event 
of special interest within 24 hours (see Section 5.5.2 and Appendix 7 for the Algorithm 
for Evaluation of Progressive Multifocal Leukoencephalopathy).  
If PML is suspected, dosing with study treatment for that patient will be suspended and 
the patient should be promptly referred to a neurologist.  Following formal evaluation by 
a neurologist, if PML cannot be ruled out, the case will be referred to an expert PML 
adjudication committee for further work-up, which may include brain MRI with and 
without contrast.  If there remains any suspicion for PML, the PML adjudication 
committee may recommend performing a lumbar puncture with CSF analysis for 
JCV DNA by PCR.  If JCV DNA is detected, the patient should be treated as a PML case 
and the patient should permanently discontinue study drug and enter safety follow-up.  
Dosing with study treatments can only be resumed in patients where PML has been 
ruled out.  Refer to Appendix 7 for the Algorithm for Evaluation of Progressive Multifocal 
Leukoencephalopathy.
PML Treatment
There is no known effective treatment for PML.  Plasmapheresis has been employed in 
some patients where the event has been thought to be due to administration of a drug 
(Tan et al. 2011). If an event of PML occurs, subsequent management of PML will be at 
the direction of the consulting neurologist. 
Additional information for the management of this potential risk is provided in Appendix 6
(Worksheet for the PML Neurologic Examination) and Appendix 7 (Algorithm for the 
Evaluation of Progressive Multifocal Leukoencephalopathy).
5.1.1.1.2
Other Serious Infections
Background
Clinical data to date have not shown an increased risk of serious infections with 
etrolizumab.  In the Phase II EUCALYPTUS study, serious infections were reported in 
2.3% of placebo-treated patients versus none in the etrolizumab-treated patients.  
Nonetheless, serious infections are a potential risk due to the mechanism of action of 
etrolizumab, which blocks trafficking of gut-selective lymphocytes.
Patient Selection
Patients who experienced a life-threatening infection or a specific de novo or reactivated 
serious viral infection, such as HBV, HCV, or HIV, during the Phase II OLE or
Phase III studies should not be enrolled in Part 1 of this study.  Similarly, patients who 
developed CMV colitis leading to early treatment discontinuation in the Phase II OLE or
Phase III studies should be excluded.  


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Patients who experienced or have an ongoing serious infection event (except for those 
listed below) should not receive study drug until the event has completely resolved and 
treatment with anti-infective medications has been completed.  Patients with hepatitis B 
infection who test positive only for core antibody (anti-HBc ) and test negative for HBV 
DNA test are eligible for the study; however, these patients must undergo periodic 
monitoring for HBV DNA during the study.  
Education, Monitoring, and Management
Patients should be monitored closely for other serious infections during the study.  
Patients and study staff should be informed of the possibility of increased susceptibility 
to infectious pathogens.  Investigators will be encouraged to promptly evaluate and 
aggressively treat any signs and symptoms consistent with an infection.  
Patients who experience a serious infection event should not receive further study drug 
until the event has completely resolved and treatment with anti-infective medications has 
been completed. All efforts should be made to identify the infectious agent.  For those 
patients who recover from a serious infection, study medication may be restarted 
following consultation with the Medical Monitor.  
Patients who develop life-threatening infections, including specific de novo or reactivated 
serious viral infection, such as HBV, HCV, HIV, during the study should discontinue 
study drug.  Any patient who develops CMV colitis should not receive further study drug 
until the event has resolved and treatment with appropriate anti-viral medication has 
been completed.  Re-initiation of study treatment requires consultation with the 
Medical Monitor.
5.1.1.2
Hypersensitivity Reactions
Background
In completed Phase I/II clinical trials of etrolizumab, one serious adverse event of 
hypersensitivity (Grade 2) has been reported.  No anaphylactic, anaphylactoid, or severe 
hypersensitivity reactions were observed; however, anaphylaxis and hypersensitivity 
reactions will be closely monitored during the study.  
Patient Selection
Patients who developed an anaphylactic/anaphylactoid or severe allergic reaction to 
study medication during the Phase II OLE or Phase III studies will be excluded from 
participation in Part 1 of this study.
Education, Monitoring, and Management
The first four injections should be administered in the clinic in order to monitor for any 
possible hypersensitivity reactions, given that patients who received blinded placebo in 
the randomized studies may receive their first active etrolizumab dose upon enrolling in 
the OLE-SM study.  After each of these four injections, the patient must be monitored for 
60 minutes.  Epinephrine must be readily available for immediate use if required to treat 


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anaphylaxis.  Adjunctive medications such as parenteral diphenhydramine and inhaled
bronchodilators may be used IN ADDITION to epinephrine if necessary.  Resuscitation 
equipment should also be available.  Site personnel must be able to detect and treat 
such reactions.
Patients should be instructed to recognize the symptoms of any anaphylactic, 
anaphylactoid, or hypersensitivity reaction and to contact a HCP or seek immediate care 
in case of any such symptoms.  Patients are to be provided with alert cards to remind 
them and a caregiver or partner of the above.
If the patient develops any systemic hypersensitivity or anaphylactic or anaphylactoid 
reaction, the event should be expeditiously reported to the Sponsor as an adverse event 
of special interest or serious adverse event, as appropriate, within 24 hours.
If a patient has symptoms of anaphylaxis or severe hypersensitivity, the administration of 
etrolizumab must be discontinued permanently. 
Refer to Appendix 9 (Clinical Criteria for Diagnosis Anaphylaxis).
5.1.1.3
Local Injection-Site Reactions
Background
A local injection-site reaction is any local reaction occurring at the site of injection 
following study drug administration.  In completed Phase I/II trials, injection-site reactions 
were reported at a rate of 10%, all of which were of mild intensity.
Monitoring
In the clinic setting, patients should be monitored for signs of injection-site reactions in 
the period immediately following injections.  Patients will be given guidance on reporting 
injection-site reactions when administering drug at home or after the patient leaves the 
clinic.
5.1.1.4
Hepatic Effects
Background
Liver toxicity has been reported with other drugs that target 4 integrins (natalizumab) 
and 47 integrins (vedolizumab).  Therefore, this potential risk is being monitored in all 
etrolizumab studies.  In nonclinical chronic toxicology studies, no abnormalities 
indicating liver toxicity with etrolizumab were observed.  The risk in humans is currently 
unknown.
Education, Monitoring, and Management
Patients should receive guidance on reporting liver problems if they occur.  Liver function 
tests should continue to be monitored according to the schedule of assessments and as 
clinically indicated.  Significant hepatic events should be evaluated promptly and 
managed accordingly.


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5.1.1.5
Malignancies
Background
There have been no reports of malignancy or evidence for increased incidence of 
malignancy in completed Phase I/II trials and nonclinical studies to date.  Nonetheless, 
given the elevated risk of malignancy in this patient population a priori, the trial includes 
selection criteria and additional information to minimize any hypothetical risk. 
Patient Selection
Patients who developed a malignancy (with the exception of local and resected basal or 
squamous cell carcinoma of the skin) during the Phase II OLE or Phase III studies, 
including AIS, HSIL, or CIN of Grade 1 or colonic dysplasia, are to be excluded from 
the study. 
Monitoring and Management
Investigators should remain vigilant for signs or symptoms of cancer in scheduled study 
assessments, including those of potential lymphoma.
Any signs or symptoms that could be suggestive of malignancy should be promptly and 
aggressively evaluated and reported to the Sponsor.  Incident hematologic abnormalities 
(e.g., new or worsening neutropenia, anemia, thrombocytopenia, macrocytosis, or 
atypical cells in the WBC differential) should be carefully evaluated.
Patients who develop a malignancy (with the exception of local and resected basal or 
squamous cell carcinoma of the skin) or who develop AIS, HSIL, or CIN of Grade 1 on 
cervical Pap smear or who develop colonic dysplasia during the study should be 
withdrawn from study drug and must not receive additional doses of study drug.
5.1.1.6
Immunogenicity
Background
As with administration of any exogenous protein, a potential exists for the development 
of ATAs.  Such antibodies can be neutralizing with potential for reducing therapeutic 
effect of the drug and/or sensitizing, producing the potential for allergic reactions.  On 
the basis of clinical experience to date, approximately 5% of patients develop ATAs to 
etrolizumab; however, this has not been correlated with any efficacy or safety sequelae.
Monitoring
To assess for the potential development of immunogenicity, antibody samples will be 
obtained at baseline, at regular intervals during treatment, and during the Safety 
Follow-Up Period (see Schedule of Assessments) and stored appropriately for further 
evaluation as needed.
5.1.1.7
Decreased Effectiveness of Immunizations
Background
The effect of etrolizumab upon the efficacy of vaccinations is unknown. 


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Patient Selection and Risk Mitigation
Patients who received a live attenuated vaccine during the Phase II OLE or Phase III 
studies or within 4 weeks prior to enrollment in the OLE are excluded from the study.  
Patients should not receive live attenuated vaccines during the study and for 
approximately 5 half-lives (approximately 12 weeks) after final study drug administration.
5.1.2
Risks Associated with Worsening of Ulcerative Colitis
The worsening of UC may result in the use of rescue medications.  In severe cases, 
worsening of UC may lead to hospitalization and, at worst, colectomy. 
At any time during the study, patients who have worsening of their UC will be permitted 
to receive additional therapy with steroids (IV, oral, or topical). Addition of or increases 
in doses of 5-ASA (oral or topical) and/or immunosuppressants (i.e., AZA, 6-MP, or 
MTX) will also be allowed if clinically indicated by the Principal Investigator. 
Rescue therapy with TNF inhibitors (including TNF inhibitor biosimilars), cyclosporine, 
tacrolimus, sirolimus, MMF, anti-adhesion molecules, JAK inhibitors, natalizumab, 
vedolizumab, efalizumab, rituximab, other lymphocyte-depleting agents (except AZA and 
6-MP), or other biological or investigational therapeutics will not be allowed in 
conjunction with etrolizumab because of the level of immunosuppression anticipated with 
the use of these agents. Patients who receive any of these prohibited rescue 
medications are not to receive further treatment with etrolizumab.  
See Section 4.4.3.3 and Appendix 1 for the schedule of assessments to be performed in 
the event of worsening of UC, which may lead to an unscheduled visit.  
5.2
SAFETY PLAN (PART 2 SAFETY MONITORING)
PML Monitoring Part 2 (SM)
Following the 12-week safety follow-up period in either the Phase II OLE or Phase III 
controlled studies or in Part 1 (OLE) of the OLE-SM, all patients are to continue to be 
monitored for PML for an additional 92 weeks (extended PML monitoring) in Part 2 (SM) 
of this study, providing a total of 2 years PML follow-up after the last dose of study drug.  
No etrolizumab will be administered during this time. 
PML monitoring during this period will consist of the PML assessment interview 
conducted by telephone at intervals of approximately 6 months. If there are any signs or 
symptoms suggestive of PML identified on the subjective checklist during the telephone 
call, the patient will be asked to come into the clinic for a neurologic examination, 
including administration of the PML Objective Checklist (see Appendix 3).  Any signs or 
symptoms suggestive of PML or cases of suspected PML (see Appendix 6) should be 
documented, handled, and expeditiously reported to the sponsor as adverse events of 
special interest or serious adverse events, as appropriate, within 24 hours, as described 
in Sections 5.1 and 5.3.3, and Appendix 7 (PML algorithm).  Study site personnel and 
patient participants will be educated regarding the signs and symptoms of PML and 


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suspected cases of PML will be managed as in Section 5.1.  Patients are to be 
instructed to contact the investigator immediately if they experience signs and/or 
symptoms suspected to be PML between the 6-month telephone intervals. 
5.3
SAFETY PARAMETERS AND DEFINITIONS
Safety Assessments during Part 1 (OLE)
Safety assessments in Part 1 (OLE) will consist of monitoring and recording adverse 
events, including serious adverse events and adverse events of special interest; 
protocol-specified safety laboratory assessments; measurement of protocol-specified 
vital signs; and other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.5.
Safety Assessments during Part 2 (SM)
Safety assessment in Part 2 (SM) will consist of only PML monitoring with use of the 
PML Subjective Checklist conducted by telephone at intervals of approximately 
6 months (see Appendix 3) during which any signs or symptoms suggestive of PML 
(see Appendix 6) will be documented and handled as described in Section 5.1.1.1.1 and 
Appendix 7 (PML algorithm). 
5.3.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation patient administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Sections 5.4.6.8 and 5.4.6.9

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., invasive procedures such as 
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5.3.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
All serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.5.2 for 
reporting instructions).  A serious adverse event is any adverse event that meets any of 
the following criteria:

Fatal (i.e., the adverse event actually causes or leads to death)

Life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.4.6.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe or according to National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] criteria; 
see Section 5.4.4); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
5.3.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.5.2 for reporting instructions).  Adverse events of special interest for this study 
include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 5.4.6.6)


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
Suspected transmission of an infectious agent by etrolizumab as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected.

Adverse events of special interest specific to etrolizumab:
Systemic hypersensitivity reactions and anaphylactic and anaphylactoid 
reactions (see Section 5.1.1.2 and Sampson’s Criteria in Appendix 9)
Neurological signs, symptoms, and adverse events that may suggest possible 
PML on the basis of a positive finding on the PML Subjective Checklist that is 
accompanied by a positive finding on the PML Objective Checklist or if there is 
strong clinical suspicion for PML (see Appendix 7 PML algorithm and
Section 5.1.1.1.1, above)
5.4
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
5.4.1
Adverse Event Reporting Period for Part 1 (OLE)
After informed consent has been obtained, all adverse events, regardless of relationship 
to study drug, will be reported until the patient completes Part 1 (OLE).
During Part 1 (OLE), the investigator is responsible for ensuring that all adverse events 
(see Section 5.3.1 for definition) are recorded on the Adverse Event eCRF and reported 
to the Sponsor in accordance with instructions provided in this section and in 
Sections 5.5, 5.6, and 5.7.  The investigator is also responsible for reporting medical 
device complaints (see Section 4.3.3.3).
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.3.2 for seriousness criteria), severity (see 
Section 5.4.4), and causality (see Section 5.4.5).


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Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.  Past resolved 
adverse events will be recorded in the medical history according to their medical 
relevance.  Adverse events reported ongoing at the end of the Phase II OLE or Phase III 
controlled studies will be stated unresolved in those studies and reopened in Study 
GA28951.  The adverse event will be reported in Study GA28951 with the start date and 
adverse event term identical to those in the parent study (i.e., the Phase II OLE study or 
a Phase III controlled study).  The severity (NCI CTCAE grade) should be evaluated by 
the investigator at the start of Part I (OLE) and recorded in the "AE initial NCI CTCAE 
grade" field of the Adverse Event eCRF for Study GA28951.  The most extreme NCI 
CTCAE grade for the event should also be recorded, taking into account the severity of 
the event since it was first reported during the parent study.
Adverse events reported as ongoing at the end of Part 1 (OLE) (i.e., the end of the 
12-week safety follow-up) will be recorded as unresolved. 
Some patients may not enroll into Part 2 (SM), although all patients will be strongly 
encouraged to enter.  For those patients who do not enroll into Part 2 (SM) 
(i.e., withdraw consent from the study), investigators are not required to actively monitor 
patients for adverse events after the patient completes the 12-week safety follow-up in 
Part 1 (OLE).  However, if they become aware of any serious adverse events that are
believed to be related to prior study drug treatment, these should be reported to the 
sponsor (see Section 5.7). In addition, the Sponsor should be notified if the investigator 
becomes aware of any post-study events of confirmed or suspected PML, regardless of 
relationship to study drug, for up to 2 years after the patient’s last dose of study drug.
5.4.2
Adverse Event Reporting Period for Part 2 (SM)
Part 2 (SM) of the OLE-SM study is focused on extended follow-up for PML.  During 
Part 2 (SM) the investigator will use the PML assessment interview to monitor for signs 
and symptoms of PML.  The investigator is not required to actively monitor patients for 
other adverse events in Part 2 (SM); however, if he or she becomes aware of any other 
non-PML serious adverse events that are believed to be related to any prior study drug 
treatment, these should be reported to the Sponsor.
The investigator should report such events directly to Roche or its designee either by 
faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of Special 
Interest Reporting form with use of the fax number or email address provided to 
investigators.


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5.4.3
Eliciting Adverse Event Information in Part 1 (OLE)
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?”
5.4.4
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (Version 4.0) will be used 
for assessing adverse event severity.  Table 3 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 3
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.5.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.3.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.5.2 or 
reporting instructions), per the definition of serious adverse event in Section 5.3.2.


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5.4.5
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly (see Table 4).  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or re-introduction of study drug (where applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event
Table 4
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
Adverse events will be considered related, unless they fulfill the criteria as specified 
below. 
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed two days after 
first dose of study drug).
5.4.6
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.


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5.4.6.1
Diagnosis versus Signs and Symptoms
Injection-Site Reactions
Local cutaneous adverse events that occur at or around the injection site during or within 
24 hours after study drug injection should be captured separately as individual signs 
(e.g., erythema, induration/swelling at injection site) and symptoms (e.g., pain, pruritus at 
injection site) rather than a diagnosis of allergic reaction or injection-site reaction.
Other Adverse Events 
For adverse events other than injection-site reactions, a diagnosis (if known) should be 
recorded on the Adverse Event eCRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the Adverse Event eCRF.  If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on the
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis.
5.4.6.2
Adverse Events Occurring Secondary to Other Events
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF.

If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.


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5.4.6.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (NCI CTCAE grade) of the event should be 
recorded at the time the event is first reported during Study GA28951.  If a persistent 
adverse event becomes more severe, the most extreme NCI CTCAE grade should also 
be recorded on the Adverse Event eCRF.  For adverse events reported as ongoing at 
the end of a parent study (i.e., the Phase II OLE study or a Phase III controlled study), 
the severity (NCI CTCAE grade) should be evaluated by the investigator at the start of 
Part 1 (OLE) and recorded in the "AE initial NCI CTCAE grade" field of the Adverse 
Event eCRF for Study GA28951.  The most extreme NCI CTCAE grade for the event 
should also be recorded, taking into account the severity of the event since it was first 
reported during the parent study.
If the event becomes serious, it should be reported to the Sponsor immediately (i.e., 
no more than 24 hours after learning that the event became serious; see Section 5.5.2
reporting instructions).  The Adverse Event eCRF should be updated by changing the 
event from “non-serious” to “serious,” providing the date that the event became serious, 
and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF.
5.4.6.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5upper limit of normal [ULN] associated with 
cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded on the Adverse 
Event eCRF.


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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level 
of 7.0 mEq/L should be recorded as “hyperkalemia.”
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.4.6.3 for 
details on recording persistent adverse events).
5.4.6.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.4.6.3 for 
details on recording persistent adverse events).
5.4.6.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3 ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN, in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN, in combination with clinical jaundice


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The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.4.6.4) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.5.2).
5.4.6.7
Deaths
Part 1 OLE (Including the 12-Week Safety Follow-Up Period)
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.4.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.5.2).  This 
includes death attributed to progression of UC.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed to progression of ulcerative colitis, "ulcerative colitis progression” 
should be recorded on the Adverse Event eCRF.
Part 2 (SM) 
If the investigator is made aware of an event of death, it should be reported directly to 
the Sponsor either by faxing or by scanning and emailing the Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form with use of the fax number or 
email address provided to investigators (see "Protocol Administrative and Contact 
Information & List of Investigators").
5.4.6.8
Preexisting Medical Conditions
Past resolved adverse events will be recorded in the medical history according to their 
medical relevance.  Adverse events reported ongoing at the end of the Phase II OLE or 
Phase III studies will be stated unresolved in those studies and reopened in 
Study GA28951.  
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”).


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5.4.6.9
Lack of Efficacy or Worsening of Ulcerative Colitis
Medical occurrences or symptoms of deterioration that are anticipated as part of UC 
should be recorded as an adverse event if judged by the investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study.  When recording an unanticipated worsening UC on the Adverse Event eCRF, 
it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., “accelerated ulcerative colitis” or “worsening of ulcerative 
colitis”).
5.4.6.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.3.2), except as outlined 
below.  The duration of hospitalization should also be noted on the eCRF.
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease.
The patient has not suffered an adverse event.
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.4.6.11
Adverse Event Associated with Overdose or Error in Drug 
Administration
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  An overdose or error in administration of study drug is not 
itself an adverse event, unless it results in an adverse event.
Any study drug overdose or error in administration of study drug (e.g., dosing outside of 
the allowed window and injection without completion of full volume administration) 
should be noted on the Study Drug Administration eCRF.


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All adverse events associated with an overdose or error in administration of study drug 
(e.g., dosing outside of the allowed window and injection without completion of full 
volume administration) should be recorded on the Adverse Event eCRF. If the 
associated adverse event fulfills serious criteria, the event should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.5.2).
5.4.6.12
Patient-Reported Outcome Data
Adverse event reports will not be derived from patient-reported outcome (PRO) data by 
the Sponsor, and safety analyses will not be performed using PRO data.  Sites are not 
expected to review the PRO data for adverse events.
5.5
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR DURING PART 1 AND PART 2
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  See Section 5.5.2
for reporting requirements in Part 1 (OLE) and Part 2 (SM).
The following is a list of events that the investigator must report to the Sponsor within 
24 hours after learning of the event, regardless of relationship to study drug:

Serious adverse events (see Section 5.5.2 for further details)

Adverse events of special interest (see Section 5.5.2 for further details)

Pregnancies (see Section 5.5.3 for further details)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.


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5.5.1
Emergency Medical Contacts
Medical Monitor Contact Information
Primary Contact
Medical Monitor:
 M.B., Ch.B.
Primary:
Secondary:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the IQVIA Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with an IQVIA
Medical Monitor, and track all calls. The Emergency Medical Call Center Help Desk will 
be available 24 hours per day, 7 days per week. A primary global contact number and 
additional back up number for the Help Desk and Medical Monitor contact information 
will be distributed to all investigators (see "Protocol Administrative and Contact 
Information & List of Investigators").
5.5.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
Part 1 (OLE)
For reports of serious adverse events and adverse events of special interest, 
investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the EDC system.  A report will be generated and sent to Roche Safety Risk 
Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form with use of the fax numbers or email address provided to investigators.  Once 
the EDC system is available, all information will need to be entered and submitted via 
the EDC system.
Part 2 (OLE)
Reports of non-PML serious adverse events, that the investigator becomes aware of and 
believes to be related to prior study drug treatment will be reported via a direct report to 
the Sponsor either by faxing or by scanning and emailing the Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form with use of the fax number or 
email address provided to investigators (see "Protocol Administrative and Contact 
Information & List of Investigators"). 
Instructions for reporting post-study adverse events are provided in Section 5.7.


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5.5.3
Reporting Requirements for Pregnancies
5.5.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 24 weeks after the last 
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.
In addition, the investigator will submit a paper Clinical Trial Pregnancy Reporting Form 
when updated information on the course and outcome of the pregnancy becomes
available.
5.5.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
24 weeks after the last dose of study drug.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  When 
permitted by the site, the pregnant partner would need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
If the authorization has been signed, the investigator should submit a paper Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician.
5.5.3.3
Abortions
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.5.2).


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5.5.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see
Section 5.5.2).
5.5.4
Reporting Requirements for Medical Device Complaints
See Section 4.3.3.3 for reporting requirements for medical devices.
5.6
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.6.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or study-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.6.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.7
POST-STUDY ADVERSE EVENTS
5.7.1
Post-Study Adverse Events Part 1 (OLE)
Patients Who Exit Part 1 (OLE) and Do Not Enter Part 2 (SM) 
All patients should be encouraged to enter Part 2 (SM) to allow for long-term PML 
monitoring and timely assessment of any symptoms that could be related to PML. 
For those patients who do not enter Part 2 (SM), investigators are not required to 
actively monitor patients for adverse events after the end of the 12-week safety follow-up 
period; however, if he or she becomes aware of any serious adverse events that are 
believed to be related to prior study drug treatment, these should be reported to the 
Sponsor. In addition, the Sponsor should be notified if the investigator becomes aware 


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of any post-study events of confirmed or suspected PML, regardless of relationship to 
study drug, for up to 2 years after the patient’s last dose of study drug.  
The investigator should report these events directly to Roche or its designee either by 
faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form with use of the fax number or 
email address provided to the investigators.
Patients Who Exit Part 1 (OLE) and Enter Part 2 (SM)
Investigators should continue to provide follow-up data, if they receive it, to the Sponsor
on unresolved adverse events.
5.7.2
Post-Study Adverse Events Part 2 (SM)
Post-study adverse event information for Part 2 will be reported the same as for patients 
in Part 1 who do not enter Part 2 (SM) (see Section 5.7.1).
5.8
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events for etrolizumab with use of the following 
reference document:

Etrolizumab Investigator's Brochure. 
Within the Investigator’s Brochure, the reference safety information is provided 
in Section 6.4 (Identified Risks and Adverse Drug Reactions [Reference 
Safety Information]).
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
All serious related (as assessed by the investigator and/or Sponsor) adverse events 
occurring in a patient administered etrolizumab at any time during the trial and 
assessed as unexpected per the reference safety information will be considered 
Suspected Unexpected Serious Adverse Reactions (SUSARs) for the purpose of 
regulatory reporting to all health authorities, with the exception of the U.S. Food and 
Drug Administration (FDA). For the FDA, SUSARs will be submitted as Investigational 


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New Drug (IND) Safety Reports, in line with the FDA guidance “Safety Reporting 
Requirements for INDs and BA/BE Studies” dated December 2012.
The Sponsor will report all SUSARs into the EudraVigilance database in accordance 
with the "Detailed guidance on the collection, verification and presentation of adverse 
event/reaction reports arising from clinical trials on medicinal products for human 
use (‘CT-3’)."
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Because of the non-comparative character of the study, no statistical tests are planned.  
Efficacy in Part 1 will be assessed by change from baseline in pMCS and proportion of 
patients achieving pMCS remission. Additionally, remission and endoscopic remission 
by MCS at Week 108 will be summarized. All efficacy parameters will be summarized 
descriptively.  Demographic and baseline characteristics such as age, sex, race, region, 
use of corticosteroids and immunosuppressants, duration of disease, and pMCS will be 
summarized by use of descriptive statistics.
Further analysis details for Part 1 and Part 2 of the study will be provided in the 
Statistical Analysis Plan.
6.1
NUMBER OF PATIENTS
The maximum number of patients enrolled in the OLE-SM study is approximately 2100 
(i.e., all patients enrolled in the Phase II OLE protocol and the five UC Phase III 
protocols).  No formal sample size calculations were performed.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enrolled in Part 1 and Part 2 will be tabulated by country 
and study site.  The number of patients who discontinued early (early discontinuation of 
OLE treatment or early termination from the study) or completed the study will be 
tabulated.  Reasons for early discontinuation of treatment or early termination from the 
study will be listed and summarized.  Any eligibility criteria exceptions and other major 
protocol deviations will also be summarized.  The data will also be summarized by origin 
of the patient (i.e., by original Phase II OLE protocol or Phase III controlled protocol).  
6.3
SAFETY ANALYSES FOR PART 1 (OLE)
The safety analyses will include all patients who received at least one dose of 
etrolizumab.
Safety will be assessed through descriptive summaries of adverse events, laboratory 
test results (serum chemistry, hematology including complete blood count with 
differential and platelet counts, and urinalysis), and antibodies to etrolizumab.


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6.3.1
Adverse Events
Verbatim descriptions of treatment-emergent adverse events will be coded and their 
incidence and observation time-adjusted rate will be summarized, as appropriate.  A 
treatment-emergent adverse event is defined as any new adverse event reported or any 
worsening of an existing condition on or after the first dose of study drug.  In addition, 
separate summaries will be generated for serious adverse events, deaths, and adverse 
events leading to discontinuation of etrolizumab. Adverse events will be summarized by 
mapped term, appropriate thesaurus level, and toxicity grade.
Analyses will be performed for:

Systemic hypersensitivity events
Specific analyses will be performed for anaphylactic reactions with use of the 
anaphylactic reaction Sampson’s criteria (see Appendix 9).

Serious infections, in particular GI infections 

Opportunistic infections

Malignancies

Injection-site reactions
6.3.2
Laboratory Tests
Descriptive summaries of laboratory values at baseline and throughout the study will be 
tabulated.  For selected parameters, changes from baseline and the proportion of 
patients experiencing clinically significant changes relative to baseline will be 
summarized.
The number and percentage of patients with positive serum antibodies to etrolizumab at 
baseline and during the study will be tabulated.
6.4
SAFETY ANALYSES FOR PART 2 (SM)
In Part 2, any suspected or confirmed PML events will be listed and described by means 
of safety narratives.
Serious adverse events (including serious infections) and deaths will also be described 
as narratives.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
Sponsor, contract research organization (CRO), and Data Management vendor will 
responsible for the data management of this study, including quality checking of the data.  
Sites will be responsible for data entry into the eCRF via the EDC system.  In the event 
of discrepant data, data queries will be issued to the sites and resolved by the sites via 
the EDC system.  The Sponsor will produce an EDC Study Specification document that 


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describes the quality checking to be performed on the data.  In addition, eCRF Help Text 
will be provided to the sites through the EDC system.  eCRFs and correction 
documentation will be maintained in the EDC system’s audit trail.
Central laboratory data will be transferred directly to the Sponsor with use of the 
Sponsor’s standard procedures to handle and process the electronic transfer of 
these data.
7.2
ELECTRONIC CASE REPORT FORMS
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and have access to Help Text Medidata RAVE for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
Patient-reported data will be collected electronically through use of electronic devices 
provided by an electronic patient-reported outcome (ePRO) vendor.  The electronic 
device, e-diary, is designed for entry of data in a way that is attributable, secure, and 
accurate, in compliance with FDA regulations for electronic records (21 Code of Federal 
Regulations, Part 11).  The data will be transmitted to a centralized database at the 
ePRO vendor.  The data from the e-devices are available for view access only via 
secure access to a Web portal provided by the ePRO vendor.  Only identified and 
trained users may view the data, and their actions become part of the audit trail.  The 
Sponsor will have view access only.  Regular data transfers will occur from the 
centralized database at the vendor to the database at the Sponsor.
Once the study is complete, the ePRO data, audit trail, and trial and system 
documentation will be archived.  The Sponsor will receive all data entered by patient on 
the e-diary and tablet device and all the study documentation.
Details regarding patient reported data and the electronic device is available in the Study 
Reference Manual.  System backups for data stored by the Sponsor and records 
retention for the study data will be consistent with the Sponsor’s standard procedures.


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7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, MRIs, ECGs, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The investigational site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research.  An acceptable computerized data collection system allows 
preservation of the original entry of data.  If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, patient data (including patient-reported outcomes [PRO]), 
Informed Consent Forms, laboratory test results, and medication inventory records, must 
be retained by the Principal Investigator for at least 15 years after completion or 


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discontinuation of the study or for the length of time required by relevant national or local 
health authorities, whichever is longer.  After that period of time, the documents may be 
destroyed, subject to local regulations.
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. IND 
application will comply with U.S. FDA regulations and applicable local, state, and federal 
laws.  Studies conducted in the EU/EEA will comply with the EU Clinical Trial Directive 
(2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the “Consent Forms”) before IRB/EC 
submission.  The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 


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Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.


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Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient last visit 
in PML monitoring).
9.
STUDY DOCUMENTATION, MONITORING, AND
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, which includes an audit trail containing a complete record of all changes 
to data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.


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9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial is sponsored by F. Hoffmann-La Roche Ltd.  A CRO will be contracted to 
manage the study and perform monitoring activities.
Centralized facilities (vendors) will be used to collect MCS (with the exception of 
endoscopy data) and pMCS symptom data.
A central laboratory (i.e., Roche or a vendor) will be used for most laboratory 
assessments.  A selected group of assessments will be performed on site or by a local 
laboratory.
The eCRF data will be recorded via a Sponsor-designated EDC system.  An IxRS will be 
used for study drug inventory management and to randomize patients to study drug.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following website: 
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses. For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.


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In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1
Open-Label Extension (Part 1, OLE) Schedule of Assessments
Part 1 (OLE)
In-Clinic Etrolizumab 
Administration Every 4 Weeks
At-Home Etrolizumab Administration Every 4 Weeks 
(or in clinic administration if unable to perform at home)
Clinic Visit at Every 4 Weeks, 
Starting at Day 1 of Week 0
(3 days)
Clinic Visit at 
Every 12 Weeks, 
Starting at Day 1 
of Week 0
(3 days)
Clinic Visit at 
Every 48 Weeks, 
Starting at Day 1 
of Week 0
(7 days)
Clinic Visit at 
Week 108
(14 days)
Unscheduled 
Visit c
Early 
Withdrawal 
from Treatment 
Visit d
0 a, b
4
8
12
Informed consent
x
Review eligibility criteria
x
Vital signs (BP, pulse rate)
x
x
x
x
x
x
ECG
x
x
x
Concomitant medications
x
x
x
x
x
x
x
x 
x
Adverse events e
x
x
x
x
x
x
x
x 
x
Limited/symptom driven physical 
examination, including GI
x
x
x
x
x
x
x c
x
PML neurologic examination f
x
x
x
x
x
x c
x
Partial Mayo Clinic Score (pMCS) g
x
x
x
x
x
x
x h
Mayo Clinic Score (MCS) i
x
x j


Appendix 1
Open-Label Extension (Part 1, OLE) Schedule of Assessments (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
93/Protocol GA28951, Version 9
Part 1 (OLE)
In-Clinic Etrolizumab 
Administration Every 4 Weeks
At-Home Etrolizumab Administration Every 4 Weeks
(or in clinic administration if unable to perform at home)
Clinic Visit at Every 4 Weeks, 
Starting at Day 1 of Week 0
(3 days)
Clinic Visit at 
Every 12 Weeks, 
Starting at Day 1 
of Week 0
(3 days)
Clinic Visit at 
Every 48 Weeks, 
Starting at Day 1 
of Week 0
(7 days)
Clinic Visit at 
Week 108
(14 days)
Unscheduled 
Visit c
Early 
Withdrawal 
from Treatment 
Visit d
0 a, b
4
8
12
Flexible sigmoidoscopy (or 
colonoscopy, IF REQUIRED)
with colonic biopsies k
x l
x j
Pregnancy test m
x
x
x
x
x
x
x
x
Hematology n
x
x
x
x
x
x c
x h
Chemistry o
x
x
x
x
x
x c
x h
Hepatitis B DNA p
x
x
x
x
x
Serum (CRP)
x
x
x c
x h
Etrolizumab administration
x
x
x
x
x
x
x
Etrolizumab PK sample (serum) q
x
x
x
x
Anti-therapeutic antibody sample 
(serum) q
x
x
x
x
x c
x h
ATAanti-therapeutic antibody; BPblood pressure; CRPC-reactive protein; ECG electrocardiogram; eCRF electronic case report form;
GIgastrointestinal; LFT liver function test; PKpharmacokinetic; PMLprogressive multifocal leukoencephalopathy.
Note:  All assessments and blood draws are to be conducted prior study medication administration.  All visit intervals based on Day 1 of Week 0.
a Day 1 of Week 0.
b Week 0 procedures and laboratory assessments that have been collected as part of the final visit for the Phase II OLE and Phase III controlled 
studies do not need to be repeated, with the exception of ATAs, which must be collected at Week 0 if the Week 0 visit occurs 7 days after the 
final visit of the Phase II OLE or Phase III controlled study.


Appendix 1
Open-Label Extension (Part 1, OLE) Schedule of Assessments (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
94/Protocol GA28951, Version 9
c Unscheduled visit represents a visit that is not as per Schedule of Assessments and is required for an adverse event or for potential relapse 
assessment.  All indicated assessments are NOT performed at each unscheduled visit.  Assessments would be symptom driven (e.g., only
perform PML neurologic examination if patient reports symptoms suspected to indicate PML). pMCS to be conducted if patient experiences 
disease worsening and if stool frequency and rectal bleeding are available in the e-diary.  Assessments corresponding to items noted in this 
column should be recorded on the eCRF.
d
Denotes the early withdrawal from treatment visit for the open-label treatment period.  To be performed within 30 days of last dose of study drug.  
Study drug is not administered at the Early Withdrawal from Treatment visit.
e Patients will be given patient alert cards that provide information regarding the signs and symptoms of PML.  Patients will be instructed to contact 
the study site at any time if they develop any new neurological signs or symptoms suggestive of PML.
f
PML neurologic examination consists of the PML Subjective Checklist and the PML Objective Checklist.  Administer before other assessments, as 
per Appendix 5.
g Rectal bleeding assessmentstool frequency assessmentphysician’s global assessment. Patients are to complete the e-diary for the stool 
frequency and rectal bleeding score daily during the initial 12 weeks for the pMCS.  After the Week 12 visit, the stool frequency and rectal bleeding 
components of the pMCS (performed every 12 weeks) and MCS (for the Week 108 assessment) will be collected by the patient daily for 4 weeks 
prior to clinic visit.  The Week 0 pMCS score is derived from data collected as part of the final visit from the Phase II OLE or the Phase III 
controlled studies.
h Not required if unscheduled visit leads to withdrawal and assessment previously conducted at unscheduled visit.
i
Endoscopy, rectal bleeding assessment, stool frequency assessment, Physician’s Global Assessment. Patients are to complete the e-diary on a 
daily basis for 3 weeks prior to clinic visit for the stool frequency and rectal bleeding score (for MCS).
j
If early withdrawal visit is prior to Week 108 visit, then flexible sigmoidoscopy/colonoscopy with biopsies and full MCS should be conducted if 
e-diary data are available.  If early withdrawal visit is after the Week 108 visit, then flexible sigmoidoscopy/colonoscopy with biopsies should not 
be conducted, but pMCS should be conducted if e-diary data are available.
k The flexible sigmoidoscopy/colonoscopy should be conducted on the day of the clinic visit or within 14 days prior to the clinic visit. 
l
Each patient entered into the study will have one paired colonic biopsy sample (2 samples) taken during flexible sigmoidoscopy/colonoscopy 
procedure at Week 108 and placed in formalin and then paraffin embedded.  The paired biopsy sample should be taken from the worst affected 
segment visualized (up to and including the descending colon).  For patients without inflammation on endoscopy, the paired biopsy sample should 
be taken from the worst affected area visualized in the last endoscopy (up to and including the descending colon).  In RCR consenting patients 
only, any residual or not entirely consumed colonic biopsy sample obtained at Week 108 will be stored in the RCR and will be destroyed no later 
than 15 years after the date of final closure of the associated clinical database.  Original biopsy location and endoscopic depth should be clearly 
indicated.


Appendix 1
Open-Label Extension (Part 1, OLE) Schedule of Assessments (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
95/Protocol GA28951, Version 9
m For women of childbearing potential, including those who have had a tubal ligation.  Perform a urine pregnancy test; if the urine pregnancy test 
result is positive, perform a confirmatory serum pregnancy test.  Pregnancy test will be carried out at home once the patient starts etrolizumab 
administration at home.  Patient is to report the pregnancy test result via e-diary.  Patients must be reminded throughout the study that in case of a 
positive pregnancy test, they should stop self-administration of study drug and call the site immediately.  Do not administer etrolizumab unless the 
serum pregnancy test result is negative.
n Includes hemoglobin, hematocrit, platelet count, RBC count, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular 
hemoglobin concentration, red cell distribution width, WBC count, and differential.
o Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, creatinine, calcium, phosphorus, magnesium, total and direct 
bilirubin, total protein, albumin, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, creatine
phosphokinase, and uric acid.
p Only enrolled patients who were hepatitis B core antibody positive in the Phase III study of origin should have hepatitis B DNA measured at these 
timepoints.
q Samples are to be collected prior to dose administration at all timepoints indicated (see footnote ‘’b’’) and whenever serum sickness is suspected.  
If serum sickness or a clinically significant allergic drug reaction is suspected, the Sponsor should be notified, and serum for etrolizumab PK 
measurement and ATAs should be drawn and sent to the central laboratory.  ATA samples may also be utilized for exploratory PD assessments 
or assessment of drug concentrations.


Etrolizumab—F. Hoffmann-La Roche Ltd
96/Protocol GA28951, Version 9
Appendix 2
12-Week Safety Follow-Up (Part 1, OLE)
Schedule of Assessments
Part 1 (OLE)
Week (7 days)
Unscheduled Visit c
6 a
12/Early Withdrawal Visit b
Concomitant medications
x
x
x
Adverse events
x
x
x
Urine pregnancy test d
x
Partial physical examination
x
PK sampling (serum)
x
Anti-therapeutic antibody 
sample (serum) e
x
PML neurologic examination f
x
ATAanti-therapeutic antibody; PKpharmacokinetic; PMLprogressive multifocal 
leukoencephalopathy.
a Week 6 study assessments are to be made by telephone call and not by clinic visit.
b If the patient discontinues prior to completion of the 12-week safety follow-up, the indicated 
assessments for the 12-week safety follow-up clinic visit should be performed as the early 
termination visit of the safety follow-up period.
c Unscheduled visit for safety monitoring.
d For women of childbearing potential, including those who have had a tubal ligation, perform a 
urine pregnancy test; if the urine pregnancy test result is positive, confirm with a serum 
pregnancy test.
e If serum sickness or a clinically significant allergic drug reaction is suspected, Sponsor should 
be notified and serum for etrolizumab PK and ATAs should be drawn and sent to the central 
laboratory. ATA samples may be used for PK and/or exploratory PD assessments.
f
PML neurologic examination consists of the PML Subjective Checklist and the PML Objective 
Checklist. Administer before other assessments as per Appendix 5.


Etrolizumab—F. Hoffmann-La Roche Ltd
97/Protocol GA28951, Version 9
Appendix 3
Extended Progressive Multifocal Leukoencephalopathy Safety Monitoring
(Part 2, SM) Schedule of Assessments
Part 2 (SM)
92-week Extended PML Monitoring Period a
24, 48, 68, and 92 Weeks after Patient Discontinuation 
from Study OR
Symptom-Driven Unscheduled Telephone Call b OR
Early Termination c
Unscheduled 
Visit d
PML Subjective Checklist (telephone only)
x
PML Objective Checklist e
x
Adverse event reporting to the Sponsor f
x
x
OLE-SMopen-label extensionsafety monitoring; PMLprogressive multifocal leukoencephalopathy.
Note:  The extended PML monitoring period is to be conducted for patients completing or discontinuing from OLE-SM Part 1 AND for patients entering OLE-SM 
Part 2 from blinded Phase III studies after completion of 12-week safety follow-up in the Phase III studies AND for patients entering OLE-SM Part 2 from the Phase 
II OLE study (GA27927).
a
The total length of the PML monitoring period is 104 weeks after the patient discontinues from the study (12-week safety follow-up plus 92-week extended PML 
monitoring period).  The extended PML monitoring period telephone calls will occur at the indicated timepoints for the 92-week extended PML monitoring period.  
The extended PML monitoring will be conducted using a PML Subjective Checklist over the telephone.  PML monitoring should occur within 7 days of the 
specified day.
b
Unscheduled telephone call represents a call that is not as per Schedule of Assessments and it is symptom driven. 
c
If the patient discontinues after the 12-week safety follow-up visit but prior to study completion (end of extended PML monitoring period), the early termination 
visit from the extended PML monitoring period should be performed (a subjective checklist by telephone).
d
Unscheduled visit represents a visit that is not as per Schedule of Assessments and it is symptom driven. 
e
If there are any signs or symptoms suggestive of PML identified on the subjective checklist during the telephone call, the patient will be asked to come into the 
clinic for a neurologic examination, including administration of the PML Objective Checklist.
f
Investigators are not required to actively monitor patients for adverse events; however, if he or she becomes aware of any other serious adverse events that are 
believed to be related to prior study drug treatment, these should be reported directly to Roche or its designee either by faxing or by scanning and emailing the 
Serious Adverse Event/Adverse Event of Special Interest Reporting Form with use of the fax number or email address provided to the investigators.  The 
investigator may become aware of such events at these timepoints or via other means, but the data are not to be collected routinely.


Etrolizumab—F. Hoffmann-La Roche Ltd
98/Protocol GA28951, Version 9
Appendix 4
Childbearing Potential, Pregnancy Testing, and Contraception
All women of childbearing potential (including those who have had a tubal ligation) will 
have a urine pregnancy test prior to administration of study drug at subsequent visits.  If 
a urine pregnancy test result is positive, study drug will not be administered that day.  
The result must be confirmed by a serum pregnancy test (conducted by the central 
laboratory).  Refer to Section 5.5.3 of the protocol for management of a patient with a 
confirmed pregnancy.
All female patients are considered to be of childbearing potential unless they meet one 
of the following criteria:

The patient has been postmenopausal (nontherapy-induced amenorrhea) for at 
least 12 months

The patient had a surgical bilateral oophorectomy (with or without hysterectomy) 
more than 6 weeks prior to enrollment

The patient had a hysterectomy
Female patients of reproductive or childbearing potential who are unwilling to use a 
highly effective method of contraception or remain abstinent during the treatment period 
and for at least 24 weeks after the last dose of study drug will be excluded from study 
participation.
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of contraception.
Examples of highly effective contraception include the following:

Combined oral contraception pill

Contraceptive transdermal patch

Intrauterine device

Implants for contraception

Injections for contraception (with prolonged release)

Hormonal vaginal device

Sterilization, surgical tubal ligation

Sole sexual partner consisting of surgically sterilized male partner with appropriate 
postsurgical verification of the absence of spermatozoa in the ejaculate

Double-barrier methods:  condom and occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository (Note: a female condom 
and male condom should not be used together because friction between the two 
can result in either product failing)


Appendix 4
Childbearing Potential, Pregnancy Testing, and Contraception
(cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
99/Protocol GA28951, Version 9
Patients may provide verbal confirmation that the partner completed appropriate 
follow-up after vasectomy.  Sites are not required to obtain partner medical records.
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined 
below: 
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at least 
24 weeks after the last dose of study drug.  Men must refrain from donating sperm 
during this same period. 
For men and women:  The reliability of sexual abstinence should be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, and postovulation 
methods) and withdrawal are not acceptable methods of contraception.  


Etrolizumab—F. Hoffmann-La Roche Ltd
100/Protocol GA28951, Version 9
Appendix 5
Mayo Clinic Score Measurement
Mayo Clinic Score (MCS) is a composite endpoint with four components.  The score
ranges from 0 to 12 with higher scores indicating more severe disease.
The Mayo Clinic components are as follows:
STOOL FREQUENCY
0 Normal number of stools for this patient
11 to 2 stools more than normal
23 to 4 more stools than normal
35 or more stools than normal
Subscore 03
RECTAL BLEEDING
0 No blood in stool
1Streaks of blood with stool less than half the time
2Obvious blood with stool most of the time
3Blood alone passed
Subscore 03
ENDOSCOPY
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) 
Subscore 03
PHYSICIAN'S GLOBAL ASSESSMENT
0 Normal (Subscores are 0)
1 Mild disease (Subscores are mostly 1s)
2 Moderate disease (Subscores are 1 to 2)
3 Severe disease (Subscores are 2 to 3) 
Subscore 03


Appendix 5
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
101/Protocol GA28951, Version 9
DATA COLLECTION REQUIREMENTS
Data will be collected on e-diary and other electronic media; during conversion to 
these media the format of the questions may change.

A CRITICAL DATA POINT TAKEN AT BASELINE FROM THE PREVIOUS STUDY
IS THE PATIENT’S NORMAL NUMBER OF STOOLS.  This is defined as the
number of stool passed when a patient is in remission/not in flare.  This is to be
taken from the most recent available data in the patient’s medical notes or taken
during patient interview at screening in the Phase II and Phase III controlled study.

Normal number of stools is to be rounded up (e.g., normal number of stools12 
would be rounded to 2).

The NORMAL number of stools is to be recorded on the e-diary and made visible to 
the patient to assist with their scoring relative to this number.
NOTE:  Data recorded during bowel preparation procedures and day of endoscopy 
are to be ignored (bowel preparation and endoscopy procedure days are to be 
loaded onto the e-diary by the patient and excluded from the MCS calculation).
1.
Stool frequency

Stool frequency is to be recorded during the study in the e-diary.  E-diary entries are 
to be made daily during the initial 12 weeks.  After the 12-week visit, the stool 
frequency component of the partial Mayo Clinic Score (pMCS; performed every 
12 weeks) and MCS (for the Week 108 assessment) will be collected daily for 
4 weeks prior to clinic visit.

The stool frequency is to be compared with the patient’s normal stool frequency and 
is entered as a score between 0 and 3 (see 1 above) (e.g., a patient normally has 
1 stool per day and today has 4 stools; therefore, the patient has 3 stools more than 
“normal,” which yields a value of 2 for that day).

The stool frequency will 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 stool.

The stool frequency value for endpoint assessment will be calculated as the 
average (rounded to the nearest integer) from the three most recent stool frequency 
scores that were entered in the e-diary prior to the clinic visit (and prior to 
endoscopy) and prior to the days devoted to bowel preparation and endoscopy.
2.
Rectal bleeding

Rectal bleeding is to be recorded during the study in the e-diary. E-diary entries 
are to be made daily during the initial 12 weeks.  After the 12-week visit, the rectal 
bleeding component of the pMCS (performed every 12 weeks) and MCS (for the 
Week 108 assessment) will be collected daily for 4 weeks prior to clinic visit.


Appendix 5
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
102/Protocol GA28951, Version 9

The rectal bleeding score is to be categorized from 03 according to the definition 
given in 2 above.

The rectal bleeding value for endpoint assessment will be determined by the worst 
of the three most recent rectal bleeding scores that were entered in the e-diary prior 
to the clinic visit and prior to the days devoted to bowel preparation and endoscopy.  

Patients are to be instructed to ignore any blood which is caused by menstruation or 
hemorrhoids.
3.
Endoscopy Subscore

This score is provided by the local endoscopy reading as a subscore of 0 to 3.

Findings on endoscopy will be documented by photographic evidence.

The score will be based upon the worst affected segment visualized (up to and 
including the descending colon).
4.
Physician's Global Assessment
The physician’s global assessment WILL:

Be based on the patient’s overall status 

Reflect how the patient is doing at present.  Assessment SHOULD NOT reflect past
disease severity or complexity or the number/kinds of medicines the patient is 
receiving
Be based on the:

Rectal bleeding score, stool frequency score, and endoscopic evaluation

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 (e.g., do not automatically give a 
high PGA to patients with pancolitis or severe/complicated disease or patients 
requiring multiple medications
The physician’s global assessment will be provided by the Investigator as a score of 
0 to 3 and entered into the tablet.


Appendix 5
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
103/Protocol GA28951, Version 9
CALCULATION OF THE MAYO CLINIC SCORE
1.
Mayo Clinic Score assessment will be performed at Week 108 and at early 
withdrawal if the early withdrawal visit occurs prior to Week 108, as outlined in the
protocol Schedule of Assessments.
2.
MCS Remission
MCS2, a rectal bleeding score of 0, physician’s global assessment of 01, stool 
frequency subscore of 01, endoscopy score of 01
3.
Endoscopic remission
Endoscopic subscore0
PARTIAL MAYO CLINIC SCORE
The pMCS is identical to the MCS BUT EXCLUDES THE ENDOSCOPY SUBSCORE

Timepoints for pMCS can be found in the protocol Schedule of Assessments

pMCS is also required if a patient experiences disease worsening
E-DIARY MALFUNCTION OR LOSS
The help desk for the e-diary vendor (CRF Health) should be contacted in the event of 
e-diary malfunction or loss.  Until a working e-diary can be provided to the patient, site 
staff should, after the e-diary malfunction or loss, retrospectively collect the previous 
day's stool frequency and rectal bleeding subscores from the patient via telephone 
interview within the next working day following the e-diary failure or loss.  These data will 
then be transcribed into a data clarification form within CRF Health’s TrialManager 
system for approval.
REFERENCE
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;317:1625–9)


Etrolizumab—F. Hoffmann-La Roche Ltd
104/Protocol GA28951, Version 9
Appendix 6
Worksheet for the PML Neurologic Examination
PML SUBJECTIVE AND OBJECTIVE CHECKLISTS OF NEUROLOGIC
ASSESSMENTS TO MONITOR FOR PROGRESSIVE MULTIFOCAL
LEUKOENCEPHALOPATHY (PML) IN THE ETROLIZUMAB PHASE III STUDIES
PML usually manifests with subacute, progressive neurologic deficits including:
Neurologic Domain
Signs/Symptoms
Relevant PML 
Subjective/Objective 
Checklist Question
Altered mental status
Can encompass a variety of presenting signs
and symptoms including cognitive changes
(confusion, difficulty concentrating, memory loss) 
and altered behavior (including personality
changes)
Q2, Q5, Q6
Higher cortical dysfunction
Impaired comprehension and/or formulation of
language (aphasia), loss of ability to recognize
objects, persons, sounds, shapes, or smells
(agnosia)
Q2, Q5, Q6
Visual changes
Loss of visual fields (homonymous 
hemianopsia), double vision (diplopia)
Q1
Motor deficits
Weakness (hemiparesis or monoparesis), 
seizures (generalized or partial), difficulties with
speech (dysarthria) or swallowing (dysphagia)
Q2, Q3
Sensory deficits
Sensory loss (i.e. paresthesia)
Q7
Coordination
Difficulty walking and maintaining balance 
(ataxia), lack of voluntary coordination of limb
movement (limb ataxia)
Q4
In order to monitor patients for PML, a neurologic exam (including evaluation of cranial
nerves, motor and sensory function, coordination, and mental status) will be performed
as per the schedules of assessments (see Appendix 1 and Appendix 2). This neurologic
exam will consist of administration of the PML Subjective Checklist and the PML
Objective Checklist.
At screening, the PML Subjective Checklist and the PML Objective Checklist (including
the components listed as optional, e.g. muscle group strength testing, recall of 3 objects
in 1 minute, and sensory testing) should be performed.
At all other visits, the PML Subjective Checklist and the PML Objective Checklist
(bolded items) should be performed, and the optional items should only be performed 
when there is an abnormal finding on the corresponding PML Subjective Checklist (i.e.
complaints of focal weakness or focal sensory change would prompt a more detailed
objective neurologic evaluation).


Appendix 6
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
105/Protocol GA28951, Version 9
PML Subjective Checklist
Symptoms
“Compared to 
how you usually
feel, have you 
had a significant 
change in any of
the following?”
If the answer is “Yes”,
obtain a description of
the symptom(s) with 
examples
Applicable Objective 
Test(s): Document result 
on PML Objective 
Checklist Worksheet
YES
NO
1. Have you been 
experiencing any persistent
difficulty with your vision such
as loss of vision or double 
vision? Have you been having
trouble with reading?

Test visual fields and 
ocular motility
2. Have you been 
experiencing any persistent
difficulty speaking or having
your speech understood by 
others?

Casual observation of 
speech output for 
dysarthria or aphasia.
3. Have you been 
experiencing any persistent
weakness in an arm or a leg?

Test for pronator drift 
(Barre maneuver).

Assess gait.

Test muscle strength
(only if indicated).
4. Have you noticed yourself
regularly bumping into things
or having difficulty writing?

Observe tandem gait
and finger to nose.
5. Have you regularly been
experiencing difficulty
understanding others?

Test ability to follow 
serial commands.
6. Have you had persistent
problems with your memory or
thinking?

Recall of 3 objects over 
1 minute with distraction 
(only if indicated).
7. Have you been 
experiencing any persistent
numbness or other loss of
sensation?

Test sensation side to 
side with either pinprick
or cold (only if
indicated).


Appendix 6
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
106/Protocol GA28951, Version 9
PML Objective Checklist
Neurologic function 
being assessed
Instructions 
(bold text indicates parts of exam 
required at each visit, as specified in 
Schedule of Assessments)
Abnormal 
exam?
If the answer is 
“Yes”, describe the 
abnormal objective 
exam finding
YES
NO
1. Visual fields and 
ocular motility

Visual Field Testing 

Ocular Motility Testing
2. Speech

Observe the patient’s speech 
output for dysarthria or aphasia.
3. Strength

Pronator drift test (Barre 
maneuver)

Gait testing (normal, heel and 
toe walk)

ONLY if the patient has any 
subjective complaints of weakness,
test muscle strength of the relevant 
4. Coordination

Observe tandem gait and finger 
to nose
5. Comprehension

Test ability to follow serial 
commands

“Take a piece of paper in your 
hand, fold it in half, and put it on 
the floor.”
6. Memory and thinking

ONLY if the patient has subjective 
complaints about their memory or 
thinking, test the ability of the 
patient to recall 3 objects over 1 
minute with distraction
7. Sensation

ONLY if the patient has subjective 
sensory complaints, evaluate 
relevant areas based on patient’s 
subjective complaints by comparing
left vs. right side sensation to cold
(e.g. alcohol swab or cold
stethoscope) or pinprick (e.g. 
broken Q-tip)


Appendix 6
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
107/Protocol GA28951, Version 9
Please refer to the PML Algorithm in the Protocol Appendix for details.

If there is an abnormal finding on the PML Subjective Checklist, this should be
appropriately documented on the worksheet and in the eCRF.

If there is an abnormal finding on the PML Objective Checklist, this should be
appropriately documented on the worksheet and in the eCRF.

If there are any abnormalities found on the PML Subjective Checklist that are
accompanied by the corresponding abnormality on the PML Objective Checklist, or if
there is high clinical suspicion for PML (in the opinion of the investigator):

This must be reported as an adverse event of special interest (AESI) within 
24 hours

An urgent referral to a neurologist should be made.

Dosing with study drug will be suspended until PML can be ruled out.

Further evaluation will proceed according to the PML Algorithm in the 
Protocol Appendix.

Any confirmed diagnosis of PML should be reported as a serious adverse 
event (SAE).
Please complete the PML eCRF.
Was the PML Subjective Checklist administered? (Yes/No)
If yes, date of administration of PML Subjective Checklist (Date)
If yes, were there any abnormalities on the PML Subjective Checklist? (Yes/No) 
Was the PML Objective Checklist administered? (Yes/No)
If yes, were there any abnormalities on the PML Objective Checklist? (Yes/No) 
Is PML suspected? (Yes/No)


Appendix 6
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
108/Protocol GA28951, Version 9
More detailed instructions for the PML Objective Checklist Neurologic Evaluations
(please refer to the PML Neurologic Exam Video for more information):
1. Visual fields and ocular motility
Visual Field Testing:

Position yourself approximately 3 feet away from the patient, with eyes at the same
level.

Keeping both eyes open, ask the patient to cover one eye and ask if all parts of your
face and head are clear to them. Ask them to repeat, covering the other eye.

Have the patient cover one eye and stare at your nose, and then ask them how
many fingers you are holding up, testing each of the 4 visual quadrants. Repeat with
the other eye covered.
Ocular Motility Testing:

Evaluate the patient for conjugate eye movement.

Starting about 3 feet from center, move in a big “H”, pausing at the center and at 
lateral gaze, and finishing with convergence (finger to their nose). Watch for
nystagmus in lateral gaze, smooth pursuits, and pupillary constriction with
convergence. Note: a couple of beats of nystagmus upon extreme lateral gaze is
considered normal.
2. Speech

Observe the patient’s speech output for dysarthria or aphasia.

Dysarthria is a motor speech disorder. Findings can include “slurred” speech, 
decreased volume, slow rate of speech, limited tongue, lip, and jaw movement,
abnormal rhythm when speaking, changes in vocal quality, and drooling or poor 
control of saliva.

Aphasia is a disorder that results from damage to parts of the brain that control 
language, and can lead to problems with any or all of the following: speaking, 
listening, reading or writing.
3. Strength
Pronator drift test (Barre maneuver):

Ask the patient to stand with their feet together and extend their arms out in front of 
them at 90 degrees (parallel to floor) with palms facing upwards toward the ceiling.

Ask the patient to close their eyes and keep their arms extended for 15 seconds.

If either arm drifts downward, upward, or starts to pronate (i.e. thumb turns up), this
is considered an abnormal exam.


Appendix 6
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
109/Protocol GA28951, Version 9
Gait testing:

Ask the patient to walk across the room (~10 feet).  The patient should have a
normal gait, with their left arm swinging forward when the right foot leads, and vice
versa.  Be certain to note whether there is symmetric arm swinging, because a
slight decrease in arm swinging may be an indicator of upper extremity weakness.

Ask the patient to walk on their heels across the room (~10 feet). Carefully observe
whether they have any difficulty maintaining their toes off the ground or loss of
balance.

Ask the patient to walk on their toes across the room (~10 feet). Carefully observe if
they have any difficulty maintaining their heels off the ground or loss of balance.
Additional strength testing (ONLY if the patient has any subjective complaints of 
weakness):

Test muscle strength of the relevant muscle groups based on the patient’s
subjective complaints.

General guidelines for a basic muscle strength exam:

Upper extremity:
o
Finger grip strength
o
Flexion at elbow
o
Extension at elbow
o
Deltoid strength: Maintain bent arms up (perpendicular to floor) and
resist while investigator pushes down
o
Shoulder shrug against resistance

Lower extremity: (examine while patient is sitting down)
o
Raise thigh (while bent)
o
Straighten leg
o
Flex leg
o
Flex foot
o
Extend foot
4. Coordination
Tandem gait:

As the patient is looking at his feet, ask them to walk 8 steps with one foot touching
in front of the other (demonstrate for them).


Appendix 6
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
110/Protocol GA28951, Version 9
Finger to nose:

Hold your finger out so they need to reach out and lean. Start near the center, and
move your finger slowly so that they reach across their body. Make sure they
alternate touching your finger and their nose at a good speed. Inability to perform 
this accurately is considered an abnormal test.
5. Comprehension

Test ability to follow serial commands

“Take a piece of paper in your hand, fold it in half, and put it on the floor.”
6. Memory and Thinking

(ONLY if the patient has subjective complaints about their memory or thinking) test
the ability of the patient to recall 3 objects over 1 minute with distraction.
7. Sensation

(ONLY if the patient has subjective sensory complaints) evaluate relevant areas
based on the patient’s subjective complaints by comparing left vs. right side
sensation to cold (e.g. alcohol swab or cold stethoscope) or pinprick (e.g. broken
Q-tip). Confirm that the patient is able to feel the sensation symmetrically.




Etrolizumab—F. Hoffmann-La Roche Ltd
112/Protocol GA28951, Version 9
Appendix 8
Patient Daily Diary


Etrolizumab—F. Hoffmann-La Roche Ltd
113/Protocol GA28951, Version 9
Appendix 9
Clinical Criteria for Diagnosing Anaphylaxis
These criteria are taken from a summary report from the second symposium on the 
definition and management of anaphylaxis, conducted by the National Institute of Allergy 
and Infectious Disease/Food Allergy and Anaphylaxis Network.1  Anaphylaxis is highly 
likely when any one of the following three criteria is fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen
lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING:

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow, hypoxemia)

Reduced blood pressure or associated symptoms of end-organ dysfunction
(e.g., hypotonia, syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):

Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen 
lips-tongue-uvula)

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow, hypoxemia)

Reduced blood pressure or associated symptoms (e.g., hypotonia, syncope, 
incontinence)

Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
3.
Reduced blood pressure after exposure to known allergen for that patient (minutes to
several hours):

Infants and children:  low systolic blood pressure (age specific)2 or greater than 30% 
decrease in systolic blood pressure

Adults:  systolic blood pressure of less than 90 mmHg or greater than 30% decrease 
from that person’s baseline
                                           
1
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and 
management of anaphylaxis: summary report—second National Institute of Allergy and Infectious
Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 
2006;117:3917.
2
Low systolic blood pressure for children is defined as less than 70 mmHg from 1 month to 1 year, less
than (70 mmHg + [2 age]) from 1 to 10 years, and less than 90 mmHg from 11 to 17 years.

SAP_001.pdf: 
 
Official Title: 
An Open-Label Extension and Safety Monitoring Study of Moderate 
to Severe Ulcerative Colitis Patients Previously Enrolled in 
Etrolizumab Phase II/III Studies 
NCT Number: 
NCT02118584 
Document Date: 
SAP Version 1: 27-Sep-2022 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL 
 
SPONSOR: 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
DATE FINAL: 
See electronic date stamp on the last page of this 
document  
CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Etrolizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GA28951 
STATISTICAL ANALYSIS PLAN 
STUDY 
TITLE: 
AN OPEN-LABEL EXTENSION AND SAFETY MONITORING 
STUDY OF PATIENTS WITH MODERATELY TO SEVERELY 
ACTIVE ULCERATIVE COLITIS PATIENTS PREVIOUSLY 
ENROLLED IN THE ETROLIZUMAB PHASE II/III STUDIES 
STUDY NUMBER: 
GA28951 
STUDY NAME:  
COTTONWOOD 
VERSION NUMBER: 
1 
ROCHE COMPOUND(S): 
Etrolizumab (PRO145223, RO5490261) 
EUDRACT NUMBER: 
2013-004435-72 
IND NUMBER: 
100366 
NCT NUMBER: 
NCT02118584 
PLAN PREPARED BY: 
 M.Sc. 
 Ph.D. 


 
Etrolizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GA28951 
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STATISTICAL ANALYSIS PLAN VERSION HISTORY 
This SAP was developed based on Roche SAP model document v2.0, Revised 28 Feb 
2022. 
SAP Version 
Approval Date 
Based on Protocol  
(Version, Approval Date) 
1 
see electronic date stamp 
on the last page of the 
document 
V9, 12 February 2019 


 
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Statistical Analysis Plan GA28951 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................. 7 
1.1 
OBJECTIVES AND ENDPOINTS .............................................. 9 
1.2 
STUDY DESIGN ...................................................................... 10 
1.2.1 
Protocol Synopsis .................................................................... 10 
1.3 
OUTCOME MEASURES FOR GA28951 PART 1 (OLE) ......... 10 
1.3.1 
Efficacy Outcome Measures .................................................... 10 
1.3.2 
Safety Outcome Measures ...................................................... 11 
1.3.3 
Exploratory Outcome Measures .............................................. 11 
1.4 
ANALYSIS TIMING .................................................................. 11 
2. 
STATISTICAL HYPOTHESES AND SAMPLE SIZE 
DETERMINATION ........................................................................ 12 
2.1 
STATISTICAL HYPOTHESES ................................................. 12 
2.2 
SAMPLE SIZE DETERMINATION ........................................... 12 
3. 
ANALYSIS SETS .......................................................................... 12 
4. 
STATISTICAL ANALYSES ........................................................... 12 
4.1 
GENERAL CONSIDERATIONS .............................................. 12 
4.1.1 
Analysis of Study Conduct ....................................................... 12 
4.1.2 
Analysis of OLE Treatment ...................................................... 13 
4.1.3 
Primary Efficacy Analysis......................................................... 15 
4.1.3.1 
Endoscopic Improvement and Remission at Week 108 ........... 17 
4.1.3.2 
MCS Remission at Week 108 .................................................. 17 
4.1.3.3 
pMCS Remission ..................................................................... 18 
4.2 
SAFETY ANALYSES ............................................................... 19 
4.2.1 
Extent of Exposure .................................................................. 19 
4.2.2 
Adverse Events ........................................................................ 19 
4.2.3 
Additional Safety Assessments ................................................ 21 
4.2.3.1 
Laboratory Data ....................................................................... 21 
4.2.3.2 
Vital Signs ................................................................................ 22 
4.2.3.3 
ECGs ....................................................................................... 22 
4.2.3.4 
Medical History ........................................................................ 22 


 
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Statistical Analysis Plan GA28951 
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4.2.3.5 
Concomitant Medications ........................................................ 22 
4.2.4 
Open-Label Extension Timeframe ........................................... 22 
4.3 
INTERIM ANALYSES .............................................................. 22 
4.4 
CHANGES TO PROTOCOL-PLANNED ANALYSES .............. 23 
5. 
SUPPORTING DOCUMENTATION .............................................. 23 
6. 
REFERENCES.............................................................................. 23 
 
 
LIST OF TABLES 
Table 1 
Key Characteristics of GA28951 OLE-SM Study in UC 
(Cottonwood) ................................................................................ 9 
Table 2 
Analysis Populations ................................................................... 12 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema for Part I (OLE) of the OLE-SM Study ................... 8 
Figure 2 
Study Schema for Part II (SM) of the OLE-SM Study ................... 8 
 


 
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Statistical Analysis Plan GA28951 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or Term 
Description 
5-ASAs 
5-aminosalicylic acid 
AE 
adverse event 
AEGT 
Adverse Events Group Terms 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AP 
abdominal pain 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CCOD 
clinical cutoff date 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
Coronavirus Disease 2019 
CRP 
C-reactive protein 
CS 
corticosteroids 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
e-CRF 
electronic Case Report Form 
EQ-5D 
EuroQL 5 Dimension Questionnaire 
HLGT 
High Level Group Terms 
HLT 
High Level Terms 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICE 
intercurrent event 
iDMC 
independent Data Monitoring Committee 
IS 
immunosuppressant 
IxRS 
interactive voice/Web based response system 
LOCF 
last-observation-carried-forward 
MAR 
missing at random 
MCS 
Mayo Clinical Score 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MICE 
multivariate imputation by chained equations 
mITT 
modified intent to treat 
MMRM 
mixed models for repeated measures 
NRI 
non-responder imputation 
OLE 
open label extension 


 
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Statistical Analysis Plan GA28951 
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PD 
pharmacodynamics 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PRO2 
patient-reported outcomes-2 
PT 
preferred term 
Q4W 
every 4 weeks 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
Subcutaneous 
SES-CD 
simplified endoscopic score for Crohn’s disease 
SF 
stool frequency 
SM 
safety monitoring 
SMQ 
Standard MedDRA Query 
SOC 
system organ class 
TNF 
tumor necrosis factor 
TNF-IR 
TNF-inadequate responder 
UC 
Ulcerative Colitis 
UC-PRO/SS 
Ulcerative Colitis- Patient Reported Outcome/ Signs and Symptoms 
ULN 
upper limit of normal 
WOCF 
worst-observation-carried-forward 
 
 
 


 
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Statistical Analysis Plan GA28951 
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1. 
INTRODUCTION 
The analyses described in this Statistical Analysis Plan (SAP) will supersede those 
specified in Protocol GA28951 for the purposes of reporting. 
The purpose of this document is to describe the definitions and data handling rules for 
producing outputs to report out Part 1 of the Open-Label-Extension Safety Monitoring 
(OLE-SM) study for GA28951 (Cottonwood). 
This OLE-SM study is composed of two parts: 
1. 
Part 1 is the OLE for eligible patients, during which etrolizumab, 105 mg SC, will be 
administered Q4W followed by a 12-week safety follow-up post-treatment. 
2. 
Part 2 is the 92-week PML SM for all patients, during which no etrolizumab will be 
administered. 
 
Patients who are enrolled in Part 1 (OLE) should participate in Part 2 (SM). 
There may be patients who are ineligible for or choose not to participate in Part 1 (OLE) 
who will directly enroll in Part 2 (SM) only. 
Key characteristics of the GA28951 OLE-SM  are provided in Table 1.  Treatment arms 
and rollover of patients to GA28951 OLE-SM from their parent UC study are depicted in 
Figure 1 and Figure 2. 
The OLE-SM study will be conducted in centers that have participated in the Phase II 
OLE Study GA27927 and/or the double-blinded Phase III Studies GA28948, GA28949, 
GA28950, GA29102, and GA29103.  The maximum number of patients potentially 
enrolling in this study will be all patients from the studies; approximately 2100 patients.  
Patients will be allocated the same subject number they had in the initial Phase II OLE 
study or Phase III study. 
 
 


 
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Statistical Analysis Plan GA28951 
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Figure 1 Study Schema for Part I (OLE) of the OLE-SM Study 
 
Figure 2 Study Schema for Part II (SM) of the OLE-SM Study 
 
 


 
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Statistical Analysis Plan GA28951 
9 
 
Table 1 
Key Characteristics of GA28951 OLE-SM Study in UC (Cottonwood) 
Study 
GA28951 (Phase III) 
Treatment 
(Number 
Exposed) 
Open-label etrolizumab 105 mg SC Q4W (n=up to ~2100) 
Study Phases 
OLE up to 10 years from FPI 
12-week safety follow-up 
92-week PML monitoring 
Key Eligibility 
Criteria 
Part 1 (OLE) 
 
Part 2 (SM)** 
● 
Patients who were previously 
enrolled in the Phase II OLE 
study or a Phase III controlled 
study and meet the eligibility 
criteria for treatment with open-
label etrolizumab as described 
in the GA28951 protocol in 
Table 1 may enroll in Part 1 
(OLE) of the study. 
● 
Patients whose safety follow-up or 
PML follow-up is not completed 
within Study GA27927 and patients 
who had their last dose of 
etrolizumab in July 2016 in Study 
GA27927 and are not eligible or 
choose not to enroll in Part 1 (OLE) 
● 
Patients who participated in one of 
the etrolizumab Phase III studies 
(GA28948, GA28949, GA28950, 
GA29102, and GA29103) and are 
not eligible or chose not to enroll in 
Part 1 (OLE) 
● 
Participated in Part 1 (OLE) and 
completed the 12-week SFU 
FPI=first patient in; OLE=open- label extension; PML=progressive multifocal leukoencephalopathy; 
Q4W=every 4 weeks; SC=subcutaneous; SM=safety monitoring, SFU = safety follow-up, UC = 
Ulcerative Colitis. 
**All patients must have completed the 12- week safety follow-up in either the parent study or 
GA28951 Part 1 (OLE), as applicable, prior to entering Part 2 (SM). 
Outputs for this primary CSR will solely focus on reporting data collected during Part 1 
(OLE) of GA28951.  
Changes to the protocol-planned analyses are described in Section 4.4.  
1.1 
OBJECTIVES AND ENDPOINTS 
The objectives of this OLE-SM study are as follows: 
Part 1 (OLE) 
 
To assess the long-term safety and efficacy of etrolizumab in patients eligible for 
Part 1 (OLE) 
Part 2 (SM) 
 
PML safety monitoring 
This SAP will only cover analyses for the GA28951 Part 1 (OLE) objective. 


 
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Statistical Analysis Plan GA28951 
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Other Safety Objectives: 
 
To evaluate the incidence and severity of infection-related adverse events 
 
To evaluate the incidence of malignancies 
 
To evaluate the incidence and severity of hypersensitivity reactions 
 
Exploratory:  
 
To evaluate histology at Week 108 
 
The following endpoint was de-prioritised as a safety objective to an exploratory 
objective from Protocol GA28951, version 9.  Rationale for this is detailed in Section 4.4: 
 
To evaluate the incidence and the clinical significance of anti-therapeutic antibodies 
(ATAs) 
  
1.2 
STUDY DESIGN 
Details of the Part 1 (OLE) study design can be found in the Protocol Section 3 and 
Study Schema in Figure 1 of Protocol Version 9. 
1.2.1 
Protocol Synopsis 
The Protocol Synopsis is in Protocol Synopsis Section of Protocol Version 9.  For 
additional details, see the Schedule of Assessments in Appendices 1 and 2 of Protocol 
Version 9. 
1.3 
OUTCOME MEASURES FOR GA28951 PART 1 (OLE) 
1.3.1 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
 
pMCS remission assessed at Weeks 0, 4, 8 and then in 12-week intervals during 
GA28951 Part 1 (OLE) 
 
MCS remission assessed at Week 108 during GA28951 Part 1 (OLE) 
 
Endoscopic remission at Week 108 during GA28951 Part 1 (OLE) 
The efficacy outcome definitions are provided below: 
Outcome Measure 
Definition 
Mayo Clinic Score (MCS) 
MCS (0−12) is a composite of 4 assessments, each rated from 
0‑3: stool frequency, rectal bleeding, endoscopy, and PGA 
Partial Mayo Clinic Score 
(pMCS) 
pMCS (0−9) is a composite of 3 assessments, each rated from 
0‑3: stool frequency, rectal bleeding, and PGA 


 
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Statistical Analysis Plan GA28951 
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MCS Remission 
MCS ≤ 2 with individual subscores ≤1 and a rectal bleeding 
subscore of 0 
MCS Clinical Response 
MCS with ≥ 3-point decrease and 30% reduction from baseline as 
well as ≥ 1-point decrease in rectal bleeding subscore or an 
absolute rectal bleeding score of 0 or 1 
pMCS Remission 
pMCS ≤ 2, with, rectal bleeding score of 0, PGA 0−1 and stool 
frequency subscore 0−1 
Improvement in endoscopic 
appearance of the mucosa 
Endoscopy subscore ≤ 1 
Endoscopic Remission 
Endoscopy subscore = 0 
ES= Endoscopic Subscore; PGA = Physician’s Global Assessment. 
Endoscopy Score=1 includes mild friability criteria unless identified in the description of an 
endpoint above. 
  
1.3.2 
Safety Outcome Measures 
The safety outcome measures for GA28951 Part 1 (OLE) of this study are as follows: 
 
Incidence and severity of adverse events 
 
Incidence of serious adverse events 
 
Incidence, rate per subject-year, and severity of infection-related adverse events 
 
Incidence of serious infection-related adverse events 
 
Incidence and severity of injection-site reactions 
 
Incidence of adverse events leading to etrolizumab discontinuation 
 
Incidence of laboratory abnormalities 
 
Incidence and rate per subject-year of malignancies 
 
Incidence and severity of hypersensitivity reactions 
 
1.3.3 
Exploratory Outcome Measures 
The exploratory outcome measures for GA28951 Part 1 (OLE) are as follows: 
 
Histologic appearance of mucosa at Week 108 
 
Incidence of ATAs to etrolizumab (de-prioritised from a safety outcome measure. 
See Section 4.4 for details) 
Due to termination of study GA28951, exploratory outcome measures will not be 
reported in the Primary CSR. 
 
1.4 
ANALYSIS TIMING 
GA28951 Part 1 (OLE) will be formally, analyzed and reported in a primary CSR after 
the last patient has completed the 12-week safety follow up, following last dosing on 


 
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Statistical Analysis Plan GA28951 
12 
 
15th May 2022.  Note that a database snapshot rather than a database lock for reporting 
Part 1 (OLE) of GA28951 will take place. 
2. 
STATISTICAL HYPOTHESES AND SAMPLE SIZE 
DETERMINATION 
2.1 
STATISTICAL HYPOTHESES 
Due to the non-comparative character of the study, no statistical tests or hypotheses are 
planned; all efficacy parameters will be summarized descriptively. 
2.2 
SAMPLE SIZE DETERMINATION 
The maximum number of patients that could have been enrolled in the OLE-SM study is 
approximately 2100 (i.e., all patients enrolled in the Phase II OLE protocol and the five 
UC Phase III protocols).  No formal sample size calculations were performed. 
3. 
ANALYSIS SETS 
The analysis population for the purposes of analyses are presented in below: 
Table 2 
Analysis Populations 
Open-Label 
Extension 
Patients who receive at least one dose of study drug in Study 
GA28951 Part 1 OLE 
Timeframe is from first dose of study drug in the GA28951 Part 1 
(OLE) to the patient’s last visit in GA28951 Part 1 (OLE), or safety 
follow-up, whichever is latest. Summaries will primarily focus on safety 
events arising after first dose of study drug in Study GA28951 Part 1 
(OLE). 
  
4. 
STATISTICAL ANALYSES 
For reporting, a synoptic CSR will be reported.  Due to this synoptic nature, limited 
efficacy data will be reported. All safety outcome measures will be reported, in the CSR. 
4.1 
GENERAL CONSIDERATIONS 
4.1.1 
Analysis of Study Conduct 
The number of patients who enrolled in Part 1 (OLE) and Part 2 (SM) will be tabulated 
The number of patients who discontinued early (early discontinuation of OLE treatment 
or early termination from the study) or completed the study will be tabulated.  
Reasons for early discontinuation of treatment or early termination from the study will be 
listed and summarized.  Any eligibility criteria exceptions and other major protocol 
deviations will also be summarized.  The data will also be summarized by origin of the 
patient (i.e., by original Phase II OLE protocol or Phase III controlled protocol).   


 
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Statistical Analysis Plan GA28951 
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Since Part 1 (OLE) of GA28951 was terminated by the Sponsor on 15th February 2022, 
no patients are expected to reach treatment completion.  As a result of this, the end of 
Part 1 (OLE) of GA28951 is defined from the last dose date in GA28951 on 15th May 
2022. 
In summary, the following will be summarized for GA28951 Part 1 (OLE): 
 
Analysis populations 
 
Patient disposition 
 
Study treatment completion/discontinuation 
 
Study completion/discontinuation 
 
Major protocol deviations 
 
Exposure 
Treatment Labels 
For the OLE population, the only treatment arm to be summarized is: 
Group 
Patients Included 
OLE Etrolizumab 
Patients in the OLE population who receive at least one dose of 
etrolizumab in Study GA28951 Part 1 (OLE) 
OLE  Open-Label-Extension  
  
Part 1 (OLE) Day 1 
OLE Study Day 1 is defined as the day patient has the first receipt of study drug in 
GA28951 Part 1 (OLE). 
Baseline 
For patients who were previously enrolled in one of the Phase III studies, baseline is 
defined as the last available assessment prior to first receipt of study drug in the 
Induction Phase of the parent studies: GA28948, GA28949, GA28950, GA29102, and 
GA29103. 
For patients who were previously enrolled in the Phase II trial GA27927, baseline is 
defined as the last available assessment prior to first receipt of study drug in their parent 
trial ABS4986g.  
4.1.2 
Analysis of OLE Treatment 
The following demographic and baseline disease characteristics will be summarized for 


 
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Statistical Analysis Plan GA28951 
14 
 
the OLE population using baseline from the original parent studies.  No treatment 
comparisons will be made since GA28951 is a single-arm open-label study. 
For continuous variables, descriptive statistics including n, mean, median, standard 
deviation, minimum, and maximum will be calculated.  For categorical variables, number 
and percentage in each category will be displayed. 
Demography 
 
Age 
 
Age Category (≥18 to < 40, ≥40 to  < 65,  ≥65) 
 
Sex 
 
Race 
 
Ethnicity 
 
Region 
 
Smoking status history 
 
Body mass index 
 
Weight 
Disease Characteristics 
 
Duration of disease (years) 
 
Duration of disease category (years) (  3,   3 to < 8,   8) 
 
Disease extent (Left-sided colitis, Extensive/Pancolitis, Other) 
 
MCS score 
 
MCS score category (MCS ≤ 9, MCS ≥ 10) (IxRS and Rave) 
 
Mean Stool Frequency (SF) 
 
Worst Rectal Bleeding (RB) 
 
Physician’s Global Assessment (PGA) 
 
pMCS score 
 
Endoscopic Subscore 
 
Ulcerative Colitis Patient-Reported Outcomes, Signs and Symptoms (UC-PRO/SS) 
– Functional score 
 
UC-PRO/SS – Bowel score 
 
UC-PRO/SS – Systemic score 
 
Inflammatory Bowel Disease Questionnaire (IBDQ) total score 
 
Extraintestinal Manifestations 


 
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 
Fecal calprotectin (g/g) 
 
Fecal calprotectin category (<250 g/g,   250 to  < 500 g/g,   500 g/g) 
 
C-reactive protein (CRP) levels (mg/L) 
 
CRP category (  2.87 mg/L,   2 .87 to   10 mg/L,   10 mg/L) 
 
Baseline Treatments 
 
Use of oral CS at Baseline (yes vs. no) (IxRS and Rave) 
 
Use of IS at Baseline (yes vs. no) (IxRS and Rave) 
 
Prior anti-TNF exposure (yes vs. no) (IxRS and Rave) 
 
Prior anti-TNF History 
 
Corticosteroid and Immunosuppressant categories 
 
Prior Corticosteroid (CS) History 
The patients with prior anti-TNF exposure at baseline will be further evaluated to include 
the number of TNFs previously received and status (e.g., primary non-responder, 
secondary non-responder, Intolerant, etc). 
4.1.3 
Primary Efficacy Analysis 
To evaluate the efficacy of etrolizumab during long-term open-label treatment, efficacy 
will be summarized within the population of patients who enroll into the Study GA28951.  
All data available up until the clinical cut‑off date (CCOD) will be reported.  The 
endpoints to be summarized are described below.  Due to the open-label nature of the 
study, no treatment comparisons will be made. 
Concerning missing data and treatment withdrawal imputation, there will be 3 strategies 
employed, described below. 
Hybrid LOCF 
Within this strategy, at each visit only patients who had the possibility of reaching the 
visit will be considered in the analysis for that specified visit.  Patients will be deemed 
evaluable at a visit if it was possible for them to have reached this visit based on their 
enrollment date and the date of the closure of Part 1 of the study. 
 
Patients for whom it is not possible to have reached the visit at the time of the 
clinical cut off are termed non-evaluable and will not be included in the analysis at 
that visit.  
 
For evaluable patients with missing data, Last Observation Carried Forward (LOCF) 
will be used from their most recent available data.  


 
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 
For evaluable patients who previously withdrew from treatment, they will be imputed 
as a non-responder until their maximum hypothetical visit (i.e., the maximum visit 
that they could have attended if they had remained within the study). 
o For visits after a patient's maximum hypothetical evaluable visit, they will 
be removed from the analysis. 
As Observed 
Within this analysis only the available data at each visit will be summarized.  No 
imputation will be performed for missing data or treatment withdrawals. 
Non-Responder 
Within this strategy, at each visit only patients who had the possibility of reaching the 
visit will be considered in the analysis for that specified visit.  Patients will be deemed 
evaluable at a visit if it was possible for them to have reached this visit based on their 
enrollment date and the date of the closure of Part 1 of the study. 
 
Patients for whom it is not possible to have reached the visit at the time of the 
clinical cut off are termed non-evaluable and will not be included in the analysis at 
that visit.  
 
Evaluable patients with missing data will be set as a non-responder. 
 
For evaluable patients who previously withdrew from treatment, they will be imputed 
as a non-responder until their maximum hypothetical visit (i.e., the maximum visit 
that they could have attended if they had remained within the program). 
o For visits after a patient's maximum hypothetical evaluable visit, they will 
be removed from the analysis. 
Maximum Hypothetical Evaluable Visit 
A patient’s maximum hypothetical study day (i.e., the maximum visit that they could have 
attended if they had remained within the study) is calculated as follows: 
 
Maximum hypothetical study day = (15th May 2022 - Patient’s Day 1 OLE 
enrollment date) 
 
For the hybrid LOCF analysis and non-responder analyses, this will impute patients who 
have withdrawn as non-responders until the 15th May 2022, which was the latest day of 
dosing reported in the closure of the study announcement.  This excludes patients who 
withdrew from study drug with reason being stated as “study terminated by sponsor” 
after 15th February 2022, these patients will not be imputed as non-responders and will 
be considered ‘treatment completers’ for the efficacy analysis with data included “as 
observed” 
 


 
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4.1.3.1 
Endoscopic Improvement and Remission at Week 108 
As endoscopy data is only collected at a common time point of Week 108 during the 
OLE Study GA28951, the endpoints of endoscopic improvement and remission will be 
summarized at this time point.  These endpoints will be examined overall and also with 
patients separated by their previous endoscopic improvement status at their latest visit 
prior to OLE (e.g., at Week 10/14 or Week 54/62/66 in their parent study). 
Population:  All patients who enrolled into Part 1 of the OLE Study GA28951. 
Baseline:  The original baseline value from the parent study will be used. 
Sub-groups:   
 
Table outputs: All patients overall and split by prior endoscopic improvement status 
and their prior aTNF exposure status. 
Analysis 1 - Non-responder 
Missing Data:   
Patients who are non-evaluable at Week 108 (i.e., it is not possible for them to have 
reached this visit at the time of the clinical cut-off date) will be removed from the 
analysis.  Patients who remain in Study GA28951 Part 1 (OLE) but are missing 
endoscopy scores will be imputed as non-responders within the analysis, as LOCF is not 
appropriate when endoscopy data is not collected routinely.  
Intercurrent events:  Patients who withdraw during Study GA28951 will be set to non-
responders using the composite strategy if they could have reached OLE Week 108 at 
the time of the clinical cut-off date had they not withdrawn from treatment.  This excludes 
patients who withdrew from study drug with reason being stated as “study terminated by 
sponsor” after 15th February 2022. 
Analysis 2 - As Observed 
Intercurrent events: No imputation will be performed for treatment withdrawals 
Missing data:  If a patient has missing data at a visit, they will be removed from the 
analysis and no imputation will be performed. 
 
4.1.3.2 
MCS Remission at Week 108 
As endoscopy data is only collected at a common time point of Week 108 during the 
OLE Study GA28951, a full MCS score can only be calculated at this visit.  Therefore, 
the endpoint of MCS remission (clinical remission, response?) will be summarized at this 
time point.  These endpoints will be examined overall and also with patients separated 
by their previous MCS remission status at their latest visit prior to OLE at Week 10/ 14 or 
Week 54/62/66 in their parent study. 
Population:  All patients who enrolled into Part 1 of the OLE Study GA28951. 


 
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Baseline:  The original baseline value from the parent study will be used. 
Sub-groups:   
 
Table outputs: All patients overall and split by prior MCS remission status and their 
prior aTNF exposure status. 
Analysis 1 - Non-responder 
Missing Data: Patients who are non-evaluable at Week 108 (i.e., it is not possible for 
them to have reached this visit at the time of the clinical cut-off date) will be removed 
from the analysis.  Patients who remain in Study GA28951 but are missing MCS scores 
will be imputed as non-responders within the analysis, as LOCF is not appropriate when 
endoscopy data, which comprises part of the MCS score, is not collected routinely.  
Intercurrent events:  Patients who withdraw during Study GA28951 will be set to non-
responders using the composite strategy if they could have reached OLE Week 108 at 
the time of the clinical cut-off date had they not withdrawn from treatment.  This excludes 
patients who withdrew from study drug with reason being stated as “study terminated by 
sponsor” after 15 February 2022. 
Analysis 2 - As Observed 
Missing data: No imputation will be performed for missing data 
Intercurrent events: No imputation will be performed for treatment withdrawals 
 
4.1.3.3 
pMCS Remission 
The percentage of patients in remission defined using the pMCS will be summarized for 
each OLE visit for patients who entered Study GA28951.  All OLE visits will be 
summarized until a minimum of 20 evaluable patients overall remain within the analysis 
(i.e., an evaluable patient either reached the visit or could have reached the visit if they 
had remained within the OLE). 
Population:  Patients who enroll into Part 1 of Study GA28951. 
Baseline:  The original baseline value from the parent study will be used. 
Sub-groups:  
 
Table outputs: All patients overall, split by aTNF exposure status and by OLE Day 1 
pMCS remission status. 
 
Figure outputs: All patients overall and split by OLE Day 1 pMCS remission status. 
Analysis 1 - Hybrid LOCF 


 
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Statistical Analysis Plan GA28951 
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Missing data: If patients who remain in Study GA28951 at the specified visit are missing 
data then LOCF will be used to impute.  For visits where patients are non-evaluable (i.e., 
it is not possible for them to have reached the specified visit at the time of the clinical 
cut-off date) they will be removed from the analysis. 
Intercurrent Events:  Using the composite strategy in the case where patients have 
withdrawn from the Study GA28951, they will be set to non-responders for all visits 
where they are evaluable.  This excludes patients who withdrew from study drug with 
reason being stated as “study terminated by sponsor” after 15th February 2022. 
 
Analysis 2 - As Observed 
Missing data:  If a patient has missing data at a visit, they will be removed from the 
analysis and no imputation will be performed. 
Intercurrent events: No imputation will be performed for treatment withdrawals 
4.2 
SAFETY ANALYSES 
Safety data will be assessed through descriptive summaries using the OLE population.  
All data available up until the clinical cut‑off date (CCOD) will be reported 
Safety evaluations for the OLE population will include data from the first dose of 
treatment in Part 1 until the patient completes/withdraws from the Part 1 (OLE) of the 
study GA28951, this includes any 12-week safety follow-up data. 
4.2.1 
Extent of Exposure 
Exposure to study treatment will be summarized by: 
 
treatment duration (weeks) 
 
number of patients receiving a dose at each visit 
 
number of doses received/missed for a patient 
 
4.2.2 
Adverse Events 
Verbatim descriptions of AEs will be mapped to the latest version of the Medical 
Dictionary for Regulatory Activities (MedDRA).   
Adverse events (AEs) will include all terms recorded on the AE Case Report Form (CRF) 
pages (except pregnancies).  For each recorded AE, the term entered by the investigator 
describing the event (the “reported term”) will be assigned a standardized term (the 
“preferred term”) and assigned to a superclass term on the basis of the Medical 
Dictionary for Regulatory Activities (MedDRA) World Health Organization (WHO) 
dictionary of terms.  All analyses of AE data will be performed using the preferred terms 
and system organ class unless otherwise specified. 


 
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For the etrolizumab program, the adverse events of special interest (AESIs) are the 
following: 
 
Systemic hypersensitivity reactions and anaphylactic and anaphylactoid reaction 
which will be reported using the MedDRA anaphylactic reaction Standard MedDRA 
Query (SMQ) algorithmic and Hypersensitivity SMQ narrow. 
 
Neurological signs, symptoms, and AEs that may suggest possible progressive 
multifocal leukoencephalopathy (see Appendices 5 and 6 of Protocol)  
 
Suspected transmission of an infectious agent by the study drug  
 
Cases of potential drug-induced liver injury that include an elevated alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with 
either an elevated bilirubin or clinical jaundice, as defined by Hy’s Law  
Specific AEs listed below will also be reported: 
 
Serious infections 
 
Gastrointestinal Infections 
 
Opportunistic infections 
 
Malignancies 
 
Injection site reactions 
A listing or summary table (e.g., n  10) of all AEs suspected or confirmed, and AEs 
associated with COVID-19 will be generated.  Associated AEs are defined as all AEs 
reported within a time window of 7 days prior and 30 days after the confirmed COVID-19 
start date (dates inclusive).  Additionally, a listing of patients experiencing ‘long 
COVID‑19’ will be generated.  This listing will include all AEs with a duration >30 days 
occurring after a confirmed COVID-19 infection or a positive PCR test. 
All AESIs and specific AEs will be determined using a selection of eCRF tick box or 
MedDRA SMQs, Adverse Events Group Terms (AEGTs), High Level Term (HLTs), High 
Level Group Terms (HLGTs), System Organ Class (SOC), as appropriate. 
Summary tables will be generated for AEs, serious adverse events (SAEs), deaths, AEs 
leading to discontinuation of study drug, and AESIs.  A listing will be generated for AEs, 
deaths, selected AESIs/specific AEs, and COVID-19 AEs.  Pregnancies will be reported 
as narratives in the study CSR. 
Summary tables of AEs will summarize the incidence of treatment-emergent AEs only.  
Treatment-emergent events are defined as any new AE reported on or after the first 
dose of OLE study drug or any worsening of an existing condition.  Note that worsening 
of existing conditions include AEs ongoing from the UC parent studies (GA28948, 
GA28949, GA28950, GA29102, and GA29103).  Otherwise, only AEs reported on or 
after the first dose of OLE study drug are included.  If the onset date of the AE is prior to 


 
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Statistical Analysis Plan GA28951 
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the day of first dose, the AE will be considered treatment emergent only if the most 
extreme intensity is greater than the initial intensity (i.e., the intensity for a given AE 
increases and its end date is on or after the date of the first dose).  For all summary 
tables, the AEs will be sorted by SOC (in decreasing order of overall incidence) and then 
by preferred term (PT) (in decreasing order of overall incidence). 
For OLE etrolizumab treatment, the incidence count for each AE PT will be defined as 
the number of patients reporting at least one treatment-emergent occurrence of the 
event (multiple occurrences of the same AE in 1 patient will be counted only once).  The 
proportion of patients with an AE will be calculated as the incidence count divided by the 
total number of patients in the population.  Each table will also present the total number 
of AEs reported where multiple occurrences of the same AE in an individual are counted 
separately. 
Rate tables will be generated for selected AEs of interest.  The rate per 100 patient 
years and 95% CIs will be summarized by treatment group and will be calculated by: 
𝐴𝐸 𝑅𝑎𝑡𝑒 (𝑝𝑒𝑟 100 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑦𝑒𝑎𝑟𝑠) 
= 
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝐴𝐸𝑠 (𝑖𝑛 𝑂𝐿𝐸 𝑜𝑛𝑙𝑦)
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑦𝑒𝑎𝑟𝑠 𝑎𝑡 𝑟𝑖𝑠𝑘 (𝑖𝑛 𝑂𝐿𝐸 𝑜𝑛𝑙𝑦) × 100 
where the total patient-years at risk is the sum over all patients of the time intervals (in 
years) from the first dose of study treatment in Part 1 (OLE) until the patient 
completes/withdraws from the study (including the 12-week safety follow-up, if 
applicable).  Only treatment emergent AEs with an onset date after the first dose of open 
label etrolizumab in GA28951 will be included within these outputs. 
All summary tables and listings will report AEs using the OLE population.  
4.2.3 
Additional Safety Assessments  
4.2.3.1 
Laboratory Data 
Selected laboratory parameters for safety reporting will be described further in the OLE 
population by summarizing the marked abnormalities and shift tables.  Marked 
abnormalities will be identified according to a Sponsor-defined standard, which generally 
captures post- baseline laboratory values both outside a reference range and achieving 
a threshold percent change from baseline.  Where needed, laboratory values will be 
linearly transformed to a standard reference range in order to account for intrinsic 
differences between males and females or measurement differences between laboratory 
standards. 
Laboratory abnormalities and the patient’s worst Common Terminology Criteria for 
Adverse Events (CTCAE) grade during study will be summarized for hematology and 
serum chemistry parameters, in addition to change from Baseline summaries. 


 
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Statistical Analysis Plan GA28951 
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Elevated liver enzyme tests will be summarized by the following upper limit of normal 
(ULN) categories as these are indicators of severe liver injury: 
 
ALT or AST>3ULN and total bilirubin>2 ULN as defined by Hy’s law 
 
ALT or AST>3 ULN 
  
4.2.3.2 
Vital Signs 
Vital signs will be summarized using summary statistics and change from baseline.  The 
proportion of patients experiencing clinically significant changes relative to baseline will 
be reported if appropriate. 
4.2.3.3 
ECGs 
A shift table for the qualitative ECG assessments will be produced, summarizing the 
Baseline and worst post-baseline results. 
4.2.3.4 
Medical History 
Medical history data collected in the electronic-CRF (eCRF) from OLE Day 1 will be 
summarized using summary statistics, reporting the proportion of patients with at least 
one medical condition and the total number of medical conditions.  The medical 
conditions will then be split out by type. 
4.2.3.5 
Concomitant Medications 
Concomitant medications include any medication being used at any time from first dose 
of OLE study drug through to 7 days after last dose of OLE study drug.  The data will be 
summarized, and report the total number of patients taking at least one medication, and 
total number of medications.  Summaries will also be split by medication class and 
preferred medication.  Medication terms will be mapped and reported using the WHO 
drug dictionary. 
4.2.4 
Open-Label Extension Timeframe 
For the open-label extension population, the safety reporting timeframe is defined to 
capture safety information within the OLE treatment period only.  It begins at first dose of 
study drug in Study GA28951 Part 1 (OLE).  The end of the time-frame coincides with 
the last patient's last visit, this includes safety follow-up in Study GA28951 Part 1 (OLE). 
All outputs focus only on safety events after first dose in Study GA28951; these can be 
handled by flagging events that arise during the OLE treatment period in a manner 
similar to the identification of treatment-emergent AEs. 
4.3 
INTERIM ANALYSES  
There are no planned interim analyses for study GA28951. 


 
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4.4 
CHANGES TO PROTOCOL-PLANNED ANALYSES  
The incidence of ATAs to etrolizumab was extensively evaluated in the Ulcerative Colitis 
and Crohn’s Disease within the phase 3 program where, no obvious impact on injection 
site reactions or other relevant safety parameters such as hypersensitivity was found.  
Following this evaluation ATAs has been de-prioritised from a safety objective and 
outcome measure in GA28951 to an exploratory objective and outcome measure. 
5. 
SUPPORTING DOCUMENTATION 
This section is not applicable, since there is no additional supporting document. 
6. 
REFERENCES 
Not Applicable. 


Signature Page for Statistical Analysis Plan - GA28951 - Published
System identifier: RIM-CLIN-452483
Approval Task
Scientific content approver
27-Sep-2022 09:14:10 GMT+0000