Clinical trial NCT02165215
Conditions: Colitis, Ulcerative
Sponsor: Hoffmann-La Roche
Start date: 2014-08-12; Completion date: 2020-04-06
Enrollment: 359 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase III, randomized, double-blind, parallel-grouped, placebo-controlled, multicenter study will investigate the efficacy and safety of etrolizumab in maintenance of remission in participants with moderately to severely active UC who are naive to TNF inhibitors and refractory to or intolerant of prior immunosuppressant and/or corticosteroid treatment.

Detailed description:

Arms: arm 1: All participants will receive treatment with open-label etrolizumab 105 milligrams (mg) subcutaneous (SC) injection once every 4 weeks (Q4W) up to Week 10. arm 2: Participants who achieved a clinical response at Week 10 during the induction phase and randomized to this arm for the double-blind maintenance phase will receive etrolizumab 105 mg SC injection Q4W from Week 12 up to Week 62. arm 3: Participants who achieved a clinical response at Week 10 during the induction phase and randomized to this arm for the double-blind maintenance phase will receive placebo (matched to etrolizumab) SC injection Q4W from Week 12 up to Week 62.
Interventions: intervention 1: Etrolizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive 105 mg etrolizumab SC injection Q4W. intervention 2: Participants will receive placebo (matched to etrolizumab) SC injection Q4W.

Protocol documents:
Prot_002.pdf: 
 
Official Title: 
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 
NCT Number: 
NCT02165215 
Document Date: 
Protocol Version 7: 27-Aug-2018 
 
 


Clinical Study Report: etrolizumab  - F. Hoffmann-La Roche Ltd
Protocol GA29102     Report Number 1099518
2002
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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 GA29102, Version 7
PROTOCOL
TITLE:
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
PROTOCOL NUMBER:
GA29102
VERSION NUMBER:
7
EUDRACT NUMBER:
2013-004280-31
IND NUMBER:
100366
TEST PRODUCT:
Etrolizumab (PRO145223, RO5490261)
MEDICAL MONITOR:
, M.D., M.S.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  20 December 2013
DATES AMENDED:
Version 2:  3 April 2014
Version 3:  8 July 2014
Version 4:  22 August 2014
Version 5:  28 August 2015
Version 6:  24 August 2017
Version 7:  See electronic date stamp below.
 
27-Aug-2018 07:34:08
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Clinical Study Report: etrolizumab  - F. Hoffmann-La Roche Ltd
Protocol GA29102     Report Number 1099518
2003
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2/Protocol GA29102, Version 7
PROTOCOL AMENDMENT, VERSION 7:
RATIONALE
Protocol GA29102 has primarily been amended primarily to reflect changes in efficacy 
endpoints.  The endpoint changes will not impact study conduct at the site level. The 
changes made to the protocol are as follows:

The primary efficacy endpoint has been changed to remission at Week 62 for 
patients who achieve clinical response (rather than remission) at Week 10.  This
change has been made to align with clinical practice standards whereby patients 
who experience a clinical response during treatment induction continue on treatment 
and are assessed for remission at a later time point (Sections 2.1, 3.4.1, 6.1, and 
6.4.1, Figure 1 and Figure 3).

To assess the onset of action of etrolizumab, a secondary efficacy endpoint of 
change in Mayo Clinic Score (MCS) rectal bleeding and stool frequency subscores 
from baseline to Week 6 has been added (Sections 2.1, 3.4.1, and 6.4.2).

Secondary and exploratory efficacy endpoints have been amended to align with the 
revision of the primary efficacy endpoint (Sections 2.1, 3.4.1 and 6.4.2).

Histologic remission, defined as a Nancy histological index of 1, has been added 
as a secondary efficacy outcome measure. The definition is based on consensus 
guidelines recommending that histologic remission should be defined by the 
absence of neutrophils in the crypts and lamina propria (Section 2.1, 3.4.1, 6.4.2 
Appendix 12 and Table 1).

Janus kinase inhibitors have been added to the list of rescue therapies prohibited at 
any time during the study (Sections 3.1.1.2, 4.3.2.2, and 4.4.2).

Exclusion criteria have been amended to include any treatment with tofacitinib 
during screening as this drug has been approved for use in the United States and 
European Union and is no longer an investigational product (Section 4.1.2).

The exclusion criterion related to eligibility following receipt of investigational 
treatments has been modified to account for current molecules in development for 
the treatment of inflammatory bowel disease.  The allowable time period after 
treatment has been reduced to 5 half-lives of the investigational product or 28 days 
after the last dose, (whichever is greater) prior to Day 1 of the study (Section 4.1.2).

Derivation of the MCS endoscopic subscore at post-baseline timepoints has been 
amended to be consistent with emerging normative standards of endoscopic 
assessment in clinical trials (Sandborn et al. 2017).  The sigmoid colon MCS 
endoscopic subscore will be used (rather than the score from the worst affected 
segment, i.e., rectum, sigmoid colon, or descending colon) if the baseline sigmoid 
colon MCS endoscopic subscore is 23. The sigmoid colon MCS endoscopic 
subscore is considered to be more reliable in assessing earlier treatment response 
(Section 4.5.1.4 and Appendix 4).


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2004
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
Histologic activity on colon biopsies will be measured using the Nancy histological 
index instead of the Geboes scale.  The Geboes scale was designed to characterize 
all types of mucosal inflammation related to ulcerative colitis but was not designed 
to easily compare differences in histologic activity over time in the context of a 
clinical trial.  On the other hand, the Nancy histological index was developed and 
validated to capture meaningful changes in key histologic features of ulcerative 
colitis and can be easily applied in a clinical trial setting (Sections 4.5.1.5 and 
Appendix 12).

Procedures for adverse event reporting have been updated to clarify that adverse 
event reports will not be derived from patient-reported outcome (PRO) data and 
safety analyses will not be performed using PRO data.  Sites are not expected to 
review the PRO data for adverse events (Section 5.3.5.12).

Language regarding local injection-site reactions has been clarified in Table 5, 
"Guidelines for Managing Specific Adverse Events" (Section 5.1.5).

Information regarding the reporting of adverse events related to medical device 
complaints in individuals other than the study patient is covered in Section 4.3.6.  
Hence, Section 5.3.5.13 has been removed to eliminate redundancy and to ensure 
consistency with current standard protocol language.

Text differentiating immunosuppressant use for patients recruited from U.S. and 
Canadian sites, which had been eliminated in Version 5 but inadvertently retained in 
the Synopsis, has been removed.
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. 


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Protocol GA29102     Report Number 1099518
2005
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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 26
1.1
Background on Ulcerative Colitis........................................... 26
1.2
Background on Etrolizumab................................................... 27
1.3
Study Rationale and Benefit-Risk Assessment...................... 29
2.
OBJECTIVES.............................................................................................. 30
2.1
Efficacy Objectives ................................................................ 30
2.2
Safety Objectives................................................................... 33
2.3
Pharmacokinetic Objectives .................................................. 33
2.4
Exploratory Pharmacodynamic and Diagnostic 
Objectives.............................................................................. 33
3.
STUDY DESIGN......................................................................................... 34
3.1
Description of Study .............................................................. 34
3.1.1
Overview of Study Design ..................................................... 34
3.1.1.1
Definition of Clinical Relapse................................................. 37
3.1.1.2
Rescue Therapy .................................................................... 37
3.1.1.3
Number of Patients................................................................ 40
3.1.2
Data Monitoring Committee................................................... 40
3.2
End of Study and Length of Study......................................... 40
3.3
Rationale for Study Design.................................................... 41
3.3.1
Rationale for Test Product Dosage........................................ 41
3.3.2
Rationale for Patient Population ............................................ 43
3.3.3
Rationale for Control Group................................................... 43
3.3.4
Rationale for Biomarker Assessments................................... 43
3.4
Outcome Measures ............................................................... 44
3.4.1
Efficacy Outcome Measures.................................................. 44
3.4.2
Safety Outcome Measures .................................................... 45
3.4.3
Pharmacokinetic Outcome Measures.................................... 46
3.4.4
Exploratory Biomarker Outcome Measures........................... 46


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4.
MATERIALS AND METHODS .................................................................... 46
4.1
Patients.................................................................................. 46
4.1.1
Inclusion Criteria.................................................................... 46
4.1.2
Exclusion Criteria................................................................... 49
4.2
Method of Treatment Assignment and Blinding..................... 52
4.3
Study Treatments .................................................................. 55
4.3.1
Formulation, Packaging, and Handling.................................. 56
4.3.1.1
Etrolizumab and Placebo....................................................... 56
4.3.1.2
Concomitant Background Treatment for 
Ulcerative Colitis.................................................................... 57
4.3.2
Dosage, Administration, and Compliance.............................. 57
4.3.2.1
Etrolizumab and Placebo....................................................... 57
4.3.2.2
Concomitant Background Treatment and Rescue 
Therapy ................................................................................. 59
4.3.3
Investigational Medicinal Product Accountability ................... 61
4.3.4
Assessment of Compliance ................................................... 62
4.3.5
Destruction of the Investigational Medicinal 
Product .................................................................................. 63
4.3.6
Reporting of Prefilled Syringe Complaints/Events ................. 63
4.4
Concomitant Therapy ............................................................ 64
4.4.1
Permitted Therapy................................................................. 64
4.4.2
Prohibited Therapy ................................................................ 64
4.4.3
Definition of Clinical Relapse................................................. 64
4.5
Study Assessments ............................................................... 65
4.5.1
Description of Study Assessments ........................................ 65
4.5.1.1
Medical History and Demographic Data ................................ 65
4.5.1.2
Physical Examinations........................................................... 65
4.5.1.3
Vital Signs.............................................................................. 65
4.5.1.4
Ulcerative Colitis Disease Activity Assessments ................... 65
4.5.1.5
Laboratory Assessments ....................................................... 69
4.5.1.6
Chest X-Ray .......................................................................... 72
4.5.1.7
Electrocardiograms................................................................ 72
4.5.1.8
Patient-Reported Outcomes .................................................. 73
4.5.1.9
Medication Use and Compliance........................................... 74


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4.5.1.10
Samples for Roche Clinical Repository.................................. 74
4.5.2
Timing of Study Assessments ............................................... 77
4.5.2.1
Screening and Pretreatment Assessments............................ 77
4.5.2.2
Assessments during Treatment............................................. 80
4.5.2.3
Assessments at Study Completion/Early 
Withdrawal from Treatment Visit............................................ 81
4.5.2.4
Safety Follow-Up Assessments............................................. 85
4.5.2.5
Assessments at Unscheduled Visits...................................... 85
4.6
Patient, Study, and Site Discontinuation................................ 86
4.6.1
Patient Discontinuation.......................................................... 86
4.6.1.1
Discontinuation from Study Drug........................................... 86
4.6.1.2
Withdrawal from Study........................................................... 87
4.6.2
Study and Site Discontinuation.............................................. 87
5.
ASSESSMENT OF SAFETY....................................................................... 87
5.1
Safety Plan ............................................................................ 87
5.1.1
Potential Risks for Etrolizumab.............................................. 88
5.1.2
Progressive Multifocal Leukoencephalopathy........................ 88
5.1.2.1
Screening and Patient Selection............................................ 88
5.1.2.2
Monitoring and Management................................................. 89
5.1.3
Monitoring for Other Serious Infections ................................. 90
5.1.4
Monitoring for Hypersensitivity Reactions.............................. 90
5.1.5
Management of Specific Adverse Events .............................. 91
5.2
Safety Parameters and Definitions ........................................ 95
5.2.1
Adverse Events ..................................................................... 95
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 95
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 96
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 97
5.3.1
Adverse Event Reporting Period ........................................... 97
5.3.2
Eliciting Adverse Event Information....................................... 97
5.3.3
Assessment of Severity of Adverse Events ........................... 98
5.3.4
Assessment of Causality of Adverse Events ......................... 98


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5.3.5
Procedures for Recording Adverse Events............................ 99
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 99
5.3.5.2
Adverse Events Occurring Secondary to Other 
Events.................................................................................. 100
5.3.5.3
Persistent or Recurrent Adverse Events.............................. 100
5.3.5.4
Abnormal Laboratory Values ............................................... 101
5.3.5.5
Abnormal Vital Sign Values ................................................. 101
5.3.5.6
Abnormal Liver Function Tests............................................ 102
5.3.5.7
Deaths ................................................................................. 102
5.3.5.8
Preexisting Medical Conditions............................................ 103
5.3.5.9
Lack of Efficacy or Worsening of Ulcerative 
Colitis................................................................................... 103
5.3.5.10
Hospitalization or Prolonged Hospitalization........................ 103
5.3.5.11
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 104
5.3.5.12
Patient-Reported Outcome Data ......................................... 104
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 104
5.4.1
Emergency Medical Contacts.............................................. 105
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 105
5.4.3
Reporting Requirements for Pregnancies............................ 106
5.4.3.1
Pregnancies in Female Patients.......................................... 106
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 106
5.4.3.3
Abortions ............................................................................. 107
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 107
5.4.4
Reporting Requirements for Medical Device 
Complaints........................................................................... 107
5.5
Follow-Up of Patients after Adverse Events ........................ 107
5.5.1
Investigator Follow-Up......................................................... 107
5.5.2
Sponsor Follow-Up .............................................................. 107
5.6
Post-Study Adverse Events................................................. 108
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 108


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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 109
6.1
Determination of Sample Size ............................................. 109
6.2
Summaries of Conduct of Study.......................................... 110
6.3
Summaries of Treatment Group Comparability ................... 110
6.4
Efficacy Analyses ................................................................ 110
6.4.1
Primary Efficacy Endpoint.................................................... 111
6.4.2
Secondary Efficacy Endpoints............................................. 111
6.4.3
Exploratory Efficacy Endpoints............................................ 112
6.5
Safety Analyses................................................................... 113
6.5.1
Adverse Events ................................................................... 113
6.5.2
Laboratory Tests.................................................................. 114
6.6
Pharmacokinetic, Pharmacodynamic, and 
Biomarker Analyses............................................................. 114
7.
DATA COLLECTION AND MANAGEMENT ............................................. 114
7.1
Data Quality Assurance....................................................... 114
7.2
Electronic Case Report Forms............................................. 114
7.3
Electronic Patient-Reported Outcome Data......................... 115
7.4
Source Data Documentation................................................ 115
7.5
Use of Computerized Systems ............................................ 116
7.6
Retention of Records........................................................... 116
8.
ETHICAL CONSIDERATIONS.................................................................. 116
8.1
Compliance with Laws and Regulations .............................. 116
8.2
Informed Consent................................................................ 117
8.3
Institutional Review Board or Ethics Committee.................. 118
8.4
Confidentiality...................................................................... 118
8.5
Financial Disclosure ............................................................ 119
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 119
9.1
Study Documentation .......................................................... 119
9.2
Protocol Deviations.............................................................. 119
9.3
Site Inspections ................................................................... 119
9.4
Administrative Structure....................................................... 120


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9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 120
9.6
Protocol Amendments ......................................................... 121
10. REFERENCES ......................................................................................... 122




Clinical Study Report: etrolizumab  - F. Hoffmann-La Roche Ltd
Protocol GA29102     Report Number 1099518
2012
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11/Protocol GA29102, Version 7
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
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 
PROTOCOL NUMBER:
GA29102
VERSION NUMBER:
7
EUDRACT NUMBER:
2013-004280-31
IND NUMBER:
100366
TEST PRODUCT:
Etrolizumab (PRO145223, RO5490261)
MEDICAL MONITOR:
, M.D., M.S.
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.


Clinical Study Report: etrolizumab  - F. Hoffmann-La Roche Ltd
Protocol GA29102     Report Number 1099518
2013
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PROTOCOL SYNOPSIS
TITLE:
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
PROTOCOL NUMBER:
GA29102
VERSION NUMBER:
7
EUDRACT NUMBER:
2013-004280-31
IND NUMBER:
100366
TEST PRODUCT:
Etrolizumab (PRO145223, RO5490261)
PHASE:
III
INDICATION:
Ulcerative colitis
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Efficacy Objectives
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of etrolizumab (105 mg subcutaneous [SC] every 4 weeks [Q4W]) 
compared with placebo remission at Week 62 among patients with a clinical response at 
Week 10, as determined by the Mayo Clinic Score (MCS)
The secondary efficacy objectives for this study are as follows:

To evaluate maintenance of clinical remission at Week 62 for patients in clinical remission 
at Week 10

To evaluate clinical remission at Week 62

To evaluate remission at Week 62 among patients in remission at Week 10

To evaluate improvement in endoscopic appearance of the mucosa at Week 62

To evaluate endoscopic remission at Week 62

To evaluate histologic remission at Week 62

To evaluate onset of action, defined as change from baseline in rectal bleed subscore at 
Week 6

To evaluate onset of action, defined as change from baseline in stool frequency subscore at 
Week 6

To evaluate corticosteroid-free clinical remission at Week 62 (off corticosteroids for at least 
24 weeks prior to Week 62) in patients who were receiving corticosteroids at baseline

To evaluate corticosteroid-free remission at Week 62 (off corticosteroids for at least 
24 weeks prior to Week 62) in patients who were receiving corticosteroids at baseline


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
To evaluate change from baseline to Week 62 in UC bowel movement signs and 
symptoms, as assessed by the Ulcerative Colitis Patient-Reported Outcome Signs and 
Symptoms (UC-PRO/SS) measure

To evaluate change from baseline to Week 62 in UC abdominal symptoms, as assessed by 
the UC-PRO/SS measure

To evaluate change from baseline to Week 62 in patient-reported health-related QOL, as 
assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ)
The exploratory efficacy objectives for this study are as follows:

To evaluate clinical response at Week 62 among patients with a clinical response at 
Week 10 

To evaluate remission achieved at Week 62 among patients in clinical remission at 
Week 10

To evaluate corticosteroid-free clinical remission at Week 62 (off corticosteroids for at least 
12 weeks prior to Week 62) in patients who were receiving corticosteroids at baseline

To evaluate change in histologic disease activity from baseline to Week 10 and Week 62

To evaluate improvement in histologic and/or endoscopic disease activity

To evaluate change in health utilities, as assessed by the EuroQoL Five-Dimension 
Questionnaire (EQ-5D), from Week 10 to Week 62

To evaluate improvement in endoscopic appearance of mucosa at Week 10

To evaluate endoscopic remission at Week 10

To evaluate the frequency and duration of hospitalizations from Week 10 to Week 62

To evaluate response, remission, and corticosteroid-free endpoints, as determined by the 
mMCS
Safety Objectives
The safety objectives for this study are as follows:

To evaluate the overall safety and tolerability of etrolizumab over a period of 62 weeks

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)
Pharmacokinetic Objectives
The pharmacokinetic (PK) assessment will be performed in all patients during the 
Induction Phase and in all patients who were randomized into the Maintenance Phase.
The PK objectives for this study are as follows:

To evaluate etrolizumab serum concentration at the time of primary endpoint evaluation 
(Week 62) and predose concentration at the steady state during the maintenance 
dosing period

To evaluate the interindividual variability and potential covariate effects on etrolizumab 
serum exposure
Exploratory Pharmacodynamic and Diagnostic Objectives
The exploratory pharmacodynamics (PD) and diagnostic objectives for this study are as follows:

To evaluate the relationship between baseline colonic mucosal biomarkers and/or 
peripheral blood and response to study drug, including, but not limited to, the E integrin

To evaluate the levels of biomarkers in colonic tissue and/or peripheral blood at baseline 
and during the treatment period, including, but not limited to, the E integrin


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
To evaluate the PD effects on biomarkers in colonic tissue and/or peripheral blood following 
study treatment or placebo

To evaluate biomarkers in stool at baseline and during the treatment period through 
assessments that may include, but are not limited to, analyses of the microbiota and 
bacterial cultures
Study Design
Description of Study
This is a multicenter, Phase III, randomized, double-blind, parallel-group study to evaluate the 
safety, efficacy, and tolerability of etrolizumab (105 mg SC Q4W) compared with placebo in the 
treatment of UC.  Safety and efficacy of continued etrolizumab treatment will be evaluated in 
patients achieving a clinical response after 10 weeks.
Patients enrolled in this study may be eligible to participate in an open-label extension and 
safety monitoring (OLE-SM) study (GA28951), which consists of two parts: Part 1 (designated 
OLE [open-label extension]) and Part 2 (designated SM [safety monitoring]).
Disease severity will be measured using the MCS, which is the current outcome measure 
accepted by regulatory authorities for drug development in UC.  The target population is 
patients with moderately to severely active UC (defined as MCS 612, endoscopy subscore of 
2 as determined by the central reading procedure described in the protocol, a rectal bleeding 
subscore 1, and a stool frequency subscore 1) and involvement that extends a minimum of 
20 cm from the anal verge.
All patients are to be naive to tumor necrosis factor (TNF) inhibitors.
Patients must have had an inadequate response, loss of response, or intolerance to prior 
immunosuppressant and/or corticosteroid treatment.
Patients who are on background immunosuppressant therapy (6-MP, AZA, MTX) may be 
enrolled if they have received a stable dose for at least 8 weeks prior to Day 1.  Such patients 
should continue on stable doses of their background immunosuppressant therapy during the 
study unless dose reduction or discontinuation is required due to toxicity.
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 remains at the discretion of the investigator.
Patients on oral corticosteroid therapy (prednisone at a stable dose of 30 mg, or equivalent) 
may be enrolled according to the following criteria:

If corticosteroid therapy is ongoing or has recently been initiated, the dose has to be stable 
for at least 4 weeks immediately prior to Day 1

If corticosteroids are being tapered, the dose has to be stable for at least 2 weeks 
immediately prior to Day 1
Such patients should continue stable doses of their background corticosteroid until Week 10, 
at which point a corticosteroid taper will be initiated.
Initiation of corticosteroid or an increase in corticosteroid dose above the patients’ entry dose 
(up to a maximum of 30 mg/day prednisone [or equivalent]) will not be permitted during 
screening.  Use of budesonide will be allowed at stable doses (9 mg) provided that the dose 
has been stable for 4 weeks prior to Day 1.  Oral 5-ASA treatment and probiotics for the 
treatment of UC may be continued at a stable dose as long as the dose(s) had been stable for 
4 weeks and 2 weeks, respectively, prior to Day 1.  Certain concomitant treatments are 
prohibited (see the protocol for list of all prohibited concomitant treatments).
A total of approximately 350 patients will be recruited (see the protocol) from approximately 
125 sites.  The study will be divided into:

Screening period of up to 35 days

Open-label etrolizumab treatment period of 10 weeks (Induction Phase)

Double-blind treatment period of 52 weeks (Maintenance Phase)

Safety follow-up period of 12 weeks.


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All patients entering the study will receive induction treatment with open-label etrolizumab 
(105 mg SC Q4W) for 10 weeks.  Eligibility for entry into the Maintenance Phase will be 
determined between Weeks 10 and 12.  Patients who achieved a clinical response at Week 10 
(see the protocol for definition of clinical response) will be randomized in a 1:1 ratio by Week 12 
into the Maintenance Phase and will receive either etrolizumab (105 mg SC Q4W) or placebo 
(n≈105 for each arm).  Randomization will be stratified by their remission status at Week 10, 
concomitant treatment with corticosteroids (including budesonide) at baseline, concomitant 
treatment with immunosuppressants after Week 10, and disease activity measured during 
screening (MCS 9/MCS 10).
Patients not achieving clinical response at Week 10 and patients completing the Maintenance 
Phase at Week 62 should enroll in Part 1 (OLE) of Study GA28951, if eligible, where they will 
receive open-label etrolizumab.  If they do not enroll in Part 1 (OLE) of Study GA28951, they 
will enter the 12-week safety follow-up period of this study and then be requested to enroll in 
Part 2 (SM) of Study GA28951 for 92 weeks of extended for progressive multifocal 
leukoencephalopathy (PML) monitoring.
Number of Patients
Approximately 350 patients are to be enrolled for this study.  Following 10 weeks of open-label 
induction with etrolizumab, it is estimated that approximately 60% of patients will achieve clinical 
response, which will provide approximately 105 patients in each treatment arm for the 
Maintenance Phase.  Additional patients may be enrolled in the Induction Phase if needed to 
meet sample size requirements for the Maintenance Phase.
Target Population
Patients must meet the following criteria for study entry:

Able and willing to provide written informed consent

1880 years of age, inclusive

Diagnosis of UC established at least 3 months prior to Day 1 by clinical and endoscopic
evidence.  This diagnosis should be corroborated by histopathology conducted at any time
prior to screening and documented by a histopathology report.  (Note that histopathology
may be performed at screening if no prior report is readily available.)

Moderately to severely active UC as determined by an MCS of 612 with an endoscopic
subscore 2 as determined by the central reading procedure, a rectal bleeding subscore 1,
and a stool frequency subscore 1 during the screening period (prior to Day 1)

Evidence of UC extending a minimum of 20 cm from the anal verge as determined by
baseline endoscopy (flexible sigmoidoscopy or colonoscopy) performed during screening,
416 days prior to Day 1.  See protocol for additional information regarding the time
window.

Naive to treatment with TNF inhibitors

Patients must have had an inadequate response, loss of response, or intolerance to prior
immunosuppressant and/or corticosteroid treatment.
Inadequate response to, loss of response to, or intolerance to prior immunosuppressant
treatment is defined as one or more of the following:
Persistent signs and symptoms of active disease despite a history of at least one 
12-week regimen of oral AZA (1.5 mg/kg) or 6-MP (0.75 mg/kg) and/or
MTX (15 mg/week) within the previous 5 years
Persistent signs and symptoms of active disease despite a 6-TG level of 
230 pmol/8108 RBCs during at least one 12-week regimen of oral AZA or 6-MP at a 
stable or increasing dose within the previous 5 years
History of intolerance to AZA, 6-MP, or MTX (including, but not limited to,
nausea/vomiting, abdominal pain, pancreatitis, LFT abnormalities, lymphopenia, TPMT 
genetic mutation, infection) within the previous 5 years


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Inadequate response, loss of response, or intolerance to corticosteroid treatment is defined 
as one or more of the following: 
Steroid refractory:  persistent symptoms of active disease despite treatment with at 
least one 4-week induction regimen that included a dose of 30 mg prednisone (oral) 
daily (or equivalent) for at least 2 weeks or intravenously for at least 1 week within the 
previous 5 years
Steroid dependent:  two failed attempts to taper steroids below a dose equivalent to 
10 mg prednisone (oral) daily
Steroid intolerant:  history of intolerance to corticosteroids (including, but not limited to,
Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, infection) 
within the previous 5 years

Any ongoing UC therapy must be at stable doses:
May be receiving oral 5-ASA compounds provided that the dose has been stable for 
4 weeks immediately prior to Day 1
May be receiving oral corticosteroid therapy (prednisone at a stable dose of 30 mg a 
day, or equivalent steroid).
If corticosteroid therapy is ongoing or has recently been initiated, the dose has to 
be stable for at least 4 weeks immediately prior to Day 1.  If corticosteroids are 
being tapered, the dose has to be stable for at least 2 weeks immediately prior to 
Day 1.
May be receiving budesonide therapy at a stable dose of up to 9 mg a day for 
4 weeks prior to Day 1
May be receiving probiotics (e.g., Culturelle, Saccharomyces boulardii), provided 
that the dose has been stable for 2 weeks immediately prior to Day 1
May be receiving AZA, 6-MP, or MTX, provided that the dose has been stable for 
8 weeks immediately prior to Day 1

For women who are not postmenopausal (at least 12 months of nontherapy-induced 
amenorrhea) or surgically sterile (e.g., 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.

Must have received a colonoscopy within the past year or be willing to undergo a 
colonoscopy in lieu of a flexible sigmoidoscopy at screening.  This colonoscopy must:
Confirm disease extent (defined as 1) left-sided colitis [up to the splenic flexure], 
2) extensive colitis [beyond the splenic flexure but not involving the entire colon], and 
3) pancolitis; see the protocol) 
Include removal of any adenomatous polyps 
Document evidence of surveillance for dysplasia for all patients with left-sided colitis 
of 12 years’ duration and total/extensive colitis of 8 years duration 


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Patients who meet any of the following criteria will be excluded from study entry:
Exclusion Criteria Related to Inflammatory Bowel Disease

Prior extensive colonic resection, subtotal or total colectomy, or planned surgery for UC

Past or present ileostomy or colostomy

Diagnosis of indeterminate colitis 

Suspicion of ischemic colitis, radiation colitis, or microscopic colitis

Diagnosis of toxic megacolon within 12 months of initial screening visit 

Any diagnosis of Crohn’s disease

Past or present fistula or abdominal abscess

A history or current evidence of colonic mucosal dysplasia

Patients with any stricture (stenosis) of the colon

Patients with history or evidence of adenomatous colonic polyps that have not 
been removed
Exclusion Criteria Related to Prior or Concomitant Therapy

Any prior treatment with etrolizumab or other anti-integrin agents (including natalizumab, 
vedolizumab, and efalizumab)

Any prior treatment with anti-adhesion molecules (e.g., anti-MAdCAM-1)

Any prior treatment with rituximab

Any treatment with tofacitinib during screening

Use of intravenous (IV) steroids within 30 days prior to screening with the exception of a 
single administration of IV steroid

Use of agents that deplete B or T cells (e.g., alemtuzumab or visilizumab) within 12 months 
prior to Day 1, with the exception of AZA and 6-MP

Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF) within 4 weeks 
prior to Day 1

Chronic nonsteroidal anti-inflammatory drug (NSAID) use (Note: occasional use of NSAIDs 
and acetaminophen [e.g., headache, arthritis, myalgias, or menstrual cramps] and aspirin 
up to 325 mg daily is permitted.)

Patients who are currently using anticoagulants including, but not limited to, warfarin, 
heparin, enoxaparin, dabigatran, apixaban, rivaroxaban.  (Note that antiplatelet agents such 
as aspirin up to 325 mg daily or clopidogrel are permitted.)

Patients who have received treatment with corticosteroid enemas/suppositories and/or 
topical (rectal) 5-ASA preparations within 2 weeks prior to Day 1

Apheresis (i.e., Adacolumn apheresis) within 2 weeks prior to Day 1

Received any investigational treatment including investigational vaccines within 5 half-lives 
of the investigational product or 28 days after the last dose, whichever is greater, prior to 
Day 1

History of moderate or severe allergic or anaphylactic/anaphylactoid reactions to chimeric, 
human, or humanized antibodies, fusion proteins, or murine proteins or hypersensitivity to 
etrolizumab (active drug substance) or any of the excipients (L-histidine, L-arginine, 
succinic acid, polysorbate 20)

Patients administered tube feeding, defined formula diets, or parenteral 
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Exclusion Criteria Related to General Safety

Pregnant or lactating

Lack of peripheral venous access

Hospitalized (other than for elective reasons) during the screening period

Inability to comply with study protocol, in the opinion of the investigator

Significant uncontrolled comorbidity, such as cardiac (e.g., moderate to severe heart failure 
New York Heart Association [NYHA] Class III/IV), pulmonary, renal, hepatic, endocrine, or 
gastrointestinal disorders (excluding UC)

Neurological conditions or diseases that may interfere with monitoring for PML

History of demyelinating disease

Clinically significant abnormalities on screening neurologic examination (PML Objective 
Checklist)

Clinically significant abnormalities on the screening PML Subjective Checklist

History of alcohol, drug, or chemical abuse 6 months prior to screening

Conditions other than UC that could require treatment with 10 mg/day of prednisone 
(or equivalent) during the course of the study

History of cancer, including hematologic malignancy, solid tumors, and carcinoma in situ, 
within 5 years before screening with the following exceptions:
Local basal or squamous cell carcinoma of the skin that has been excised and is 
considered cured is not exclusionary.
A history of chronic myelogenous leukemia, hairy cell leukemia, melanoma, renal cell 
carcinoma, or Kaposi sarcoma is exclusionary, irrespective of the duration of time 
before screening.
History of a cervical smear indicating the presence of adenocarcinoma in situ (AIS), 
high-grade squamous intraepithelial lesions (HSIL), or cervical intraepithelial neoplasia 
(CIN) of Grade 1 is exclusionary, irrespective of the duration of time before screening.
Exclusion Criteria Related to Infection Risk

Congenital or acquired immune deficiency

Patients must undergo screening for HIV and test positive for preliminary and confirmatory 
tests

Positive hepatitis C virus (HCV) antibody test result, unless the patient (1) has undetectable 
HCV RNA levels for 6 months after completing a successful course of HCV anti-viral 
treatment and an undetectable HCV RNA at screening or (2) has a known history of HCV 
antibody positivity with a history of undetectable HCV RNA and undetectable HCV RNA at 
screening in the absence of history of HCV anti-viral treatment.

Patients must undergo screening for hepatitis B virus (HBV).  This includes testing for 
HBsAg (HBV surface antigen), anti-HBc total (HBV core antibody total), and HBV DNA 
(patients who test negative for these tests are eligible for this study):
Patients who test positive for surface antigen (HBsAg ) are not eligible for this study, 
regardless of the results of other hepatitis B tests.
Patients who test positive only for core antibody (anti-HBc ) must undergo further 
testing for hepatitis B DNA (HBV DNA test).
If the HBV DNA test is positive, the patient is not eligible for this study.
In the event the HBV DNA test cannot be performed, the patient is not eligible for 
this study. 
If the HBV DNA test is negative, the patient is eligible for this study).  These 
patients will undergo periodic monitoring for HBV DNA during the study.


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Evidence of or treatment for Clostridium difficile (as assessed by C. difficile toxin testing) 
within 60 days prior to Day 1 or other intestinal pathogens (as assessed by stool culture and 
ova and parasite evaluation) within 30 days prior to Day 1

Evidence of or treatment for clinically significant cytomegalovirus (CMV) colitis (based on 
the investigator’s judgment) within 60 days prior to Day 1.  Laboratory confirmation of CMV 
from colon biopsy sample is required during screening evaluation only if clinical suspicion is 
high and to determine the need for CMV treatment

History of active or latent treated tuberculosis (TB), regardless of treatment history
(see protocol)
Patients with a history of active or latent TB (based on a positive screening assay, 
either purified protein derivative [PPD] skin test or QuantiFERONTB Gold test), are 
not eligible for this study.
Patients with a chest X-ray (posteroanterior [PA] and lateral) within 3 months of Day 1 
suspicious for pulmonary TB are not eligible for this study.

History of recurrent opportunistic infections and/or history of severe disseminated viral
infections (e.g., herpes)

Any serious opportunistic infection within the last 6 months

Any current or recent signs or symptoms (within 4 weeks before screening and during 
screening) of infection, except for the following:
Minor infections (e.g., common cold) that have, in the investigator’s judgment, 
completely resolved prior to Day 1
Fungal infections of the nail beds
Oral or vaginal candidiasis that has resolved with or without treatment prior to Day 1

Any major episode of infection requiring treatment with IV antibiotics within 8 weeks prior to 
screening or oral antibiotics within 4 weeks prior to screening
Treatment with antibiotics as adjunctive therapy for UC in the absence of documented 
infection is not exclusionary.

Received a live attenuated vaccine within 4 weeks prior to Day 1

History of organ transplant
Exclusion Criteria Related to Laboratory Values (at Screening)

Serum creatinine 2 times upper limit of normal (ULN)

ALT or AST 3 ULN, or alkaline phosphatase 3 ULN, or total bilirubin 2.5 ULN 
(unconjugated hyperbilirubinemia that is associated with known Gilbert's syndrome is not an 
exclusion criterion)

Platelet count 100,000/L

Hemoglobin 8 g/dL

Absolute neutrophil count 1500/L

Absolute lymphocyte count 500/L
Length of Study
The total length of the treatment period will be 62 weeks. Patients who do not achieve a clinical 
response at Week 10, patients who have clinical relapse during the Maintenance Phase, 
patients who receive defined rescue treatment (see protocol), and patients who complete 
62 weeks of the study may be given the option of enrolling in Part 1 (OLE) of Study GA28951, 
where they will receive open-label etrolizumab treatment.  Those who do not enroll in Part 1 
(OLE) of Study GA28951 will continue to 12 weeks of safety follow-up in this study, and then be 
requested to enroll in Part 2 (SM) of Study GA28951 for 92 weeks of PML monitoring.
The total length of the study is expected to last from the first patient screened to either the last 
patient in last follow-up visit in this protocol or last patient enrolled into Study GA28951 
(OLE-SM), whichever is later.


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End of Study
The end of the study is defined as the last patient last safety follow-up visit in this protocol or 
last patient in this protocol enrolled into Study GA28951 (OLE-SM), whichever is later.
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:
Primary Outcome Measure

Remission at Week 62 among patients with a clinical response at Week 10, as determined 
by the MCS
Secondary Outcome Measures

Clinical remission at Week 62 among patients in clinical remission at Week 10

Clinical remission at Week 62

Remission at Week 62 among patients in remission at Week 10

Improvement in endoscopic appearance of the mucosa at Week 62

Endoscopic remission at Week 62

Histologic remission at Week 62

Change from baseline in rectal bleed subscore at Week 6

Change from baseline in stool frequency subscore at Week 6

Corticosteroid-free clinical remission at Week 62 (off corticosteroids for at least 24 weeks 
prior to Week 62) in patients who are receiving corticosteroids at baseline

Corticosteroid-free remission at Week 62 (off corticosteroids for at least 24 weeks prior to 
Week 62) in patients who are receiving corticosteroids at baseline

Change from baseline to Week 62 in UC bowel movement signs and symptoms as 
assessed by the UC-PRO/SS measure

Change from baseline to Week 62 in UC abdominal symptoms as assessed by the 
UC-PRO/SS measure

Change from baseline to Week 62 in patients’ health-related QOL as assessed by the 
overall score of the IBDQ
Exploratory Efficacy Outcome Measures 

Clinical response at Week 62 among patients with a clinical response at Week 10

Remission at Week 62 among patients in clinical remission at Week 10

Corticosteroid-free clinical remission at Week 62 (off corticosteroids for at least 12 weeks 
prior to Week 62) in patients who are receiving corticosteroids at baseline

Histologic disease activity change from baseline to Week 10 and Week 62

Improvement in histologic and/or endoscopic disease activity

Change in health utilities, as assessed by the EQ-5D, from baseline to Weeks 10 and 62

Improvement in endoscopic appearance of the mucosa at Week 10

Endoscopic remission at Week 10

Frequency and duration of hospitalizations from Week 10 to Week 62

Response, remission and corticosteroid-free endpoints as determined by the mMCS


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Safety Outcome Measures
The safety outcome measures for 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 study drug discontinuation

Incidence of laboratory abnormalities

Incidence of malignancies

Incidence of ATAs to etrolizumab

Incidence and severity of hypersensitivity reaction events
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:

Serum trough concentration at steady state during the dosing period from Week 12 to 
Week 62

Serum concentration at primary endpoint time (Week 62)
Exploratory Biomarker Outcome Measures
The exploratory biomarker outcome measures for this study are as follows:

Remission at Week 10 and maintenance of remission at Week 62 in patients according to 
baseline levels of colonic tissue biomarkers and/or peripheral blood, including, but not 
limited to, E integrin

Changes in levels of exploratory colonic tissue and/or peripheral blood biomarkers during 
the Induction and Maintenance Phases

Changes in stool biomarkers, which may include, but are not limited to, those in the 
microbiota and bacterial cultures, during the Induction and Maintenance Phases
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 Q4W.
Comparator
Placebo PFS:  etrolizumab SC matching placebo given in the amount of 0.7-mL solution will be 
administered by SC injection Q4W.
Non-Investigational Medicinal Products
Patients are to continue on their baseline dose of corticosteroid (including budesonide) to the 
end of the Induction Phase (Week 10).  Tapering of corticosteroid (including budesonide) is to 
be attempted during the Maintenance Phase.
All patients are to continue on their baseline dose of immunosuppressants (AZA, 6-MP, MTX) to 
the end of Induction Phase (Week 10), unless dose reduction or discontinuation is required due 
to toxicity.  
Probiotics and oral 5-ASA may be continued at a stable dose throughout the study.
Occasional use of NSAIDs and acetaminophen (e.g., headache, arthritis, myalgias, and 
menstrual cramps) and aspirin up to 325 mg daily are permitted throughout the study.
Antidiarrheals (e.g., loperamide, diphenoxylate with atropine) for control of chronic diarrhea are 
permitted throughout the study.


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Statistical Methods
Primary Analysis
The analysis of data from the 62-week treatment period will be performed when all data from 
this period are in the database and data have been cleaned and verified.
Whereas Sponsor personnel will be unblinded to treatment assignment to perform the primary 
Week 62 analyses, patients and study site personnel will remain blinded to individual treatment 
assignment during the Maintenance Phase until after the study is completed (after all patients 
have either completed the safety follow-up period or discontinued early from the study) and the 
database is locked.
Detailed specifications of the statistical methods will be described in the Statistical Analysis Plan.
Determination of Sample Size  
The study sample size was selected so that sufficient patients are enrolled to evaluate the 
primary endpoint in the Maintenance Phase.  Approximately 350 patients will be enrolled in the 
open-label Induction Phase. 
Under the assumption of clinical response at Week 10 of approximately 60% (based on the 
Phase II Week 10 response results for the TNF-naive subgroup), the planned size of 
350 patients in the open-label Induction Phase would provide approximately 210 patients 
randomized into the Maintenance Phase.  A sample size of approximately 105 patients per arm 
is required in the Maintenance Phase to achieve 90% power to detect a 25% absolute 
difference in remission rates between the etrolizumab and placebo arms, for a 2 test at the 
two-sided 5% significance level, under the assumption of a placebo true remission rate of 
30%45%.  If clinical response rates at Week 10 are lower than projected, the total enrollment 
in the open-label induction cohort may be increased to ensure that a sufficient number of 
Week-10 clinical responders are randomized into the Maintenance Phase.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
5-ASA 
5-aminosalicylate
6-MP
6-mercaptopurine
AIS
adenocarcinoma in situ
ATA
anti-therapeutic antibody
AZA
azathioprine
BCG 
bacille Calmette-Guérin 
CD
Crohn’s disease
CHO
Chinese hamster ovary
CIN
cervical intraepithelial neoplasia 
CMV
cytomegalovirus
CRO
Contract Research Organization
CRP
C-reactive protein
CSF
cerebrospinal fluid
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
ePRO 
electronic Patient-Reported Outcomes
EQ-5D
EuroQoL Five-Dimension Questionnaire
FDA
U.S. Food and Drug Administration
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCP
health care professional
HCV
hepatitis C virus
HIPAA
U.S. Health Insurance Portability and 
Accountability Act
HSIL
high-grade squamous intraepithelial lesions 
IBD
inflammatory bowel disease
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Council for Harmonisation
iDMC
independent Data Monitoring Committee
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IV 
intravenous


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Abbreviation
Definition
IxRS
interactive voice/Web-based response system 
JAK
Janus kinase 
JCV
John Cunningham virus
LD
loading dose
LFT
liver function test
MAb
monoclonal antibody
MAdCAM-Fc
mucosal addressin cell adhesion molecule 
fragment crystallizable region
MCS
Mayo Clinic Score
mMCS
modified Mayo Clinic Score
MMF
mycophenolate mofetil
MP
mercaptopurine
MRI
magnetic resonance imaging
MTX
methotrexate
NCI CTCAE
National Cancer Institute Common Terminology 
Criteria for Adverse Events
NSAID 
nonsteroidal anti-inflammatory drug 
OLE
open-label extension
OLE-SM
open-label extension and safety monitoring
PA
posteroanterior
PCR
polymerase chain reaction
PD
pharmacodynamic
PEG
polyethylene glycol
PFS
prefilled syringes 
PGA
Physician’s Global Assessment
PK
pharmacokinetic
pMCS
partial Mayo Clinic Score
PML
progressive multifocal leukoencephalopathy
PPD
purified protein derivative 
PRO
patient-reported outcome
Q4W
every 4 weeks
QOL
quality of life 
qPCR
quantitative polymerase chain reaction
RCR
Roche Clinical Repository
SAP
Statistical Analysis Plan
SC
subcutaneous
SM
safety monitoring


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Abbreviation
Definition
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse 
Reaction
TB
tuberculosis
TNF
tumor necrosis factor
TNF-
tumor necrosis factor-alpha
TNF-IR
inadequate response to anti-tumor necrosis factor
UC
ulcerative colitis
UC-PRO/SS
Ulcerative Colitis Patient-Reported Outcome 
Signs and Symptoms
ULN
upper limit of normal


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1.
BACKGROUND
1.1
BACKGROUND ON 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 health-related 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.
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.


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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, 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, hematologic, and cardiovascular systems), no effects were 
seen in embryo-fetal development, and there was no evidence of increased rates 
of infection.

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.


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1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Although there are therapeutic options including TNF inhibitors, a significant proportion of 
patients with UC will not experience a durable clinical benefit with those treatment 
options.  Furthermore, adverse events associated with TNF inhibitors include elevated 
rates of serious bacterial infection, including TB, and (more rarely) lymphoma and 
demyelination (Chang and Lichtenstein 2006).  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 who have 
chronic disease (Hanauer et al. 2002; Sandborn et al. 2005; Feagan et al. 2013).  As 
noted above, etrolizumab distinguishes itself from other anti-integrins on the basis of gut 
selectivity combined with a potential dual mechanism of action.  It binds E7 in addition 
to 47 and so regulates retention as well as trafficking leukocyte/lymphocyte 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 three doses in the multidose stage of the Phase I study.
A global, Phase II, multicenter study (Study ABS4986g; EUCALYPTUS) designed to 
determine the exposure-response relationship and to further characterize the safety and 
tolerability of etrolizumab in treatment of adult patients with moderately to severely active 
UC has been completed.  Patients were randomized in a 1:1:1 ratio to receive 100 mg 
etrolizumab SC (0.7 mL of 150 mg/mL solution via vial and syringe, with an intended 
nominal dose of 100 mg) at Weeks 0, 4, and 8 or 420 mg SC at Week 0 (loading dose 
[LD]) followed by 300 mg SC (three injections of 0.7 mL of 150 mg/mL solution via vial 
and syringe, with an intended nominal dose of 300 mg) at Weeks 2, 4, and 8 (40 patients 
per dose arm) versus matching placebo SC (40 patients per arm).  The primary objective 
of the study was to obtain evidence of clinical efficacy of etrolizumab as measured by 
induction of clinical remission (Mayo Clinic Score [MCS] 2 and no individual subscore 
1) at Week 10 (2 weeks after the final dose).
In EUCALYPTUS, etrolizumab showed clinically meaningful efficacy for both doses 
relative to placebo for the primary endpoint:  the proportion of patients in clinical 
remission at Week 10 was 20.5% in the 100-mg dose group and 10.3% in 
the 300-mgLD group versus 0% in the placebo group (p0.004 and p0.048, 
respectively).  In the TNF-naive subgroup, clinical remission at Week 10 was observed 
in 43.8% versus 0% of patients in the 100-mg etrolizumab versus placebo group, and 
in 25% of 300-mgLD group.


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In summary, favorable safety (see Section 1.2) and efficacy data were observed in the 
Phase II EUCALYPTUS study and in the OLE study (SPRUCE).  Overall, etrolizumab 
showed compelling efficacy compared with placebo and there were no clinically 
significant safety signals.  Additionally, etrolizumab distinguishes itself from vedolizumab 
by blocking E7 in addition to 47, which is involved in lymphocyte retention and may 
contribute to its efficacy and/or safety profile.  Etrolizumab is a gut-selective
anti-trafficking agent and does not bind to 41 (target for natalizumab), which regulates 
trafficking to both mucosal and non-mucosal tissues, including the CNS.  Although 
natalizumab has been associated with an increased risk of PML, no events of PML to 
date have been reported during 2-year PML extensive monitoring in the Phase II study, 
EUCALYPTUS, and OLE SPRUCE study.
Refer to the most recent Etrolizumab Investigator’s Brochure for additional details on 
clinical and nonclinical studies.
2.
OBJECTIVES
2.1
EFFICACY OBJECTIVES
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of etrolizumab (105 mg SC every 4 weeks [Q4W]) 
compared with placebo for remission at Week 62 among patients with a clinical 
response at Week 10, as determined by the MCS 
The secondary efficacy objectives for this study are as follows:

To evaluate maintenance of clinical remission at Week 62 for patients in clinical 
remission at Week 10

To evaluate clinical remission at Week 62

To evaluate remission at Week 62 among patients in remission at Week 10 

To evaluate improvement in endoscopic appearance of the mucosa at Week 62

To evaluate endoscopic remission at Week 62

To evaluate histologic remission at Week 62

To evaluate onset of action, defined as change from baseline in rectal bleed subscore 
at Week 6

To evaluate onset of action, defined as change from baseline in stool frequency 
subscore at Week 6  

To evaluate corticosteroid-free clinical remission at Week 62 (off corticosteroids for 
at least 24 weeks prior to Week 62) in patients who were receiving corticosteroids at 
baseline

To evaluate corticosteroid-free remission at Week 62 (off corticosteroids for at least 
24 weeks prior to Week 62) in patients who were receiving corticosteroids at 
baseline


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
To evaluate change from baseline to Week 62 in UC bowel movement signs and 
symptoms, as assessed by the Ulcerative Colitis Patient-Reported Outcome Signs 
and Symptoms (UC-PRO/SS) measure

To evaluate change from baseline to Week 62 in UC abdominal symptoms, as 
assessed by the UC-PRO/SS measure

To evaluate change from baseline to Week 62 in patient-reported health-related 
QOL, as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ)
The exploratory efficacy objectives for this study are as follows:

To evaluate clinical response at Week 62 among patients with a clinical response at 
Week 10 

To evaluate remission achieved at Week 62 among patients in clinical remission at 
Week 10

To evaluate corticosteroid-free clinical remission at Week 62 (off corticosteroids for 
at least 12 weeks prior to Week 62) in patients who were receiving corticosteroids at 
baseline

To evaluate change in histologic disease activity from baseline to Week 10 and 
Week 62

To evaluate improvement in histologic and/or endoscopic disease activity

To evaluate change in health utilities, as assessed by the EuroQoL Five-Dimension 
Questionnaire (EQ-5D), from Week 10 to Week 62

To evaluate improvement in endoscopic appearance of mucosa at Week 10

To evaluate endoscopic remission at Week 10

To evaluate the frequency and duration of hospitalizations from Week 10 to 
Week 62

To evaluate response, remission, and corticosteroid-free endpoints, as determined 
by the mMCS
The efficacy outcomes definitions are given in Table 1.


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Table 1
Efficacy Outcomes Definitions
Outcome Measure
Outcome Measure Definition
Mayo Clinic Score
MCS is a composite of 4 assessments, each rated from 03:  stool frequency, rectal bleeding, endoscopy, 
and physician’s global assessment
Partial MCS
pMCS is a composite of 3 assessments of the MCS, each rated from 03:  stool frequency, rectal 
bleeding, and physician’s global assessment
Modified MCS
mMCS is a composite of 3 assessments of the MCS, each rated from 03:  stool frequency, 
rectal bleeding, and endoscopy
Remission
MCS 2 with individual subscores 1 and a rectal bleeding subscore of 0
Maintained remission
Remission achieved at the start of the Maintenance Phase (Week 10) and maintained at the end of the 
Maintenance Phase (Week 62).
Clinical remission
MCS 2 with individual subscores 1
Maintained clinical remission
Clinical remission achieved at the start of the Maintenance Phase (Week 10) and maintained at the end 
of the Maintenance Phase (Week 62)
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
Corticosteroid-free clinical remission
Clinical remission with no corticosteroid use for 24 weeks prior to Week 62
Corticosteroid-free remission
Remission with no corticosteroid use for 24 weeks prior to Week 62
Improvement in endoscopic appearance of 
the mucosa
Endoscopic subscore 1
Endoscopic remission
Endoscopic subscore0
Histologic remission
NHI 1 a
MCS Mayo Clinic Score; mMCS modified Mayo Clinic Score; pMCS partial Mayo Clinic Score; NHI Nancy histological index.
a See Appendix 12


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2.2
SAFETY OBJECTIVES
The safety objectives for this study are as follows:

To evaluate the overall safety and tolerability of etrolizumab over a period of 
62 weeks

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
PHARMACOKINETIC OBJECTIVES
The pharmacokinetic (PK) assessment will be performed in all patients during the 
Induction Phase and in all patients who were randomized into the Maintenance Phase.
The PK objectives for this study are as follows:

To evaluate etrolizumab serum concentration at the time of primary endpoint 
evaluation (Week 62) and predose concentration at the steady state during the 
maintenance dosing period

To evaluate the interindividual variability and potential covariate effects on 
etrolizumab serum exposure
2.4
EXPLORATORY PHARMACODYNAMIC AND DIAGNOSTIC 
OBJECTIVES
The exploratory pharmacodynamics (PD) and diagnostic objectives for this study are as 
follows:

To evaluate the relationship between baseline colonic mucosal biomarkers and/or 
peripheral blood and response to study drug, including, but not limited to, the 
E integrin

To evaluate the levels of biomarkers in colonic tissue and/or peripheral blood at 
baseline and during the treatment period, including, but not limited to, the E 
integrin 

To evaluate the PD effects on biomarkers in colonic tissue and/or peripheral blood 
following study treatment or placebo

To evaluate biomarkers in stool at baseline and during the treatment period through
assessments that may include, but are not limited to, analyses of the microbiota and 
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3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
3.1.1
Overview of Study Design
This is a multicenter, Phase III, randomized, double-blind, parallel-group study to 
evaluate the safety, efficacy, and tolerability of etrolizumab (105 mg SC Q4W) compared 
with placebo in the treatment of UC.  Safety and efficacy of continued etrolizumab 
treatment will be evaluated in patients achieving a clinical response after 10 weeks.
Patients enrolled in this study may be eligible to participate in an open-label extension
and safety monitoring (OLE-SM) study (GA28951), which consists of two parts: Part 1 
(designated OLE [open-label extension]) and Part 2 (designated SM [safety 
monitoring]).
Disease severity will be measured using the MCS (Appendix 4), which is the current 
outcome measure accepted by regulatory authorities for drug development in UC.  The 
target population is patients with moderately to severely active UC (defined as 
MCS 612, endoscopy subscore of 2 as determined by the central reading procedure 
described in Section 4.5.1.4, a rectal bleeding subscore 1, and a stool frequency 
subscore 1) and involvement that extends a minimum of 20 cm from the anal verge.
All patients are to be naive to tumor necrosis factor (TNF) inhibitors.
Patients must have had an inadequate response, loss of response, or intolerance to 
prior immunosuppressant and/or corticosteroid treatment. 
Patients who are on background immunosuppressant therapy (6-MP, AZA, MTX) may 
be enrolled if they have received a stable dose for at least 8 weeks prior to Day 1.  
Such patients should continue on stable doses of their background immunosuppressant 
therapy during the study unless dose reduction or discontinuation is required due
to toxicity.
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 remains at 
the discretion of the investigator.


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Patients on oral corticosteroid therapy (prednisone at a stable dose of 30 mg, or 
equivalent) may be enrolled according to the following criteria:

If corticosteroid therapy is ongoing or has recently been initiated, the dose has to be
stable for at least 4 weeks immediately prior to Day 1

If corticosteroids are being tapered, the dose has to be stable for at least 2 weeks 
immediately prior to Day 1 
Such patients should continue stable doses of their background corticosteroid until 
Week 10, at which point a corticosteroid taper will be initiated.
Initiation of corticosteroid or an increase in corticosteroid dose above the patients’ entry 
dose (up to a maximum of 30 mg/day prednisone [or equivalent]) will not be permitted 
during screening.  Use of budesonide will be allowed at stable doses (9 mg) provided 
that the dose has been stable for 4 weeks prior to Day 1.  Oral 5-ASA treatment and 
probiotics for the treatment of UC may be continued at a stable dose as long as the 
dose(s) had been stable for 4 weeks and 2 weeks, respectively, prior to Day 1.  
Certain concomitant treatments are prohibited (see Section 4.1.2 for list of all prohibited 
concomitant treatments).
A total of approximately 350 patients will be recruited (see Figure 1) from approximately 
125 sites.  The study will be divided into:

Screening period of up to 35 days (for details see Section 4.5.2.1)

Open-label etrolizumab treatment period of 10 weeks (Induction Phase)

Double-blind treatment period of 52 weeks (Maintenance Phase)

Safety follow-up period of 12 weeks
All patients entering the study will receive induction treatment with open-label 
etrolizumab (105 mg SC Q4W) for 10 weeks.  Eligibility for entry into the Maintenance 
Phase will be determined between Weeks 10 and 12.  Patients who achieved a clinical 
response at Week 10 (see Table 1 for definition of clinical response) will be randomized 
in a 1:1 ratio by Week 12 into the Maintenance Phase and will receive either etrolizumab 
(105 mg SC Q4W) or placebo (n≈105 for each arm).  Randomization will be stratified by 
their remission status at Week 10, concomitant treatment with corticosteroids (including 
budesonide) at baseline, concomitant treatment with immunosuppressants after 
Week 10, and disease activity measured during screening (MCS 9/MCS 10).
Patients not achieving clinical response at Week 10 and patients completing the 
Maintenance Phase at Week 62 should enroll in Part 1 (OLE) of Study GA28951, if 
eligible, where they will receive open-label etrolizumab.  If they do not enroll in 
Part 1 (OLE) of Study GA28951, they will enter the 12-week safety follow-up period of 
this study and then will be requested to enroll in Part 2 (SM) of Study GA28951 for 
92 weeks of extended PML monitoring.


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Study Drug Administration
The first two doses of study medication will be administered via a prefilled syringe (PFS) 
by a health care professional (HCP) in the clinic.  The subsequent two doses will be 
self-administered by the patient or administered by his or her caregiver in the clinic and 
monitored by the HCP.  If deemed appropriate by the HCP, the remaining doses of study 
drug, starting at Week 16, will be self-administered by the patient or administered by his 
or her caregiver at home Q4W (action to be taken as a result of a hypersensitivity 
reaction is provided in Section 5.1.5).  The administration of the study medication at 
home by the patients or their caregivers will occur after their study assessments in the 
clinic setting.  If necessary, patients or their HCPs may choose to continue 
administration of study medication in the clinic.  The details of study medication 
administration are provided in Section 4.3.2.
Oral Corticosteroids during the Study
During the Induction Phase, patients are to maintain their stable, baseline corticosteroid 
dose.  Corticosteroids are to be tapered starting from Week 10 for patients entering the 
Maintenance Phase.  Patients receiving prednisone at a dose of 10 mg/day (or 
equivalent) are to have their dose reduced at a rate of 5 mg per week until a 10 mg/day 
dose is achieved.  Patients receiving prednisone at doses 10 mg/day (or equivalent), or 
once a 10 mg/day dose (or equivalent) is achieved by tapering, are to have their dose 
reduced at a rate of 2.5 mg/week until discontinuation.  Beginning at Week 10, patients 
receiving budesonide should taper their dose of 9 mg every day to 9 mg every other day 
for 2 weeks and then discontinue budesonide treatment.  For patients who cannot 
tolerate the corticosteroid taper without recurrence of clinical symptoms of either UC or 
steroid withdrawal, corticosteroid dose may be increased (up to the dose at study entry if 
required), but tapering must begin again within 2 weeks.
Immunosuppressants during the Study
Patients should continue stable doses of immunosuppressants throughout the 
study.
Patients should remain on their stable baseline doses of immunosuppressants (AZA, 
6-MP, MTX) throughout the study unless dose reduction or discontinuation is required 
because of a toxicity related to the medication.  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 remains at the discretion of the investigator.


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3.1.1.1
Definition of Clinical Relapse
Clinical relapse is defined as an:

Increase in partial Mayo Clinic Score (pMCS) 3 points compared with induction 
timepoint (Week 10) AND absolute pMCS 5 AND endoscopic subscore 2
If a patient meets criteria for clinical relapse during the Maintenance Phase of the study, 
he or she may withdraw from this study and enroll in Part 1 (OLE) of Study GA28951 to 
receive open-label etrolizumab treatment, if eligible.
3.1.1.2
Rescue Therapy
Rescue Therapy that Can Be Given with Study Medication for the Treatment 
of UC
During the Induction Phase (Prior to Week 10):
Patients are required to maintain stable doses of their concomitant medications 
(oral 5-ASA, corticosteroids, immunosuppressants) for UC.
In the Induction Phase, any patient who requires initiation of an immunosuppressant 
(AZA, 6-MP, or MTX), corticosteroid, or oral or topical 5-ASA, or who requires an
increase in dose over baseline levels for treatment of worsening disease symptoms 
should stay in the study until Week 10, at which time the patient can enroll in Part 1 
(OLE) of Study GA28951 to receive open-label etrolizumab, if eligible, or enter the 
12-week safety follow-up in this study and then enroll in Part 2 (SM) of Study GA28951
for extended PML monitoring.  These patients will be classified as non-responders at 
Week 10 and may not continue into the Maintenance Phase of the study.
During the Maintenance Phase:
Initiation or escalation of oral 5-ASA should be avoided but is permitted if deemed 
clinically necessary by the investigator.  Patients who initiate or escalate oral 5-ASA 
therapy may continue blinded treatment.
Use of topical or IV corticosteroids or topical 5-ASA is not desired as concomitant 
medication.  If these are used to treat clinical symptoms of UC, the patient may remain in 
the blinded study or may enroll in Part 1 (OLE) of Study GA28951, if eligible, based on 
the investigator’s discretion.  Patients who leave the treatment phase early to enroll in 
Part 1 (OLE) of Study GA28951 should complete the early withdrawal from treatment 
visit prior to enrollment.
Patients must begin the specified corticosteroid taper at Week 10 during the 
Maintenance Phase.  For patients who cannot tolerate the corticosteroid taper without 
recurrence of clinical symptoms of UC or symptoms of steroid withdrawal, corticosteroids 
may be increased (up to the baseline dose, only if required).  In such cases, the tapering 
regimen must be reinitiated within 2 weeks.  An increase in corticosteroid dose back to 
baseline is not considered rescue medication if it occurs during the corticosteroid taper.  
These patients should remain in the blinded study.


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Patients who were not receiving corticosteroids at baseline and patients who have 
completed the steroid taper who subsequently require oral corticosteroids at a dose 
greater than 10 mg for 5 days or longer for the treatment of worsening UC symptoms or 
steroid withdrawal may remain in the blinded study or may enroll in to Part 1 (OLE) of 
Study GA28951, if eligible, based on the investigator’s discretion.  Patients who leave 
the treatment phase early to enroll in Part 1 (OLE) of Study GA28951 should complete 
the early withdrawal from treatment visit prior to enrollment in Study GA28951.
Endoscopy to document disease activity for patients exiting the treatment period early 
for any reason is strongly recommended.
Immunosuppressants (AZA, 6-MP, or MTX):  Patients are to remain on their stable, 
baseline dose of immunosuppressant therapy throughout the study unless dose 
reduction or discontinuation is required due to toxicity.  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 remains at the discretion of the investigator.  
Patients who do initiate or escalate immunosuppressant therapy may remain in the 
blinded study or may be given the option to enroll in Part 1 (OLE) Study GA28951, if 
eligible, based on the investigator’s discretion.  Patients who leave the treatment phase 
early to enroll in Part 1 (OLE) Study GA28951 should complete the early withdrawal from 
treatment visit prior to enrollment in Study GA28951.
Endoscopy to document disease activity for patients exiting the treatment period early 
for any reason is strongly recommended.
Rescue Therapy that Cannot Be Given with Study Medication for the 
Treatment of UC
At ANY time during the conduct of the study, use of other immunosuppressive agents 
including, but not limited to, anti-integrins, T- or B-cell depleters (except AZA and 6-MP), 
TNF inhibitors (including TNF inhibitor biosimilars), anti-adhesion molecules, Janus 
kinase (JAK) inhibitors, cyclosporine, tacrolimus, or investigational agents are 
prohibited.  Patients who receive such therapies are not to receive further study 
treatment or open-label treatment and will be required to enter the 12-week safety 
follow-up period of this study (see Appendix 2).  These patients will also subsequently be 
requested to enroll in Part 2 (SM) of Study GA28951 protocol for 92 weeks of extended 
PML monitoring.
A complete list of study visits and assessments can be found in the Schedule of 
Assessments (see Appendix 1). 


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Figure 1
Study Schema
6-MP6-mercaptopurine; AZAazathioprine; dday; CS corticosteroid; MTXmethotrexate; OLEopen-label extension; 
OLE-SMopen-label extension and safety monitoring; Q4Wevery 4 weeks; QODevery other day; SCsubcutaneous; SMsafety monitoring;
TNFtumor necrosis factor; UCulcerative colitis; wk week. 
a
Stable budesonide at 9 mg/day.  Taper from Week 10 to QOD for 2 weeks and then discontinue.


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3.1.1.3 
Number of Patients
Approximately 350 patients are to be enrolled for this study.  Following 10 weeks of 
open-label induction with etrolizumab, it is estimated that approximately 60% of patients 
will achieve clinical response, which will provide approximately 105 patients in each 
treatment arm for the Maintenance Phase.  Additional patients may be enrolled in the 
Induction Phase if needed to meet sample size requirements for the Maintenance Phase.
3.1.2
Data Monitoring Committee
An independent Data Monitoring Committee (iDMC) will monitor safety and study
conduct on an ongoing basis.  Members of the iDMC will be external to the Sponsor and 
will follow a charter that outlines the iDMC roles and responsibilities.  The iDMC will 
meet approximately every 6 months (frequency adjustable as required) to review 
unblinded safety and study conduct data prepared by an independent data coordinating 
center (IDCC).  If the iDMC deems a benefit-risk assessment necessary, the iDMC may 
also review unblinded efficacy data.  The iDMC may recommend stopping the study 
early for safety reasons.  However, the iDMC may not recommend stopping the trial 
early for positive efficacy or solely for futility.
3.2
END OF STUDY AND LENGTH OF STUDY
Length of Study
The total length of the treatment period will be 62 weeks. Patients who do not achieve a 
clinical response at Week 10, patients who have clinical relapse during the Maintenance 
Phase, patients who receive defined rescue treatment (see Section 4.3.2.2), and 
patients who complete 62 weeks of the study may be given the option of enrolling in 
Part 1 (OLE) of Study GA28951, where they will receive open-label etrolizumab
treatment.  Those who do not enroll in Part 1 (OLE) of Study GA28951 will continue to 
12 weeks of safety follow-up in this study and then be requested to enroll in Part 2 (SM) 
of Study GA28951 for 92 weeks of PML monitoring.
The total length of the study is expected to last from the first patient screened to either 
the last patient in last follow-up visit in this protocol or last patient enrolled into 
Study GA28951 (OLE-SM), whichever is later.
End of Study
The end of the study is defined as the last patient last safety follow-up visit in this 
protocol or last patient in this protocol enrolled into Study GA28951 (OLE-SM), 
whichever is later.


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3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Test Product Dosage
Data from Phase I (Study ABS4262g) and Phase II (Study ABS4986g; EUCALYPTUS) 
indicated that the 100-mg Q4W regimen is sufficient to maintain 7 receptor occupancy 
both in blood and in colonic tissue, is well tolerated, and results in meaningful clinical 
efficacy, and therefore, will be evaluated further in this Phase III study.  The rationale for 
proposing a 105-mg Q4W SC regimen is discussed below.

The Phase II 100-mg Q4W SC dose (0.7 mL of 150 mg/mL solution via vial and 
syringe, with an intended nominal dose of 100 mg) showed clinically meaningful 
efficacy without clinically meaningful safety imbalances (see Section 1.2).  The 
Phase III formulation is a PFS containing 0.7 mL of 150 mg/mL etrolizumab solution, 
corresponding to delivering a dose of 105 mg etrolizumab per injection.
In the Phase II EUCALYPTUS study, the 100-mg SC Q4W dose resulted in an 
increased clinical remission rate in TNF-naive patients (43.8%; p0.007), as 
well as in the combined TNF-naive and inadequate response to anti-tumor 
necrosis factor (TNF-IR) group (20.5%; p0.004) at Week 10 as compared with 
the clinical remission rate in placebo patients (0%).  These data suggest that 
the 100-mg SC Q4W dose regimen is efficacious in patients with moderately 
and severely active UC.

Up to a 45-fold higher exposure did not result in a greater PD effect or an increase 
in clinical benefit.
A higher dose (420 mg SC at Week 0 followed by 300 mg at Weeks 2, 4, and 8) 
was also tested in the EUCALYPTUS study without any major safety concerns.  
However, there was no clear distinction in observed pharmacological effects 
(including clinical efficacy outcome and PD response, such as 7 receptor 
occupancy) between high-dose and the 100-mg dose cohorts.  Although the 
study was not powered to enable a formal comparison of the two active arms, 
the data suggest that the observed clinical remission rate at Week 10 in the 
low-dose cohort was not further improved in the high-dose cohort. 
Preliminary concentration quartile-response analysis was conducted, for the 
data pooled from both low- and high-dose cohorts, to see whether patients in 
the higher concentration quartiles had better remission rate.  The results did not 
show any exposure response relationship.


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
Exposure lower than 100 mg Q4W is likely not sufficient to maintain 7 integrin 
receptor occupancy.
In the Phase I study (Study ABS4262g), the etrolizumab PK profile appears 
nonlinear at a dose level of 1 mg/kg IV.  The duration of 7 receptor 
occupancy is dose dependent.  A single dose of 0.3 mg/kg IV maintained 
7 receptor occupancy for only approximately 2 weeks, which is likely 
insufficient to ensure maximal 7 receptor occupancy at all times within a 
Q4W dosing interval.
On the basis of data from the Phase II EUCALYPTUS study, it is assumed that 
maximal/near maximal occupancy of 7 receptors both in the blood and in 
colonic tissue is minimally necessary for etrolizumab’s clinical activity.  Per this 
assumption, population PK simulations were performed and results showed that 
a 100-mg SC Q4W regimen can provide steady-state serum trough 
concentration (Ctrough,ss) of at least 1.7 g/mL (the minimum serum concentration 
observed that maintained colonic tissue 7 occupancy) in 84% of patients, 
whereas a dose lower than the 100-mg SC Q4W regimen (e.g., 50 mg Q4W SC) 
is likely not sufficient for maintaining 7 receptor occupancy at all times during 
the Q4W dosing interval, since only 56% of patients were predicted to reach a 
1.7 g/mL level in their Ctrough,ss (see Table 2).
Lower doses are also anticipated to result in etrolizumab serum level falling into 
the nonlinear PK concentration range and hence are likely to increase variability 
in exposure.
Table 2
Population Pharmacokinetic Modeling Predicted Percentage of 
Patients Achieving 1.7-g/mL Steady-State Trough Concentration 
under Different Dosing Scenarios
Q4W SC Dosing
300 mg
100 mg
50 mg
Percentage of patients expected 
to have Ctrough,ss 1.7 g/mL
98
84
56
Ctrough,sssteady-state trough concentrations; PKpharmacokinetic; 
Q4Wevery 4 weeks; SCsubcutaneous.
Note:  1.7 g/mL is the minimum serum concentration observed in the 
Phase II study that maintained 7 occupancy in the colonic tissue.
In conclusion, on the basis of available etrolizumab efficacy, PK, PD, and safety data 
(see Section 6.6), a PFS delivering a dose of 105 mg Q4W is considered the most 
appropriate dosing regimen for this Phase III study.


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3.3.2
Rationale for Patient Population 
There is a high unmet medical need in moderately to severely active UC due to current 
treatments being associated with significant adverse events, low rates of sustained 
remission, or being highly invasive (i.e., colectomy) (see Section 1.1 for details).  
The Phase II EUCALYPTUS trial of etrolizumab versus placebo provided evidence of 
efficacy, including induction of remission at Week 10, in patients with moderately to 
severely active UC refractory to or intolerant of conventional and/or TNF inhibitor
therapies.  Results from this trial showed that in the TNF-naive subgroup, clinical 
remission (defined as MCS 2 and all subscores 1) at Week 10 was observed in 
43.8% versus 0% of patients in the 100-mg etrolizumab versus placebo group,
suggesting substantial efficacy in the TNF-naive population at Week 10.
In summary, because of the limitations of the currently available therapies for the 
treatment of moderately to severely active UC and the favorable benefit-risk observed in 
the TNF-naive population in EUCALYPTUS, this Phase III trial is designed to test the 
efficacy and safety of etrolizumab in this patient population. 
3.3.3
Rationale for Control Group
A placebo-treated control group will be used in this study in the Maintenance Phase to 
assess the differences in efficacy, safety, and tolerability in patients who receive 
etrolizumab plus background UC therapy compared with patients who receive placebo 
plus background UC therapy.  The use of a control group during the maintenance period 
is necessary given the inherent variability in disease flares and the use of subjective 
assessments, such as the patient-reported outcomes (PROs).  Patients in the control 
group will undergo the same study assessments as the etrolizumab-treated patients.
3.3.4
Rationale for Biomarker Assessments
A biomarker that may predict an increased chance of response to therapy would be 
valuable to patients and treating physicians to aid in guiding treatment decisions.  
Etrolizumab binds to the 7 integrin and blocks 47:MAdCAM and E7:E-cadherin 
binding.  In exploratory analyses from the Phase II EUCALYPTUS study, patients with 
higher baseline biopsy E gene expression by quantitative polymerase chain reaction 
(qPCR) and E+ cell counts by immunohistochemistry (IHC) had a higher rate of 
remission at Week 10 (see Figure 2).  The baseline levels of E and other biomarkers 
will be evaluated in this Phase III study to further assess whether they may function as 
predictive response biomarkers.


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Figure 2
Effects of High and Low Baseline Expression of the E Biomarker in 
Colon on the Remission Status of Patients with Ulcerative Colitis 
Treated with Etrolizumab in EUCALYPTUS (Observed Data)
LDloading dose; SCsubcutaneous.
All patients enrolled in the current study will have mandatory colonic mucosal sampling 
at the screening visit to analyze the relationship of E levels (and potentially other 
biomarkers) with response to treatment.  In addition, samples will be collected at 
Weeks 10 and 62 for potential exploratory biomarker analyses that include, but are not 
limited to, E expression.
3.4
OUTCOME MEASURES 
3.4.1
Efficacy Outcome Measures
Primary Outcome Measure

Remission at Week 62 among patients with a clinical response at Week 10, as 
determined by the MCS
Secondary Outcome Measures

Clinical remission at Week 62 among patients in clinical remission at Week 10

Clinical remission at Week 62

Remission at Week 62 among patients in remission at Week 10

Improvement in endoscopic appearance of the mucosa at Week 62

Endoscopic remission at Week 62

Histologic remission at Week 62

Change from baseline in rectal bleed subscore at Week 6

Change from baseline in stool frequency subscore at Week 6

Corticosteroid-free clinical remission at Week 62 (off corticosteroids for at least 
24 weeks prior to Week 62) in patients who are receiving corticosteroids at baseline


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
Corticosteroid-free remission at Week 62 (off corticosteroids for at least 24 weeks 
prior to Week 62) in patients who are receiving corticosteroids at baseline

Change from baseline to Week 62 in UC bowel movement signs and symptoms as 
assessed by the UC-PRO/SS measure 

Change from baseline to Week 62 in UC abdominal symptoms as assessed by the 
UC-PRO/SS measure 

Change from baseline to Week 62 in patients’ health-related QOL as assessed by 
the overall score of the IBDQ
Exploratory Efficacy Outcome Measures 

Clinical response at Week 62 among patients with a clinical response at Week 10

Remission at Week 62 among patients in clinical remission at Week 10 

Corticosteroid-free clinical remission at Week 62 (off corticosteroids for at least 
12 weeks prior to Week 62) in patients who are receiving corticosteroids at baseline

Histologic disease activity change from baseline to Week 10 and Week 62

Improvement in histologic and/or endoscopic disease activity

Change in health utilities, as assessed by the EQ-5D, from baseline to 
Weeks 10 and 62

Improvement in endoscopic appearance of the mucosa at Week 10

Endoscopic remission at Week 10

Frequency and duration of hospitalizations from Week 10 to Week 62

Response, remission and corticosteroid-free endpoints as determined by the mMCS
3.4.2
Safety Outcome Measures
The safety outcome measures for 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 study drug discontinuation

Incidence of laboratory abnormalities

Incidence of malignancies

Incidence of ATAs to etrolizumab

Incidence and severity of hypersensitivity reaction events


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3.4.3
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:

Serum trough concentration at steady state during the dosing period from Week 12 
to Week 62

Serum concentration at primary endpoint time (Week 62)
3.4.4
Exploratory Biomarker Outcome Measures
The exploratory biomarker outcome measures for this study are as follows:

Remission at Week 10 and maintenance of remission at Week 62 in patients 
according to baseline levels of colonic tissue biomarkers and/or peripheral blood,
including, but not limited to, E integrin

Changes in levels of exploratory colonic tissue and/or peripheral blood biomarkers 
during the Induction and Maintenance Phases

Changes in stool biomarkers, which may include, but are not limited to, those in the 
microbiota and bacterial cultures, during the Induction and Maintenance Phases
4.
MATERIALS AND METHODS
4.1
PATIENTS
The target population is patients who are naive to TNF inhibitors with moderately to 
severely active UC (defined as MCS of 612, endoscopy subscore of 2 as determined 
by the central reading procedure described in Section 4.5.1.4, a rectal bleeding subscore 
1, a stool frequency subscore 1, and colonic involvement extending a minimum of 
20 cm from the anal verge).
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Able and willing to provide written informed consent

1880 years of age, inclusive

Diagnosis of UC established at least 3 months prior to Day 1 by clinical and 
endoscopic evidence.  This diagnosis should be corroborated by histopathology 
conducted at any time prior to screening and documented by a histopathology 
report.  (Note that histopathology may be performed at screening if no prior report is 
readily available.)

Moderately to severely active UC as determined by an MCS of 612 with an 
endoscopic subscore 2 as determined by the central reading procedure described 
in Section 4.5.1.4, a rectal bleeding subscore 1, and a stool frequency subscore 
1 during the screening period (prior to Day 1).  See also Section 4.5.2.1 for 
additional information regarding the time window


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Evidence of UC extending a minimum of 20 cm from the anal verge as determined 
by baseline endoscopy (flexible sigmoidoscopy or colonoscopy) performed during 
screening, 416 days prior to Day 1.  See also Section 4.5.2.1 for additional 
information regarding the time window

Naive to treatment with TNF inhibitors

Patients must have had an inadequate response, loss of response, or intolerance to 
prior immunosuppressant and/or corticosteroid treatment 
Inadequate response to, loss of response to, or intolerance to prior 
immunosuppressant treatment, is defined as one or more of the following: 
Persistent signs and symptoms of active disease despite a history of at least 
one 12-week regimen of oral AZA (1.5 mg/kg) or 6-MP (0.75 mg/kg) and/or 
MTX (15 mg/week) within the previous 5 years
Persistent signs and symptoms of active disease despite a 6-TG level of 
230 pmol/8108 RBCs during at least one 12-week regimen of oral AZA or 6-
MP at a stable or increasing dose within the previous 5 years
History of intolerance to AZA, 6-MP, or MTX (including, but not limited to,
nausea/vomiting, abdominal pain, pancreatitis, LFT abnormalities, 
lymphopenia, TPMT genetic mutation, infection) within the previous 5 years

Inadequate response, loss of response, or intolerance to corticosteroid treatment is 
defined as one or more of the following: 
Steroid refractory:  persistent symptoms of active disease despite treatment 
with at least one 4-week induction regimen that included a dose of 30 mg 
prednisone (oral) daily (or equivalent) for at least 2 weeks or intravenously for 
at least 1 week within the previous 5 years
Steroid dependent:  two failed attempts to taper steroids below a dose 
equivalent to 10 mg prednisone (oral) daily
Steroid intolerant:  history of intolerance to corticosteroids (including, but not 
limited to, Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, 
insomnia, infection) within the previous 5 years

Any ongoing UC therapy must be at stable doses:
May be receiving oral 5-ASA compounds provided that the dose has been 
stable for 4 weeks immediately prior to Day 1
May be receiving oral corticosteroid therapy (prednisone at a stable dose 
of 30 mg a day, or equivalent steroid)
If corticosteroid therapy is ongoing or has recently been initiated, the dose 
has to be stable for at least 4 weeks immediately prior to Day 1.  If 
corticosteroids are being tapered, the dose has to be stable for at least 
2 weeks immediately prior to Day 1.


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May be receiving budesonide therapy at a stable dose of up to 9 mg a day for 
4 weeks prior to Day 1
May be receiving probiotics (e.g., Culturelle, Saccharomyces boulardii), 
provided that the dose has been stable for 2 weeks immediately prior to Day 1
May be receiving AZA, 6-MP, or MTX, provided that the dose has been stable 
for 8 weeks immediately prior to Day 1

For women who are not postmenopausal (at least 12 months of
nontherapy-induced amenorrhea) or surgically sterile (e.g., 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 3).
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.

Must have received a colonoscopy within the past year or be willing to undergo a 
colonoscopy in lieu of a flexible sigmoidoscopy at screening.  This colonoscopy 
must:
Confirm disease extent (defined as 1) left-sided colitis [up to the 
splenic flexure], 2) extensive colitis [beyond the splenic flexure but not involving 
the entire colon], and 3) pancolitis; see Section 4.5.1.4) 
Include removal of any adenomatous polyps 
Document evidence of surveillance for dysplasia for all patients with left-sided 
colitis of 12 years’ duration and total/extensive colitis of 8 years duration 


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4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Exclusion Criteria Related to Inflammatory Bowel Disease

Prior extensive colonic resection, subtotal or total colectomy, or planned surgery 
for UC

Past or present ileostomy or colostomy

Diagnosis of indeterminate colitis 

Suspicion of ischemic colitis, radiation colitis, or microscopic colitis

Diagnosis of toxic megacolon within 12 months of initial screening visit 

Any diagnosis of Crohn’s disease

Past or present fistula or abdominal abscess

A history or current evidence of colonic mucosal dysplasia

Patients with any stricture (stenosis) of the colon

Patients with history or evidence of adenomatous colonic polyps that have not 
been removed
Exclusion Criteria Related to Prior or Concomitant Therapy

Any prior treatment with etrolizumab or other anti-integrin agents (including 
natalizumab, vedolizumab, and efalizumab)

Any prior treatment with anti-adhesion molecules (e.g., anti-MAdCAM-1)

Any prior treatment with rituximab

Any treatment with tofacitinib during screening

Use of IV steroids within 30 days prior to screening with the exception of a single 
administration of IV steroid

Use of agents that deplete B or T cells (e.g., alemtuzumab or visilizumab) within 
12 months prior to Day 1, with the exception of AZA and 6-MP

Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF) within 
4 weeks prior to Day 1

Chronic nonsteroidal anti-inflammatory drug (NSAID) use.  (Note: occasional use of 
NSAIDs and acetaminophen [e.g., headache, arthritis, myalgias, or menstrual 
cramps] and aspirin up to 325 mg daily is permitted.)

Patients who are currently using anticoagulants including, but not limited to,
warfarin, heparin, enoxaparin, dabigatran, apixaban, rivaroxaban.  (Note that 
antiplatelet agents such as aspirin up to 325 mg daily or clopidogrel are permitted.)

Patients who have received treatment with corticosteroid enemas/suppositories 
and/or topical (rectal) 5-ASA preparations within 2 weeks prior to Day 1

Apheresis (i.e., Adacolumn apheresis) within 2 weeks prior to Day 1


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Received any investigational treatment including investigational vaccines within 
5 half-lives of the investigational product or 28 days after the last dose, whichever is 
greater, prior to Day 1

History of moderate or severe allergic or anaphylactic/anaphylactoid reactions to 
chimeric, human, or humanized antibodies, fusion proteins, or murine proteins or 
hypersensitivity to etrolizumab (active drug substance) or any of the excipients 
(L-histidine, L-arginine, succinic acid, polysorbate 20)

Patients administered tube feeding, defined formula diets, or parenteral 
alimentation/nutrition who have not discontinued these treatments 3 weeks prior 
to Day 1
Exclusion Criteria Related to General Safety

Pregnant or lactating

Lack of peripheral venous access

Hospitalized (other than for elective reasons) during the screening period

Inability to comply with study protocol, in the opinion of the investigator

Significant uncontrolled comorbidity, such as cardiac (e.g., moderate to severe heart 
failure New York Heart Association [NYHA] Class III/IV), pulmonary, renal, hepatic, 
endocrine, or gastrointestinal disorders (excluding UC)

Neurological conditions or diseases that may interfere with monitoring for PML

History of demyelinating disease

Clinically significant abnormalities on screening neurologic examination (PML 
Objective Checklist)

Clinically significant abnormalities on the screening PML Subjective Checklist

History of alcohol, drug, or chemical abuse 6 months prior to screening

Conditions other than UC that could require treatment with 10 mg/day of 
prednisone (or equivalent) during the course of the study

History of cancer, including hematologic malignancy, solid tumors, and carcinoma 
in situ, within 5 years before screening with the following exceptions:
Local basal or squamous cell carcinoma of the skin that has been excised and 
is considered cured is not exclusionary.
A history of chronic myelogenous leukemia, hairy cell leukemia, melanoma, 
renal cell carcinoma, or Kaposi sarcoma is exclusionary, irrespective of the 
duration of time before screening.
History of a cervical smear indicating the presence of adenocarcinoma in situ 
(AIS), high-grade squamous intraepithelial lesions (HSIL), or cervical 
intraepithelial neoplasia (CIN) of Grade 1 is exclusionary, irrespective of the 
duration of time before screening.


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Exclusion Criteria Related to Infection Risk

Congenital or acquired immune deficiency

Patients must undergo screening for HIV and test positive for preliminary and 
confirmatory tests

Positive hepatitis C virus (HCV) antibody test result, unless the patient (1) has 
undetectable HCV RNA levels for 6 months after completing a successful course 
of HCV anti-viral treatment and an undetectable HCV RNA at screening or (2) has 
a known history of HCV antibody positivity with a history of undetectable HCV RNA 
and undetectable HCV RNA at screening in the absence of history of HCV anti-viral 
treatment.

Patients must undergo screening for hepatitis B virus (HBV).  This includes testing 
for HBsAg (HBV surface antigen), anti-HBc total (HBV core antibody total), and 
HBV DNA (patients who test negative for these tests are eligible for this study):
Patients who test positive for surface antigen (HBsAg ) are not eligible for this 
study, regardless of the results of other hepatitis B tests.
Patients who test positive only for core antibody (anti-HBc ) must undergo 
further testing for hepatitis B DNA (HBV DNA test). 
If the HBV DNA test is positive, the patient is not eligible for this study.
In the event the HBV DNA test cannot be performed, the patient is not 
eligible for this study. 
If the HBV DNA test is negative, the patient is eligible for this study.  These 
patients will undergo periodic monitoring for HBV DNA during the study.

Evidence of or treatment for Clostridium difficile (as assessed by C. difficile toxin 
testing) within 60 days prior to Day 1 or other intestinal pathogens (as assessed by 
stool culture and ova and parasite evaluation) within 30 days prior to Day 1

Evidence of or treatment for clinically significant cytomegalovirus (CMV) colitis 
(based on the investigator’s judgment) within 60 days prior to Day 1.  Laboratory 
confirmation of CMV from colon biopsy sample is required during screening 
evaluation only if clinical suspicion is high and to determine the need for CMV 
treatment.

History of active or latent TB, regardless of treatment history (see Section 4.5.1.5)
Patients with a history of active or latent TB (based on a positive screening 
assay, either purified protein derivative [PPD] skin test or QuantiFERON-TB 
Gold test), are not eligible for this study.
Patients with a chest X-ray (posteroanterior [PA] and lateral) within 3 months of 
Day 1 suspicious for pulmonary TB are not eligible for this study.

History of recurrent opportunistic infections and/or history of severe disseminated 
viral infections (e.g., herpes)

Any serious opportunistic infection within the last 6 months


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Any current or recent signs or symptoms (within 4 weeks before screening and 
during screening) of infection, except for the following:
Minor infections (e.g., common cold) that have, in the investigator’s judgment, 
completely resolved prior to Day 1
Fungal infections of the nail beds
Oral or vaginal candidiasis that has resolved with or without treatment prior 
to Day 1

Any major episode of infection requiring treatment with IV antibiotics within 8 weeks 
prior to screening or oral antibiotics within4 weeks prior to screening
Treatment with antibiotics as adjunctive therapy for UC in the absence of 
documented infection is not exclusionary.

Received a live attenuated vaccine within 4 weeks prior to Day 1

History of organ transplant
Exclusion Criteria Related to Laboratory Values (at Screening)

Serum creatinine 2 times upper limit of normal (ULN)

ALT or AST 3ULN, or alkaline phosphatase 3ULN, or total bilirubin 
2.5ULN (unconjugated hyperbilirubinemia that is associated with known 
Gilbert's syndrome is not an exclusion criterion)

Platelet count 100,000/L

Hemoglobin 8 g/dL

Absolute neutrophil count 1500/L

Absolute lymphocyte count 500/L
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
After written informed consent has been obtained, all patients will receive a screening 
number, which will be assigned by an interactive voice/Web-based response system 
(IxRS).  Following completion of the screening period and after all patient eligibility
requirements are confirmed, patients will be assigned an identification number (a 
different number from the screening number) on Day 1 and will receive treatment with 
open-label etrolizumab for 10 weeks in the Induction Phase.  Patients achieving a 
clinical response at Week 10 (see Table 1 for definition of clinical response) will undergo 
randomization in a 1:1 ratio to either 105 mg etrolizumab SC or placebo (Maintenance 
Phase), stratified by remission status at Week 10, concomitant treatment with 
corticosteroids (yes/no), concomitant treatment with immunosuppressants after Week 10 
(yes/no), and disease activity measured during screening (MCS 9/MCS 10). In order 
to facilitate Maintenance Phase sensitivity analyses of outcomes for patients who 
achieved remission in the Induction Phase using alternative remission definitions 
(i.e., not including the Physician’s Global Assessment [PGA] subscore of the MCS 
among remission criteria), the Week 10 remission status stratification variable will 


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consist of three levels according to whether remission was achieved with or without 
inclusion of the PGA criteria described in Table 1.
A permuted blocks randomization method will be used to obtain an approximately 
1:1 ratio between the treatment and placebo arms within each stratum. Patients will 
receive either etrolizumab (105 mg SC Q4W) or placebo in a 1:1 ratio in a blinded 
manner until Week 62 (see Figure 3 for details of study drug administration schedule).
During the 52-week maintenance double-blind treatment period, the IxRS will make 
etrolizumab/etrolizumab placebo study treatment kit assignments.  Each kit will consist 
of one prefilled 1-mL syringe (0.7 mL nominal volume).  At each dosing visit (occurring 
every 4 weeks) during the blinded treatment period, one study drug kit will be assigned 
for administration to each patient.  The placebo and active kits are filled and packaged to 
look identical.  Patients performing study drug administration at home may receive two 
or three kits at a time beginning at Week 24 in order to allow sufficient supply until their 
next in-clinic visit.
Patients, all study site personnel, and the Sponsor and its agents will be blinded to 
treatment assignment throughout the 52-week maintenance double-blind treatment 
period.  The IxRS service provider and personnel responsible for performing PK assays 
(in order to identify appropriate dilutions of PK samples to be analyzed) will be unblinded 
to patients’ randomized treatment assignments.  As described in Section 6, treatment 
assignment will be unblinded to the Sponsor personnel performing the analysis when all 
data through Week 62 are in the database and the data have been cleaned and verified.  
However, patients and all study site personnel will remain blinded to individual treatment 
assignment until after the study is completed (after all patients have either completed the 
treatment and safety follow-up period or discontinued early from the study) and the 
database is locked.
If unblinding is necessary for patient management (in the case of a serious adverse 
event), the investigator will be able to break the treatment code by contacting the IxRS.  
Treatment codes should not be broken except in emergency situations.  If the 
investigator wishes to know the identity of the study drug for any other reason, he or she 
should contact the Medical Monitor.  The investigator should document and provide an 
explanation for any premature unblinding (e.g., accidental unblinding, unblinding due to 
a serious adverse event per health authority reporting requirements).  The 
Sponsor Safety Reporting Department (independent from the study team) will break the 
treatment code for all unexpected serious adverse events (see Section 5.2.2) that are 
considered by the investigator to be related to study drug for the purpose of regulatory 
reporting. The study team will remain blinded to study treatment.


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Figure 3
Schedule of Study Drug Administration
CScorticosteroids; dday; HCPhealth care professional; ISimmunosuppressant; OLE-SMopen-label extension and safety monitoring study; 
QODonce every other day; TCtelephone call; wk week.


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4.3
STUDY TREATMENTS
Table 3
Treatment/Concomitant Background Treatments
Treatment/Concomitant Background Treatment
Investigational medicinal product
Etrolizumab, 105 mg SC every 4 weeks
Placebo SC every 4 weeks
Non-investigational medicinal products
Induction Phase
Continuation of stable baseline doses of the following:
oral 5-ASA; AZA; 6-MP; MTX
Corticosteroids up to 30 mg/day of prednisone (or equivalent)
Budesonide up to 9 mg/day
Maintenance Phase
Responders who enter the Maintenance Phase should continue immunosuppressants (AZA, 6-MP, MTX) at a 
stable dose unless dose reduction or discontinuation is required due to immunosuppressant-related toxicity. 
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 remains at the discretion of the investigator.
During the Maintenance Phase, patients receiving prednisone at a dose of 10 mg/day (or equivalent) are to have 
their dose reduced at a rate of 5 mg per week until a 10 mg/day dose is achieved.  Patients receiving prednisone at 
doses 10 mg/day (or equivalent), or once a 10 mg/day dose (or equivalent) is achieved by tapering, are to have 
their dose reduced at a rate of 2.5 mg/week until discontinuation.  Patients receiving budesonide at study entry are 
to taper their dose starting from Week 10 from 9 mg QD to 9 mg QOD for 2 weeks, and then discontinue.  For 
patients who cannot tolerate the corticosteroid taper without recurrence of clinical symptoms of either ulcerative 
colitis or steroid withdrawal, corticosteroid dose may be increased (up to the dose at study entry if required), but 
tapering must begin again within 2 weeks.
Throughout study
Probiotics and oral 5-ASA may be continued at a stable dose throughout.
Occasional use of NSAIDs and acetaminophen (e.g., headache, arthritis, myalgias, and menstrual cramps) and 
aspirin up to 325 mg daily are permitted throughout the study.
Antidiarrheals (e.g., loperamide, diphenoxylate with atropine) for control of chronic diarrhea are permitted.
5-ASA5-aminosalicylic acid; 6-MP6-mercaptopurine; AZAazathioprine; MTXmethotrexate; NSAIDnonsteroidal anti-inflammatory drug; QDonce a day; 
QODonce every other day; SCsubcutaneous.




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4.3.1.2
Concomitant Background Treatment for Ulcerative Colitis
For concomitant background treatment for UC see Table 3.
For further details, refer to respective Summary of Product Characteristics (SmPCs) or 
product label, local prescribing dosage, administration, and compliance information for 
the formulation, packaging, and handling details of agents prescribed as concomitant 
background treatment for UC.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Etrolizumab and Placebo
All patients will receive one 0.7-mL injection with use of a PFS device once Q4W.  The
device is a 1 mL long glass syringe with a staked-in stainless steel needle. 
 
 
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.  Patients will in turn be trained 
in the use of the device by an HCP and 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 site is to be used for caregiver and not patient 
administration of study treatment.
For the initial four 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 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 with severe hypersensitivity reactions (e.g., stridor, angioedema, life-threatening 
change in vital signs) must be withdrawn from study treatment.  These patients will not 
be eligible to receive open-label etrolizumab in Part 1 (OLE) of Study GA28951 but are 
to enter the 12-week safety follow-up in this study followed by PML monitoring in 
Part 2 (SM) of Study GA28951.


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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 completion of this first 3-month period training in a clinical setting, study drug 
administration (Week 16 and then Q4W onward) 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 patients’ home after return from the clinic visit.  
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.  Compliance in the home setting is to be 
monitored using an e-diary to record drug administration and return of used and unused 
medication syringes (see Appendix 7).  Patients and/or the caregiver will be provided 
with alert cards for 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.  Following the delay, 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 (including those following an injection in the home setting) 
(see Section 5.1.5) should be documented on the appropriate adverse event electronic 
Case Report Form (eCRF) page.  Patients administering at home should be taught to 
report any injection-site reactions as adverse events (e.g., redness and/or swelling). 
Guidelines for treatment interruption or discontinuation are provided in Sections 4.6.1.1 
and 5.1.
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4.3.2.2
Concomitant Background Treatment and Rescue Therapy
Patients must have had an inadequate response, loss of response, or intolerance to 
prior immunosuppressant and/or corticosteroid treatment, as described in Section 4.1.1
and as described below.
All patients are to be defined as refractory, dependent, or intolerant in the eCRF, if 
appropriate, irrespective of whether corticosteroid inadequate response forms part of the 
eligibility criteria.
Inadequate response to, loss of response to, or intolerance to prior immunosuppressant 
treatment is defined as one or more of the following: 

Persistent signs and symptoms of active disease despite a history of at least one 
12-week regimen of oral AZA (1.5 mg/kg) or 6-MP (0.75 mg/kg) and/or 
MTX (15 mg/week) within the previous 5 years

Persistent signs and symptoms of active disease despite a 6-TG level of 
230 pmol/8108 RBCs during at least one 12-week regimen of oral AZA or 6-MP 
at a stable or increasing dose within the previous 5 years

History of intolerance to AZA, 6-MP, or MTX (including, but not limited to,
nausea/vomiting, abdominal pain, pancreatitis, LFT abnormalities, lymphopenia, 
TPMT genetic mutation, infection) within the previous 5 years
Inadequate response, loss of response, or intolerance to corticosteroid treatment is 
defined as one or more of the following:

Steroid refractory:  persistent symptoms of active disease despite treatment with at 
least one 4-week induction regimen that included a dose of 30 mg prednisone 
(oral) daily (or equivalent) for at least 2 weeks or intravenously for at least 1 week 
within the previous 5 years

Steroid dependent:  two failed attempts to taper steroids below a dose equivalent to 
10 mg prednisone (oral) daily

Steroid intolerant:  history of intolerance to corticosteroids (including, but not limited 
to, Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, 
infection) within the previous 5 years
Management of Concomitant Medications during the Study 
During Induction Phase (Prior to Week 10)
Patients are required to maintain stable doses of their concomitant medications 
(oral 5-ASA, corticosteroids, immunosuppressants) for UC.
During Maintenance Phase (after Week 10)
Corticosteroids
Corticosteroids are to be tapered starting from Week 10 in patients who achieve a 
clinical response (patients not achieving clinical response will be allowed to enroll in 


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Part 1 (OLE) of Study GA28951).  Patients receiving prednisone at a dose of 
10 mg/day (or equivalent) are to have their dose reduced at a rate of 5 mg per week 
until a10 mg/day dose is achieved.  Patients receiving prednisone at doses 10 mg/day 
(or equivalent), or once a 10 mg/day dose (or equivalent) is achieved by tapering, are to 
have their dose reduced at a rate of 2.5 mg/week until discontinuation.  Patients 
receiving budesonide at study entry should taper their dose of 9 mg every day to 9 mg 
every other day for 2 weeks and then discontinue budesonide treatment.  For patients 
who cannot tolerate the corticosteroid taper without recurrence of clinical symptoms of 
either UC or steroid withdrawal, corticosteroid dose may be increased (up to the dose at 
study entry, if required), but tapering must begin again within 2 weeks.
Immunosuppressants
Patients should remain on their stable baseline doses of immunosuppressants (AZA, 
6-MP, MTX) throughout the study unless dose reduction or discontinuation is required 
due to a toxicity related to the medication (see Section 3.1.1 for symptoms of toxicity to 
AZA, 6-MP, or MTX).
Rescue Therapy that Can Be Given with Study Medication for the Treatment 
of Ulcerative Colitis
Induction Phase
In the Induction Phase, any patient who requires initiation of an immunosuppressant, 
oral or topical 5-ASA, or corticosteroid, or increase in dose over baseline levels for 
treatment of worsening disease symptoms should stay in the study until Week 10, at 
which time he or she should enroll in Part 1 (OLE) of Study GA28951 to receive 
open-label etrolizumab, if eligible, or enter the 12-week safety follow-up.  These patients 
may not continue into the Maintenance Phase of the study.
Maintenance Phase (after Week 10)
Initiation or escalation of oral 5-ASA should be avoided but is permitted if deemed 
clinically necessary by the investigator.  Patients who initiate or escalate oral 5-ASA 
therapy should continue blinded treatment.
Use of topical or IV corticosteroids or topical 5-ASA should also be avoided as 
concomitant medications.  However, if these are clinically required to treat symptoms of 
UC, then the patient may either remain in this blinded phase of the study or may be 
given the option to enroll in Part 1 (OLE) of Study GA28951, if eligible, based on the 
investigator’s discretion.  Patients who leave the treatment phase early to enroll in Part 1 
(OLE) of Study GA28951 should complete the early withdrawal from treatment visit prior 
to enrollment in Study GA28951.
Patients who were not receiving corticosteroids at baseline and patients who have 
completed the steroid taper who subsequently receive oral corticosteroids at a dose 
greater than 10 mg for 5 days or longer for the treatment of clinical symptoms of either 


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UC or steroid withdrawal may either remain in this blinded phase of the study or may be 
given the option to enroll in Part 1 (OLE) of Study GA28951, if eligible, based on the 
investigator’s discretion.  Patients who leave the treatment phase early to enroll in 
Part 1 (OLE) of Study GA28951 should complete the early withdrawal from treatment 
visit prior to enrollment in Study 28951.
Endoscopy to document disease activity for all patients exiting the treatment period early 
is strongly recommended.
Immunosuppressants (AZA, 6-MP, or MTX) 
Patients are to remain on their stable baseline dose of immunosuppressant therapy 
throughout the study unless dose reduction or discontinuation is required because of 
toxicity.  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 remains at 
the discretion of the investigator.  However, patients who do initiate or escalate 
immunosuppressant therapy may remain in this blinded phase of the study or may be 
given the option to enroll in Part 1 (OLE) of Study GA28951, if eligible, based on the 
investigator’s discretion.  Patients who leave the treatment phase early to enroll in 
Part 1 (OLE) of Study GA28951 should complete the early withdrawal from treatment 
visit prior to enrollment in the Study GA28951.
Endoscopy to document disease activity for patients exiting the treatment period early 
for any reason is strongly recommended.
Rescue Therapy that Cannot Be Given with Study Medication for the 
Treatment of UC
At ANY time during the conduct of the study, use of other immunosuppressive agents 
including, but not limited to, anti-integrins, T- or B-cell depleters (except for AZA and 
6-MP), TNF inhibitors (including TNF inhibitor biosimilars), cyclosporine, tacrolimus, 
anti-adhesion molecules, JAK inhibitors, or investigational agents are prohibited.  
Patients who receive such therapies are not to receive further study treatment or 
open-label treatment, and will be required to enter 12 weeks of safety follow-up in this 
study (see Appendix 2).  After completion of safety follow-up, these patients will be 
asked to enroll in Part 2 (SM) of Study GA28951 for 92 weeks of extended PML 
monitoring.
4.3.3
Investigational Medicinal Product Accountability
All investigational medicinal products (IMPs) required for completion of this study, 
namely, etrolizumab and etrolizumab placebo, 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 


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disposition (e.g., drug dispensing log).  Accountability will be assessed by maintaining 
adequate drug dispensing and return records.  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. 
4.3.4
Assessment of Compliance
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 PFSs 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.  Patients should also bring their 
e-diary to the clinic during 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.


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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).  The investigator's copy of the Drug Return 
Record(s) must accurately document the return of all study drug supplies to Sponsor.
4.3.5
Destruction of the Investigational Medicinal Product 
Any used PFS will be placed into 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 investigator 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 4.3.6).
4.3.6
Reporting of Prefilled Syringe Complaints/Events
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 5.4.2.


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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 as a spontaneous adverse event to the 
Sponsor (see Section 5.3.5).
4.4
CONCOMITANT THERAPY
4.4.1
Permitted 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 8 weeks prior to Day 1 to the study 
completion/early termination visit.  All concomitant medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF.
Patients who use oral contraceptives or maintenance therapy for comorbidities should 
continue their use. 
For concomitant therapy for UC and rescue treatment see Section 4.3.2.2.
4.4.2
Prohibited Therapy
Use of the following therapies is prohibited during the study:

Any investigational treatment including investigational vaccines

Use of lymphocyte depleting agents, (e.g., alemtuzumab or visilizumab), except for 
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

Use of JAK inhibitors
Patients who receive these specified rescue therapies are not to receive further study 
treatment or open-label treatment and are to be withdrawn into safety follow-up.
4.4.3
Definition of Clinical Relapse
Clinical relapse is defined as an:

Increase in pMCS 3 points compared with induction timepoint (Week 10) AND 
absolute pMCS 5 AND endoscopic subscore 2
If a patient meets criteria for clinical relapse during the Maintenance Phase of the study, 
he or she may withdraw from this study and enroll in Part 1 (OLE) of Study GA28951 for 
open-label etrolizumab treatment, if eligible.


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4.5
STUDY ASSESSMENTS 
4.5.1
Description of Study Assessments
4.5.1.1
Medical History and Demographic Data
Medical history includes clinically significant diseases, procedures, and all medication 
taken in the 8 weeks prior to Day 1 (including prescription, over-the-counter, and 
herbal/homeopathic remedies and therapies).  A detailed history of medication used for 
UC is required for the 5 years prior to screening.
Demographic data, including age, sex, whether the patient is a fraternal or identical twin,
and self-reported race/ethnicity, will be collected during screening.
4.5.1.2
Physical Examinations
A complete physical examination should include the evaluation of head, eye, ear, nose, 
and throat and cardiovascular, dermatological, musculoskeletal, respiratory, GI, and 
neurological systems, including administration of the PML Subjective Checklist and the 
PML Objective Checklist by the investigator (see Appendix 5 for PML assessment 
details and Appendix 6 for PML algorithm).  New or worsened abnormalities from 
screening should be recorded as adverse events if appropriate.  In addition, a 
symptom-driven examination should be conducted as indicated in the Schedule of 
Assessments (see Appendix 1).
4.5.1.3
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 visits only.
4.5.1.4
Ulcerative Colitis Disease Activity Assessments
Extent and duration of patient’s disease is to be recorded on the eCRF from the patient 
medical records and should include therapies from the last 5 years.  Extent of disease 
should be defined as follows:  1) left-sided colitis (up to the splenic flexure), 2) extensive 
colitis (beyond the splenic flexure but not involving the entire colon), and 3) pancolitis.
All measurable disease must be documented at screening and re-assessed at each 
subsequent evaluation.  Responses will be assessed by the investigator or designee 
with use of the MCS and pMCS.  The MCS has a range of 012, whereas pMCS has a 
range of 09, with higher scores indicating more severe disease.  The MCS is a 
composite of four assessments, each rated from 03:  stool frequency, rectal bleeding, 
endoscopy, and PGA.  The pMCS is a composite of three assessments, each rated from 
03:  stool frequency, rectal bleeding, and PGA.


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During screening, patients will be instructed on how to appropriately use and complete 
questions on the e-diary.  The patients’ normal number of stools is to be recorded.  This 
is defined as the number of stools 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. 
One of the components of the MCS is the endoscopic subscore.  The time window for 
performing endoscopy during the screening is 416 days prior to Day 1 (i.e., Day16 to 
Day 4).  Medical Monitor approval is not required for endoscopies conducted within 
this window. Under no circumstances will an endoscopy be accepted more than 16 
days or less than 4 days prior to Day 1.  Note that the total screening period is up to 35 
days (see Section 4.5.2.1).
The symptoms of UC must be recorded throughout the study, including the screening 
period.  The e-diary entries will be reviewed by site personnel during screening (prior to 
dosing, if applicable) and during study visits, including the early withdrawal from 
treatment visit and any unscheduled visits due to disease exacerbation.  Because the 
colonoscopy/flexible sigmoidoscopy and bowel cleansing preparations can 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 4.
Colonoscopy/Flexible Sigmoidoscopy with Colonic Biopsies
Patients are to prepare their bowel prior to the colonoscopy/flexible sigmoidoscopy 
procedures.  Medications used for bowel preparation should be recorded on concomitant 
medications pages of eCRF.
Stool samples for analysis of fecal calprotectin and other exploratory biomarkers (such 
as analyses of the microbiota and bacterial cultures) are to be collected prior to bowel 
preparation (polyethylene glycol [PEG]based preparation or enema).
Full colonoscopy within a year of screening is required to ensure against enrollment of 
patients with colonic carcinoma and dysplasia.  If full colonoscopy has not been 
performed within the year before screening, it should be conducted in place of the 
flexible sigmoidoscopy at screening.  For patients not requiring a colonoscopy, a flexible 
sigmoidoscopy will be performed on all patients for inclusion in the study.  Endoscopy 
will be performed during screening 416 days prior to Day 1.
Endoscopy will be also performed at Weeks 10 and 62 and/or at withdrawal from study 
(early withdrawal from treatment visit, see Appendix 1).
Central reading of endoscopies will be performed throughout this study, and a detailed 
charter will address the standardization of endoscopic procedures, video recordings, and 


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equipment, as well as the criteria for endoscopic assessment.  For each patient, video 
recording of the entire endoscopic procedure will be performed as specified in the Video 
Submission Guidelines.  All video recordings will be edited by central read vendor to 
produce video clips that are representative of each segment of the colon visualized up to 
the splenic flexure only (rectum, sigmoid, and descending colon).  The video clips will be 
read centrally for mucosal lesions and endoscopic severity by an independent 
gastroenterologist experienced in IBD who is blind to the patient’s clinical activity and 
treatment allocation.  The MCS endoscopic subscore is to be determined both locally (at 
the investigator site) and centrally as described above.  Each segment of the colon up to 
the splenic flexure (rectum, sigmoid, and descending colon) will be assigned an 
endoscopic subscore. The score from the worst affected segment up to the splenic 
flexure is to be used for the MCS calculation for study conduct, except at post-baseline 
time points, when the sigmoid colon MCS endoscopic subscore will be used if the 
baseline sigmoid colon MCS endoscopic subscore is 23.
In the event that there is a discrepancy between the endoscopic subscore obtained by 
the local versus the central reader, a third read (by a second central reader) is to be 
conducted. From these three endoscopic MCS subscores, the score with which two 
readers agree will be reported as the final overall MCS endoscopic subscore.  If no two 
readers agree on an MCS endoscopic subscore, the median score of the three 
completed reads (i.e., local read, central read #1, and central read #2) will be chosen as 
the final reported overall MCS endoscopic subscore.
In all cases the video recordings are to be taken prior to biopsy.
Each patient entered into the study will have colonic biopsy samples obtained during 
flexible sigmoidoscopy/full colonoscopy as follows.
At Screening
A total of five to six paired biopsy samples (10 to 12 samples) will be taken at screening.

Four paired biopsy samples (8 samples) from the most inflamed area of the colon 
within 2040 cm from the anal verge (sigmoid colon).  Two pairs (4 samples) will go 
into formalin, and two pairs (4 samples) will be placed in stabilization buffer (such as 
RNAlater or a similar buffer) and be shipped to a central laboratory for storage 
at 80 C.

One paired biopsy sample (2 samples) from the most inflamed area of the worst 
affected segment (descending, sigmoid, or rectum).  This biopsy pair (2 samples) 
will go into formalin.

ONLY if there is suspicion of clinically significant CMV colitis, one biopsy sample 
should be taken from the base of an ulcer to evaluate for histological presence of 
CMV but otherwise is not necessary for inclusion in the study.  Analysis should be 
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
ONLY if histopathologic confirmation of UC is needed to meet study eligibility, an 
additional biopsy sample can be used for histopathologic confirmation of UC, if 
necessary (analysis should be performed locally if possible or can be sent to a 
central laboratory, if necessary).

If neither CMV testing nor histopathologic confirmation of UC is needed, these 
additional 2 biopsy samples should not be obtained.
At Weeks 10 and 62 and/or at early withdrawal from treatment visit 
A total of four paired biopsy samples (8 samples) will be taken at Weeks 10 and 62 as 
specified in Appendix 1.

Two paired biopsy samples (4 samples) to be taken from the most inflamed area of 
the colon within 2040 cm from the anal verge (sigmoid colon, approximately at the 
same endoscopic depth of the original screening endoscopy).  If there is no clearly 
inflamed area, a blind biopsy sample should be taken.  One pair will go into formalin, 
and one pair will be placed in stabilization buffer (such as RNAlater or a similar 
buffer) and shipped to a central laboratory for storage at 80 C.

One paired biopsy sample (2 samples) to be taken from the most inflamed area of 
the rectum.  If there is no clearly inflamed area, a blind biopsy sample should be 
taken.  This paired biopsy sample will go into formalin.

One paired biopsy sample (2 samples) to be taken from the most inflamed area of 
the descending colonic segment.  If there is no clearly inflamed area, a blind biopsy 
sample should be taken.  This paired biopsy sample will go into formalin.
Necrotic areas of ulcerated mucosa should be avoided during biopsy.  Original location 
(colonic segment and endoscopic depth) of biopsy specimen should be clearly indicated. 
Samples will all initially be sent to the laboratory vendor (unless analysis is to be 
performed locally, as indicated).
Progressive Multifocal Leukoencephalopathy Assessment
Study site personnel and patient 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) 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 at screening 
and as indicated on the Schedule of Assessments.
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 5.2.3) (see Appendix 6 for the Algorithm for 


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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, further 
work-up may include brain magnetic resonance imaging (MRI) performed with and 
without contrast.  If PML cannot be ruled out, the case will be referred to an expert PML 
adjudication committee. 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 polymerase chain reaction (PCR).  If JCV 
is detected, the patient should be treated as a PML case, permanently discontinue study 
drug, and transfer to safety follow-up.
Dosing with study treatments can be resumed only in patients where PML has been 
ruled out.  See Appendix 6 for the Algorithm for Evaluation of Progressive Multifocal 
Leukoencephalopathy.
After completing this study, patients not enrolling in Part 1 (OLE) of Study GA28951 to 
receive treatment with open-label etrolizumab will enter the 12-week safety follow-up in 
this study (see Appendix 2).  The PML neurologic examination is to be performed at 
Week 12 of this safety follow-up.
Following 12-week safety follow-up, all patients will be requested to continue to be 
monitored for PML for an additional 92 weeks by enrolling in Part 2 (SM) of Study 
GA28951; thus, providing a total of 2 years PML follow-up after the last dose of study 
medication.  During the SM portion of Study GA28951, patients will not be administered 
study drug.
4.5.1.5
Laboratory Assessments
Laboratory assessments will be performed as indicated on the Schedule of 
Assessments; see the Study Flowchart in Appendix 1.  All laboratory investigations will 
be sent to one or more central laboratories for analysis with the exception of CMV.  If 
there is suspicion for clinically significant CMV colitis, a colonic biopsy sample should be 
sent for CMV evaluation, which may be conducted locally depending on local 
requirements for the timing of the test result.  Urine pregnancy testing will be conducted 
locally or in the home setting.  If a full colonoscopy is required at screening, laboratory 
samples should be drawn prior to the initiation of bowel preparation.
On days of study drug administration, laboratory samples should be drawn before the 
administration of study drug.  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 
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
Serum chemistries (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)

Urinalysis

Tuberculosis
The PPD skin test and QuantiFERON-TB Gold are acceptable screening 
assays for latent Mycobacterium TB infection.
A positive PPD tuberculin skin test reaction is considered 5 mm.
Patients with a history of bacille Calmette-Guérin (BCG) vaccination should be 
screened using the QuantiFERON-TB Gold test only.
An indeterminate QuantiFERON-TB Gold test should be repeated.  The 
follow-up test can be either a repeat of the previous test or a PPD tuberculin 
skin test in patients who are eligible to have a PPD tuberculin skin test 
performed.
The patient is considered to have a positive diagnostic test for TB if at least 
one of the following circumstances applies:
–
A positive QuantiFERON-TB Gold test
–
Two successive indeterminate QuantiFERON-TB Gold tests
–
A positive PPD tuberculin skin test
The patient is considered to have a negative diagnostic test for TB if at least 
one of the following circumstances applies:
–
A negative QuantiFERON-TB Gold test
–
A negative PPD tuberculin skin test
If a negative TB screening test has been documented within 3 months of 
screening, no new test is needed.

C-reactive protein (CRP)

C. difficile toxin assay in stool, stool culture and sensitivity testing, stool ova and 
parasites analysis

Pregnancy test:  All women of childbearing potential (including those who have had 
a tubal ligation) will have a serum pregnancy test at screening.
Urine pregnancy tests will be performed at specified subsequent visits.  If a 
urine pregnancy test result is positive, it must be confirmed by a serum 
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
Viral serology and detection
HBV (HBsAg, anti-HBc, and HBV DNA)
HCV antibody
HCV RNA:  Measurement of HCV RNA with use of the Amplicor assay is only 
required when the patient has a known history of HCV antibody positivity with 
past documentation of undetectable HCV RNA, either with or without history of 
anti-viral treatment.  Patients with newly diagnosed HCV antibody positivity are 
not eligible for this study and, therefore, do not require measurement of HCV 
RNA.
HIV

Flow cytometry (fluorescence-activated cell sorting subsets)
Whole blood samples will be collected to determine B-cell counts (CD19)
T cell counts (CD3+, CD4+, CD8+) and natural killer cell counts (CD16, 
CD56) by flow cytometry

ATA assays
Serum samples will be collected for the detection and characterization of 
antibodies against etrolizumab in all patients.  Samples will be analyzed using 
validated assays.  For ATA samples without matched PK determinations, 
etrolizumab concentrations may be measured for the purpose of helping 
interpret ATA data.  ATA samples may also be utilized for exploratory PD 
biomarkers.

JCV antibodies 
A blood sample to test for antibodies to JCV will be taken and stored for 
possible later assessment of how widespread the JCV infection is in the study 
population.  Sample testing for the presence of JCV antibodies is not helpful in 
predicting risk for PML or for evaluating neurologic symptoms.  The sample 
may be tested if there is a strong belief that this information will be helpful in 
managing a patient's condition.

PK assays
Serum samples will be collected for determination of etrolizumab 
concentrations in all patients during the Induction Phase and in all patients who 
were randomized into the Maintenance Phase.  Samples will be analyzed using 
a validated ELISA.

CMV testing of colonic biopsy sample, if there is suspicion for clinically significant 
CMV colitis
Baseline colon biopsy sample (to be obtained at the base of the ulcer) will be 
analyzed for histologic presence of CMV

Fecal calprotectin testing


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
Exploratory diagnostic biomarker assays
Peripheral blood, serum, stool, and colon biopsy samples will be assessed 
using qualified methods (including, but not limited to, ELISA, IHC, and/or qPCR) 
for exploratory diagnostic biomarker analysis.

Exploratory PD biomarker assays
Peripheral blood, serum, stool, and colon biopsy samples will be collected and 
qualified methods (including, but not limited to, ELISA, IHC, bacterial culture, 
and/or qPCR) will be utilized for exploratory PD biomarker analysis for samples 
that are assessed.  Biopsy tissue may also be used for exploratory 
determination of drug concentration.  Stool samples may be used for 
assessments that include, but are not limited to, analyses of the microbiota and 
bacterial cultures.

Histology
Colon biopsy samples will be collected and evaluated for histologic changes.  
Histologic activity on colon biopsies will be categorized using the Nancy 
histological index (see Appendix 12). 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.1.10), 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 for PK or 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.

Blood samples (RNA Paxgene, serum for exploratory PD) and stool samples 
collected for biomarker research 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.
4.5.1.6
Chest X-Ray
A chest X-ray will be performed at screening.  If a chest X-ray has been documented 
within the previous 3 months and has shown no clinically significant abnormalities, no 
additional chest X-ray is required.
4.5.1.7
Electrocardiograms
ECGs for each patient should be obtained from the same machine whenever possible.  
To minimize variability, it is important that patients be in a resting position for 
10 minutes prior to each ECG evaluation.  Body position should be consistently 
maintained for each ECG evaluation to prevent changes in heart rate.  Environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG 


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resting period and during ECG recording.  ECGs should be performed prior to meals and 
any scheduled vital sign measurements and blood draws.
For safety monitoring purposes, the investigator or designee must review, sign, and date 
all ECG tracings.  Paper copies will be kept as part of the patient's permanent study file 
at the site.  ECG outputs will be stored at site.
4.5.1.8
Patient-Reported Outcomes
Patient-reported outcomes (IBDQ, UC-PRO/SS, EQ-5D, and the stool frequency and 
rectal bleeding components of the MCS and pMCS) and physician-reported outcomes 
(PGA of the MCS and pMCS) and the endoscopic component of MCS data will be 
collected to help characterize the clinical profile of etrolizumab.  The instruments will be 
translated as required in the local language.
In order to ensure instrument validity and that data standards meet health authority 
requirements, the PROs completed at the sites (IBDQ, EQ-5D, and the stool frequency 
and rectal bleeding components of the MCS and pMCS) should be administered at the 
investigational site prior to the completion of non-PRO assessments and before the 
patient receives any disease-status information or study drug during that visit.  At 
Week 0 (Day 1), however, IBDQ and EQ-5D do not have to be performed prior to
non-PRO assessments. Patients will complete the UC-PRO/SS measure for at least 
912 days consecutive days around the time of each scheduled visit, as programmed in 
the e-diary.
PRO data will be collected electronically using electronic patient-reported outcome 
(ePRO) devices (i.e., e-diary or tablet).  The format of the questionnaires may change 
when they are converted to electronic format.  Electronic data captured by the patient 
since the previous study visit should be reviewed with the patient at each clinic visit.  
ePRO data will be collected and assessed at visits according to the Schedule of 
Assessments in Appendix 1.
Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms 
Measure 
The UC-PRO/SS measure will be used to assess patient-reported UC signs and 
symptoms.  The 14-item questionnaire (some questions contain supplementary 
questions regarding severity/frequency) contains three domains:  bowel movement signs 
and symptoms, abdominal symptoms, and systemic symptoms.  The UC-PRO/SS 
assesses the presence of UC symptoms and in some cases the severity or frequency of 
the symptoms.  The UC-PRO/SS measure has a recall specification of 24 hours.  A copy 
of the UC PRO/SS measure is provided in Appendix 9.


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Inflammatory Bowel Disease Questionnaire 
The IBDQ will be used to assess patients’ health-related QOL (Guyatt et al. 1989; 
Irvine 1999).  The 32-item questionnaire contains four domains:  bowel symptoms 
(10 items), systemic symptoms (5 items), emotional function (12 items), and social 
function (5 items).  The items are scored on a 7-point Likert scale with a higher score 
indicating better health-related QOL.  The IBDQ has a recall specification of 2 weeks.  
A copy of the IBDQ is provided in Appendix 10.
Mayo Clinic Score and Partial Mayo Clinic Score
The MCS is a composite of four assessments, each rated from 03:  stool frequency, 
rectal bleeding, endoscopy, and PGA (Schroeder et al. 1987).  The endoscopy subscore 
of the MCS is derived from an evaluation of findings on endoscopy and as determined 
by the central reading procedure described in Section 4.5.1.4.  The pMCS is a 
composite of three assessments, each rated from 03:  stool frequency, rectal bleeding, 
and PGA.  The MCS has a range of 012 and the pMCS has a range of 09.  Higher 
scores indicate more severe disease.  Copies of the MCS and pMCS scoring system are 
provided in Appendix 4.
EuroQoL 5-Dimension Questionnaire
The EQ-5D is a generic preference-based health-related QOL questionnaire that 
provides a single index value for health status (Rabin and deCharro 2001).  This tool 
includes questions about mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression that are used to build a composite of the patient’s health status.  The 
EQ-5D questionnaire will be utilized in this study for economic modeling.  A copy of the 
assessment is provided in Appendix 11.
4.5.1.9
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.
4.5.1.10
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.  In addition, any residual colonic biopsy and blood 
samples for biomarkers left over at the end of the study and analyses 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 Institutional 
Review Board or Ethics Committee (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
Whole blood (DNA) will be collected for genetic analysis from consenting patients 
(RCR ICF).
Samples that are obtained for exploratory analysis of biomarkers (listed below) but were 
not utilized or were not entirely consumed will be transferred to the RCR.
Specimen types include the following:

Blood collected in RNA Paxgene tubes (for exploratory pharmacodynamics; see 
Appendix 1 for specific collection timepoints)

Serum for exploratory pharmacodynamics (see Appendix 1 for specific collection 
timepoints)

Stool samples may be used for exploratory biomarker analyses (see Appendix 1 for 
specific collection timepoints)

Colon biopsy samples (formalin and stabilization buffer [such as RNAlater or a 
similar buffer]; see Appendix 1 for specific collection timepoints)
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.


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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.
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.


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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.
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 GA29102 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 GA29102.
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.
4.5.2
Timing of Study Assessments
4.5.2.1
Screening and Pretreatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations. Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.  


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All screening tests and evaluations will be performed within 35 days prior to Day 1 
except for flexible sigmoidoscopy/colonoscopy, which should be performed 416 days 
prior to Day 1 (see Figure 4).  The screening period will not exceed 35 calendar days.
Laboratory samples should be collected from the patient early in the screening period to 
allow time for the laboratory results to be available for review by the site for eligibility
(see Section 4.5.1.5).  The ECG and chest X-ray can be obtained any time before Day 1 
(see Section 4.5.1.6 and Section 4.5.1.7 for additional details on the chest X-ray and 
ECG).  Colon biopsy specimen collection is detailed in Section 4.5.1.4.
A blood sample to test for antibodies to JCV will be taken and stored for possible later 
assessment of how widespread the JCV infection is in the study population.  Sample 
testing for the presence of JCV antibodies is not helpful in predicting risk for PML or for 
evaluating neurologic symptoms.  The sample may be tested if there is a strong belief 
that this information will be helpful in managing a patient's condition.
The screening endoscopy for MCS should be performed 416 days prior to Day 1 
(i.e., Day 16 to Day 4).  The endoscopy score from the worst affected segment up to 
the splenic flexure (rectum, sigmoid, and descending colon) is to be used for the MCS 
calculation (see Section 4.5.1.4).
The symptoms of UC must be recorded during the screening period.  The e-diary entries 
will be reviewed by site personnel during screening.  Because the colonoscopy/flexible 
sigmoidoscopy and bowel cleansing preparations can 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 4.
The endoscopy and the stool frequency and rectal bleeding subscores will be 
considered, along with other PGA components, when determining the PGA for the MCS 
calculation at Day 1 (i.e., prior to initiation of study drug), as described in detail in 
Appendix 4.


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Figure 4
Overview of Screening Activities
Note:  Endoscopy should be performed 416 days prior to Day 1.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before Day 1.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2.1.1
Re-Testing for Laboratory Inclusion and Exclusion Criteria
Two re-tests are permitted for laboratory inclusion and exclusion criteria.  If a patient 
does not meet laboratory criteria for a third time, he or she will be considered a 
screen failure.  
Laboratory testing that is repeated because of administrative or technical issues 
(e.g., breakage of a sample vial during transit to the central laboratory or degradation of 
a sample during transportation) is not considered to be re-screening.
4.5.2.1.2
Re-Screening
Re-screening is required if a patient has not met all the eligibility criteria within 35 days 
after the original screening visit.  Patients who are found to be ineligible for entry into the 
study may be re-screened once onlyfor example, if the patient develops additional 
manifestations of UC, a worsening of existing manifestations at a later time, if patients’ 
clinical status has changed such that the abnormal laboratory value may be directly 
affected (e.g., transfusion).  Each patient must be re-consented before re-screening 
occurs.


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Re-screening is not required for the HIV preliminary and confirmatory tests, HCV 
antibody test, and hepatitis B assessment (i.e., HBsAg, HBcAb, and, if required, HBV 
DNA), provided that the following criteria are met:

Test results are available from the initial screening 

Eligibility criteria for the assessments are satisfied

Date of the initial screening assessment was 6 weeks prior to Day 1 following the 
second screening

In the investigator’s judgment, the patient is not deemed to have been at risk for HIV, 
hepatitis C, or hepatitis B infection (based on medical history, or geographical or 
social circumstance)
As described in Section 4.5.1.5, if a negative TB screening test result has been 
documented within 3 months before screening or re-screen, no repeat test is required.
The screening endoscopy and colonic biopsies do not need to be repeated during 
re-screening provided that all of the following criteria are met:

All endoscopy-related inclusion criteria have been met

The initial endoscopy has been performed within 28 days prior to Day 1 following 
the second screening

Colon biopsies as specified by the protocol have been obtained
If the initial screening endoscopy does not meet the conditions outlined above, the 
endoscopy and protocol-specified colon biopsies should be repeated 416 days prior 
to Day 1.
Re-Screening in the Event Of Screen Failure due to C. Difficile or CMV 
Infection
Patients who are classified as screen failures due to the presence of C. difficile or CMV 
infection may be re-screened 60 days after successful treatment.  For patients who 
screen failed due to CMV infection, laboratory analysis of CMV from colon biopsy 
sample is required during re-screening evaluation to rule out CMV infection.
See Appendix 1 for the schedule of screening and pretreatment assessments.
4.5.2.2
Assessments during Treatment
All assessments will be performed on the day of the specified visit, except where a time 
window is specified.  Assessments scheduled on the day of study drug administration 
should be performed prior to dosing, unless otherwise noted.  When study drug 
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.


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For induction (Week 10) and maintenance (Week 62) visits that are associated with an 
MCS requiring endoscopy, every effort should be made to schedule the endoscopy on 
the same day as the clinic visit.  If this is not possible, endoscopy should be performed 
as close to the clinic visit as possible, with a maximal window of 3 days prior to and 
5 days after the visit.  The endoscopy score should be considered when determining the 
PGA (as applicable), a component of the MCS (see Appendix 4).
On a number of occasions during the Maintenance Phase (see Appendix 1 and Figure 3), 
patients will be contacted by telephone for the purpose of study assessment, rather than 
making a clinic visit.  During these telephone visits, data will be collected as for a clinic 
visit with the exception of blood sample and in clinic PRO assessments (see Appendix 1, 
Schedule of Assessments).  All adverse events and concomitant medications will be 
recorded and the patient questioned regarding a potential clinical relapse.  An 
unscheduled visit is to be conducted as required (see Section 4.5.2.5).
All patients will receive hands-on training in use of the e-diary and tablet.  Patients will 
also be instructed to contact the site promptly if they have any questions about the use 
of the e-diary during screening or at any time during the study.
See Appendix 1 for the schedule of assessments performed during the treatment period.
4.5.2.3
Assessments at Study Completion/Early Withdrawal from 
Treatment Visit
The completion of study treatment period is defined as the Week 62 visit. Patients who 
complete the treatment medication will be asked to visit the clinic for Week 62 
assessments.  Eligible patients who consent to receive open-label etrolizumab in 
Part 1 (OLE) of Study GA28951 are to receive their first dose of open-label etrolizumab 
4 weeks after their last dose of study medication in this study.  On occasions where this 
first dose of etrolizumab in Part 1 (OLE) of Study GA28951 cannot be administered in 
accordance with these requirements, the first dose of etrolizumab is to be administered 
with a maximum delay of 2 weeks from the scheduled dosing day in Study GA28951. 
If a patient leaves the study prior to Week 62, an early withdrawal from treatment visit is 
to be conducted at his or her next scheduled visit, including for those patients who are 
enrolling in Study GA28951 (OLE-SM).  Assessments are specified in the Schedule of 
Assessments in Appendix 1.  Following completion of assessments at this early 
withdrawal from treatment visit, eligible patients are to receive their first dose of open-
label etrolizumab in Part 1 (OLE) of Study GA28951 4 weeks after their last dose of 
study medication in this study, with a maximum delay of 2 weeks from the scheduled 
dosing day in Study GA28951.
At any timepoint, patients who are not eligible or who choose not to enroll in Part 1 (OLE) 
of Study GA28951 are to enroll in Part 2 (SM) of Study GA28951 for extended PML 
follow-up after completion of the 12-week safety follow-up in this study.


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Patients who were treated with prohibited medication are to have their early withdrawal 
from treatment visit at their next scheduled visit followed by the 12-week safety follow-up 
phase of this study (telephone call at Week 6 and clinic visit at Week 12; see 
Appendix 2).  Patients are to enroll in Part 2 (SM) of Study GA28951 for extended 
PML monitoring.
4.5.2.3.1
Eligibility for Entry to Open-Label Extension and Safety 
Monitoring Study
The OLE-SM (Study GA28951) study will be conducted under a separate protocol and 
eligible patients as described below (also see Table 4) will need to be willing and able to 
provide separate informed consent to enter this study. 
Note:  Patients who are not eligible or who do not wish to receive open-label etrolizumab 
in Part 1 (OLE) of Study GA28951 will be requested to enroll in the 92-week extended 
PML monitoring (Part 2 [SM] of Study GA28951) after completing the 12-week safety 
follow-up in this study.
The following patients may be eligible to enroll in Part 1 (OLE) of Study GA28951:

In the Induction Phase, any patients who requires initiation of an 
immunosuppressant (ASA, 6-MP, MTX), corticosteroid, or oral or topical 5-ASA, or 
increase in dose of these medications over baseline levels for treatment of 
worsening disease symptoms may enroll in Part 1 (OLE) of Study GA28951 after 
the Week 10 assessment, if eligible.

Patients who do not achieve a clinical response at Week 10

Patients who meet the criteria for relapse (see Section 3.1.1.1 for definition) at any 
time between Week 10 and Week 62 

Patients who were not receiving corticosteroids at baseline and patients who have 
completed the steroid taper may be eligible for Part 1 (OLE) of Study GA28951 if 
they receive oral corticosteroids at a dose greater than 10 mg for 5 days or longer 
for the treatment of clinical symptoms of either UC or steroid withdrawal.

Patients who use IV or topical corticosteroids, who use topical 5-ASA, or who initiate 
or escalate dose of oral 5-ASA to treat worsening symptoms of UC in the 
Maintenance Phase

Patients who require initiation of or an increase in the dose of immunosuppressants 
during the Maintenance Phase 

All remaining patients at end of Week 62


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The following patients are NOT eligible to enroll in Part 1 (OLE) of Study GA28951:

Patients who discontinue study treatment prior to Week 10 or do not perform the 
Week 10 visit

Patients who require rescue medications that are prohibited in conjunction with 
etrolizumab (see Section 4.3.2.2)

Patients with severe hypersensitivity reactions (see Section 4.6.1.1), specific 
malignancies, specific de novo or reactivated serious viral infections, PML, or other 
life-threatening infections during the study (see Table 5 and Sections 4.6.1.1
and 5.1.5)


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Table 4
Eligibility for Enrollment into Part 1 (OLE) of Study GA28951 or Transfer to 12-Week Safety Follow-Up
Time Period
Rationale
May Enroll in Part 1 (OLE), if 
Eligible (from Week 10 Onward)
Must Transfer to 12-Week 
Safety Follow-Up of this 
Study
Day 1 to Week 10
Initiation of an immunosuppressant (AZA, 6-MP, MTX) oral or 
topical 5-ASA, or corticosteroid, or increase dose in these 
medications over baseline levels
Yes (may enroll at the 10-week 
timepoint)
Yes (must transfer to SFU if 
patient does not 
choose OLE)
Week 10
Did not achieve a clinical response at Week 10
Yes
Week 10 to Week 62
Met criteria for clinical relapse (see Section 4.4.3) at any time 
between Week 10 and Week 62
Yes
Yes (must transfer to SFU if 
patient does not choose to 
receive study medication in 
Maintenance Phase or to 
participate in OLE)
Day 1 to Week 62
Use of oral corticosteroids at a dose greater than 10 mg for 
5 days or longer for patients who were not receiving 
corticosteroids at baseline and patients who have completed the 
steroid taper
Yes
Day 1 to Week 62
Use of IV or topical corticosteroids or oral or topical 5-ASA,or 
increase in dose of oral 5-ASA over baseline level
Yes
Week 62
End of treatment period (all remaining patients) 
Yes
Yes (must transfer to SFU if 
patient does not 
choose OLE)
Day 1 to Week 10
Discontinuation of study treatment or missing the Week 10 visit
No
Yes (after dosing 
termination visit)
Day 1 to Week 62
Patients requiring rescue medications that are prohibited 
(see Section 4.3.2.2)
No
Day 1 to Week 62
Occurrence of severe hypersensitivity reactions (see 
Section 4.6.1.1), specific malignancies, specific de novo or 
reactivated serious viral infections, PML or other life-threatening 
infections during the study (see Table 5 and Sections 4.6.1.1 and 
5.1.5)
No
5-ASA5-aminosalicylic acid; 6-MP6-mercaptopurine; AZAazathioprine; IVintravenous; MTXmethotrexate; OLEopen-label extension; 
PMLprogressive multifocal leukoencephalopathy; SFUsafety follow-up.


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4.5.2.4
Safety Follow-Up Assessments
Safety follow-up will be conducted in this study for a period of 12 weeks for patients not 
enrolling in Part 1 (OLE) of Study GA28951 (see Table 4 for patients who should enter 
the 12-week safety follow-up phase within this protocol, Appendix 2).  Patients will be 
assessed at 6-week intervals during this period, one assessment by telephone and one 
in-person clinic visit.  The visits should be scheduled based on the date of the last dose 
of study drug (e.g., the Week 6 telephone visit should take place 6 weeks after the last 
dose of study drug).  Patients enrolling in Part 1 (OLE) of Study GA28951 will not enter 
the 12-week safety follow-up period in this study.  Adverse events should be followed as 
outlined in Section 5.4.
Following the 12-week safety follow-up period, patients should enroll in Part 2 (SM) of 
Study GA28951 where they will be monitored for PML for an additional 92 weeks.  
Patients enrolling in Part 2 (SM) for the extended PML monitoring will NOT receive 
treatment with open-label etrolizumab.  During the extended PML follow-up period in 
Study GA28951, patients will have telephone assessments every 6 months to assess 
emergence of symptoms and signs of PML.  In total, follow-up for the development of 
any signs or symptoms of PML will be conducted for a period of 2 years after last dose 
of study drug.
Patients who discontinue from the study prior to completion of the 12-week safety 
follow-up will be asked to return to the clinic within 30 days (7 days) after the last dose 
of study drug or last scheduled visit for an early termination visit (see Appendix 2).
See Appendix 1 for the schedule of assessments performed at the study 
completion/early withdrawal from treatment visit.
After the study completion adverse events should be followed as outlined in Sections 5.5
and 5.6.
See Appendix 2  for the schedule of 12-week Safety Follow-Up assessments.
4.5.2.5
Assessments at Unscheduled Visits
An unscheduled visit may occur at any time during the study, (i.e., due to relapse of 
disease or an adverse event).  Patients who are seen by the investigator or site staff at a 
timepoint not required by the protocol because of assessment of potential relapse will 
undergo the following:

Review of e-diary data

Recording of concomitant medications and procedures

Collection of adverse events and serious adverse events

Clinical chemistry, hematology, and CRP, if indicated

Stool sample collection, if indicated

Partial or complete MCS, if indicated


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Flexible sigmoidoscopy, if indicated

Colonic biopsy to evaluate for CMV, if clinically indicated

Collection of PK and ATA sample, if indicated
See Appendix 1 for assessments that are required to be performed in case of an 
unscheduled visit. 
4.6
PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
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 or 
non-adherence with background medications
4.6.1.1
Discontinuation from Study Drug
Patients must discontinue study drug if they experience any of the following:

Pregnancy

Anaphylaxis or other severe hypersensitivity reaction

Develop colonic mucosal dysplasia

Malignancy (with the exception of local and resected basal or squamous cell 
carcinoma of the skin) or cervical Pap test with AIS, HSIL, or CIN of Grade 1

Specific serious infection (see Table 5 for details on serious infection):
Any patient who experiences a de novo or reactivated serious viral infection, such 
as HBV, HCV, HIV, should discontinue study medication.
Any patient who develops life-threatening infections during the study should 
discontinue study medication.

Any medication for rescue outside defined limits of the protocol (see Section 4.3.2)


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Patients who discontinue study drug prematurely for the reasons listed above will be 
asked to return to the clinic for a study drug completion/early withdrawal from treatment
visit (see Section 4.5.2.3) and will continue to undergo safety follow-up assessments for 
12 weeks within this study.  Patients should then enroll in Part 2 (SM) of Study GA28951
for 92 weeks of monitoring for PML (see Section 4.5.2.4).  The primary reason for 
premature study drug discontinuation should be documented on the appropriate eCRF.  
Patients who discontinue study drug prematurely will not be replaced.
4.6.1.2
Withdrawal from Study
Every effort should be made to obtain information on patients who withdraw 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.
4.6.2
Study and Site Discontinuation
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.

Patient enrollment is unsatisfactory.
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:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
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. 


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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 is not known at this time and will be further 
characterized during the etrolizumab Phase III program.  
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 for a complete 
summary of safety information.
5.1.2
Progressive Multifocal Leukoencephalopathy
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.
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, given the observation of PML risk with 
natalizumab, the Sponsor will continue to conduct extensive risk-monitoring procedures 
during the Phase III trials.
5.1.2.1
Screening and Patient Selection
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.  At study screening, patients with a history of demyelinating disease, PML, or 
clinically significant abnormalities noted on baseline neurologic examination will be 
excluded from the study.  Patients who have received natalizumab, efalizumab, or 
rituximab will also be excluded.


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A blood sample to test for antibodies to JCV will be taken and stored for possible later 
assessment of how widespread the JCV infection is in the study population.  Sample 
testing for the presence of JCV antibodies is not helpful in predicting risk for PML or for 
evaluating neurologic symptoms.  The sample may be tested if there is a strong belief 
that this information will be helpful in managing a patient's condition.
5.1.2.2
Monitoring and Management
Study site personnel and patient participants will be educated regarding the signs and 
symptoms of PML and provided with alert cards.  Close monitoring during the course of 
the study for any new signs or symptoms suggestive of PML will be performed with 
regular neurologic examinations (including evaluation of cranial nerves, motor and 
sensory function, coordination, and mental status) 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 5) by a 
qualified HCP and will be performed at screening and as indicated on the Schedule of 
Assessments (see Appendix 1).
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 5.2.3 and Appendix 6 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 by PCR.  If JCV 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.  See Appendix 6 for the 
Algorithm for Evaluation of Progressive Multifocal Leukoencephalopathy.
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).


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5.1.3
Monitoring for Other Serious Infections
Patients will also be monitored closely for other serious infections during the study 
(see Table 5 for details).  Patients and investigators will 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.
5.1.4
Monitoring for Hypersensitivity Reactions
In addition, throughout the study, patients will be monitored closely for hypersensitivity 
reactions (see Table 5 for details).  Patients should be instructed to recognize the 
symptoms of any anaphylactic, anaphylactoid, or hypersensitivity reaction and to contact 
an HCP or seek immediate care in case of any such symptoms.  Patients will be 
provided with alert cards to remind them and a caregiver or partner of the symptoms.


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5.1.5
Management of Specific Adverse Events
Table 5
Guidelines for Managing Specific Adverse Events
Action to Be Taken
Serious Infections

Patients who experience a serious infection event (i.e., an infection that is a serious adverse 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.

Any patient who experiences a de novo or reactivated serious viral infection such as HBV, HCV, HIV, should 
immediately 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 therapy requires 
consultation with the Medical Monitor.

Patients who develop life-threatening infections during the study should discontinue study drug.
Signs and symptoms of possible 
PML
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, then the investigator is required to follow the 
process described in the PML algorithm (see Appendix 6).  If PML is suspected, a neurology consultation should be 
promptly arranged.  Based on this evaluation, brain magnetic resonance imaging and cerebral-spinal fluid JCV 
analysis may be performed (see Appendix 6).
The following are signs and symptoms that may potentially indicate PML:

Alteration in mental status (cognitive changes, including confusion, difficulty concentrating, memory loss) and 
altered behavior (including personality changes)

Higher cortical dysfunction, including impaired comprehension and/or formulation of language (aphasia), loss of 
ability to recognize objects, persons, sounds, shapes, or smells (agnosia)

Visual changes, including loss of visual fields (homonymous hemianopsia), double vision (diplopia)

Motor deficits, including weakness (hemiparesis, monoparesis), seizures, (generalized or partial), difficulties with 
speech (dysarthria,) or swallowing (dysphagia)


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Table 5
Guidelines for Managing Specific Adverse Events (cont.)
Action to Be Taken
Signs and symptoms of possible 
PML (cont.)

Sensory deficits, including sensory loss (paresthesia)

Coordination deficits, including difficulty walking and maintaining balance (ataxia), lack of voluntary coordination 
of limb movement (limb ataxia)
If PML is suspected then all investigational treatment should be withheld in that patient and may only be restarted if it 
is confirmed that the patient does not have PML.
Vaccinations
For 4 weeks prior, during, and for 12 weeks after the last dose of study medication, patients should not receive live 
vaccines.
Malignancies

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.

If any dysplasias or abnormalities are noted that could be consistent with malignancy, an oncologist or 
appropriate specialist should be consulted and no further doses of investigational product should be 
administered until a thorough clinical evaluation has been completed.

Patients who develop a malignancy (with the exception of local and resected basal or squamous cell carcinoma 
of the skin), or who develop adenocarcinoma in situ, high-grade squamous intraepithelial lesions, or cervical 
intraepithelial neoplasia 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.
Hepatic effects
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.

Patients with significant liver function test abnormalities should be excluded from the etrolizumab clinical 
studies.

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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Table 5
Guidelines for Managing Specific Adverse Events (cont.)
Action to Be Taken
Hypersensitivity reactions
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.

Patients with a history of moderate or severe allergic or anaphylactic/anaphylactoid reactions to chimeric, 
human, or humanized antibodies, fusion proteins, or murine proteins are excluded from study participation.

The first four injections will be administered in the clinic.  After the first four injections, the patient must be 
monitored for 60 minutes after each injection.

Health care professionals administering the study medication in the clinic must be trained in the appropriate 
administration procedures and be able to recognize the symptoms associated with potential anaphylactic, 
anaphylactoid, or hypersensitivity reactions and should be familiar with Sampson’s criteria for defining 
anaphylaxis (Sampson et al. 2006; see Appendix 8).

Investigators and HCPs should also be trained to accurately and appropriately report these events immediately 
to the Sponsor as adverse events of special interest and as serious adverse events, if appropriate 
(see Section 5.2).

Medicinal products for the treatment of hypersensitivity reactions (e.g., epinephrine, antihistamines, and 
glucocorticoids. Epinephrine must be readily available for immediate use if required to treat 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.

If a patient has symptoms of anaphylaxis or severe hypersensitivity, the administration of etrolizumab must be 
discontinued permanently.

HCPs should also instruct patients how to recognize the symptoms of any anaphylactic, anaphylactoid, or 
hypersensitivity reaction and to contact a HCP or seek emergency care in case of any such symptoms.

Subsequent injections can be administered at home.  The patient will be advised to seek emergency care in 
response to any potential symptom of hypersensitivity and will receive two alert cards to remind them and a 
caregiver or partner of the symptoms.
Detailed information regarding anaphylactic, anaphylactoid, or hypersensitivity reactions that occur during the study 
will be collected, regardless of whether the events are serious (see Section 5.2.2) or non-serious (see Section 5.2.3).


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Table 5
Guidelines for Managing Specific Adverse Events (cont.)
Action to Be Taken
Local injection-site reactions
A local injection-site reaction is any local reaction occurring at the site of injection following study drug 
administration.  In completed Phase I/II studies in patients with UC, injection-site reactions were reported at a 
rate of 10%, all of which were of mild intensity. In the clinic setting, patients will 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 patient leaves clinic.
Pregnancies
Patients who become pregnant should be withdrawn from study drug and followed-up for the duration of the 
pregnancy (see Section 5.4.3 for details).
CMVcytomegalovirus; HBVhepatitis B virus; HCPhealth-care professional; HCVhepatitis C virus; JCVJohn Cunningham virus; PMLprogressive 
multifocal leukoencephalopathy.


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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest; performing 
protocolspecified safety laboratory assessments; measuring protocolspecified vital 
signs; and conducting 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 5.4.
5.2.1
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) (see Sections 5.3.5.8
and 5.3.5.9)

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., screening invasive 
procedures such as biopsy sample collection)
5.2.2
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 5.4.2 for 
reporting instructions).  A serious adverse event is any adverse event that meets any of 
the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is 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 5.3.5.10)


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
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)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a 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 (e.g., rated as mild, moderate, or severe or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] criteria; 
see Section 5.3.3); 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.
5.2.3
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 5.4.2 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 5.3.5.6) 

Suspected transmission of an infectious agent by the study drug 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 5.1.5 and Sampson’s Criteria in Appendix 8)
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 6 and Table 5)


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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 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 5.4, 5.5, and 5.6.  
The investigator is also responsible for reporting medical device complaints 
(see Section 5.4.4).
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
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.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocolmandated intervention (e.g., serious 
adverse events related to invasive procedures such as biopsies, discontinuation of 
medications) should be reported (see Section 5.4.2 for instructions for reporting serious 
adverse events).
After initiation of study drug, all adverse events, regardless of relationship to study drug, 
will be reported until the patient completes his or her last study visit.  After this period, 
patients who enter the GA28951 study should follow the adverse event reporting 
requirements of that study.
If the patient does not enter the GA28951 study, the Sponsor should be notified if the 
investigator becomes aware of any post-study serious adverse events that are believed 
to be related to prior study drug treatment.  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 (see Section 5.6).
5.3.2
Eliciting Adverse Event Information
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?”


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5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 6 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 6
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 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
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.  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 reintroduction 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


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
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 7
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
An adverse event will be considered related, unless it fulfills 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 2 days after 
first dose of study drug).
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF; the use of colloquialisms and abbreviations should 
be avoided.
Only one adverse event term should be recorded in the event field on the Adverse 
Event eCRF.
5.3.5.1
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 following study drug injection should be separately captured as individual signs 
(e.g., erythema, induration/swelling at injection site) or 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 


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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.
5.3.5.2
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.  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 gastrointestinal 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.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should be recorded only once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should be recorded on the Adverse Event eCRF.  
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 5.4.2 for 
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.


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5.3.5.4
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:

Is 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

Is 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 ULN associated with cholecystitis), only the 
diagnosis (i.e., cholecystitis) should be recorded on the Adverse Event eCRF.
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 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.5
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:

Is 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

Is 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.


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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 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.6
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
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 5.3.5.1) 
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 5.4.2).
5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  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 UC, "ulcerative colitis progression” should be 
recorded on the Adverse Event eCRF.
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.


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5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
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”).
5.3.5.9
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”).
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Section 5.2.2), 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 
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5.3.5.11
Adverse Events Associated with an 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 incorrect administration of study drug is not 
an adverse event unless it results in untoward medical effects.
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF.
All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).
5.3.5.12
Patient-Reported Outcome Data
Adverse event reports will not be derived from 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. 
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
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.  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 (defined in Section 5.2.2; see Section 5.4.2 for further
details on reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
further details on reporting requirements)

Pregnancies (see Section 5.4.3 for further details on reporting requirements)
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


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
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.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information
Primary Contact
Medical Monitor:
, M.B., Ch.B.
Primary:
1 973 659 6677
Secondary:
1 570 819 8565
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Quintiles Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Quintiles 
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, as well as Medical Monitor contact 
information, will be distributed to all investigators.
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
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 using the fax number or 
email address provided to investigators.
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until the patient completes his or her last study visit.  
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.


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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 number 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.
Instructions for reporting serious adverse events that occur after the final dose of study 
treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
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 final 
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.
5.4.3.2
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 final 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 
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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.
5.4.3.3
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 5.4.2).
5.4.3.4
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 5.4.2).
5.4.4
Reporting Requirements for Medical Device Complaints
See Section 4.3.6 for reporting requirements for medical devices.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
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 trial-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.
5.5.2
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.


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5.6
POST-STUDY ADVERSE EVENTS
Patients who enter the GA28951 study should follow the adverse event reporting 
requirements for that study.
Post-study, if the patient does not enter the GA28951 study, the Sponsor should be 
notified if the investigator becomes aware of any serious adverse event occurring after 
the end of the adverse event reporting period (defined as the last study visit [see 
Section 5.3.1]) if the event is believed to be related to prior study drug treatment.  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.
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 investigators.
5.7
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 using 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 study and 
assessed as unexpected per the reference safety information will be considered 
Suspected Unexpected Serious Adverse Reactions (SUSARs) for the purpose of 


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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 
New Drug Application (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’).”
To satisfy local regulatory reporting criteria while maintaining the blind, investigators will 
be informed of all unexpected serious adverse events regardless of study drug 
assignment (i.e., they may also receive reports of patients on placebo).
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The analysis of data from the 62-week treatment period will be performed when all data 
from this period are in the database and data have been cleaned and verified.
Whereas Sponsor personnel will be unblinded to treatment assignment to perform the 
primary Week-62 analyses, patients and study site personnel will remain blinded to 
individual treatment assignment during the Maintenance Phase until after the study is 
completed (after all patients have either completed the safety follow-up period or 
discontinued early from the study) and the database is locked.
Detailed specifications of the statistical methods will be described in the Statistical 
Analysis Plan (SAP).
6.1
DETERMINATION OF SAMPLE SIZE
The study sample size was selected so that sufficient patients are enrolled to evaluate 
the primary endpoint in the Maintenance Phase.  Approximately 350 patients will be 
enrolled in the open-label Induction Phase. 
Under the assumption of clinical response at Week 10 of approximately 60% (based on 
the Phase II Week 10 response results for the TNF-naive subgroup), the planned size of 
350 patients in the open-label Induction Phase would provide approximately 210 patients 
randomized into the Maintenance Phase.  A sample size of approximately 105 patients 
per arm is required in the Maintenance Phase to achieve 90% power to detect a 25% 
absolute difference in remission rates between the etrolizumab and placebo arms, for a 
2 test at the two-sided 5% significance level, under the assumption of a placebo true 
remission rate of 30%45%.  If clinical response rates at Week 10 are lower than 
projected, the total enrollment in the open-label induction cohort may be increased to 
ensure that a sufficient number of Week-10 clinical responders are randomized into the 
Maintenance Phase.


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6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients enrolled in the open-label induction and the number of patients 
randomized into the Maintenance Phase will be tabulated by country, study site, and 
treatment arm (for the Maintenance Phase).  Patient disposition (the number of patients 
enrolled, randomized, treated, and completing each study period) will be tabulated by 
treatment arm.  Reasons for premature study drug discontinuation or withdrawal from 
study, any eligibility criteria deviations, and other major protocol deviations will be 
summarized by treatment arm.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics such as age, sex, race, region, use of 
corticosteroids and immunosuppressants, duration of disease, and MCS and its 
subscores will be summarized for all enrolled patients as well as for patients randomized 
into the Maintenance Phase by treatment group with use of descriptive statistics.  
Exposure to open-label etrolizumab/study drug (number of study treatments and 
duration of treatment) will be summarized.
6.4
EFFICACY ANALYSES
Analyses of the efficacy endpoints will include all patients randomized into the 
Maintenance Phase (i.e., patients who achieved a clinical response at Week 10 in the 
open-label Induction Phase) with patients grouped according to the treatment assigned 
at randomization (intent-to-treat population).
To manage the overall type I error, the primary and secondary endpoints in the 
Maintenance Phase will be tested sequentially.  Each endpoint will be tested at a 
two-sided 5% significance level.  The testing hierarchy for the secondary endpoints will 
be described in the SAP.
Patients who are non-evaluable for efficacy at a specific timepoint (e.g., because of 
missing data or transfer to the OLE treatment protocol) will be considered 
non-responders for all response/remission type endpoints.  In addition, for the 
Maintenance Phase, patients who initiated an agent not allowed in combination with 
etrolizumab (see Section 4.4.2), an immunosuppressant or corticosteroid (administered 
for the treatment of UC), or who had an increase in dose over baseline levels for 
treatment of worsening disease symptoms will be considered non-responders thereafter.  
In the Induction Phase, initiation of an agent not allowed in combination with etrolizumab, 
an immunosuppressant, oral or topical 5-ASA, or corticosteroid, or an increase in dose 
over baseline levels will lead to non-responder classification.
For continuous outcomes (e.g., IBDQ, UC-PRO/SS), scores after the first use of rescue 
medication will be imputed using the worst post-baseline score from the following 
assessments:  the last score available prior to the start date of first rescue medication 
and all scores available after the start date of rescue medication use.


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In addition to the analyses described herein and in Section 6.4.1 and Section 6.4.2, the 
following analyses will be performed for the primary efficacy endpoint and key secondary 
efficacy endpoints.  Details of these analyses will be described in the SAP:

Sensitivity analyses to evaluate the robustness of results to the primary analysis 
methods (e.g., handling of dropouts)

Subgroup analyses to evaluate the consistency of results across prespecified 
subgroups (e.g., based on age, sex, race/ethnicity, baseline UC medications, 
baseline corticosteroid dose)
Further details, including additional missing data handling rules, and further definitions 
of exploratory endpoints will be provided in the SAP.
6.4.1
Primary Efficacy Endpoint
The primary endpoint for the Maintenance Phase is Week 62 remission among patients 
with a clinical response at Week 10. Patients who are randomized into the 
Maintenance Phase (i.e., clinical responders at Week 10) will be evaluated. The 
difference in remission rates between the etrolizumab and placebo arms will be 
compared using the Cochran-Mantel-Haenszel test statistic stratified by concomitant 
treatment with corticosteroids at baseline (yes/no), concomitant treatment with 
immunosuppressants after Week 10 (yes/no), and baseline disease activity (MCS 9, 
MCS 10).  The absolute difference in remission rates and 95% CIs for the point 
estimate will be provided.
6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints for the Maintenance Phase are as follows:

Proportion of patients in clinical remission at Week 62 among patients in clinical 
remission at Week 10 

Proportion of patients in clinical remission at Week 62

Proportion of patients in remission at Week 62 among patients in remission at 
Week 10

Proportion of patients with improvement in endoscopic appearance of the mucosa at 
Week 62

Proportion of patients in endoscopic remission at Week 62

Proportion of patients in histologic remission at Week 62

Change from baseline in rectal bleed subscore at Week 6

Change from baseline in stool frequency subscore at Week 6

Proportion of patients in corticosteroid-free remission at Week 62 (off corticosteroids 
for at least 24 weeks prior to Week 62) in patients who were receiving 
corticosteroids at baseline


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
Proportion of patients in corticosteroid-free clinical remission at Week 62 (off
corticosteroids for at least 24 weeks prior to Week 62) in patients who were
receiving corticosteroids at baseline

Change from baseline to Week 62 in UC bowel movement signs and symptoms as
assessed by the UC-PRO/SS measure

Change from baseline to Week 62 in UC abdominal symptoms as assessed by the
UC-PRO/SS measure

Change from baseline to Week 62 in health-related QOL, as assessed by the overall
IBDQ score.
All the responder/remitter type secondary endpoints will be analyzed in the same fashion 
as the primary endpoint.  The continuous secondary endpoints will be analyzed using an 
analysis of covariance (ANCOVA) model with Week 10 remission status, concomitant 
treatment with corticosteroids, concomitant treatment with immunosuppressants, 
baseline disease activity (MCS 9, MCS 10) as stratification variables, and the 
baseline value of the studied measure as a covariate.
6.4.3
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints are as follows:

Proportion of patients with a clinical response at Week 62 among patients with 
clinical response at Week 10

Proportion of patients with remission at Week 62 among patients in clinical 
remission at Week 10

Proportion of patients in corticosteroid-free clinical remission at Week 62 (off 
corticosteroids for at least 12 weeks prior to Week 62) in patients who are receiving 
corticosteroids at baseline

Proportion of patients with change in histologic disease activity from baseline to 
Week 10 and Week 62

Proportion of patients with improvement in histologic and/or endoscopic disease 
activity

Proportion of patients with improvement in endoscopic appearance of the mucosa at 
Week 10

Proportion of patients with endoscopic remission at Week 10

Frequency and duration of hospitalizations from Week 10 to Week 62

Proportion of patients with response, remission and corticosteroid-free endpoints as 
determined by the mMCS 
The endpoints listed above will be analyzed using the same statistical methods as the 
primary endpoint.

Change in health utilities, as assessed by the EQ-5D, from Week 10 to Week 62

Change in histologic disease activity, from baseline to Week 10 to Week 62 


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These endpoints will be analyzed using the same statistical methods as the UC/PRO 
and IBDQ continuous endpoints.
6.5
SAFETY ANALYSES
The safety analyses will include all patients who received at least one dose of study drug 
in the Induction Phase.  Separate summaries of adverse events will be provided for the 
open-label Induction Phase and the Maintenance Phase.
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 the incidence of antibodies 
to etrolizumab.
Additional details will be provided in the SAP.
6.5.1
Adverse Events
Verbatim descriptions of treatment-emergent adverse events will be coded and their 
incidence will be summarized by treatment arm, 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 study drug.  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 using the 
anaphylactic reaction Sampson’s criteria (see Appendix 8).

Serious infections
The frequency of serious infections, in particular GI infections, will be 
summarized for each treatment arm.

Opportunistic infections
The occurrence of opportunistic infections will be summarized for each 
treatment arm.

Malignancies
Events that occur in the Neoplasms, Benign, Malignant, and Unspecified 
(Including Cysts and Polyps) System Organ Class will also be summarized for 
each treatment arm.

Injection-site reactions
The frequency of injection-site reactions will be summarized for each 
treatment arm.


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6.5.2
Laboratory Tests
Descriptive summaries of laboratory values at baseline and throughout the study will be 
tabulated by treatment arm.  For selected parameters, changes from baseline and the 
proportion of patients experiencing clinically significant changes relative to baseline will 
be summarized by treatment arm.
The number and percentage of patients with serum antibodies to etrolizumab at baseline 
and during the study will be tabulated by treatment arm.
6.6
PHARMACOKINETIC, PHARMACODYNAMIC, AND 
BIOMARKER ANALYSES
For PK assessment, group average serum etrolizumab concentration versus time data 
will be tabulated and plotted.  The serum pharmacokinetics of etrolizumab will be 
summarized with a mean serum concentration at steady state (trough) and at the 
primary endpoint time (Week 62).  Estimates for these parameters will be tabulated and 
summarized (mean, SD, coefficient of variation, median, minimum, and maximum).
Additional PK analyses may be conducted as appropriate.
PD and biomarkers analyses will include examination of changes over time in 
exploratory biomarkers after treatment.  Results will be summarized descriptively.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
Sponsor, contract research organization (CRO), and Data Management vendor will be 
responsible for the data management of this study, including quality checking of the data.  
Sites will be responsible for data entry into an 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 
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 in the 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.


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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 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 
ePRO 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 all the study documentation.
Details regarding patient-reported data and the electronic device are 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.
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, PRO questionnaires, 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 


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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 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 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 


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Application will comply with FDA regulations and applicable local, state, and federal laws.  
Studies conducted in the European Union/European Economic Area will comply with the 
E.U. 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 Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  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 allow 
any remaining specimens to be used for exploratory research.  Patients who decline to 
participate will not provide a separate signature.
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 
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.


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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.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only 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 FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.


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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).
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 include 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.
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.


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9.4
ADMINISTRATIVE STRUCTURE
This trial is sponsored by F. HoffmannLa Roche Ltd.  Approximately 125 international 
study centers will participate in this study to enroll approximately 350 patients.
A CRO will be contracted to manage the study and perform monitoring activities.
Centralized facilities (vendors) will be used to collect QOL data and endoscopy reading 
and interpretation; however, the investigator or a designee will also read the endoscopy 
if required for clinically indicated safety reasons.
A central laboratory (i.e., Roche or a vendor) will be used for most laboratory 
assessments, including histologic grading of colonic biopsy samples per the laboratory 
manual.  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.
An iDMC will be established to perform regular review of the safety data to ensure the 
ongoing safety of participating patients.  Its composition and a description of its 
responsibilities will be provided in an iDMC charter.
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.
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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.
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
Schedule of Assessments
Assessments
Screening 
Day a
35 to1
Study Week (3 days)
0 b
4
8
10
12 16 20 24
28 c
32
36 c
40 c
44
48 c 52 c 56 60 c
62
Unscheduled 
Visit d
Early 
Withdrawal  
from 
Treatment 
Visit
Informed consent
x
Review eligibility criteria
x
x e
Demographic data
x
Pregnancy test f
x
x e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
X
Vital signs (BP and 
pulse)
x
x e
x
x
x
x
x
x
x
x
x
x
X
ECG
x
x
X
Chest X-ray g
x
Height 
x
Weight
x
Medical history
x
Physical examination h
x
x
x
x
x
x
x
X
PML neurologic 
examination i
x
x
x
x
x
x
x
x
x d
X
Hematology
x
x e
x
x
x
x
x d
x j
Chemistry
x
x e
x
x
x
x
x d
x j
Urinalysis
x
x e
x d
TB screen k
x


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Schedule of Activities (cont.)
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Assessments
Screening 
Day a
35 to1
Study Week (3 days)
0 b
4
8
10
12 16 20 24
28 c
32
36 c
40 c
44
48 c 52 c 56 60 c
62
Unscheduled 
Visit d
Early 
Withdrawal  
from 
Treatment 
Visit
HIV test
x
Hepatitis B and C 
serology l
x
Hepatitis B DNA m
x
x
x
x
x
x
Hepatitis C RNA 
(Amplicor) n
x
Flow cytometry
x
x
x
PK sampling (serum) o
x
x
x
x
x
x d
x j
Anti-therapeutic 
antibody sample 
(serum) o, p
x
x
x
x
x
x q
x d
x j, q
Plasma sample r
(storage for JCV 
antibody testing)
x
MCS (includes 
endoscopy) s, t
x u
x
x
x d
x j
pMCS (excludes 
endoscopy) v
x u
x
x
x
x
x
x
x
x
x
x d
x j
Stool sample
x w
x x
x x
x x
x d
xx


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Schedule of Activities (cont.)
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Assessments
Screening 
Day a
35 to1
Study Week (3 days)
0 b
4
8
10
12 16 20 24
28 c
32
36 c
40 c
44
48 c 52 c 56 60 c
62
Unscheduled 
Visit d
Early 
Withdrawal  
from 
Treatment 
Visit
Colonic biopsy (CMV if 
required)
x y
x d
Colonic biopsy 
(histopathological 
confirmation of UC if 
required)
x z
Colonic biopsy 
(formalin)
x aa
x bb
x bb
x d, bb
x j, bb
Colonic biopsy (RNA 
later)
x aa
x bb
x bb
x d, bb
x j, bb
Serum sample (CRP)
x e
x
x
x d
x j
Blood sample for 
genetic analysis (DNA) 
(optional)
x
Serum sample (future 
exploratory PD) o
x
x
x
x
x
X
Blood sample (RNA 
Paxgene) o, cc
x
x
x
x
X
UC-PRO/SS measure t
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
IBDQ dd
x
x
x


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Appendix 1
Schedule of Activities (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
128/Protocol GA29102, Version 7
Assessments
Screening 
Day a
35 to1
Study Week (3 days)
0 b
4
8
10
12 16 20 24
28 c
32
36 c
40 c
44
48 c 52 c 56 60 c
62
Unscheduled 
Visit d
Early 
Withdrawal  
from 
Treatment 
Visit
EQ-5D dd
x
x
x
x
Concomitant 
medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Randomization of 
responders to 
Maintenance Phase
x ee
Etrolizumab 
administration
x
x
x
Etrolizumab/ 
etrolizumab placebo 
administration ff
x
x
x
x
x
x
x
x
x
x
x
x
x
ATAanti-therapeutic antibody; BPblood pressure; CMVcytomegalovirus; CRPC-reactive protein; EQ-5DEuroQoL Five-Dimension Questionnaire; 
HBc HBV core antibody total; HBsAgHBV surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; IBDQInflammatory Bowel Disease Questionnaire; 
JCVJohn Cunningham virus; MCSMayo Clinic Score; PDpharmacodynamics; PKpharmacokinetic; pMCSpartial Mayo Clinic Score; PMLprogressive
multifocal leukoencephalopathy; qPCRquantitative polymerase chain reaction; TBtuberculosis; tc telephone call; UC-PRO/SSUlcerative Colitis 
Patient-Reported Outcome Signs and Symptoms.
Notes:  All study assessments and blood draws are to be conducted prior to study drug administration.  All colonic biopsy samples will be taken during flexible 
sigmoidoscopy/colonoscopy procedure.
a
All assessments must be performed after obtaining informed consent.  Endoscopy should be performed 416 days prior to Day 1 (i.e., Day 16 to Day 4).  The 
total screening period is 35 days. Under no circumstances will either window be extended.
b
Day 1 of Week 0.


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Appendix 1
Schedule of Activities (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
129/Protocol GA29102, Version 7
c
Telephone contact for patients performing home administration:  Patients requiring in-clinic drug administration throughout the study will have their study 
assessments conducted in clinic or via telephone call after their clinic visit at the sites’ discretion.
d
Unscheduled visit represents a visit that is not 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 of PML; for disease worsening, infectious etiologies may be investigated if clinically indicated; and confirmation of clinical 
relapse is performed by the MCS assessment).  Assessments corresponding to items noted in this column should be recorded on the eCRF.
e
Perform prior to administration of etrolizumab.
f
Serum test at screening for all female patients except those who are more than 1 year postmenopausal or have had a hysterectomy.  Urine test at other visits; if 
urine test result is positive, perform a confirmatory serum test.  Pregnancy test will be carried out at home once patient starts etrolizumab administration at home.  
Patient is to report the pregnancy test via the e-diary.  Patients must be instructed at screening and reminded throughout the study that in case of positive 
pregnancy test they must stop self-administration of study drug and call the site immediately.  Do not administer etrolizumab unless the serum pregnancy test 
result is negative.
g
Not required if normal chest X–ray result within 3 months prior to screening.
h
Full physical examination required at screening; symptom-driven physical examination at all other timepoints indicated.
i
PML neurologic examination consists of the PML Subjective Checklist and the PML Objective Checklist. Administer before other assessments, per Appendix 5.
j
Not required if unscheduled visit leads to withdrawal and assessment previously conducted at unscheduled visit.
k
The following tests are acceptable screening assays for latent TB in this study:  purified protein derivative (a tuberculin skin test reaction; e.g., Mantoux test), 
INF-based test (e.g., QuantiFERON-TB Gold).
l
Patients must undergo screening for HBV and HCV. This includes testing for HBsAg, anti-HBc, and hepatitis C antibody.
m Enrolled patients who are hepatitis B core antibody positive should have hepatitis B DNA measured at these timepoints.
n Measurement of HCV RNA with use of the Amplicor assay is required when the patient has a known history of HCV antibody positivity with past documentation 
of undetectable HCV RNA, either with or without history of anti-viral treatment.  Patients with newly diagnosed HCV antibody positivity are not eligible for this 
study and, therefore, do not require measurement of HCV RNA.
o
All samples to be collected prior to administration of etrolizumab.  Serum baseline, Week 4, and blood sample (RNA Paxgene) are to be collected prior to dose of 
etrolizumab from all patients.  All subsequent samples (serum and Paxgene whole blood) will be collected only from those who were eligible to be randomized 
into the Maintenance Phase.
p
If serum sickness or a clinically significant allergic drug reaction is suspected, Sponsor should be notified, and serum for etrolizumab level 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.
q
Collection of sample for ATA is required at final or early withdrawal visit, unless it coincides with first visit in Part 1 of Study GA28951 (where a sample for ATA 
must be collected).


Clinical Study Report: etrolizumab  - F. Hoffmann-La Roche Ltd
Protocol GA29102     Report Number 1099518
2131
Appendix 1
Schedule of Activities (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
130/Protocol GA29102, Version 7
r
A blood sample to test for antibodies to JCV will be taken and stored for possible later assessment of how widespread the JCV infection is in the 
study population.  Sample testing for the presence of JCV antibodies is not helpful in predicting risk for PML or for evaluating neurologic 
symptoms.  The sample may be tested if there is a strong belief that this information will be helpful in managing a patient's condition.
s
Endoscopy rectal bleeding assessment stool frequency assessment Physician’s Global Assessment.  Patients who have not undergone full colonoscopy 
with documented results within 1 year prior to screening should undergo colonoscopy in lieu of sigmoidoscopy at the screening visit to allow for screening for 
cancer/dysplasia (yes/no).
t
During screening, patients must be trained on the use of the e-diary.  Patients are to complete the e-diary on a daily basis for the stool frequency and rectal 
bleeding score (for MCS/pMCS), starting from the first screening visit, and for at least 912 consecutive days around the time of each scheduled visit for the 
UC-PRO/SS.
u
Screening endoscopy (for the MCS) should be performed 416 days prior to Day 1 (i.e., Day 16 to Day 4).  For baseline measurements, the Physician’s 
Global Assessment will be obtained only once, on Day 1 (prior to enrollment), and the Physician’s Global Assessment score will be used to calculate both the 
baseline (screening) MCS and the baseline (Day 1) pMCS.
v
Rectal bleeding assessment stool frequency assessment Physician’s Global Assessment.
w For culture and sensitivity testing; ova, parasites, and Clostridium difficile toxin testing.  
x
Sample analyses may include, but are not limited to, analyses of fecal calprotectin and other exploratory PD biomarkers (such as analyses of the microbiota and 
bacterial cultures).
y
IF REQUIRED:  Only if there is suspicion for clinically significant CMV colitis, one biopsy sample should be obtained from the base of the ulcer to evaluate for 
histological presence of CMV.  Analysis should be performed locally if possible, or can be sent to a central laboratory if necessary. Result must be negative for 
CMV prior to dosing on Day 1.  
z
IF REQUIRED:  If patient does not have previously documented histopathologic confirmation of UC as defined in the inclusion criteria, one biopsy sample can be 
obtained from the base of the ulcer read locally for histopathologic confirmation of UC.
aa In addition to the optional biopsy samples noted in footnote “y” and “z” above, five pairs (10 biopsy samples) will be obtained at screening.  These five biopsy 
pairs will be sent to the central laboratory for further storage or distribution.  Two pairs (taken from the most inflamed area of colon within 2040 cm of anal verge 
[sigmoid]) will be placed in stabilization buffer (such as RNAlater or a similar buffer) and stored at 80C (one pair for diagnostic qPCR and one pair for PD 
biomarkers qPCR).  The other three pairs (two pairs from most inflamed area of colon within 2040 cm of anal verge [sigmoid] and one pair from the most 
inflamed area of the worst affected segment) will be placed in formalin and then paraffin embedded (one pair will be used for histopathology and exploratory PD 
biomarkers and the other two pairs will be used for diagnostic).  Original biopsy location and endoscopic depth should be clearly indicated.
bb A total of four pairs (8 biopsy samples) will be obtained.  All will be sent to the central laboratory for further storage or distribution.  One pair will be placed in 
stabilization buffer (such as RNAlater or a similar buffer) and stored at 80C for exploratory PD or diagnostic biomarker qPCR.  The other three pairs, 
representing three different segments (rectum, sigmoid, descending colon), will be placed in formalin and then paraffin embedded; these biopsy samples will be 
used for histopathology, exploratory PD biomarkers, and/or diagnostic biomarker.  Original biopsy location and endoscopic depth should be clearly indicated.


Clinical Study Report: etrolizumab  - F. Hoffmann-La Roche Ltd
Protocol GA29102     Report Number 1099518
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Appendix 1
Schedule of Activities (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
131/Protocol GA29102, Version 7
cc Paxgene blood RNA samples must be collected after all other blood and serum samples.
dd With the exception of Week 0, the IBDQ and the EQ-5D will be completed in-clinic by the patient after the PML neurological examination but before any other 
non-PRO assessments and before the patient receives any disease status information or study drug during that visit.
ee Randomization to occur within 2 weeks starting from Week 10 timepoint.
ff
Where indicated, patients must be instructed to administer study drug at home within 3 days (maximum) after clinic visit.


Clinical Study Report: etrolizumab  - F. Hoffmann-La Roche Ltd
Protocol GA29102     Report Number 1099518
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Etrolizumab—F. Hoffmann-La Roche Ltd
132/Protocol GA29102, Version 7
Appendix 2
12-Week Safety Follow-Up 
Assessment
Week (3 days)
Unscheduled 
Visit c
6 a
12/Early 
Termination b
ECG
x
PML neurologic examination d
x
PD sampling (serum)
x
PK sampling (serum)
x
Anti-therapeutic antibody sample 
(serum) e
x
Medication changes
x
x
x
Adverse events
x
x
x
ATAanti-therapeutic antibody; ECG electrocardiogram; PKpharmacokinetic; 
PDpharmacodynamic; PMLprogressive multifocal leukoencephalopathy.
a Week 6 study assessments are to be made by telephone call and not by clinic 
visit.
b Denotes early termination visit from safety follow-up period.
c Unscheduled visit for safety monitoring.
d PML neurologic examination consists of the PML Subjective Checklist and the 
PML Objective Checklist.  Administer before other assessments per 
Appendix 5
e At all timepoints indicated and whenever serum sickness is suspected.  ATA 
samples may be used for PK and/or exploratory PD assessments.


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Appendix 3
Childbearing Potential, Pregnancy Testing, and Contraception
All women of childbearing potential (including those who have had a tubal ligation) will 
have a serum pregnancy test at screening and 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 until pregnancy is ruled out.  The result 
must be confirmed by a serum pregnancy test (conducted by the central laboratory).  
See Section 5.4.3 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 contraceptive 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)


Clinical Study Report: etrolizumab  - F. Hoffmann-La Roche Ltd
Protocol GA29102     Report Number 1099518
2135
Appendix 3
Childbearing Potential, Pregnancy Testing,
and Contraception (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
134/Protocol GA29102, Version 7
Patients may provide verbal confirmation that the partner completed appropriate 
follow-up after vasectomy.  Sites are not required to obtain partner medical records.
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, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.


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Etrolizumab—F. Hoffmann-La Roche Ltd
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Appendix 4
Mayo Clinic Score Measurement
Mayo Clinic Score 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:
1.
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
2.
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
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
4.
PHYSICIAN GLOBAL
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


Clinical Study Report: etrolizumab  - F. Hoffmann-La Roche Ltd
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Appendix 4
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
136/Protocol GA29102, Version 7
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 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.
This value will remain stable throughout the 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 is
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 daily from start of screening to the end of the study
in the e-diary

The stool frequency is to be compared with the patient’s normal stool frequency and
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 DOES NOT COUNT as stool.

The baseline stool frequency value will be taken from patient e-diary recordings that 
are entered between Day 22 (inclusive) and bowel preparation for the screening 
endoscopy and will be calculated as the average (rounded to the nearest integer) 
from the three most recent stool frequency scores that were entered just prior to the 
day of bowel preparation.  However, up to three post-endoscopy scores, starting 
with the score recorded 2 days after the endoscopy, may be used to calculate 
baseline stool frequency, but ONLY when fewer than three scores are available 
between Day 22 and bowel preparation (see Figure 1 below).  The days selected 
for this calculation are intended to prevent the use of stool frequency recordings 
during the screening period that are impacted by bowel preparation and endoscopy, 
including the day immediately following the endoscopy.


Clinical Study Report: etrolizumab  - F. Hoffmann-La Roche Ltd
Protocol GA29102     Report Number 1099518
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Appendix 4
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
137/Protocol GA29102, Version 7

The post-baseline 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 within the 7 days prior to the clinic 
visit and prior to the days devoted to bowel preparation and endoscopy. 
2.
Rectal bleeding

Rectal bleeding is to be recorded daily from screening to the end of the study in the
e-diary

The rectal bleeding score is to be categorized from 03 according to the definition
given in 2 above

Patients are to be instructed to ignore any blood which is caused by menstruation or
hemorrhoids

The baseline value for the rectal bleeding score will be taken from patient e-diary 
recordings that are entered between Day 22 (inclusive) and bowel preparation for 
the screening endoscopy and will be determined by the worst recording from the 
three most recent scores that were entered just prior to the day of bowel preparation.  
However, up to three post-endoscopy scores, starting with the score recorded 2 
days after the endoscopy, may be used to calculate baseline rectal bleeding, but 
ONLY when fewer than three scores are available between Day 22 and bowel 
preparation (see Figure 1 below).  The days selected for this calculation are 
intended to prevent the use of rectal bleeding recordings during the screening 
period that are impacted by bowel preparation and endoscopy, including the day 
immediately following the endoscopy.

The post-baseline 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 within the 7 days prior to the clinic visit and prior to the days devoted to 
bowel preparation and endoscopy. 
3.
Endoscopy Subscore
This score is provided by the endoscopy reading vendor as a subscore of 0 to 3.

Findings on endoscopy will be documented by photographic evidence (central
reading of endoscopy videos)

The score will be based upon the worst affected segment (if mucosal appearance 
varies) for study conduct, except at post-baseline time points, when the sigmoid 
colon MCS endoscopic subscore will be used if the baseline sigmoid colon MCS 
endoscopic subscore is 23.
Note:  The time window for performing endoscopy during the screening is 416 days
prior to Day 1 (i.e., Day 16 to Day4).


Clinical Study Report: etrolizumab  - F. Hoffmann-La Roche Ltd
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2139
Appendix 4
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
138/Protocol GA29102, Version 7
4.
Physician 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.
CALCULATION OF THE MAYO CLINIC SCORE
Timepoints for MCS assessments can be found in the protocol Schedule of Assessments.
Eligibility for Enrollment
Moderately to severely active ulcerative colitis as determined by a Mayo Clinic 
Score of 612 with an endoscopic subscore 2, a rectal bleeding subscore 1, 
and a stool frequency subscore 1
Achievement of Clinical Response at Week 10
MCS with 3-point decrease and 30% reduction from baseline as well as 
1-point decrease in rectal bleeding subscore or an absolute score of 0 or 1
Identification of Clinical Relapse
Clinical relapse is defined as an increase in pMCS 3 points compared to 
induction timepoint (Week 10) AND absolute pMCS of 5 AND an endoscopy
subscore of 2


Clinical Study Report: etrolizumab  - F. Hoffmann-La Roche Ltd
Protocol GA29102     Report Number 1099518
2140
Appendix 4
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
139/Protocol GA29102, Version 7
Figure 1
Derivation of Stool Frequency and Rectal Bleeding Subscores at Screening


Clinical Study Report: etrolizumab  - F. Hoffmann-La Roche Ltd
Protocol GA29102     Report Number 1099518
2141
Appendix 4
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
140/Protocol GA29102, Version 7
Figure 1
Derivation of Stool Frequency and Rectal Bleeding Subscores at Screening (cont.)
Endoendoscopy; MCSMayo Clinic Score; preppreparation; RBrectal bleeding; SFstool frequency.
Notes:

If 3 days of e-diary data are available between Day 22 (inclusive) and bowel preparation, use e-diary data from the 3 most 
recent days prior to the bowel preparation day.

Up to 3 days of post-endoscopy e-diary data, starting 2 days after the endoscopy, may be used, but ONLY when 3 days of 
e-diary data are available between Day 22 and bowel preparation.

If 2 days of e-diary data are available between Day 22 and bowel preparation, use those data and supplement with data from the 
first available e-diary entry after the endoscopy, starting 2 days after the endoscopy.

If 1 day of e-diary data is available between Day 22 and bowel preparation, use those data and supplement with data from the 
first two available e-diary entries after the endoscopy, starting 2 days after the endoscopy.

If 0 days of e-diary data are available between Day 22 and bowel preparation, use data from the first three available e-diary 
entries after the endoscopy, starting 2 days after the endoscopy.


Clinical Study Report: etrolizumab  - F. Hoffmann-La Roche Ltd
Protocol GA29102     Report Number 1099518
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Appendix 4
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
141/Protocol GA29102, Version 7
PARTIAL MAYO CLINIC SCORE
The partial Mayo Clinic Score is identical to the Mayo Clinic Score BUT EXCLUDES THE
ENDOSCOPY SUBSCORE

Timepoints for partial Mayo Clinic Score can be found in the protocol Schedule of 
Assessments

Partial MCS is also required at time of suspected clinical relapse. If partial MCS 3
points compared to induction timepoint AND absolute partial MCS 5 an endoscopy
would be conducted and endoscopy subscore and full MCS calculated
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)


Clinical Study Report: etrolizumab  - F. Hoffmann-La Roche Ltd
Protocol GA29102     Report Number 1099518
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Etrolizumab—F. Hoffmann-La Roche Ltd
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Appendix 5
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).


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Worksheet for the PML Neurologic Examination (cont.)
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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
(
l if
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
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


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Appendix 5
Worksheet for the PML Neurologic Examination (cont.)
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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
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
muscle groups
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)
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.


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Appendix 5
Worksheet for the PML Neurologic Examination (cont.)
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
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)
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.


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Worksheet for the PML Neurologic Examination (cont.)
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
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.
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.


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Worksheet for the PML Neurologic Examination (cont.)
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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).
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.”


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Appendix 5
Worksheet for the PML Neurologic Examination (cont.)
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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.




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Appendix 7
Patient Daily Diary


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Appendix 8
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 x age]) from 1 to 10 years, and less than 90 mmHg from
11 to 17 years.


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Appendix 10
Quality of Life in Inflammatory Bowel Disease Questionnaire 
(IBDQ)
























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Appendix 11
EuroQoL Five-Dimension Questionnaire (EQ-5D)


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Health Questionnaire
   
(English version for the US)
© 1998 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group
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By placing a checkmark in one box in each group below, please indicate which 
statements best describe your own health state today.
Mobility
I have no problems in walking about

I have some problems in walking about

I am confined to bed

Self-Care
I have no problems with self-care

I have some problems washing or dressing myself

I am unable to wash or dress myself

Usual Activities (e.g. work, study, housework, family or
leisure activities)
I have no problems with performing my usual activities

I have some problems with performing my usual activities

I am unable to perform my usual activities

Pain/Discomfort
I have no pain or discomfort

I have moderate pain or discomfort

I have extreme pain or discomfort

Anxiety/Depression
I am not anxious or depressed

I am moderately anxious or depressed

I am extremely anxious or depressed

© 1998 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group
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Appendix 12
Nancy Histological Index
Histologic activity on colon biopsies will be measured using the Nancy histological 
index (below).  Histologic remission is defined as a Nancy histological index of 01 
based on consensus guidelines recommending that histologic remission should be 
defined by the absence of neutrophils in the crypts and lamina propria.
Nancy Histological Index (NHI)
Marker
Assessment
NHI Grade
Erosion or ulceration
Present
4: Severely active disease
Acute inflammatory 
infiltrate
Moderate to severe
3: Moderately active disease
Mild
2: Mildly active disease
Chronic inflammatory 
infiltrate
Moderate or marked 
increase
1: Chronic inflammatory infiltrate with no 
acute inflammatory infiltrate
No or mild increase
0: No histologically significant disease
Histologic remission: NHI 1
References
Marchal-Bressenot A, Salleron J, Boulagnon-Rombi C, et al. Development and 
validation of the Nancy histological index for UC. Gut 2017;66:43–9.
Marchal-Bressenot A, Scherl A, Salleron J, et al. A practical guide to assess the Nancy 
histological index for UC. Gut 2016;65:1919–20.

SAP_001.pdf: 
 
Official Title: 
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 
NCT Number: 
NCT02165215 
Document Date: 
SAP Version 3: 04-May-2020 
 
 


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STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL
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 GA29102
STATISTICAL ANALYSIS PLAN
TITLE:
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
PROTOCOL NUMBER:
GA29102 (Laurel)
STUDY DRUG:
Etrolizumab
VERSION NUMBER:
3
IND NUMBER:
100366
EUDRACT NUMBER:
2013-004280-31
SPONSOR:
F. Hoffmann-La Roche Ltd.
PLAN PREPARED BY:
, M.Sc.
DATE FINAL:
Version 1: 14 May 2019
DATE AMENDED:
Version 2: 17 December 2019
Version 3: See electronic date stamp below.
 
Date and Time(UTC)        Reason for Signing                              Name
04-May-2020 14:25:25
Company Signatory


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2/Statistical Analysis Plan GA29102
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE FOR VERSION 3

Change to Section 4.1.2.1 (Modified Intent to Treat [mITT] Population): Update 
the mITT Population definition to clarify it will not be used for histologic remission 
analysis.

Change to Section 4.4 (Efficacy Analysis): Update to methodology for handling 
for treatment discontinuation intercurrent events to set to missing and remove 
single imputation of worst observation carried forward.

Change to section 4.4.5 (Supplementary Analyses): Added in sensitivity analysis
for key secondary endpoints calculated as applicable.

Change to Section 4.1.1.2 (OLI Histology Evaluable Population) and 
Section 4.1.2.3 (Histology Evaluable Population) were made to clarify main 
analysis and sensitivity analysis populations.
Additional minor changes have been made to improve clarity and consistency.


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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE FOR 
VERSION 3................................................................................................... 2
1.
BACKGROUND ............................................................................................ 7
2.
STUDY DESIGN........................................................................................... 7
2.1
Protocol Synopsis.................................................................... 8
2.2
Outcome Measures ................................................................. 8
2.2.1
Efficacy Outcome Measures.................................................... 8
2.3
Determination of Sample Size ................................................. 9
2.3.1
Sample Size ............................................................................ 9
2.4
Analysis Timing ....................................................................... 9
3.
STUDY CONDUCT..................................................................................... 10
3.1
Randomization....................................................................... 10
3.1.1
Maintenance Phase............................................................... 10
3.2
Independent Review Facility.................................................. 11
3.3
Data Monitoring ..................................................................... 11
4.
STATISTICAL METHODS .......................................................................... 11
4.1
Analysis Populations ............................................................. 11
4.1.1
Induction Phase..................................................................... 11
4.1.1.1
Open-Label Induction (OLI) Population ................................. 11
4.1.1.2
OLI Histology Evaluable Population ...................................... 11
4.1.1.3
Safety Population .................................................................. 11
4.1.2
Maintenance Phase............................................................... 11
4.1.2.1
Modified Intent-to-Treat (mITT) Population............................ 11
4.1.2.2
Pharmacokinetic (PK)-Evaluable Population ......................... 12
4.1.2.3
Histology-Evaluable Population............................................. 12
4.1.2.4
Safety Population .................................................................. 12
4.2
Analysis of Study Conduct..................................................... 12
4.3
Analysis of Treatment Group Comparability .......................... 12
4.4
Efficacy Analysis.................................................................... 12
4.4.1
Primary Efficacy..................................................................... 13


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4.4.1.1
Primary Treatment Effect....................................................... 13
4.4.1.2
Primary Efficacy Endpoint...................................................... 14
4.4.1.3
Remission Among Clinical Responders Definition................. 14
4.4.2
Secondary Efficacy Endpoints............................................... 14
4.4.2.1
Control of Type I Error ........................................................... 14
4.4.2.2
Corticosteroid-Free Remission at Week 62 (Off 
Corticosteroid for At Least 24 Weeks Prior to 
Week 62) in Patients Who Were Receiving 
Corticosteroids at Baseline.................................................... 16
4.4.2.3
Improvement in Endoscopic Appearance of the 
Mucosa.................................................................................. 16
4.4.2.4
Remission at Week 62 (Among Patients in 
Remission at Week 10).......................................................... 16
4.4.2.5
Endoscopic Remission .......................................................... 16
4.4.2.6
Histologic Remission ............................................................. 16
4.4.2.7
UC-PRO/SS........................................................................... 17
4.4.2.8
Corticosteroid-Free Clinical Remission at 
Week 62 (Off Corticosteroid for At Least 
24 Weeks Prior to Week 62) in Patients Who 
Were Receiving Corticosteroids at Baseline.......................... 17
4.4.2.9
Clinical Remission at Week 62 (Among Patients 
in Clinical Remission at Week 10) ......................................... 17
4.4.2.10
Clinical Remission ................................................................. 17
4.4.2.11
Clinical Response.................................................................. 17
4.4.2.12
Inflammatory Bowel Disease Questionnaire 
(IBDQ) ................................................................................... 17
4.4.3
Exploratory Efficacy Endpoints.............................................. 18
4.4.4
Sensitivity Analyses............................................................... 18
4.4.5
Supplementary Analyses....................................................... 18
4.4.6
Subgroup Analyses ............................................................... 19
4.5
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 19
4.6
Safety Analyses..................................................................... 19
4.6.1
Exposure of Study Medication............................................... 19
4.6.2
Adverse Events ..................................................................... 19
4.6.3
Laboratory Data..................................................................... 19


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4.6.4
Vital Signs.............................................................................. 20
4.6.5
Concomitant Medications ...................................................... 20
4.6.6
Medical History...................................................................... 20
4.7
Missing Data.......................................................................... 20
4.8
Interim Analyses .................................................................... 20
5.
REFERENCES ........................................................................................... 20
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 7
Figure 2
Multiple Testing Procedure for Endpoints ................................... 15
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ...................................................................... 21
Appendix 2
Schedule of Assessments.......................................................... 31
Appendix 3
Rescue Therapy......................................................................... 38


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GLOSSARY OF ABBREVIATIONS
AE adverse event
CMH CochranMantelHaenszel
CCOD clinical cutoff date
CS Corticosteroids
e-CRF electronic Case Report Form
EQ-5D EuroQoL Five-Dimension Questionnaire
Etro Etrolizumab
ES endoscopic subscore
HRQoL health-related quality of life
IBDQ Inflammatory Bowel Disease Questionnaire
ICE intercurrent event
IS immunosuppressants
IxRS interactive voice/web based response system
LoPO list of planned outputs
MCS Mayo Clinic Score
mITT modified intent-to-treat
mMCS modified Mayo Clinic Score
NHI Nancy Histology Index
OLE open-label extension
OLI open-label induction
PBO Placebo
PGA Physician’s Global Assessment
PK Pharmacokinetic
pMCS partial Mayo Clinic Score
QOL quality of life
RB rectal bleeding
SAP Statistical Analysis Plan
SF stool frequency
SM safety monitoring
TNF tumor necrosis factor
UC ulcerative colitis
UC-PRO/SS Ulcerative Colitis Patient-Reported Outcome Signs 
and Symptoms


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1.
BACKGROUND
This Statistical Analysis Plan (SAP) describes the analyses to be performed for 
Study GA29102.  Study GA29102 is part of a large Phase III development program for 
etrolizumab.  Details which are common to Studies GA28950, GA29102, GA28948, 
GA28949, and GA29103 are described in the project SAP.
Study GA29102 is made up of two phases: the Induction Phase and the Maintenance 
Phase.  The Induction Phase is made up of a single open-label etrolizumab arm; 
therefore, no statistical comparisons will be made for the Induction Phase.  Induction 
Phase data will be summarized descriptively and pre-specified in the list of planned 
outputs (LoPO).  Statistical analyses will only be conducted for the Maintenance Phase 
of the study.
The Induction and Maintenance Phases will be reported once data from the Week 62 
treatment period have been collected in the database and data have been cleaned and 
verified; this will be referred to as the primary analysis.
2.
STUDY DESIGN
This is a multicenter, Phase III, double-blind, placebo-controlled study evaluating the 
safety, efficacy, and tolerability of etrolizumab in patients who achieved a clinical 
response to etrolizumab treatment after 10 weeks.  The population is made up of 
moderate to severe ulcerative colitis (UC) patients who are naive to tumor necrosis 
factor (TNF) inhibitors (see Figure 1).
Figure 1
Study Schema


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Following participation in this study, patients may be eligible to participate in an 
open-label extension and safety monitoring (OLE-SM) Study GA28951, which consists 
of two parts: Part 1 (designated OLE [open-label extension]) and Part 2 (designated 
SM [safety monitoring]).
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2.
2.2
OUTCOME MEASURES 
Baseline throughout this document is defined as the last available assessment prior to 
first receipt of study drug in the Induction Phase. The efficacy outcome measures listed 
below deviate from the current Study GA29102 Protocol Version 7. The current protocol 
includes change from baseline in stool frequency (SF) and rectal bleeding (RB) at 
Week 6 as secondary outcomes measures, and endoscopic remission at Week 10, 
histologic disease activity change from baseline to Week 10, improvement in the 
endoscopic mucosa at Week 10, and change in health utilities, as assessed by the 
EuroQoL Five-Dimension Questionnaire (EQ-5D) from baseline to Week 10 as 
exploratory outcome measures.  These outcomes measures cannot be analyzed due to 
no comparator arm at Week 6 or Week 10; therefore, they have been removed from the 
list below.  The safety and pharmacokinetic (PK) measures can be found in the Protocol 
Synopsis in Appendix 1.
2.2.1
Efficacy Outcome Measures
Primary Outcome Measure

Remission at Week 62 among patients with a clinical response at Week 10, as 
determined by the Mayo Clinic Score (MCS)
Secondary Outcome Measures

Clinical remission at Week 62 among patients in clinical remission at Week 10

Clinical remission at Week 62

Remission at Week 62 among patients in remission at Week 10

Improvement in endoscopic appearance of the mucosa at Week 62

Endoscopic remission at Week 62

Histologic remission at Week 62

Corticosteroid-free clinical remission at Week 62 (off corticosteroids [CS] for at least 
24 weeks prior to Week 62) in patients who are receiving corticosteroids at baseline

Corticosteroid-free remission at Week 62 (off corticosteroids for at least 24 weeks 
prior to Week 62) in patients who are receiving corticosteroids at baseline

Change from baseline to Week 62 in UC bowel movement signs and symptoms as 
assessed by the Ulcerative Colitis Patient-Reported Outcome Signs and Symptoms 
(UC-PRO/SS) measure


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
Change from baseline to Week 62 in UC functional symptoms as assessed by the 
UC-PRO/SS measure

Change from baseline to Week 62 in patients’ health-related quality of life (HRQoL) 
as assessed by the overall score of the Inflammatory Bowel Disease Questionnaire 
(IBDQ)
Exploratory Efficacy Outcome Measures 

Clinical response at Week 62 among patients with a clinical response at Week 10

Remission at Week 62 among patients in clinical remission at Week 10

Corticosteroid-free clinical remission at Week 62 (off corticosteroids for at least 
12 weeks prior to Week 62) in patients who are receiving corticosteroids at baseline

Histologic disease activity change from baseline to Week 62

Improvement in histologic and/or endoscopic disease activity

Change in health utilities, as assessed by the EQ-5D, from baseline to Week 62

Frequency and duration of hospitalizations from Week 10 to Week 62

Response, remission and corticosteroid-free endpoints as determined by the 
modified Mayo Clinic Score (mMCS)
2.3
DETERMINATION OF SAMPLE SIZE
2.3.1
Sample Size
The study sample size was selected so that sufficient patients are enrolled to evaluate 
the primary endpoints in the Maintenance Phase.  Approximately 350 patients will be 
enrolled in the open-label induction (OLI) arm and, under the assumption of 60% of 
patients being clinical responders at Week 10, approximately 210 patients (previously 
treated with etrolizumab in the OLI phase) will be randomized into the Maintenance 
Phase.
The primary endpoint is Week 62 remission among patients in clinical response at 
Week 10.  A sample size of 105 patients per arm in the Maintenance Phase will 
provide90% power to detect a 25% absolute difference in remission rates between the 
etrolizumab and placebo Maintenance arms for a chi-squared test at the 5% significance 
level, under the assumption of a placebo true remission rate 30%45%.
2.4
ANALYSIS TIMING
The primary analysis for the Induction and Maintenance Phases will be conducted once 
the last patient has completed their Week 62 treatment period or has discontinued from 
study treatment.  The date associated with this visit will be termed the clinical cutoff date 
(CCOD) for the primary analysis, and data in the study database to the CCOD will be 
cleaned and verified.  Sponsor personnel will be unblinded to treatment assignment to 
perform the primary analysis.  Patients and study site personnel will remain blinded to 
individual Maintenance Phase treatment assignment until after the study is completed 


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(after all patients have either completed the safety follow-up periods or discontinued 
early from the study) and the database is locked.
Additional analyses will be conducted once all patients have completed 12 weeks safety 
follow-up and the database has been locked.  These analyses will report all adverse 
events (AEs) including the data collected in the 12-week safety followup period.
3.
STUDY CONDUCT
3.1
RANDOMIZATION
Details of the randomization process are included in the project SAP, Section 3.1.  The 
statistical analyses will be conducted using the stratification factors entered into the 
interactive voice/web based response system (IxRS) system at randomization.  
Sensitivity analysis of the primary endpoints using data collected in the clinical 
database will be conducted as required, if the database does not match IxRS due to 
incorrect stratification data being collected in IxRS at randomization.  Due to low or 
zero counts in any one stratum, the stratification factors may need to be combined or 
removed in the primary analysis to ensure the CochranMantelHaenszel (CMH) test is 
not invalidated. This approach has been applied to the Maintenance Phase as 
described in Section 3.1.1, however further combining or removal maybe re required to 
ensure the analysis is not invalidated due to zero counts.
3.1.1
Maintenance Phase
Patients who achieved a clinical response at Week 10 and did not receive 
(permitted/non-permitted) rescue therapy during the Induction Phase were eligible to be 
randomized into the Maintenance Phase following enrolment into the Induction Phase.  
Patients were randomized to etrolizumab or placebo using a 1:1 ratio and a permuted 
blocks stratified randomization (dynamically generated).  Patients were stratified using 
the following stratification factors:

Concomitant treatment with CS at baseline (yes/no)

Concomitant treatment with immunosuppressants (IS) after Week 10 (yes/no)

Disease activity at screening MCS ≤9/MCS≥10) 

Remission criteria at week 10 (No remission/ remission including Physician’s Global 
Assessment (PGA) subscore /remission not including PGA subscore)
The Sponsor conducted a blinded review of the study data and concluded zero or low 
counts are likely to occur within multiple stratum when using the stratification factor 
‘Remission Criteria at Week 10’.  This scenario would invalidate the CMH test, the 
Sponsor proposes not to fit ‘Remission Criteria at Week 10’ as a term within the analysis 
models.


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All maintenance analysis will, therefore, be adjusted for using the following three 
stratification factors:

Disease activity at screening (MCS ≤9/MCS≥10)

Concomitant treatment with CS at baseline (yes/no)

Concomitant treatment with IS after Week 10 (yes/no)
3.2
INDEPENDENT REVIEW FACILITY
Details are included in the project SAP, Section 3.2.
3.3
DATA MONITORING
Details are included in the project SAP, Section 3.3.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
4.1.1
Induction Phase
4.1.1.1
Open-Label Induction (OLI) Population
Patients enrolled into the Induction Phase who received study drug will be summarized 
under the OLI population for all efficacy summaries.
4.1.1.2
OLI Histology Evaluable Population
The histology evaluable patients will include all patients in the OLI population who 
provided a baseline histology sample.  Patients with absence of baseline neutrophilic 
inflammation defined by a Nancy Histology Index (NHI)1 will be excluded.
4.1.1.3
Safety Population
The safety analysis population for the Induction Phase will include all patients who 
received at least one dose of etrolizumab during the Induction Phase.
4.1.2
Maintenance Phase
4.1.2.1
Modified Intent-to-Treat (mITT) Population
Efficacy analyses for the Maintenance Phase will be performed using a modified 
intent-to-treat (mITT) analysis population (with the exception of histologic remission).  
This analysis population will include patients randomized in the Maintenance Phase who 
received at least one dose of maintenance study drug.  Patients will be grouped 
according to the treatment assigned at maintenance randomization.
To allow consistency across the program the mITT population is being used.  This differs 
to terminology in the Protocol Version 7, Section 6.4, which uses intent-to-treat 
population.


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4.1.2.2
Pharmacokinetic (PK)-Evaluable Population
The PK-evaluable population includes patients who have received at least one dose of 
study drug and have at least one quantifiable concentration measured during the 
Maintenance Phase.
4.1.2.3
Histology-Evaluable Population
The histology-evaluable patients will include all patients in the maintenance mITT 
population, who have documented neutrophilic inflammation at baseline. For the main 
analysis based on NHI, neutrophilic inflammation is characterized by NHI greater than 
1. Sensitivity analyses will be based on the Robarts Histopathological Index (RHI) and 
Geboes Grading Scale. Definitions for neutrophilic inflammation and histologic 
remission under these alternative histologic scoring systems are provided in Table 3 of 
the project SAP.
4.1.2.4
Safety Population
The safety analysis population for the Maintenance Phase will include all patients who 
receive study drug in the Maintenance Phase.  Patients will be included in the treatment 
arm for the treatment most frequently received during the Maintenance Phase.
4.2
ANALYSIS OF STUDY CONDUCT
All data available in the database up to the point the last patient has completed their 
Week 62 visit will be included to evaluate study conduct.  This will include all available 
data from the Induction and Maintenance Phases at the time of cutoff for the primary 
analysis.  The following analyses will be performed to evaluate the study conduct:

Summary of protocol deviations

Summaries of mITT, histology-evaluable, PK-evaluable, and safety populations, 
including numbers of patients in each population

Summary of patient disposition, including the number of doses received, reasons for 
patients withdrawing from the study and from study treatment, and number of 
patients taking study treatment.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Details are included in the project SAP, Section 4.3.
4.4
EFFICACY ANALYSIS
All statistical hypotheses for the primary and key secondary endpoints will be evaluated 
under a multiple testing procedure to ensure an overall type I error no greater than 5%.  
Details on this testing procedure are provided in Section 4.4.3.
Statistical comparisons will only be conducted in the Maintenance Phase.  Efficacy data 
collected during the Induction Phase will be summarized descriptively.


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All comparisons between the etrolizumab and placebo arms for binary data will use the 
CMH test statistic stratified by the three IxRS stratification factors (Disease activity at 
screening [MCS 9/MCS10], Concomitant treatment with CS at baseline [yes/no],
Concomitant treatment with IS after Week 10 [yes/no]) as described in Section 3.1.1.  
For all analyses in the Induction and Maintenance Phases, where comparisons back to 
baseline are made, baseline is defined as the last available assessment prior to first 
receipt of study drug in the Induction Phase.
In alignment with the addendum to ICH E9, the primary efficacy treatment effect 
(estimands) is described for the primary treatment effect in Section 4.4.1.1.  The 
estimand attributes include the following two intercurrent events:  treatment 
discontinuation and use of rescue medication as described below:

Treatment discontinuation:  All patients who discontinue study drug during the 
treatment period of the Maintenance Phases will not be assessed for any future 
Week 62 endpoints.  Therefore, these patients will be assumed to be 
non-responders in the categorical endpoints analyses. For continuous endpoints 
(e.g., IBDQ, UC-PRO/SS) these patients’ data will be set to missing. Handling of 
missing data is described in the project SAP, Section 4.8. 

Use of rescue therapy: Increased or new background medications compared to 
baseline for the treatment of UC is considered rescue therapy.  Rescue therapy use 
is described in the protocol and also summarized in Appendix 3.  All patients 
receiving permitted rescue therapy during the Maintenance Phases will be asked to 
continue the study through endpoint assessment and safety follow-up.  All patients 
receiving prohibited rescue therapy during the Maintenance Phases will be asked to 
enter safety follow-up, with no assessment of any future Week 62 endpoints.  
Patients who receive rescue therapy (be it permitted or prohibited) during the 
Induction Phase are not eligible to enroll in the Maintenance Phase.  Patients who 
receive (permitted or prohibited) rescue medication will be considered 
non-responders in the primary analysis for all time points following the time they 
received rescue therapy.  For continuous outcomes (e.g., IBDQ, UC-PRO/SS), 
scores collected after the first use of rescue medication will have their data imputed 
using the worst post-baseline score from the following assessments: (the last score 
available prior to the start date of first rescue medication and all scores available 
after the start date of rescue medication use).
4.4.1
Primary Efficacy
4.4.1.1
Primary Treatment Effect
The primary efficacy treatment effect (estimand) targeted is described by the following 
four attributes:
a)
Population:  Adult patients with moderate to severe active UC who are naive to 
TNF inhibitors
b)
Variable: Remission at Week 62 given the patient is an etrolizumab-induction
phase clinical responder at Week 10.


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c)
Intercurrent Event (ICE):

Treatment discontinuation

Use of rescue therapy
Details of the ICE strategy are explained in Section 4.4.
d)
Population-Level Summary: Difference in proportion of patients between 
etrolizumab and placebo treatment groups in the Maintenance Phase.
4.4.1.2
Primary Efficacy Endpoint
The primary efficacy endpoint is the difference in the proportion of patients in remission 
at Week 62 between the etrolizumab and placebo patients who achieved clinical 
response at Week 10. 
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The calculation will be done within treatment groups.  Comparisons will only be made 
between the etrolizumab patients and placebo patients included in the mITT population.
Null hypothesis H0:  Etro – PBO0; the proportion of patients achieving remission 
at Week 62 among clinical responders at Week 10 in the placebo arm is the same as the 
proportion of patients achieving remission among clinical responders in the respective 
etrolizumab arm.
Alternative hypothesis H1:  Etro – PBO ≠ 0; the proportion of patients achieving 
remission at Week 62 among clinical responders at Week 10 in the placebo arm is not 
the same as the proportion of patients achieving remission among clinical responders in 
the respective etrolizumab arm.
4.4.1.3
Remission Among Clinical Responders Definition
Details of remission and clinical responder definition are provided in the project SAP, 
Section 4.4.2.1.4.
4.4.2
Secondary Efficacy Endpoints
4.4.2.1
Control of Type I Error
The primary and key secondary endpoints (Figure 2) will be evaluated in a hierarchical 
manner with multiplicity control via multistage gatekeeping under the truncated Holm 
multiple testing procedure (Dmitrienko et al. 2008).  In Families 1 and 2 of the key 
secondary endpoints the same truncation value of 0.5 will be applied; no truncation is 
applied in Family 3, since it is prioritized lowest in the hierarchy and imposes no 
gatekeeping restrictions on subsequent families.  The truncation parameter value and 
the relative effect sizes of the endpoints influence how power is balanced over the 
secondary endpoint families.  Truncation parameter values close to 1 should generally 


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be chosen when the effect sizes in high-priority endpoints are relatively large in order to 
maximize overall power.  In other settings where the effect sizes might be smaller or 
mixed, a truncation parameter value closer to 0 could improve overall power.  A 
parameter value strictly less than one in testing families that impose parallel gatekeeping 
(i.e. at least one endpoint is considered statistically significant after multiplicity 
adjustment in order to test the next family) is needed to achieve strong overall type I 
error control (Dmitrienko et al. 2009). 
Under this multistage gatekeeping approach, multiplicity-adjusted p-values will reflect the 
gatekeeping restrictions depicted in Figure 2.  In particular, the adjusted p-values for all 
key secondary endpoints in Families 1, 2, and 3 will be no smaller than the p-value for 
the primary endpoint.  Similarly, the smallest adjusted p-value in Family 2 (3) will be no 
smaller than the smallest adjusted p-value in Family 1 (2).  Endpoints for which the 
multiplicity-adjusted p-value is greater than 5% will not be considered statistically 
significant.  These endpoints and all endpoints not under multiplicity control will be 
considered to provide supportive information.  By repeated application of Proposition 4.1 
of Dmitrienko et al. (2008), this testing strategy ensures that the overall type I error is no 
greater than 5%. 
Figure 2 Multiple Testing Procedure for Endpoints 
Hierarchy 
Endpoints 
Primary 
● Remission at Week 62 among clinical responders at 
Week 10 
 
 
↓Success on primary endpoint 
Key secondary 
 
 
(Family 1) 
● Corticosteroid-free remission at Week 62 (off corticosteroids 
for at least 24 weeks prior to Week 62) in patients who were 
receiving corticosteroids at baseline  
● Improvement of endoscopic appearance of the mucosa at 
Week 62
 
↓Success on at least one endpoint 
(Family 2) 
● Remission at Week 62 among patients in remission at 
Week 10 
● Endoscopic remission at Week 62 
Histologic remission at Week 62
 
 ↓Success on at least one endpoint 
(Family 3) 
● Change from baseline to Week 62 in UC-PRO/SS (Bowel)  
● Change from baseline to Week 62 in UC-PRO/SS 
(Functional)
RB = rectal bleeding; SF = stool frequency; UC-PRO/SS = Ulcerative Colitis Patient-Reported 
Outcome Signs and Symptoms. 
Ordering of endpoints within a family will be based on the p-value results from the hypotheses 
tests of the endpoints in Figure 2. 
  


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4.4.2.2
Corticosteroid-Free Remission at Week 62 (Off Corticosteroid 
for At Least 24 Weeks Prior to Week 62) in Patients Who Were 
Receiving Corticosteroids at Baseline
This analysis will only be conducted on a subgroup of patients who were receiving 
corticosteroids at baseline as per the data collected in electronic Case Report Form 
(e-CRF) database and were enrolled into the Maintenance Phase.  Remission is 
determined by the MCS defined in the project SAP, Section 4.4.2.1.4.  Patients are 
defined as being off CS if they have no record of taking CS since the date which is 
24 weeks prior to Week 62.  This date is defined as the Week 62 visit date168 days.
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4.4.2.3
Improvement in Endoscopic Appearance of the Mucosa
The proportion of patients with improvement in endoscopic appearance of the mucosa at 
Week 62 will be analyzed using the same methods as the primary endpoint.  Definition 
of improvement in the appearance of the endoscopic mucosa is provided in the project 
SAP, Section 4.4.2.
4.4.2.4
Remission at Week 62 (Among Patients in Remission at 
Week 10)
The proportions of patients who achieved remission at Week 62 given they achieved 
remission at Week 10 will be analyzed using the same methods as the primary endpoint, 
and include patients randomized into the maintenance mITT population. Due to low 
number of patients in this analysis the stratification factor IS use after Week 10 will not 
be included in the model, to prevent any strata with no values impacting the analysis.  
The definition of remission is the same at each time point and is described in project 
SAP, Section 4.4.2.1.4.
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4.4.2.5
Endoscopic Remission
The proportion of patients with endoscopic remission at Week 62 will be analyzed using 
the same methods as the primary endpoint.  Definition of endoscopic remission is 
provided in the project SAP, Section 4.4.2.1.4.
4.4.2.6
Histologic Remission
The proportion of patients with histologic remission at Week 62 will be analyzed using 
the same methods as the primary endpoint using the histology evaluable population.  


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Definition of histologic remission is described in the project SAP, Section 4.4.2.2.  
Further details of additional analysis to support this endpoint using different scoring 
systems are detailed in the project SAP, Section 4.4.2.2.
4.4.2.7
UC-PRO/SS
Details of UC-PRO/SS endpoints and the analyses are provided in the project SAP, 
Section 4.4.2.3.  The change from baseline at Week 62 in both the functional and bowel 
domains will be analyzed separately.
4.4.2.8
Corticosteroid-Free Clinical Remission at Week 62 (Off 
Corticosteroid for At Least 24 Weeks Prior to Week 62) in 
Patients Who Were Receiving Corticosteroids at Baseline
This endpoint will be analyzed using the same methods as Section 4.4.2.2.  Remission 
will be substituted with Clinical Remission.  Clinical Remission is determined by the MCS 
and described in the project SAP, Section 4.4.2.1.4. As detailed in Figure 2
(Section 4.4.2.1), this endpoint is not included in the multiple testing procedure for 
endpoints.
4.4.2.9
Clinical Remission at Week 62 (Among Patients in Clinical 
Remission at Week 10)
The endpoint will be analyzed using the same methods as Section 4.4.2.4.  Remission 
will be substituted with clinical remission.  Clinical Remission is determined by the MCS 
and described in the project SAP, Section 4.4.2.1.4.  As detailed in Figure 2
(Section 4.4.2.1), this endpoint is not included in the multiple testing procedure for 
endpoints.
4.4.2.10
Clinical Remission
Definition of clinical remission is provided in the project SAP, Section 4.4.2.1.4.  The 
proportion of patients in clinical remission at Week 62 will be analyzed using the same 
methods as the primary endpoint. As detailed in Figure 2 (Section 4.4.2.1), this endpoint 
is not included in the multiple testing procedure for endpoints.
4.4.2.11
Clinical Response
Definition of clinical response is provided in the project SAP, Section 4.4.2.1.4.  The 
proportion of patients in clinical response at Week 62 will be analyzed using the same 
methods as the primary endpoint. As detailed in Figure 2 (Section 4.4.2.1), this endpoint 
is not included in the multiple testing procedure for endpoints.
4.4.2.12
Inflammatory Bowel Disease Questionnaire (IBDQ)
Details of the IBDQ endpoint and the analyses are provided in the project SAP, 
Section 4.4.2.4.  The change from baseline at Week 62 in IBDQ will be analyzed. As 
detailed in Figure 2 (Section 4.4.2.1), this endpoint is not included in the multiple testing 
procedure for endpoints.


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4.4.3
Exploratory Efficacy Endpoints
Exploratory endpoints detailed in the protocol will also be analyzed.  Binary endpoints 
will use the same statistical methods used for the primary endpoint.  Continuous 
endpoints will use the same statistical methods used for the change from baseline key 
secondary endpoints.
4.4.4
Sensitivity Analyses
To support the primary analyses the following sensitivity analyses will be conducted:  
definitions of partial Mayo Clinic Score (pMCS) and mMCS are included in the project 
SAP, Section 4.4.2.1.4.

Proportion of patients in remission at Week 62 among clinical responders at 
Week 10 (remission derived using mMCS including mild friability in Mayo ES1)

Proportion of patients in remission at Week 62 among clinical responders at 
Week 10 (remission derived using pMCS)

Proportion of patients in remission at Week 62 among clinical responders at 
Week 10 (difference in proportions calculated using Fisher’s exact test)

Proportion of patients in remission (mMCS) at Week 62 among clinical responders 
(mMCS) at Week 10 (excluding friability from Mayo ES1)

Proportion of patients in remission at Week 62 among clinical responders at 
Week 10 (Tipping Point Analysis)
All key secondary endpoints included in Figure 2 which are calculated using MCS or the 
endoscopic subscore will be re analyzed as a sensitivity analyses using the modified 
Mayo Clinic Score (mMCS) excluding friability from ES1 or the endoscopic subscore 
excluding friability from ES1 if applicable. This analysis will be conducted on the mITT 
population and are listed below.

Proportion of patients corticosteroid free remission at Week 62 (Off corticosteroid for 
at least 24 weeks prior to Week 62) in patients who were receiving corticosteroids at 
baseline (remission derived using the mMCS excluding mild friability in Mayo ES1)

Proportion of patients with improvement of endoscopic appearance of the mucosa at 
Week 62 (endoscopic score excluding mild friability in Mayo ES1)

Proportion of patients remission at Week 62 among patients in remission at 
Week 10  (remission at Week 10 and Week 62 derived using the mMCS excluding 
mild friability in Mayo ES1)
4.4.5
Supplementary Analyses 
To support the primary analyses the following supplementary analyses will be conducted;

Proportion of patients in remission at Week 62 among clinical responders at 
Week 10 (including data collected whilst patients received rescue therapy)


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
Proportion of patients in remission at Week 62 among clinical responders at 
Week 10 (using logistic regression model)

Proportion of patients in remission at Week 62 among clinical responders at 
Week 10 (using clinical database derivation of clinical response at Week 10, if 
appropriate)
Definitions of clinical response are included in the project SAP, Section 4.4.2.1.4.
4.4.6
Subgroup Analyses
Subgroup analyses are detailed in the project SAP, Section 4.4.3.
4.5
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Details are included in the project SAP, Section 4.5.
4.6
SAFETY ANALYSES
Data reported during the Induction Phase using the induction safety population will 
include data for all patients enrolled into the Induction Phase, up until they are 
randomized into the Maintenance Phase.  For patients who are not randomized into the 
Maintenance Phase, data will be reported up until the patient completes/withdraws from 
the study.  If a patient is ongoing in the Induction Phase due to being in safety follow-up 
at the time of the primary data analyses, all available data at time of the primary 
analyses CCOD will be reported.
Data reported during the Maintenance Phase will include data for all patients in the 
maintenance safety population up until the patient complete/withdraws from the study.  
All safety analyses using the maintenance safety population data will be reported from 
baseline.  Baseline is defined as the last available assessment prior to first receipt of 
study drug at the beginning of the Induction Phase.  If a patient is ongoing in the 
Maintenance Phase due to being in safety follow-up at the time of the primary data 
analyses, all available data at time of the primary analyses CCOD will be reported.
Further details of the safety analyses are included in the project SAP, Section 4.7.
4.6.1
Exposure of Study Medication
The number of doses of etrolizumab or placebo injected will be summarized using 
descriptive statistics.
4.6.2
Adverse Events
Details are included in the project SAP, Section 4.7.1.
4.6.3
Laboratory Data
Details are included in the project SAP, Section 4.7.2.


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4.6.4
Vital Signs
Details are included in the project SAP, Section 4.7.3.
4.6.5
Concomitant Medications 
Details are included in the project SAP, Section 4.7.5.
4.6.6
Medical History
Details are included in the project SAP, Section 4.7.4.
4.7
MISSING DATA
Details are included in the project SAP, Section 4.8.
4.8
INTERIM ANALYSES
No efficacy interim analyses are planned or have been undertaken.
5.
REFERENCES
Dmitrienko A, Tamhane AC, Wiens BL. General multistage gatekeeping procedures. 
Biom J. 2008;50(5):66777.
Dmitrienko A, Tamhane AC, Bretz F, editors. Multiple testing problems in pharmaceutical 
statistics. CRC Press 2009;16591.


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Appendix 1
Protocol Synopsis
TITLE:
PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTICENTER STUDY TO EVALUATE THE 
EFFICACY (MAINTENANCSE OF REMISSION) AND SAFETY OF 
ETROLIZUMAB COMPARED WITH PLACEBO IN PATIENTS 
WITH MODERATE TO SEVERE ACTIVE ULCERATIVE COLITIS
WHO ARE NAIVE TO TNF INHIBITORS
PROTOCOL NUMBER:
GA29102
VERSION NUMBER:
7
EUDRACT NUMBER:
2013-004280-31
IND NUMBER:
100366
TEST PRODUCT:
Etrolizumab (PRO145223, RO5490261)
PHASE:
III
INDICATION:
Ulcerative colitis
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Efficacy Objectives
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of etrolizumab (105 mg subcutaneous [SC] every 4 weeks [Q4W]) 
compared with placebo remission at Week 62 among patients with a clinical response at 
Week 10, as determined by the Mayo Clinic Score (MCS)
The secondary efficacy objectives for this study are as follows:

To evaluate maintenance of clinical remission at Week 62 for patients in clinical remission 
at Week 10

To evaluate clinical remission at Week 62

To evaluate remission at Week 62 among patients in remission at Week 10

To evaluate improvement in endoscopic appearance of the mucosa at Week 62

To evaluate endoscopic remission at Week 62

To evaluate histologic remission at Week 62

To evaluate onset of action, defined as change from baseline in rectal bleed subscore at Week 6

To evaluate onset of action, defined as change from baseline in stool frequency subscore at Week 6

To evaluate corticosteroid-free clinical remission at Week 62 (off corticosteroids for at least 
24 weeks prior to Week 62) in patients who were receiving corticosteroids at baseline

To evaluate corticosteroid-free remission at Week 62 (off corticosteroids for at least 
24 weeks prior to Week 62) in patients who were receiving corticosteroids at baseline

To evaluate change from baseline to Week 62 in UC bowel movement signs and symptoms, 
as assessed by the Ulcerative Colitis Patient-Reported Outcome Signs and Symptoms (UC-
PRO/SS) measure


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
To evaluate change from baseline to Week 62 in UC abdominal symptoms, as assessed by 
the UC-PRO/SS measure

To evaluate change from baseline to Week 62 in patient-reported health-related QOL, as 
assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ)
The exploratory efficacy objectives for this study are as follows:

To evaluate clinical response at Week 62 among patients with a clinical response at Week 10 

To evaluate remission achieved at Week 62 among patients in clinical remission at Week 10

To evaluate corticosteroid-free clinical remission at Week 62 (off corticosteroids for at least 
12 weeks prior to Week 62) in patients who were receiving corticosteroids at baseline

To evaluate change in histologic disease activity from baseline to Week 10 and Week 62

To evaluate improvement in histologic and/or endoscopic disease activity

To evaluate change in health utilities, as assessed by the EuroQoL Five-Dimension 
Questionnaire (EQ-5D), from Week 10 to Week 62

To evaluate improvement in endoscopic appearance of mucosa at Week 10

To evaluate endoscopic remission at Week 10

To evaluate the frequency and duration of hospitalizations from Week 10 to Week 62

To evaluate response, remission, and corticosteroid-free endpoints, as determined by the mMCS
Safety Objectives
The safety objectives for this study are as follows:

To evaluate the overall safety and tolerability of etrolizumab over a period of 62 weeks

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)
Pharmacokinetic Objectives
The pharmacokinetic (PK) assessment will be performed in all patients during the 
Induction Phase and in all patients who were randomized into the Maintenance Phase.
The PK objectives for this study are as follows:

To evaluate etrolizumab serum concentration at the time of primary endpoint evaluation 
(Week 62) and predose concentration at the steady state during the maintenance 
dosing period

To evaluate the interindividual variability and potential covariate effects on etrolizumab 
serum exposure
Exploratory Pharmacodynamic and Diagnostic Objectives
The exploratory pharmacodynamics (PD) and diagnostic objectives for this study are as follows:

To evaluate the relationship between baseline colonic mucosal biomarkers and/or 
peripheral blood and response to study drug, including, but not limited to, the αE integrin

To evaluate the levels of biomarkers in colonic tissue and/or peripheral blood at baseline 
and during the treatment period, including, but not limited to, the αE integrin 

To evaluate the PD effects on biomarkers in colonic tissue and/or peripheral blood following 
study treatment or placebo

To evaluate biomarkers in stool at baseline and during the treatment period through 
assessments that may include, but are not limited to, analyses of the microbiota and 
bacterial cultures


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Study Design
Description of Study
This is a multicenter, Phase III, randomized, double-blind, parallel-group study to evaluate the 
safety, efficacy, and tolerability of etrolizumab (105 mg SC Q4W) compared with placebo in the 
treatment of UC.  Safety and efficacy of continued etrolizumab treatment will be evaluated in 
patients achieving a clinical response after 10 weeks.
Patients enrolled in this study may be eligible to participate in an open-label extension and 
safety monitoring (OLE-SM) study (GA28951), which consists of two parts: Part 1 (designated 
OLE [open-label extension]) and Part 2 (designated SM [safety monitoring]).
Disease severity will be measured using the MCS, which is the current outcome measure 
accepted by regulatory authorities for drug development in UC.  The target population is 
patients with moderately to severely active UC (defined as MCS 6−12, endoscopy subscore of 
≥2 as determined by the central reading procedure described in the protocol, a rectal bleeding 
subscore ≥1, and a stool frequency subscore ≥1) and involvement that extends a minimum of 
20 cm from the anal verge.
All patients are to be naive to tumor necrosis factor (TNF) inhibitors.
Patients must have had an inadequate response, loss of response, or intolerance to prior 
immunosuppressant and/or corticosteroid treatment.
Patients who are on background immunosuppressant therapy (6-MP, AZA, MTX) may be 
enrolled if they have received a stable dose for at least 8 weeks prior to Day 1.  Such patients 
should continue on stable doses of their background immunosuppressant therapy during the 
study unless dose reduction or discontinuation is required due to toxicity.
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 remains at the discretion of the investigator.
Patients on oral corticosteroid therapy (prednisone at a stable dose of ≤30 mg, or equivalent) 
may be enrolled according to the following criteria:

If corticosteroid therapy is ongoing or has recently been initiated, the dose has to be stable 
for at least 4 weeks immediately prior to Day 1

If corticosteroids are being tapered, the dose has to be stable for at least 2 weeks 
immediately prior to Day 1
Such patients should continue stable doses of their background corticosteroid until Week 10, at which 
point a corticosteroid taper will be initiated.
Initiation of corticosteroid or an increase in corticosteroid dose above the patients’ entry dose 
(up to a maximum of 30 mg/day prednisone [or equivalent]) will not be permitted during 
screening.  Use of budesonide will be allowed at stable doses (≤9 mg) provided that the dose 
has been stable for ≥4 weeks prior to Day 1.  Oral 5-ASA treatment and probiotics for the 
treatment of UC may be continued at a stable dose as long as the dose(s) had been stable for 
≥4 weeks and ≥2 weeks, respectively, prior to Day 1.  Certain concomitant treatments are 
prohibited (see the protocol for list of all prohibited concomitant treatments).
A total of approximately 350 patients will be recruited (see the protocol) from approximately 
125 sites.  The study will be divided into:

Screening period of up to 35 days

Open-label etrolizumab treatment period of 10 weeks (Induction Phase)

Double-blind treatment period of 52 weeks (Maintenance Phase)

Safety follow-up period of 12 weeks.
All patients entering the study will receive induction treatment with open-label etrolizumab 
(105 mg SC Q4W) for 10 weeks.  Eligibility for entry into the Maintenance Phase will be 
determined between Weeks 10 and 12.  Patients who achieved a clinical response at Week 10 
(see the protocol for definition of clinical response) will be randomized in a 1:1 ratio by Week 12 
into the Maintenance Phase and will receive either etrolizumab (105 mg SC Q4W) or placebo 


Cli ni c al St u d y R e p ort: etr oli z u m a b  - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G A 2 9 1 0 2     R e p ort N u m b er 1 0 9 9 5 1 8
3 3 4 8
Etr oli z u m a b — F. H off m a n n -L a R o c h e Lt d
2 4 /St ati sti c al A n al y si s Pl a n G A 2 9 1 0 2
( n≈1 0 5 f or e a c h ar m).  R a n d o mi z ati o n will b e str atifi e d b y t h eir r e mi s si o n st at u s at W e e k  1 0, 
c o n c o mit a nt tr e at m e nt wit h c orti c o st er oi d s (i n cl u di n g b u d e s o ni d e) at b a s eli n e, c o n c o mit a nt 
tr e at m e nt wit h i m m u n o s u p pr e s s a nt s aft er W e e k  1 0, a n d di s e a s e a cti vit y m e a s ur e d d uri n g 
s cr e e ni n g ( M C S ≤9/ M C S ≥1 0).
P ati e nt s n ot a c hi e vi n g cli ni c al r e s p o n s e at W e e k  1 0 a n d p ati e nts c o m pl eti n g t h e M ai nt e n a n c e 
P h a s e at W e e k  6 2 s h o ul d e nr oll i n P art 1 ( O L E) of St u d y G A 2 8 9 5 1, if eli gi bl e, w h er e t h e y will 
r e c ei v e o p e n-l a b el etr oli z u m a b.  If t h e y d o n ot e nr oll i n P art 1 ( O L E) of St u d y G A 2 8 9 5 1, t h e y 
will e nt er t h e 1 2 -w e e k s af et y f oll o w -u p p eri o d of t hi s st u d y a n d t h e n b e r e q u e st e d t o e nr oll i n 
P art 2 ( S M) of St u d y G A 2 8 9 5 1 f or 9 2 w e e k s of e xt e n d e d f or pr o gr e s si v e m ultif o c al 
l e u k o e n c e p h al o p at h y ( P M L) m o nit ori n g.
N u m b er of P ati e nt s
A p pr o xi m at el y 3 5 0 p ati e nt s ar e t o b e e nr oll e d f or t hi s st u d y.   F oll o wi n g 1 0 w e e k s of o p e n -l a b el 
i n d u cti o n wit h etr oli z u m a b, it i s e sti m at e d t h at a p pr o xi m at el y 6 0 % of p ati e nt s will a c hi e v e cli ni c al 
r e s p o n s e, w hi c h will pr o vi d e a p pr o xi m at el y 1 0 5 p ati e nt s i n e a c h tr e at m e nt ar m f or t h e 
M ai nt e n a n c e P h a s e.   A d ditio nal patie nts ma y be e nrolle d i n t he I n d uctio n P hase if nee de d to meet 
sa m ple size re q uire me nts for t he Mai nte na nce P hase.
T ar g et P o p ul ati o n
P ati e nt s m u st m e et t h e f oll o wi n g crit eri a f or st u d y e ntr y:

A bl e a n d willi n g t o pr o vi d e writt e n i nf or m e d c o n s e nt

1 8 −8 0 y e ar s of a g e, i n cl u si v e

Di a g n o si s of U C e st a bli s h e d at l e a st 3 m o nt h s pri or t o D a y 1 b y cli ni c al a n d e n d o s c o pi c 
e vi d e n c e.  T hi s di a g n o si s s h o ul d b e c orr o b or at e d b y hi st o p at h ol o g y c o n d u ct e d at a n y ti m e 
pri or t o s cr e e ni n g a n d d o c u m e nt e d b y a hi st o p at h ol o g y r e p ort.  ( N ot e t h at hi st o p at h ol o g y 
m a y b e p erf or m e d at s cr e e ni n g if n o pri or r e p ort i s r e a dil y a v ail a bl e.)

M o d er at el y t o s e v er el y a cti v e U C a s d et er mi n e d b y a n M C S of 6 −1 2 wit h a n e n d o s c o pi c 
s u b s c or e ≥2 a s d et er mi n e d b y t h e c e ntr al r e a di n g pr o c e d ur e, a r e ct a l bl e e di n g s u b s c or e ≥1, 
a n d a st o ol fr e q u e n c y s u b s c or e ≥1 d uri n g t h e s cr e e ni n g p eri o d ( pri or t o D a y 1)

E vi d e n c e of U C e xt e n di n g a mi ni m u m of 2 0 c m fr o m t h e a n al v er g e a s d et er mi n e d b y 
b a s eli n e e n d o s c o p y (fl e xi bl e si g m oi d o s c o p y or c ol o n o s c o p y ) p erf or m e d d uri n g s cr e e ni n g, 
4 ฀1 6 d a y s pri or t o D a y  1.  S e e pr ot o c ol f or a d diti o n al i nf or m ati o n r e g ar di n g t h e ti m e wi n d o w.

N ai v e t o tr e at m e nt wit h T N F i n hi bit or s

P ati e nt s m u st h a v e h a d a n i n a d e q u at e r e s p o n s e, l o s s of r e s p o n s e, or i nt ol er a n c e t o pri or 
i m m u n o s u p pr e s s a nt a n d/ or c orti c o st er oi d tr e at m e nt.
I n a d e q u at e r e s p o n s e t o, l o s s of r e s p o n s e t o, or i nt ol er a n c e t o pri or i m m u n o s u p pr e s s a nt 
tr e at m e nt i s d efi n e d a s o n e or m or e of t h e f oll o wi n g: 
P er si st e nt si g n s a n d s y m p t o m s of a cti v e di s e a s e d e s pit e a hi st or y of at l e a st on e 1 2 -
w e e k r e gi m e n of or al A Z A ( ≥1. 5 m g/ k g) or 6 -M P ( ≥0. 7 5 m g/ k g) a n d/ or 
M T X
(≥1 5 m g / w e e k) wit hi n t h e pr e vi o u s 5 y e ar s
P er si st e nt si g n s a n d s y m p t o m s of a cti v e di s e a s e d e s pit e a 6-T G l e v el of 
2 3 0 p m ol/ 8 1 0 8 R B C s d uri n g at l e a st o n e 1 2 -w e e k r e gi m e n of or al A Z A or 6 -M P at a 
st a bl e or i n cr e a si n g d o s e wit hi n t h e pr e vi o u s 5 y e ar s
Hi st or y of i nt ol er a n c e t o A Z A, 6 -M P, or M T X (i n cl u di n g, b ut n ot li mit e d t o, 
n a u s e a/ v o miti n g, a b d o mi n al p ai n, p a n cr e atiti s, L F T a b n or m al iti e s, l ym p h o p e ni a, T P M T 
g e n eti c m ut ati o n, i nf e cti o n) wit hi n t h e pr e vi o u s 5 y e ar s
I n a d e q u at e r e s p o n s e, l o s s of r e s p o n s e, or i nt ol er a n c e t o c orti c o st er oi d tr e at m e nt i s d efi n e d a s 
o n e or m or e of t h e f oll o wi n g: 
St er oi d r efr a ct or y :  p er si st e nt s ym p t o m s of a cti v e di s e a s e d e s pit e tr e at m e nt wit h at 
l e a st o n e 4-w e e k i n d u cti o n r e gi m e n t h at i n cl u d e d a d o s e of ≥3 0 m g pr e d ni s o n e ( or al) 
d ail y ( or e q ui v al e nt) f or at l e a st 2 w e e k s or i ntr a v e n o u sl y f or at l e a st 1 w e e k wit hi n t h e 
pr e vi o u s 5 y e ar s
St er oi d d e p e n d e nt :  t w o fail e d att e m pt s t o t a p er st er oi d s b el o w a d o s e e q ui v al e nt t o 
1 0 m g  pr e d ni s o n e ( or al) d ail y


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Steroid intolerant:  history of intolerance to corticosteroids (including, but not limited to, 
Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, infection) 
within the previous 5 years

Any ongoing UC therapy must be at stable doses:
May be receiving oral 5-ASA compounds provided that the dose has been stable for 
≥4 weeks immediately prior to Day 1
May be receiving oral corticosteroid therapy (prednisone at a stable dose of ≤30 mg a 
day, or equivalent steroid).
If corticosteroid therapy is ongoing or has recently been initiated, the dose 
has to be stable for at least 4 weeks immediately prior to Day 1.  If 
corticosteroids are being tapered, the dose has to be stable for at least 
2 weeks immediately prior to Day 1.
May be receiving budesonide therapy at a stable dose of up to 9 mg a day for 
≥4 weeks prior to Day 1
May be receiving probiotics (e.g., Culturelle, Saccharomyces boulardii), provided 
that the dose has been stable for ≥2 weeks immediately prior to Day 1
May be receiving AZA, 6-MP, or MTX, provided that the dose has been stable for 
≥8 weeks immediately prior to Day 1

For women who are not postmenopausal (at least 12 months of non−therapy-induced 
amenorrhea) or surgically sterile (e.g., 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.

Must have received a colonoscopy within the past year or be willing to undergo a 
colonoscopy in lieu of a flexible sigmoidoscopy at screening.  This colonoscopy must:
Confirm disease extent (defined as 1) left-sided colitis [up to the splenic flexure], 
2) extensive colitis [beyond the splenic flexure but not involving the entire colon], and 3) 
pancolitis; see the protocol) 
Include removal of any adenomatous polyps 
Document evidence of surveillance for dysplasia for all patients with left-sided colitis 
of • 12 years’ duration and total/extensive colitis of • 8 years duration 
Patients who meet any of the following criteria will be excluded from study entry:
Exclusion Criteria Related to Inflammatory Bowel Disease

Prior extensive colonic resection, subtotal or total colectomy, or planned surgery for UC

Past or present ileostomy or colostomy

Diagnosis of indeterminate colitis 

Suspicion of ischemic colitis, radiation colitis, or microscopic colitis

Diagnosis of toxic megacolon within 12 months of initial screening visit 


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
Any diagnosis of Crohn’s disease

Past or present fistula or abdominal abscess

A history or current evidence of colonic mucosal dysplasia

Patients with any stricture (stenosis) of the colon

Patients with history or evidence of adenomatous colonic polyps that have not 
been removed
Exclusion Criteria Related to Prior or Concomitant Therapy

Any prior treatment with etrolizumab or other anti-integrin agents (including natalizumab, 
vedolizumab, and efalizumab)

Any prior treatment with anti-adhesion molecules (e.g., anti-MAdCAM-1)

Any prior treatment with rituximab

Any treatment with tofacitinib during screening

Use of intravenous (IV) steroids within 30 days prior to screening with the exception of a 
single administration of IV steroid

Use of agents that deplete B or T cells (e.g., alemtuzumab or visilizumab) within 12 months 
prior to Day 1, with the exception of AZA and 6-MP

Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF) within 4 weeks 
prior to Day 1

Chronic nonsteroidal anti-inflammatory drug (NSAID) use (Note: occasional use of NSAIDs 
and acetaminophen [e.g., headache, arthritis, myalgias, or menstrual cramps] and aspirin 
up to 325 mg daily is permitted.)

Patients who are currently using anticoagulants including, but not limited to, warfarin, 
heparin, enoxaparin, dabigatran, apixaban, rivaroxaban.  (Note that antiplatelet agents such 
as aspirin up to 325 mg daily or clopidogrel are permitted.)

Patients who have received treatment with corticosteroid enemas/suppositories and/or 
topical (rectal) 5-ASA preparations within 2 weeks prior to Day 1

Apheresis (i.e., Adacolumn apheresis) within 2 weeks prior to Day 1

Received any investigational treatment including investigational vaccines within 5 half-lives 
of the investigational product or 28 days after the last dose, whichever is greater, prior to Day 1

History of moderate or severe allergic or anaphylactic/anaphylactoid reactions to chimeric, 
human, or humanized antibodies, fusion proteins, or murine proteins or hypersensitivity to 
etrolizumab (active drug substance) or any of the excipients (L-histidine, L-arginine, 
succinic acid, polysorbate 20)

Patients administered tube feeding, defined formula diets, or parenteral 
alimentation/nutrition who have not discontinued these treatments ≥3 weeks prior to Day 1
Exclusion Criteria Related to General Safety

Pregnant or lactating

Lack of peripheral venous access

Hospitalized (other than for elective reasons) during the screening period

Inability to comply with study protocol, in the opinion of the investigator

Significant uncontrolled comorbidity, such as cardiac (e.g., moderate to severe heart failure 
New York Heart Association [NYHA] Class III/IV), pulmonary, renal, hepatic, endocrine, or 
gastrointestinal disorders (excluding UC)

Neurological conditions or diseases that may interfere with monitoring for PML

History of demyelinating disease

Clinically significant abnormalities on screening neurologic examination (PML Objective 
Checklist)

Clinically significant abnormalities on the screening PML Subjective Checklist


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
History of alcohol, drug, or chemical abuse ≤6 months prior to screening

Conditions other than UC that could require treatment with • 10 mg/day of prednisone 
(or equivalent) during the course of the study

History of cancer, including hematologic malignancy, solid tumors, and carcinoma in situ, 
within 5 years before screening with the following exceptions:
Local basal or squamous cell carcinoma of the skin that has been excised and is 
considered cured is not exclusionary.
A history of chronic myelogenous leukemia, hairy cell leukemia, melanoma, renal cell 
carcinoma, or Kaposi sarcoma is exclusionary, irrespective of the duration of time 
before screening.
History of a cervical smear indicating the presence of adenocarcinoma in situ (AIS), 
high-grade squamous intraepithelial lesions (HSIL), or cervical intraepithelial neoplasia 
(CIN) of Grade •1 is exclusionary, irrespective of the duration of time before screening.
Exclusion Criteria Related to Infection Risk

Congenital or acquired immune deficiency

Patients must undergo screening for HIV and test positive for preliminary and confirmatory 
tests

Positive hepatitis C virus (HCV) antibody test result, unless the patient (1) has undetectable 
HCV RNA levels for 6 months after completing a successful course of HCV anti-viral 
treatment and an undetectable HCV RNA at screening or (2) has a known history of HCV 
antibody positivity with a history of undetectable HCV RNA and undetectable HCV RNA at 
screening in the absence of history of HCV anti-viral treatment.

Patients must undergo screening for hepatitis B virus (HBV).  This includes testing for 
HBsAg (HBV surface antigen), anti-HBc total (HBV core antibody total), and HBV DNA 
(patients who test negative for these tests are eligible for this study):
Patients who test positive for surface antigen (HBsAg +) are not eligible for this study, 
regardless of the results of other hepatitis B tests.
Patients who test positive only for core antibody (anti-HBc +) must undergo further 
testing for hepatitis B DNA (HBV DNA test).
If the HBV DNA test is positive, the patient is not eligible for this study.
In the event the HBV DNA test cannot be performed, the patient is not eligible for 
this study. 
If the HBV DNA test is negative, the patient is eligible for this study).  These 
patients will undergo periodic monitoring for HBV DNA during the study.

Evidence of or treatment for Clostridium difficile (as assessed by C. difficile toxin testing) 
within 60 days prior to Day 1 or other intestinal pathogens (as assessed by stool culture and 
ova and parasite evaluation) within 30 days prior to Day 1

Evidence of or treatment for clinically significant cytomegalovirus (CMV) colitis (based on 
the investigator’s judgment) within 60 days prior to Day 1.  Laboratory confirmation of CMV 
from colon biopsy sample is required during screening evaluation only if clinical suspicion is 
high and to determine the need for CMV treatment

History of active or latent treated tuberculosis (TB), regardless of treatment history 
(see protocol)
Patients with a history of active or latent TB (based on a positive screening assay, 
either purified protein derivative [PPD] skin test or QuantiFERONTB Gold test), are 
not eligible for this study.
Patients with a chest X-ray (posteroanterior [PA] and lateral) within 3 months of Day 1 
suspicious for pulmonary TB are not eligible for this study.

History of recurrent opportunistic infections and/or history of severe disseminated viral 
infections (e.g., herpes)

Any serious opportunistic infection within the last 6 months


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
Any current or recent signs or symptoms (within 4 weeks before screening and during 
screening) of infection, except for the following:
Minor infections (e.g., common cold) that have, in the investigator’s judgment, 
completely resolved prior to Day 1
Fungal infections of the nail beds
Oral or vaginal candidiasis that has resolved with or without treatment prior to Day 1

Any major episode of infection requiring treatment with IV antibiotics within 8 weeks prior to 
screening or oral antibiotics within 4 weeks prior to screening
Treatment with antibiotics as adjunctive therapy for UC in the absence of documented 
infection is not exclusionary.

Received a live attenuated vaccine within 4 weeks prior to Day 1

History of organ transplant
Exclusion Criteria Related to Laboratory Values (at Screening)

Serum creatinine •2 times upper limit of normal (ULN)

ALT or AST •3 × ULN, or alkaline phosphatase • 3 × ULN, or total bilirubin •2.5 × ULN 
(unconjugated hyperbilirubinemia that is associated with known Gilbert's syndrome is not an 
exclusion criterion)

Platelet count • 100,000/μL

Hemoglobin • 8 g/dL

Absolute neutrophil count • 1500/μL

Absolute lymphocyte count • 500/μL
Length of Study
The total length of the treatment period will be 62 weeks.  Patients who do not achieve a clinical 
response at Week 10, patients who have clinical relapse during the Maintenance Phase, 
patients who receive defined rescue treatment (see protocol), and patients who complete 
62 weeks of the study may be given the option of enrolling in Part 1 (OLE) of Study GA28951, 
where they will receive open-label etrolizumab treatment.  Those who do not enroll in Part 1 
(OLE) of Study GA28951 will continue to 12 weeks of safety follow-up in this study, and then be 
requested to enroll in Part 2 (SM) of Study GA28951 for 92 weeks of PML monitoring.
The total length of the study is expected to last from the first patient screened to either the last 
patient in last follow-up visit in this protocol or last patient enrolled into Study GA28951 (OLE-
SM), whichever is later.
End of Study
The end of the study is defined as the last patient last safety follow-up visit in this protocol or 
last patient in this protocol enrolled into Study GA28951 (OLE-SM), whichever is later.
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:
Primary Outcome Measure

Remission at Week 62 among patients with a clinical response at Week 10, as determined by the 
MCS
Secondary Outcome Measures

Clinical remission at Week 62 among patients in clinical remission at Week 10

Clinical remission at Week 62

Remission at Week 62 among patients in remission at Week 10

Improvement in endoscopic appearance of the mucosa at Week 62

Endoscopic remission at Week 62

Histologic remission at Week 62

Change from baseline in rectal bleed subscore at Week 6


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
Change from baseline in stool frequency subscore at Week 6

Corticosteroid-free clinical remission at Week 62 (off corticosteroids for at least 24 weeks 
prior to Week 62) in patients who are receiving corticosteroids at baseline

Corticosteroid-free remission at Week 62 (off corticosteroids for at least 24 weeks prior to 
Week 62) in patients who are receiving corticosteroids at baseline

Change from baseline to Week 62 in UC bowel movement signs and symptoms as 
assessed by the UC-PRO/SS measure

Change from baseline to Week 62 in UC abdominal symptoms as assessed by the UC-
PRO/SS measure

Change from baseline to Week 62 in patients’ health-related QOL as assessed by the 
overall score of the IBDQ
Exploratory Efficacy Outcome Measures 

Clinical response at Week 62 among patients with a clinical response at Week 10

Remission at Week 62 among patients in clinical remission at Week 10

Corticosteroid-free clinical remission at Week 62 (off corticosteroids for at least 12 weeks 
prior to Week 62) in patients who are receiving corticosteroids at baseline

Histologic disease activity change from baseline to Week 10 and Week 62

Improvement in histologic and/or endoscopic disease activity

Change in health utilities, as assessed by the EQ-5D, from baseline to Weeks 10 and 62

Improvement in endoscopic appearance of the mucosa at Week 10

Endoscopic remission at Week 10

Frequency and duration of hospitalizations from Week 10 to Week 62

Response, remission and corticosteroid-free endpoints as determined by the mMCS
Safety Outcome Measures
The safety outcome measures for 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 study drug discontinuation

Incidence of laboratory abnormalities

Incidence of malignancies

Incidence of ATAs to etrolizumab

Incidence and severity of hypersensitivity reaction events
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:

Serum trough concentration at steady state during the dosing period from Week 12 to 
Week 62

Serum concentration at primary endpoint time (Week 62)
Exploratory Biomarker Outcome Measures
The exploratory biomarker outcome measures for this study are as follows:

Remission at Week 10 and maintenance of remission at Week 62 in patients according to 
baseline levels of colonic tissue biomarkers and/or peripheral blood, including, but not 
limited to, αE integrin


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
Changes in levels of exploratory colonic tissue and/or peripheral blood biomarkers during 
the Induction and Maintenance Phases

Changes in stool biomarkers, which may include, but are not limited to, those in the 
microbiota and bacterial cultures, during the Induction and Maintenance Phases
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 Q4W.
Comparator
Placebo PFS:  etrolizumab SC matching placebo given in the amount of 0.7-mL solution will be 
administered by SC injection Q4W.
Non-Investigational Medicinal Products
Patients are to continue on their baseline dose of corticosteroid (including budesonide) to the 
end of the Induction Phase (Week 10).  Tapering of corticosteroid (including budesonide) is to 
be attempted during the Maintenance Phase.
All patients are to continue on their baseline dose of immunosuppressants (AZA, 6-MP, MTX) to 
the end of Induction Phase (Week 10), unless dose reduction or discontinuation is required due 
to toxicity.  
Probiotics and oral 5-ASA may be continued at a stable dose throughout the study.
Occasional use of NSAIDs and acetaminophen (e.g., headache, arthritis, myalgias, and 
menstrual cramps) and aspirin up to 325 mg daily are permitted throughout the study.
Antidiarrheals (e.g., loperamide, diphenoxylate with atropine) for control of chronic diarrhea are 
permitted throughout the study.
Statistical Methods
Primary Analysis
The analysis of data from the 62-week treatment period will be performed when all data from 
this period are in the database and data have been cleaned and verified.
Whereas Sponsor personnel will be unblinded to treatment assignment to perform the primary 
Week 62 analyses, patients and study site personnel will remain blinded to individual treatment 
assignment during the Maintenance Phase until after the study is completed (after all patients 
have either completed the safety follow-up period or discontinued early from the study) and the 
database is locked.
Detailed specifications of the statistical methods will be described in the Statistical Analysis Plan.
Determination of Sample Size  
The study sample size was selected so that sufficient patients are enrolled to evaluate the 
primary endpoint in the Maintenance Phase.  Approximately 350 patients will be enrolled in the 
open-label Induction Phase. 
Under the assumption of clinical response at Week 10 of approximately 60% (based on the Phase 
II Week 10 response results for the TNF-naive subgroup), the planned size of 350 patients in the 
open-label Induction Phase would provide approximately 210 patients randomized into the 
Maintenance Phase.  A sample size of approximately 105 patients per arm is required in the 
Maintenance Phase to achieve90% power to detect a 25% absolute difference in remission 
rates between the etrolizumab and placebo arms, for a χ2 test at the two-sided 5% significance 
level, under the assumption of a placebo true remission rate of 30%−45%.  If clinical response
rates at Week 10 are lower than projected, the total enrollment in the open-label induction 
cohort may be increased to ensure that a sufficient number of Week-10 clinical responders are 
randomized into the Maintenance Phase.


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Appendix 2
Schedule of Assessments
Assessments
Screenin
g Day a
−35 
to−1
Study Week (±3 days)
0 b
4
8
10
1
2
1
6
2
0
2
4
28 c
32
36 c
40
c
44
48
c
52
c
5
6
60
c
62
Unschedule
d Visit d
Early 
Withdraw
al from 
Treatmen
t Visit
Informed consent
x
Review eligibility 
criteria
x
x e
Demographic data
x
Pregnancy test f
x
x e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
X
Vital signs (BP and 
pulse)
x
x e
x
x
x
x
x
x
x
x
x
x
X
ECG
x
x
X
Chest X-ray g
x
Height 
x
Weight
x
Medical history
x
Physical examination h
x
x
x
x
x
x
x
X
PML neurologic 
examination i
x
x
x
x
x
x
x
x
x d
X
Hematology
x
x e
x
x
x
x
x d
x j
Chemistry
x
x e
x
x
x
x
x d
x j
Urinalysis
x
x e
x d
TB screen k
x


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Appendix 2
Schedule of Assessments (cont.)
Study Week (±3 days)
Assessments
Screenin
g Day a
−35 
to−1
0 b
4
8
10
1
2
1
6
2
0
2
4
28 c
32
36 c
40
c
44
48
c
52
c
5
6
60
c
62
Unschedule
d Visit d
Early 
Withdraw
al  from 
Treatmen
t Visit
HIV test
x
Hepatitis B and C 
serology l
x
Hepatitis B DNA m
x
x
x
x
x
x
Hepatitis C RNA 
(Amplicor) n
x
Flow cytometry
x
x
x
PK sampling (serum) o
x
x
x
x
x
x d
x j
Anti-therapeutic 
antibody sample 
(serum) o, p
x
x
x
x
x
x q
x d
x j, q
Plasma sample r
(storage for JCV 
antibody testing) 
x
MCS (includes 
endoscopy) s, t
x u
x
x
x d
x j
pMCS (excludes 
endoscopy) v
x u
x
x
x
x
x
x
x
x
x
x d
x j
Stool sample
x w
x x
x x
x x
x d
xx
Colonic biopsy (CMV if 
required)
x y
x d


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Appendix 2
Schedule of Assessments (cont.)
Study Week (±3 days)
Assessments
Screenin
g Day a
−35 
to−1
0 b
4
8
10
1
2
1
6
2
0
2
4
28 c
32
36 c
40
c
44
48
c
52
c
5
6
60
c
62
Unschedule
d Visit d
Early 
Withdraw
al  from 
Treatmen
t Visit
Colonic biopsy 
(histopathological 
confirmation of UC if 
required)
x z
Colonic biopsy 
(formalin)
x aa
x 
bb
x 
bb
x d, bb
x j, bb
Colonic biopsy (RNA 
later)
x aa
x 
bb
x 
bb
x d, bb
x j, bb
Serum sample (CRP)
x e
x
x
x d
x j
Blood sample for 
genetic analysis (DNA) 
(optional)
x
Serum sample (future 
exploratory PD) o
x
x
x
x
x
X
Blood sample (RNA 
Paxgene) o, cc
x
x
x
x
X
UC-PRO/SS measure t
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
IBDQ dd
x
x
x
EQ-5D dd
x
x
x
x
Concomitant 
medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


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Appendix 2
Schedule of Assessments (cont.)
Study Week (±3 days)
Assessments
Screenin
g Day a
−35 
to−1
0 b
4
8
10
1
2
1
6
2
0
2
4
28 c
32
36 c
40
c
44
48
c
52
c
5
6
60
c
62
Unschedule
d Visit d
Early 
Withdraw
al  from 
Treatmen
t Visit
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Randomization of 
responders to 
Maintenance Phase
x 
ee
Etrolizumab 
administration
x
x
x
Etrolizumab/ 
etrolizumab placebo 
administration ff
x
x
x
x
x
x
x
x
x
x
x
x
x
ATA=anti-therapeutic antibody; BP=blood pressure; CMV=cytomegalovirus; CRP =C-reactive protein; EQ-5D=EuroQoL Five-Dimension 
Questionnaire; HBc =HBV core antibody total; HBsAg=HBV surface antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; IBDQ =Inflammatory 
Bowel Disease Questionnaire; JCV=John Cunningham virus; MCS=Mayo Clinic Score; PD=pharmacodynamics; PK=pharmacokinetic; 
pMCS=partial Mayo Clinic Score; PML=progressive multifocal leukoencephalopathy; qPCR =quantitative polymerase chain reaction; 
TB=tuberculosis; tc =telephone call; UC-PRO/SS=Ulcerative Colitis Patient-Reported Outcome Signs and Symptoms.
Notes:  All study assessments and blood draws are to be conducted prior to study drug administration.  All colonic biopsy samples will be taken 
during flexible sigmoidoscopy/colonoscopy procedure.
a
All assessments must be performed after obtaining informed consent.  Endoscopy should be performed 416 days prior to Day 1 (i.e., 
Day 16 to Day 4).  The total screening period is 35 days. Under no circumstances will either window be extended.
b
Day 1 of Week 0.
c
Telephone contact for patients performing home administration:  Patients requiring in-clinic drug administration throughout the study will have 
their study assessments conducted in clinic or via telephone call after their clinic visit at the sites’ discretion.


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Appendix 2
Schedule of Assessments (cont.)
d
Unscheduled visit represents a visit that is not 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 of PML; for disease worsening, infectious etiologies may be investigated if 
clinically indicated; and confirmation of clinical relapse is performed by the MCS assessment).  Assessments corresponding to items noted in this 
column should be recorded on the eCRF.
e
Perform prior to administration of etrolizumab.
f
Serum test at screening for all female patients except those who are more than 1 year postmenopausal or have had a hysterectomy.  Urine 
test at other visits; if urine test result is positive, perform a confirmatory serum test.  Pregnancy test will be carried out at home once patient starts 
etrolizumab administration at home.  Patient is to report the pregnancy test via the e-diary.  Patients must be instructed at screening and reminded 
throughout the study that in case of positive pregnancy test they must stop self-administration of study drug and call the site immediately.  Do not 
administer etrolizumab unless the serum pregnancy test result is negative.
g
Not required if normal chest X–ray result within 3 months prior to screening. 
h
Full physical examination required at screening; symptom-driven physical examination at all other timepoints indicated.
i
PML neurologic examination consists of the PML Subjective Checklist and the PML Objective Checklist. Administer before other assessments, 
per Appendix 5.
j
Not required if unscheduled visit leads to withdrawal and assessment previously conducted at unscheduled visit.
k
The following tests are acceptable screening assays for latent TB in this study:  purified protein derivative (a tuberculin skin test reaction; 
e.g., Mantoux test), INF-γ based test (e.g., QuantiFERON®-TB Gold).
l
Patients must undergo screening for HBV and HCV. This includes testing for HBsAg, anti-HBc, and hepatitis C antibody.
m
Enrolled patients who are hepatitis B core antibody positive should have hepatitis B DNA measured at these timepoints.
n
Measurement of HCV RNA with use of the Amplicor assay is required when the patient has a known history of HCV antibody positivity with 
past documentation of undetectable HCV RNA, either with or without history of anti-viral treatment.  Patients with newly diagnosed HCV antibody 
positivity are not eligible for this study and, therefore, do not require measurement of HCV RNA.
o
All samples to be collected prior to administration of etrolizumab.  Serum baseline, Week 4, and blood sample (RNA Paxgene) are to be 
collected prior to dose of etrolizumab from all patients.  All subsequent samples (serum and Paxgene whole blood) will be collected only from those 
who were eligible to be randomized into the Maintenance Phase.
p
If serum sickness or a clinically significant allergic drug reaction is suspected, Sponsor should be notified, and serum for etrolizumab level 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.


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Appendix 2
Schedule of Assessments (cont.)
q
Collection of sample for ATA is required at final or early withdrawal visit, unless it coincides with first visit in Part 1 of Study GA28951 (where a 
sample for ATA must be collected).
r
A blood sample to test for antibodies to JCV will be taken and stored for possible later assessment of how widespread the JCV infection is in 
the study population.  Sample testing for the presence of JCV antibodies is not helpful in predicting risk for PML or for evaluating neurologic 
symptoms.  The sample may be tested if there is a strong belief that this information will be helpful in managing a patient's condition.
s
Endoscopy + rectal bleeding assessment + stool frequency assessment + Physician’s Global Assessment.  Patients who have not undergone 
full colonoscopy with documented results within 1 year prior to screening should undergo colonoscopy in lieu of sigmoidoscopy at the screening 
visit to allow for screening for cancer/dysplasia (yes/no).
t
During screening, patients must be trained on the use of the e-diary.  Patients are to complete the e-diary on a daily basis for the stool 
frequency and rectal bleeding score (for MCS/pMCS), starting from the first screening visit, and for at least 9 12 consecutive days around the time 
of each scheduled visit for the UC-PRO/SS.
u
Screening endoscopy (for the MCS) should be performed 416 days prior to Day 1 (i.e., Day16 to Day4).  For baseline measurements, the 
Physician’s Global Assessment will be obtained only once, on Day 1 (prior to enrollment), and the Physician’s Global Assessment score will be 
used to calculate both the baseline (screening) MCS and the baseline (Day 1) pMCS.
v
Rectal bleeding assessment + stool frequency assessment + Physician’s Global Assessment.
w
For culture and sensitivity testing; ova, parasites, and Clostridium difficile toxin testing.  
x
Sample analyses may include, but are not limited to, analyses of fecal calprotectin and other exploratory PD biomarkers (such as analyses of 
the microbiota and bacterial cultures).
y
IF REQUIRED:  Only if there is suspicion for clinically significant CMV colitis, one biopsy sample should be obtained from the base of the ulcer 
to evaluate for histological presence of CMV.  Analysis should be performed locally if possible, or can be sent to a central laboratory if necessary.  
Result must be negative for CMV prior to dosing on Day 1.  
z
IF REQUIRED:  If patient does not have previously documented histopathologic confirmation of UC as defined in the inclusion criteria, one 
biopsy sample can be obtained from the base of the ulcer read locally for histopathologic confirmation of UC.
aa
In addition to the optional biopsy samples noted in footnote “y” and “z” above, five pairs (10 biopsy samples) will be obtained at screening.  
These five biopsy pairs will be sent to the central laboratory for further storage or distribution.  Two pairs (taken from the most inflamed area of 
colon within 20−40 cm of anal verge [sigmoid]) will be placed in stabilization buffer (such as RNAlater or a similar buffer) and stored at −80°C (one 
pair for diagnostic qPCR and one pair for PD biomarkers qPCR).  The other three pairs (two pairs from most inflamed area of colon within 20−40 
cm of anal verge [sigmoid] and one pair from the most inflamed area of the worst affected segment) will be placed in formalin and then paraffin 
embedded (one pair will be used for histopathology and exploratory PD biomarkers and the other two pairs will be used for diagnostic).  Original 
biopsy location and endoscopic depth should be clearly indicated.


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37/Statistical Analysis Plan GA29102
Appendix 2
Schedule of Assessments (cont.)
bb
A total of four pairs (8 biopsy samples) will be obtained.  All will be sent to the central laboratory for further storage or distribution.  One pair will 
be placed in stabilization buffer (such as RNAlater or a similar buffer) and stored at −80°C for exploratory PD or diagnostic biomarker qPCR.  The 
other three pairs, representing three different segments (rectum, sigmoid, descending colon), will be placed in formalin and then paraffin embedded; 
these biopsy samples will be used for histopathology, exploratory PD biomarkers, and/or diagnostic biomarker.  Original biopsy location and 
endoscopic depth should be clearly indicated.
cc
Paxgene blood RNA samples must be collected after all other blood and serum samples.
dd
With the exception of Week 0, the IBDQ and the EQ-5D will be completed in-clinic by the patient after the PML neurological examination but 
before any other non-PRO assessments and before the patient receives any disease status information or study drug during that visit.
ee
Randomization to occur within 2 weeks starting from Week 10 timepoint.
ff
Where indicated, patients must be instructed to administer study drug at home within 3 days (maximum) after clinic visit.


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Appendix 3
Rescue Therapy
Study Phase
Type
Description
Induction
Permitted
Initiation or escalation beyond baseline dose of the following 
agents for the treatment of worsening UC symptoms.

Immunosuppressants (AZA, 6-MP or MTX)

Oral or topical 5-ASA or corticosteroid (use of topical at 
baseline is among the exclusion criteria; rectal is synonymous 
with topical)
Prohibited
Any use of other immunosuppressants, including:

TNF inhibitors and biosimilars thereof

Cyclosporine, tacrolimus, sirolimus, or MMF

Anti-adhesion molecules, including natalizumab and 
vedolizumab

Other biologics, such as efalizumab, alemtuzumab, 
visilizumab and rituximab

Other investigational agents, including vaccines (e.g., MAP or 
ChAdOx2 HAV, JAK inhibitors))
Maintenance
Permitted
Same definition as induction, noting that:

Maintenance period begins with an oral corticosteroid taper

All patients receiving rescue therapy during the induction 
period are ineligible to enter maintenance
Prohibited
Same definition as induction, noting that:

All patients receiving rescue therapy during the induction 
period should withdraw from the study
5-ASA5-aminosalicylic acid; 6-MP6-mercaptopurine; AZAazathioprine; ChAdOx2 
HAVchimpanzee adenovirus Oxford 2 hepatitis A vaccine; JAKJanus kinase; 
MAPMycobacterium avium subspecies paratuberculosis; MMFmycophenolate mofetil; 
MTXmethotrexate; TNFtumor necrosis factor; UCulcerative colitis.


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL
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 Project SAP
STATISTICAL ANALYSIS PLAN
TITLE:
DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER 
STUDIES OF THE EFFICACY AND SAFETY OF ETROLIZUMAB 
DURING INDUCTION AND/OR MAINTENANCE PHASES IN 
PATIENTS WITH MODERATE TO SEVERE ACTIVE ULCERATIVE 
COLITIS WHO HAVE BEEN PREVIOUSLY EXPOSED TO TNF
INHIBITORS OR PATIENTS WHO ARE aTNF NAÏVE
PROTOCOL NUMBER(S): RO5490261 (GA28948, GA28949, GA29102, 
GA29103, GA28950)
STUDY DRUG:
Etrolizumab
VERSION NUMBER:
3
IND NUMBER:
100366
EUDRACT NUMBER:
2013-004278-88, 2013-004280-31, 2013-004279-11, 
2013 004277-27, 2013-004282-14
SPONSOR:
F. Hoffmann-La Roche Ltd.
PLAN PREPARED BY:
, M.Sc.
DATE FINAL:
Version 1: 14 May 2019
DATE AMENDED:
Version 2: 17 December 2019
Version 3: See electronic date stamp below.
Date and Time(UTC)        Reason for Signing                              Name
04-May-2020 14:40:20
Company Signatory


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2/Statistical Analysis Plan Project SAP
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE FOR VERSION 3

Changes to Section 4.3.2 (Baseline Disease Characteristics):
–
Prior tumor necrosis factor (TNF) Category updated Naive to Unknown

Changes in Section 4.4.2.1.1 (Stool Frequency and Rectal Bleeding):
–
For analysis at baseline Mayo Clinic Score (MCS) subscores, stool frequency 
(SF) and rectal bleeding (RB) calculations clarified calculation when endoscopy 
occurred outside of window.

Changes in Sections 4.4.2.1.2 (Endoscopy) and 4.4.2.1.4 (Outcome Measures 
Derived from the MCS):
–
Replaced using the terminology of overall score with the Hybrid Score (HS)
–
Add definition Endoscopic Remission (excluding friability from mild subscore 1)
–
Add definition Improvement of the endoscopic mucosa (excluding friability from 
mild subscore 1)

Changes to Section 4.4.2.3 (UC-PRO):
–
PRO analysis method of analysis of covariance (ANCOVA) removed and 
mixed-model repeated measures (MMRM) has been added as the primary 
method.
–
Clarified the bowel domain score is 0-27 

Changes to Section 4.3 (Subgroups):
–
Added in anti-drug antibodies (ADA) positive Subgroups

Changes to Section 4.7.1 (Adverse Events):
–
Added in non-treatment emergent report
–
Added rates for Studies GA28948 and GA28949

Changes to Section 4.8 (Missing Data):
–
For continuous endpoints worst post baseline imputation has been removed for 
ulcerative colitis patient-reported outcome (UC-PRO) data, and observed case 
analysis added as a sensitivity analysis for SF/RB and Inflammatory Bowel 
Disease Questionnaire (IBDQ).
–
Further clarification of when non-responder imputation will be applied to 
categorical endpoints has been added.
–
Clarification the tipping point analyses will be conducted for all primary 
endpoints across all studies.
Additional minor changes have been made to improve clarity and consistency.


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3/Statistical Analysis Plan Project SAP
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE FOR 
VERSION 3................................................................................................... 2
1.
BACKGROUND ............................................................................................ 7
2.
STUDY DESIGN........................................................................................... 7
2.1
Protocol Synopsis.................................................................... 7
2.2
Outcome Measures ................................................................. 8
2.3
Determination of Sample Size ................................................. 8
2.4
Analysis Timing ....................................................................... 8
3.
STUDY CONDUCT....................................................................................... 8
3.1
Randomization......................................................................... 8
3.2
Independent Review Facility.................................................... 8
3.3
Data Monitoring ....................................................................... 9
4.
STATISTICAL METHODS ............................................................................ 9
4.1
Analysis Populations ............................................................... 9
4.2
Analysis of Study Conduct....................................................... 9
4.3
Analysis of Treatment Group Comparability ............................ 9
4.3.1
Demographics ....................................................................... 10
4.3.2
Baseline Disease Characteristics .......................................... 11
4.3.3
Baseline Disease Medications............................................... 12
4.4
Efficacy Analysis.................................................................... 12
4.4.1
Efficacy Endpoints................................................................. 12
4.4.2
Endpoint Definitions............................................................... 12
4.4.2.1
Mayo Clinic Score.................................................................. 13
4.4.2.2
Histologic Endpoints .............................................................. 17
4.4.2.3
UC-PRO ................................................................................ 1
4.4.2.4
Inflammatory Bowel Disease Questionnaire.......................... 18
4.4.3
Subgroup Analyses ............................................................... 19
4.5
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 19
4.6
Biomarker Analysis................................................................ 20
4.7
Safety Analyses..................................................................... 20


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4.7.1
Adverse Events ..................................................................... 20
4.7.2
Laboratory Data..................................................................... 22
4.7.3
Vital Signs.............................................................................. 23
4.7.4
Medical History...................................................................... 23
4.7.5
Concomitant Medications ...................................................... 23
4.8
Missing Data.......................................................................... 23
4.9
Interim Analyses .................................................................... 24
5.
REFERENCES ........................................................................................... 25
LIST OF TABLES
Table 1
Study Descriptions........................................................................ 7
Table 2
Steps for Calculating SF/RB Subscore ....................................... 14
Table 3
Outcome Measures..................................................................... 16
Table 4
Histologic Endpoints ................................................................... 17
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 26
Appendix 2
Schedule of Assessments........................................................... 27
Appendix 3
Mayo Clinic Score Measurement ................................................ 28
Appendix 4
Nancy Histological Index............................................................. 29
Appendix 5
Geboes Grading Scale and Robarts Histopathological Index ..... 30
Appendix 6
Ulcerative Colitis Patient Reported Outcomes Signs and 
Symptoms................................................................................... 31


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GLOSSARY OF ABBREVIATIONS
AE adverse event
AESIs adverse events of special interest
ALT alanine aminotransferase
ANCOVA analysis of covariance
aTNF anti-tumor necrosis factor
AST aspartate aminotransferase
CMH Cochran-Mantel-Haenszel
CRP C-reactive protein
CRF Case Report Form
CS corticosteroid
CSR Clinical Study Report
ES Endoscopic Subscore
FFPE formalin-fixed paraffin-embedded
HS Hybrid Sigmoid
IBD inflammatory bowel disease
IBDQ Inflammatory Bowel Disease Questionnaire
iDCC independent Data Coordinating Center
iDMC independent Data Monitoring Committee
IS immunosuppressant
IxRS interactive voice/web based response system
LoPO list of planned outputs
MCS Mayo Clinic Score
MedDRA Medical Dictionary for Regulatory Activities
mITT modified intent to treat
mMCS modified Mayo Clinic Score
MMRM mixed-model repeated measures
NHI Nancy Histology Index
OLE open label extension
OLI open label induction
PD pharmacodynamic
PGA Physician’s Global Assessment
PK pharmacokinetic
pMCS partial Mayo Clinic Score
RB rectal bleeding
RHI Robarts Histopathological Index
SAE serious adverse event
SAP Statistical Analysis Plan
SF stool frequency
SMQ standardized MedDRA query
TNF tumor necrosis factor
UC ulcerative colitis
UC-PRO/SS Ulcerative Colitis Patient-Reported Outcome Signs and 
Symptoms
ULN upper limit of normal


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GLOSSARY OF ABBREVIATIONS
WOCF Worse Observation Carried Forward


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1.
BACKGROUND
This etrolizumab project Statistical Analysis Plan (SAP) describes the study design and 
analyses that are common to the Phase III etrolizumab studies in ulcerative colitis (UC) 
patients detailed in Table 1.  Elements of the study design and analysis unique to the 
individual studies will be explained in the respective study SAPs.
Table 1
Study Descriptions
Study
Study Description
GA28948 (Hibiscus I)
and
GA28949 (Hibiscus II)
Two identical placebo-controlled induction studies 
assessing the efficacy and safety of etrolizumab compared 
to adalimumab and placebo in patients with moderate to 
severe active ulcerative colitis who are naive to TNF 
inhibitors
GA29102 (Laurel)
Placebo-controlled, maintenance study assessing the 
efficacy and safety of etrolizumab in patients with moderate 
to severe active ulcerative colitis who are naive to TNF 
inhibitors
GA29103 (Gardenia)
Head To Head 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
GA28950 (Hickory)
Placebo-controlled, induction and maintenance study 
assessing the efficacy and safety of etrolizumab in patients
with moderate to severe active ulcerative colitis who have 
been previously exposed to TNF inhibitors
TNFtumor necrosis factor.
Studies GA28950 and GA29102 are made up of two phases: Induction Phase and 
Maintenance Phase.  For the purpose of statistical analyses, the Induction and 
Maintenance Phases of Studies GA28950 and GA29102 will be treated as two 
independent studies and analyzed separately.  Studies GA28948 and GA28949 are 
induction studies.  Study GA29103 is a treat-through study design with no 
re-randomization into the Maintenance Phase; therefore, the Induction and Maintenance 
Phases will be analyzed as one study.
The analysis of data will be performed once all the data have been collected in the 
database for the primary analysis as described in the study SAPs.
2.
STUDY DESIGN
2.1
PROTOCOL SYNOPSIS
For individual study Protocol Synopses and Schedules of Assessments, refer to the 
study SAP Appendix 1 and Appendix 2, respectively.


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2.2
OUTCOME MEASURES
For individual study outcome measures, refer to the study SAPs.
2.3
DETERMINATION OF SAMPLE SIZE
For details of individual study sample size, refer to the study SAPs.
2.4
ANALYSIS TIMING
For details of the analysis timing for individual studies, refer to the study SAPs.
3.
STUDY CONDUCT
3.1
RANDOMIZATION 
An independent interactive voice/Web-based response system (IxRS) vendor will 
conduct the randomization for all studies and the independent Data Coordinating Center 
(iDCC) will perform regular checks of the randomization scheme using unblinded data.  
The patient randomization list will be generated by the IxRS with use of a pre-defined 
randomization specification.  During study conduct the randomization list will not be 
available to the study sites, study monitors, project statisticians, or the Sponsor’s project 
team.  The study team will remain blinded to study drug.  If unblinding is necessary for 
patient management (in the case of a serious adverse event [SAE]), the investigator will 
be able to break the treatment code by contacting the IxRS.  Treatment codes should 
not be broken except in emergency situations.  If the investigator wishes to know the 
identity of the study drug for any other reason, he or she should contact the Medical 
Monitor.  The investigator should document and provide an explanation for any 
premature unblinding (e.g., accidental unblinding, unblinding due to an SAE as per 
health authority reporting requirements).  The Sponsor safety reporting department 
(independent to the study team) will unblind the identity of the study medication for all 
unexpected SAEs that are considered by the investigator to be related to study drug per 
safety reference document(s), such as the Investigator’s Brochure, Core Data Sheet, 
and Summary of Product Characteristics (SmPC).  Details of patients who are unblinded 
during the study will be included in the individual study Clinical Study Reports (CSRs).
After the end of randomization, the data entered into the IxRS system will be reconciled 
with the data entered into the clinical database.  In particular, the kit assignments and 
stratification factors will be checked.  Discrepancies between the IxRS and clinical 
database will be listed in the CSR and raised as protocol deviations.  The statistical 
analyses will be conducted using IxRS stratification factors, and sensitivity analysis 
using clinical database data will be conducted if required. 
Further details of stratification factors for each study is included in the study SAPs.
3.2
INDEPENDENT REVIEW FACILITY
The efficacy measure Mayo Clinic Score (MCS) requires endoscopic subscores to be 
collected.  Central reading of endoscopies will be performed throughout the studies by 


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an independent review facility.  Data collected at sites as video clips are read centrally 
by an independent gastroenterologist experienced in inflammatory bowel disease (IBD).  
The independent reader will be blinded to the patient’s clinical activity and treatment 
allocation. Reads are collected and read locally and the again centrally. The 
adjudication is carried out in two stages:
1.
A second central reading is performed if the local and initial central reading do not 
agree or the initial central reading cannot be performed.
2.
The local and central reading results are combined in a final Mayo Endoscopy 
subscore using the median among readers, rounded up to the nearest integer.
Further details are available in the Independent Review Charter. 
The efficacy measure of histologic remission requires independent scoring.  The 
histologic scoring will be performed by a small pool of central readers who are blinded 
both to treatment arm and timepoint.  The scoring database will ensure that all slides for 
a given patient are scored by the same reader.  Slide image scores are based on 
formalin-fixed paraffin-embedded (FFPE) biopsies from the most inflamed region of the 
sigmoid colon.  Scores are queried for discrepancies between Nancy Histologic Index 
(NHI) and Geboes results (e.g., NHI 4, indicating no erosions/ulcerations, and Geboes 
subgrades 5.3 or 5.4, indicating the presence of erosions/ulcerations).  Queries may 
lead to the same reader reassessing the relevant slide images and revising the scores 
as they deem necessary.  Further details are available in the Image Review Charter.
3.3
DATA MONITORING
An independent Data Monitoring Committee (iDMC) will monitor safety and study 
conduct on an ongoing basis for all studies.  The iDMC will meet approximately every 
6 months.  Further details are available in the iDMC Charter.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
Analysis populations are reported in the individual study SAPs.
4.2
ANALYSIS OF STUDY CONDUCT
For details on the analysis of study conduct, refer to the individual study SAPs.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
To review treatment group comparability within each study a number of variables 
collected at baseline will be compared across treatment groups.  Baseline is defined as 
the last available assessment prior to first receipt of study drug.
For continuous variables, descriptive statistics including n, mean, median, SD, minimum, 
and maximum will be calculated.  For categorical variables, number and percentage in 


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each category will be displayed.  The units/categories to be used are indicated within the 
brackets and separated by commas.
Summaries by treatment group will be presented for all analysis populations.  
Demographics and baseline characteristics presented for patients in the Maintenance 
Phases will use the data collected from their baseline visits.
4.3.1
Demographics
Demographics presented will include;

Age at randomization (years), descriptive statistics, and number and percentage of 
patients in the following categories:  1840, 4065, 65

Gender, number and percentage of patients in the following categories:  male, 
female

Race, number and percentage of patients in the following categories:
–
American Indian or Alaskan Native
–
Asian
–
Black or African American
–
Native Hawaiian or other Pacific Islander
–
White
–
Other (includes Other, Multiple, and Unknown)
For Listings the Race Category Other, multiple and unknown will be reported. For 
summaries and subgroups the combined category ‘Other’ will be used.

Region, number and percentage of patients in the following categories:
–
Central /Eastern Europe 
–
USA 
–
Western/Northern Europe, Canada, Australia, New Zealand 
–
Asia 
–
Latin America 
–
Other

Ethnicity, number and percentage of patients in the following categories:  Hispanic 
or Latino, Not Hispanic or Latino, Not reported, Unknown

Body Weight (kg), descriptive statistics

Body Mass Index (BMI; kg/m2), descriptive statistics 

Tobacco Use, number and percentage of patients in the following categories:  Never, 
Previous, Current


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4.3.2
Baseline Disease Characteristics
Details of efficacy parameters definitions listed below are provided in Section 4.4.2.

Duration of disease (years), descriptive statistics, and number and percentage of 
patients in the following categories:  3, 3-<8, 8

Disease extent, number and percentage of patients in the following categories:  
Left-sided colitis, Extensive colitis, Pancolitis

Serum C-reactive protein (CRP) (mg/L), descriptive statistics, and number and 
percentage of patients in the following categories:  2.87, 2.8710, 10

Fecal calprotectin (g/g), descriptive statistics including median, 25th and 75th 
percentiles and number and percentage of patients in the following categories:  
250, 250500, 500

Mayo Clinic Score (MCS), descriptive statistics, and number and percentage of 
patients in the following categories:  MCS 9, MCS 10

Partial Mayo Clinic Score (pMCS) –Descriptive statistics

Modified Mayo Clinic Score (mMCS) –Descriptive statistics

Modified Mayo Clinic Score (mMCS) (excluding friability from Mayo ES1) –
Descriptive statistics

Stratification Factor MCS Score per IxRS, number and percentage of patients in 
each category:  MCS 9, MCS 10

Stool Frequency (SF) Descriptive statistics.

Rectal Bleeding (RB) Descriptive statistics.

Physician’s Global Assessment (PGA)   Descriptive statistics

Endoscopy (ES) – Descriptive statistics.

Ulcerative Colitis Patient-Reported Outcomes, Signs and Symptoms (UC-PRO/SS): 
Functional Descriptive statistics 

UC-PRO/SS: Bowel Descriptive statistics 

UC-PRO: Systemic Symptoms – Descriptive Statistics

Inflammatory Bowel Disease Questionnaire (IBDQ) Descriptive statistics 

Nancy Histological Index (NHI) – Descriptive statistics and frequencies (number and 
percentage per grade) 

Robarts Histopathological Index (RHI) – Descriptive statistics and frequencies 
(number and percentage per grade) 

Geboes Grading Scale Score – Descriptive statistics and frequencies (number and 
percentage per grade)


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4.3.3
Baseline Disease Medications
All data types are categorical and the number and percentage of patients will be 
presented for each category denoted in brackets.

Corticosteroid (CS) use at baseline (yes, no)

Stratification Factors (IxRS):  Corticosteroid (CS) use at baseline (yes, no)

Immunosuppressant (IS) use at baseline (yes, no)

Stratification Factors (IxRS):  Immunosuppressant (IS) use at baseline number (yes, 
no)

Corticosteroid and Immunosuppressant categories (CS alone, IS alone, CS and IS, 
None)

Prior anti-tumor necrosis factor (aTNF) medication (yes, no)

Prior aTNF medication (1 failure, 2 failures, Refractory Primary Non-response, 
Loss of response Secondary Loss of Response, Intolerant, Unknown) 
Prior aTNF use is only relevant for Study GA28950; all patients in other studies are 
aTNF-naive.
4.4
EFFICACY ANALYSIS
The hierarchical priority of key secondary endpoints and analysis populations are 
available in the study SAPs.  All formal statistical comparisons for binary data will use 
the Cochran-Mantel-Haenszel (CMH) test statistics stratified by the factors used at 
randomization as described in the study SAPs.  For all analyses in both the Induction 
and Maintenance Phases where comparisons back to baseline are made, baseline is 
defined as the last available assessment prior to first receipt of study drug in the 
Induction Phase.  For all analyses the point estimate, 95% CIs and p-value will be 
reported.
4.4.1
Efficacy Endpoints
All primary endpoints for the studies are derived from the MCS.  Further details of the 
individual primary endpoint evaluation and treatment effects (estimands) are provided in 
the study SAPs.  All primary endpoints are categorical and formal statistical comparisons 
between the treatment arms will use the CMH test statistics stratified by the factors used 
at randomization. In addition, a selection of secondary endpoints across the studies 
evaluating remission, clinical remission and clinical response are also derived using the 
full MCS.
4.4.2
Endpoint Definitions
This section provides endpoint definitions for endpoints common across studies.  Further 
study specific details including analysis timepoints and populations will be included in the 
study SAPs.


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4.4.2.1
Mayo Clinic Score
The MCS is a composite endpoint made up of four components.  The score ranges from 
0 to 12 with higher scores indicating more severe disease.
The MCS is used to determine a number of efficacy endpoints as described in Table 3.
MCSStool Frequency subscoreRectal Bleeding subscoreEndoscopy 
subscore PGA subscore
4.4.2.1.1
Stool Frequency and Rectal Bleeding
Stool frequency (SF) and rectal bleeding (RB) data are collected daily via patient’s 
diaries and each day a patient provides a score between 0-3 for each component.
Stool Frequency Subscore 03

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
Rectal Bleeding Subscore 03

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
–
Stool Frequency (SF) subscoreAverage of 3 days daily diary scores
–
Rectal Bleeding (RB) subscoreWorst value of 3 days daily diary scores
Table 2 summarizes the different scenarios for calculating SF/RB sub score in the 
analyses. The three days of daily diary data used to calculate the subscores described 
above are selected from the days most recent to, (but not including) a pre specified date, 
and this is called the ‘anchor date’. 


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Table 2
Steps for Calculating SF/RB Subscore
Timepoint
Scenarios to calculate SF/RB Subscore
Baseline
Scenario 1
Bowel preparation date (prior to an endoscopy) is assigned as the ‘anchor’ date.  
Three days daily diary data collected from patient’s e-diary between Day -22 and the 
day prior to the anchor date will be selected to calculate SF/RB scores. Daily dairy 
days selected closest to the anchor date will be selected first
Scenario 2 
Bowel preparation date (prior to an endoscopy) is assigned as the ‘anchor’ date.  If 
fewer than three days of daily diary data are available between Day 22 through to 
the day prior to the anchor date, then additional daily diary data collected post 
endoscopy starting with the score recorded 2 days after the endoscopy but prior to 
the randomization/enrollment will be selected to calculate SF/RB scores. Examples 
of this scenario are illustrated (see Appendix 3).
Scenario 3
Randomization/Enrollment Date is assigned as the ‘anchor’ date, if endoscopy did 
not occur between Day -21 and day prior to randomization/enrollment date. Three 
days worth of diary data prior to the ‘anchor’ date will be selected to calculate SF/RB 
scores. Daily dairy days selected closest to the anchor date will be selected first
Post 
Baseline
Scenario 1
Bowel preparation date (prior to an endoscopy) occurring within 7 days prior to the 
visit date is assigned as the ‘anchor’ date. Three daily diary days collected within the 
7 days prior to post baseline visit date will be selected, to calculate SF/RB scores. 
Daily dairy days selected closest to the anchor date will be selected first. Visit date is 
the day the PGA assessment is collected.
Scenario 2
Bowel preparation date (prior to an endoscopy) is assigned as the ‘anchor’ date. 
Three daily diary days collected within the 7 days prior to post baseline visit date will 
be selected, to calculate SF/RB scores. Daily dairy days selected closest to the 
anchor date will be selected first.
If further days are required, data collected +2 days after endoscopy within the 7 days 
prior to visit date will be used.  Visit date is the day the PGA assessment is collected.
Scenario 3
Visit date is assigned as the ‘anchor’ date. Three daily diary days collected within the 
7 days prior to post baseline visit date will be selected, to calculate SF/RB scores. 
Daily dairy days selected closest to the anchor date will be selected first.
SFstool frequency; RBrectal bleeding; PGAPhysician’s Global Assessment.
The change from baseline in the SF subscore and RB subscore at Week 6 between the 
treatment arms will be reported for GA28950, GA28949 and GA28948 studies. This 
data is considered non-parametric and will be reported using RANK analysis of 
covariance (ANCOVAs).
4.4.2.1.2
Endoscopy
EndoscopyAssessment of segments from 3 locations (Colon Descending, Colon 
Sigmoid, Rectum).


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Each location is scored using the following criteria:
Endoscopic Subscore 03

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)
At baseline all segments are reviewed and scored and the worst score from the three 
segments is recorded as the endoscopy subscore.  At baseline the endoscopy score is 
collected16 to4 days prior to Day 1, however for analyses purposes, any endoscopy 
collected prior to randomization/enrollment date will be used as the baseline endoscopy 
score. All assessments are performed via video and assessed by both a local reader 
and a central reader; adjudication process is applied if required (see Section 3.2). 
Post baseline the endoscopic score is the worst score of all segments which have been 
assessed at baseline, if the baseline endoscopy score had Sigmoid colon score 1.  If at 
baseline the sigmoid colon score was 2, the post baseline endoscopy score is the 
sigmoid colon score value.  This methodology is called the Hybrid Sigmoid (HS) model 
and is used as the primary method for all analyses across all studies and throughout the 
project and study SAP documents the HS methodology will be used when calculating
endoscopic subscore.
For mMCS (excluding friability from ES1) the patient’s endoscopic subscore will be 
updated from ES1 (mild disease) to ES2 (moderate disease) if friability is present for 
either central reader 1 or central reader 2 at any location. All other patients’ endoscopic 
subscores will remain the same. For all other analyses in Table 3 using the endoscopic 
subscore, the definition with mild friability is considered within endoscopic subscore of 1, 
will be used.
4.4.2.1.3
Physician's Global Assessment
The PGA will be provided by the investigator as a score of 0 to 3.  The status is based 
on the physician’s overall rating of the patient’s disease activity, given endoscopy, stool 
frequency, rectal bleeding, abdominal pain, well-being, fecal continence, observations, 
and physical exam findings.
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)


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4.4.2.1.4
Outcome Measures Derived from the MCS
The outcome measures calculated using the MCS or a selection of components from the 
MCS are detailed in Table 3.
Table 3
Outcome Measures
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
Modified Mayo Clinic Score 
(mMCS)
mMCS (09) is a composite of 3 assessments, each rated from 
03: stool frequency, rectal bleeding, and endoscopy
MCS Remission
MCS 2 with individual subscores 1 and a rectal bleeding 
subscore of 0
MCS Clinical Remission
MCS 2 with individual subscores 1
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
mMCS Remission 
(excluding friability from 
ES1)
mMCS 2, with, rectal bleeding score of 0, endoscopy 01 and 
stool frequency subscore 01
(Friability must be Absent for ES1)
mMCS Remission
(including friability in ES1)
mMCS 2, with, rectal bleeding score of 0, endoscopy 01 and 
stool frequency subscore 01
pMCS Clinical Remission
pMCS 2, with, rectal bleeding score of 01, PGA 01 and stool 
frequency subscore 01
mMCS Clinical Remission
(excluding friability from 
ES1)
mMCS 2, with, rectal bleeding score of 01, endoscopy 01 and 
stool frequency subscore 01
(Friability must be Absent for ES1)
mMCS Clinical Remission
(including friability in ES1)
mMCS 2, with, rectal bleeding score of 01, endoscopy 01 and 
stool frequency subscore 01
pMCS Clinical Response
A decrease in the pMCS of at least 2 points and at least 30% 
improvement from baseline, with an accompanying decrease in 
the rectal bleeding score by at least one point or an absolute rectal 
bleeding score of 0 or 1.
mMCS Clinical Response
(excluding friability from 
ES1)
A decrease in the mMCS of at least 2 points and at least 30% 
decrease (improvement) from baseline, with an accompanying 
decrease in the rectal bleeding score by at least one point or an 
absolute rectal bleeding score of 0 or 1.
(Friability must be Absent for ES1)
mMCS Clinical Response
(including friability in ES1)
A decrease in the mMCS of at least 2 points and at least 30% 
decrease (improvement) from baseline, with an accompanying 
decrease in the rectal bleeding score by at least one point or an 
absolute rectal bleeding score of 0 or 1.
Improvement in endoscopic 
appearance of the mucosa
(including friability in ES1)
Endoscopy subscore1


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Endoscopic Remission
(including friability in ES1)
Endoscopy subscore0
Improvement in endoscopic 
appearance of the mucosa
(excluding friability from 
ES1)
Endoscopy subscore 1
(Friability must be Absent for ES1)
ESEndoscopic Subscore; PGA Physician’s Global Assessment.
Endoscopy Score=1 includes mild friability criteria unless identified in the description of an 
endpoint above.
4.4.2.2
Histologic Endpoints
For each patient, scanned images of hematoxylin and eosin stained slides of FFPE 
sigmoid colon biopsies are assessed by the same pathologist from among a small pool 
of central readers.  Details of the reading process are included in Section 3.2.  Each 
slide image is evaluated using two histologic scoring systems:  NHI (Appendix 4) and 
Geboes Grading Scale (Appendix 5).  A third score, the RHI, is derived from selected 
components of Geboes Grading Scale (Appendix 5).
All histologic endpoints will be evaluated only on patients who have documented 
neutrophilic inflammation at baseline.  Neutrophilic Inflammation will be defined using the 
scoring system used within the analysis.  The main analysis of each histologic endpoint
will be conducted on the basis of NHI scoring system, and sensitivity analyses will be 
conducted using RHI and Geboes Grading Scale (Table 4). This data was not collected 
in the GA29103 study.
Table 4
Histologic Endpoints
Feature or 
Outcome
Description
Definition for each scoring system
NHI
RHI
Geboes Grading 
Scale
Indication of 
neutrophilic 
inflammation
NHI > 1
RHI > 3
Geboes 2B.1–2B.3 
or 3.1–3.3 or 4.1–4.3 
or 5.1–5.3
Histologic remission
Resolution of 
neutrophilic 
inflammation
NHI 1
RHI 3 and 
Geboes 2B.0  
and 3.0
Geboes 2B.0 and 
3.0, and 4.0, and 5.0
NHINancy Histological Index; RHIRobarts Histopathological Index.
4.4.2.3
UC-PRO
The UC-PRO questionnaire is collected in the e-diary and completed by patients for at 
least 912 consecutive days prior to a study visit as per the Schedule of Assessments in 
the protocol. The UC-PRO is being reported in three domains; two domains are key 
endpoints and reported as UC-PRO Signs and Symptoms. This data was not collected 
in the GA29103 study.


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4.4.2.3.1
Functional and Bowel Domain
Two domain scores computed for the UC-PRO Signs and Symptoms:

Functional Symptoms

Bowel Movement Signs and Symptoms
There is no single total score.  The questions contributing to each domain are shown in 
Appendix 6.  The functional domain score ranges from 012, the bowel domain score 
ranges from 027, with a higher score indicating a worse disease state.  The responder 
definition cutoffs for the Functional and Bowel domains will be pre-specified in the Data 
Analysis Plan (DAP).
The daily scores contributing to the UC-PRO/SS calculation for a visit will be selected as: 
most recent 7 daily scores available prior to but not including a visit.  (Note: a minimum 
of 4 days is required.)
For each item in the questionnaire, a score will be calculated for a visit by taking the 
average of the most recent 7 daily scores available.  The domain score for a visit will 
then be determined, taken as the sum of the (averaged) items for each question.
The endpoint using the UC-PRO/SS is the change from baseline at Week X in 
UC-PRO/SS Domain as assessed by UC-PRO/SS measure.
	 
 		  		 
= 		  /  	 −		 /  	 
A MMRM (Mixed Model Repeated Measures) analysis will be performed to assess the 
change from baseline in UC-PRO domains at Week X and will include the fixed 
categorical effects of treatment, visit, study stratification factors, and treatment-by-visit 
interaction, and the continuous covariates of the baseline continuous UC-PRO domain 
and baseline UC-PRO domain-by-visit interaction.  An unstructured covariance matrix 
will be used to model the within patient errors within the MMRM. 
4.4.2.3.2
Systemic Symptoms Domain
The systemic symptoms domain collected by the UC-PRO tool ranges from 0-20 with a 
higher score indicating a worse disease state. Details of the score are in Appendix 6.
The scores are summarized using the same methodology used for functional and bowel 
domain in Section 4.4.2.3.1.
4.4.2.4
Inflammatory Bowel Disease Questionnaire
The IBDQ is a 32-item questionnaire containing four domains:  bowel symptoms 
(10 items), systemic symptoms (5 items), emotional function (12 items), and social 
function (5 items). 


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An overall total IBDQ score will be computed by summing the individual 32-item scores.  
The range for the IBDQ total score is 32224, with higher scores denoting better 
health-related quality of life. 
The IBDQ questionnaire is administered once per visit as per the study Schedule of 
Assessments, and is completed by the patient at the clinic.
The change from baseline at Week X in total IBDQ
	 
 		  		  = 		   ! −		  !
This is analyzed by an ANCOVA model with the factors used at randomization into the 
Induction/Maintenance Phases as stratification variables, and the baseline IBDQ score 
used as a covariate.
4.4.3
Subgroup Analyses
The following subgroup analyses will be conducted on the primary endpoints for all 
studies.  The subgroup categories are listed in Section 4.3.  Study specific subgroups 
will be included in the study SAPs as required. 
The primary endpoints will be summarized by the following subgroups using data 
collected in the clinical database:

Baseline MCS

Disease Location

Age

Gender

Race

IS use at Baseline

CS use at Baseline

Anti-drug antibodies (ADA) ve/ve (ve transient or ve persistent status)
Additional subgroups analysis will be conducted as appropriate.
4.5
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Pharmacokinetic Analyses
Serum concentration at various times during Induction and Maintenance Phases will be 
listed and summarized by descriptive summary statistics including means, geometric 
means, ranges, SD, and coefficients of variation.
Individual and mean concentration versus time data will be tabulated and plotted if more 
than 2 time points are available.


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The pharmacokinetic (PK) data from each individual study may be combined with data 
from other etrolizumab studies to perform a population PK analysis.  Population typical 
value of PK parameters will be estimated for the entire study population, along with 
estimates of intra- and inter-patient variance and an estimate of random error.  Individual 
patient parameter estimates will be computed using the post hoc analysis procedure.  
Impacts of covariates on relevant PK parameters will also be evaluated.  A separate 
prospective analysis plan will be prepared, and the population PK analysis will be 
presented in a separate report for all studies, this will be separate from each study CSR.
Pharmacodynamic Analyses 
The pharmacodynamic (PD) biomarker, sMAdCAM-1 absolute concentration and 
percentage change from baseline values will be listed and summarized by descriptive 
summary statistics at each time point including but not limited to means, SD, medians, 
and ranges.  Analyses will be split by treatment group and cohort as appropriate.
Additional exploratory PK/PD analyses or modeling may be conducted as appropriate
4.6
BIOMARKER ANALYSIS
Additional biomarker strategies and analyses will be detailed in the Biomarker Analysis 
Plan.
4.7
SAFETY ANALYSES
The safety populations include all patients who received at least one dose of study drug, 
and patients will be grouped according to the treatment of the treatment arm they most 
frequently received.  In addition, data will be listed for patients who do not receive the 
treatment they are assigned to in the safety population at any time point.  All safety 
parameters will be summarized and presented in tables using the safety populations 
defined for each study.  Patients who are not randomized but who receive study drug will 
be included in the safety population and summarized according to the therapy actually 
received.  The safety data will be listed and summarized at the time of the primary 
analyses with use of all safety data available at the primary database snapshot.  
Additional summaries will be run once all patients have completed safety follow-up.
4.7.1
Adverse Events
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 
unless otherwise specified.  For all summary tables, the AEs will be sorted by System 
Organ Class (in decreasing order of overall incidence) and then by preferred term (in 
decreasing order of overall incidence).  In addition, separate summaries or listings will 


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be generated for SAEs, deaths, AEs leading to discontinuation of study drug, and 
adverse events of special interest (AESIs).  In addition to summaries or listings, 
narratives will be provided for all deaths, SAE’s, AE’s leading to treatment 
discontinuation and pregnancies as well as for all serious infections, opportunistic 
infections and malignancies in the individual CSRs.
For the etrolizumab Phase III program, the AESIs (identified by the investigator using the 
eCRF tick box) are the following:

Systemic hypersensitivity reactions and anaphylactic and anaphylactoid reaction. 
These will be further described using the MedDRA anaphylactic reaction SMQ 
(Standard MedDRA Query) algorithmic and Hypersensitivity SMQ narrow.

Neurological signs, symptoms, and AEs that may suggest possible progressive 
multifocal leukoencephalopathy (PML) (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 (including GI) – Events occurred in the MedDRA Infections and 
Infestations System Organ Class (SOC) using the primary coding events

Opportunistic infections – Events occurred in the Sponsor-defined Adverse Event 
Group Terms

Malignancies Events that occur in the MedDRA Malignant and Unspecified 
Tumours SMQ (narrow).

Injection site reactions – Events identified using the eCRF tick box indicating an 
Injection site reaction AND/OR events occurred in the MedDRA Injection Site 
Reaction High Level Term (HLT) using both primary and secondary coding.
Outputs will be summarized using the safety population split by treatment arm and 
cohort as appropriate.
Summaries of AEs will be generated to summarize the incidence of treatment-emergent 
AEs only.  Treatment-emergent events are defined as any new AE reported or any 
worsening of an existing condition on or after the first dose of study drug.  If the onset 
date of the AE is prior to 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). Non-treatment emergent AE’s collected in the database will also be reported 
separately, for each individual CSRs. 
For each treatment group, the incidence count for each AE preferred term will be defined 
as the number of patients reporting at least one treatment-emergent occurrence of the


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event (multiple occurrences of the same AE in one 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. 
The rate per 100 patient years and 95% CIs will be summarized by treatment group for 
studies (GA28950, GA29102, GA29103, GA28948, and GA28949).  Rates will be 
calculated for AEs, SAEs, and other AE grouping as appropriate.  The rate of AEs per 
100 patient years is calculated as: 
=
" #$%	 
 &'
" #$%	 
 	 (	    )**
All summaries and listings of AEs will be based on the induction safety population or the 
maintenance safety population and listed in the List of Planned Outputs (LoPO).
4.7.2
Laboratory Data
Descriptive summaries of laboratory values at baseline and throughout the studies will 
be summarized by treatment arm. 
Change from baseline will be analysed for the following parameters:  Hematology 
(hemoglobin, hematocrit, platelet count, WBC count, lymphocytes, mean corpuscular 
volume), serum chemistries (sodium, potassium, chloride, bicarbonate, glucose, blood 
urea nitrogen, creatinine, calcium, total and direct bilirubin, total protein, albumin, 
alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase), CRP, and 
fecal calprotectin
Proportion of patients experiencing clinically significant changes relative to baseline will 
be summarized by treatment arm as appropriate for the parameters listed above.
Laboratory abnormalities and the patient’s worst National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) grade during study will be 
summarized by treatment arm as appropriate for parameters listed above.
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 3 ULN

ALT or AST 3 ULN and total bilirubin 2 ULN as defined by Hy’s law:
The number and percentage of patients with positive serum antibodies to etrolizumab 
(ADA) at baseline (prevalence) and post etrolizumab treatment at any time during the 


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study (incidence) will be tabulated by treatment arm and listed alongside the primary 
efficacy outcome.
All summaries and listings of laboratory data will be based on the safety populations and 
specified in the LoPO.
4.7.3
Vital Signs
Vital signs will be summarized using summary statistics and change from baseline 
proportion of patients experiencing clinically significant changes relative to baseline will 
be reported if appropriate.
All summaries and listings of vital signs data will be based on safety population and 
specified in LoPO.
4.7.4
Medical History
Medical history data collected in the e-CRF 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.
All summaries and listings of medical history will be based on safety population and 
specified in the LoPO.
4.7.5
Concomitant Medications
Concomitant medications include any medication being used at any time from first dose 
of study drug through to day of study discontinuation/completion, or medication being 
used at any time up to the start of study treatment.  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.
All summaries and listings of concomitant medications will be based on safety population 
and specified in the LoPO.
4.8
MISSING DATA
The handling of intercurrent events explained in the individual studies will be applied 
before using the missing data handling approaches in this section. The handling of 
intercurrent events will occur in the order the intercurrent event occurs within the study. 
To assess the robustness of the primary endpoint, a tipping point analysis will be
conducted. The tipping point is defined as the difference in the number of missing
events (i.e., remission) between the treatment groups that result in a change in the 
primary outcome conclusions (Yan et al. 2009). A two-dimensional plot will be produced 
for each primary comparison of etrolizumab (105 mg) vs. the comparator to evaluate 
where the tipping point lies.


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The tipping point analysis will be used to assess the robustness of the primary endpoints 
within each study. The following groups of patients will always be considered 
nonremitters/non-responders within the tipping point analysis.
–
Patients whose remitter/responder status can be calculated as a 
non-remitter/non-responder from their available sub scores, even when not all 
four MCS subscores are available. 
–
Patients who have received rescue therapy during the study.
–
Patients who have discontinued study treatment early.
For all continuous endpoints, a MMRM model will be fitted to analyse UC-PRO domains 
assuming the data is missing at random. For missing SF/RB and IBDQ data single 
imputation worse observation carried forward (WOCF) post baseline will be applied to 
missing data, including when data is missing due to intercurrent event. An additional 
sensitivity analysis using observed case will be conducted, to assess the robustness of 
the analysis. All summary data will be reported using no imputation for missing data.
For any missing baseline data, no imputation of results data will be applied, and 
therefore, any endpoints requiring comparison back to baseline results will also be set to 
missing. To prevent a missing SF/RB subscore at baseline or post baseline which would 
lead to a missing MCS/mMCS/pMCS score, the anchor date used for selecting diary 
data to calculate RB/SF subscores can be imputed. If bowel prep date is missing, then 
endoscopy date can be used; if the endoscopy date is missing then the visit date can be 
used as the anchor date.  If the PGA visit date is missing, the visit date will be imputed 
as Day 1+x weeks to allow RB and SF scores to be calculated. 
No imputation will be applied for missing laboratory or vital signs data. 
An AE with a completely missing, non-imputed start date will be assumed to be 
treatment-emergent, unless the AE has a complete, non-imputed end date that is prior to 
the date of the first dose.
All deaths will be reported, regardless of completeness of death date.
4.9
INTERIM ANALYSES
No interim analyses are planned for these studies.


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5.
REFERENCES
Geboes K, Riddell R, Öst A, et al. A reproducible grading scale for histological 
assessment of inflammation in ulcerative colitis. Gut. 2000;47(3):4049.
Mosli MH, Feagan BG, Zou G, et al. Development and validation of a histological index 
for UC. Gut. 2017;66(1):508.
Marchal-Bressenot A, Scherl A, Salleron J, et al. A practical guide to assess the Nancy 
Histological Index for UC. Gut. 2016;65(11):191920.
Marchal-Bressenot A, Salleron J, Boulagnon-Rombi C, et al. Development and validation 
of the Nancy Histological Index for UC. Gut. 2017;66(1):439.
Yan X, Lee S, Li N. Missing data handling methods in medical device clinical trials. J 
Biopharm Stat. 2009;19(6):108598.


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Appendix 1 Protocol Synopsis
See individual study SAPs for Protocol Synopsis.


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Appendix 2 Schedule of Assessments
See individual study SAPs for Schedule of Assessments.


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Appendix 3 Mayo Clinic Score Measurement
Endoday of endoscopy; MCSMayo Clinic Score; Randday of randomization; RBrectal bleeding; SFstool frequency.


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Appendix 4 Nancy Histological Index
Nancy Histological Index (NHI): Scoring algorithm
Source: Adapted from Marchal-Bressenot et al. 2016, Marchal-Bressenot et al 2017.


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Appendix 5 Geboes Grading Scale and Robarts 
Histopathological Index
Geboes Grading Scale: Grades and Subgrades
Grade 0: Structural (architectural change)
0.0 No abnormality
0.1 Mild abnormality
0.2 Mild-moderate diffuse/multifocal 
abnormalities
0.3 Severe diffuse/multifocal abnormalities
Grade 1: Chronic inflammatory infiltrate
1.0 No increase
1.1 Mild but unequivocal increase
1.2 Moderate increase
1.3 Marked increase
Grade 2A: Eosinophils in lamina propria
2A.0No increase
2A.1Mild but unequivocal increase
2A.2Moderate increase
2A.3Marked increase
Grade 2B: Neutrophils in lamina propria
2B.0None
2B.1Mild but unequivocal increase
2B.2Moderate increase
2B.3Marked increase
Grade 3: Neutrophils in epithelium
3.0 None
3.1 < 5% crypts involved
3.2 < 50% crypts involved
3.3 > 50% crypts involved
Grade 4: Crypt destruction
4.0 None
4.1 Probable–local excess of neutrophils in 
part of crypt
4.2 Probable–marked attenuation
4.3 Unequivocal crypt destruction
Grade 5: Erosion or ulceration
5.0 No erosion, ulceration or granulation tissue
5.1 Recovering epithelium + adjacent 
inflammation
5.2 Probable erosion–focally stripped
5.3 Unequivocal erosion
5.4 Ulcer or granulation tissue
Source: Geboes et al. 2000.  
Robarts Histopathological Index (RHI): Grade-Weighted Sum of Subgrades from 
Geboes
RHI score (0-33)

1 × chronic inflammatory infiltrate (0-3)
+ 2 × neutrophils in lamina propria (0-3)
+ 3 × neutrophils epithelium (0-3)
+ 5 × erosion or ulceration (0-3)
Note: Erosion or ulceration component subgrade range of 0 to 3 is obtained by scoring Geboes 
subgrades as follows: 5.0 = 0, 5.1 or 5.2 = 1, 5.3 = 2, and 5.4 = 3.
Source: Mosli et al. 2017.


Etrolizumab — F. Hoffmann-La Roche Ltd
31/Statistical Analysis Plan Project SAP
Appendix 6 Ulcerative Colitis Patient Reported Outcomes Signs 
and Symptoms
UC-PRO/SS 
Domain
Question
Response to 
Question
Functional
Symptoms
In the past 24 hours, did you pass gas?
0No
1Rarely 
2Sometimes 
3Often 
4Very often
In the past 24 hours, did you feel pain in your belly?
0No
1Mild 
2Moderate 
3Severe 
4Very Severe
In the past 24 hours, did you feel bloating in your belly?
0No
1Mild 
2Moderate 
3Severe 
4Very Severe


Etrolizumab — F. Hoffmann-La Roche Ltd
32/Statistical Analysis Plan Project SAP
Appendix 6 Ulcerative Colitis Patient Reported Outcomes Signs 
and Symptoms (contd.)
UC-PRO/SS 
Domain
Question
Response to 
Question
Bowel Movement 
Signs and 
Symptoms
In the past 24 hours, how many bowel movements did 
you have?
00, 
11-2,  
23-4, 
35-6,  
47-9,
510-12, 
613-17, 
718 or more
In the past 24 hours, how often were your bowel 
movements mostly or completely liquid?
0Never 
1Rarely
2Sometimes 
3Often 
4Always
In the past 24 hours, did you have blood in your bowel 
movements?
0No 
1Rarely 
2Sometimes 
3Often 
4Always
In the past 24 hours, did you have mucus (white 
material) in your bowel movements?
0No 
1Rarely 
2Sometimes 
3Often 
4Always
In the past 24 hours, did stool, blood, or liquid leak out 
before you reached a toilet?
0No 
1Rarely 
2Sometimes 
3Often 
4Always
In the past 24 hours, did you feel the need to have a 
bowel movement right away?
0No 
1Mild 
2Moderate 
3Severe 
4Very Severe


Etrolizumab — F. Hoffmann-La Roche Ltd
33/Statistical Analysis Plan Project SAP
Appendix 6 Ulcerative Colitis Patient Reported Outcomes Signs 
and Symptoms (contd.)
UC-PRO/SS 
Domain
Question
Response to 
Question
Systemic 
Symptoms
In the past 24 hours, did you feel pain in your knees, 
hips, and/or elbows?
0No 
1Mild 
2Moderate 
3Severe 
4Very Severe
In the past 24 hours, did you feel tired?
0No 
1Mild 
2Moderate 
3Severe 
4Very Severe
In the past 24 hours, did you lack an appetite?
0No 
1Mild 
2Moderate 
3Severe 
4Very Severe
In the past 24 hours, did you feel weak?
0No 
1Mild 
2Moderate 
3Severe 
4Very Severe
In the past 24 hours, did you feel thirsty?
0No 
1Mild 
2Moderate 
3Severe 
4Very Severe