Conditions: Ulcerative Colitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 609
Healthy volunteers: no

Brief summary:
This Phase III, double-blind, placebo-controlled, multicenter study will investigate the efficacy and safety of etrolizumab during induction and maintenance of remission compared with placebo in the treatment of participants with moderately to severely active ulcerative colitis (UC) who have been previously exposed to TNF inhibitors.

Detailed description:

Arms:
arm 1: Participants assigned to this arm will receive treatment with open-label etrolizumab 105 milligrams (mg) subcutaneous (SC) injection once every 4 weeks (Q4W) for 14 weeks during the induction phase. arm 2: Participants randomized to this arm will receive treatment with double-blind placebo SC injection Q4W for 14 weeks during the induction phase. arm 3: Participants randomized to this arm will receive treatment with double-blind etrolizumab 105 mg SC injection Q4W for 14 weeks during the induction phase. arm 4: Participants who received placebo during the induction phase, Cohort 2: Placebo (Double-Blind Induction Phase), and achieve a clinical response with placebo at Week 14 will continue to receive blinded placebo from Week 16 up to Week 66 during the maintenance phase. arm 5: Participants who received etrolizumab during the induction phase, Cohort 1: Etrolizumab (Open-Label Induction Phase) and Cohort 2: Etrolizumab (Double-Blind Induction Phase), and achieved a clinical response at Week 14 will be re-randomized by Week 16 for the double-blind maintenance phase. Clinical responders re-randomized to this arm will receive placebo SC injection Q4W from Week 16 up to Week 66. arm 6: Participants who received etrolizumab during the induction phase, Cohort 1: Etrolizumab (Open-Label Induction Phase) and Cohort 2: Etrolizumab (Double-Blind Induction Phase), and achieved a clinical response at Week 14 will be re-randomized by Week 16 for the double-blind maintenance phase. Clinical responders re-randomized to this arm will receive etrolizumab 105 mg SC injection Q4W from Week 16 up to Week 66.

Interventions: intervention 1: Etrozulimab intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive 105 mg etrolizumab administered by SC injection Q4W. intervention 2: Participants will receive placebo (matched with etrolizumab) administered by SC injection Q4W.

Protocol document:
Prot_002.pdf: 
 
Official Title: 
Phase III, Double-Blind, Placebo-Controlled, Multicenter Study of the 
Efficacy and Safety of Etrolizumab During Induction and Maintenance 
in Patients With Moderate to Severe Active Ulcerative Colitis Who 
Have Been Previously Exposed to TNF Inhibitors 
NCT Number: 
NCT02100696 
Document Date: 
Protocol Version 8: 11-July-2018 
 
 


FINAL PROTOCOL 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 GA28950, Version 8
PROTOCOL
TITLE:
PHASE III, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER STUDY OF 
THE EFFICACY AND SAFETY OF ETROLIZUMAB 
DURING INDUCTION AND MAINTENANCE IN 
PATIENTS WITH MODERATE TO SEVERE ACTIVE 
ULCERATIVE COLITIS WHO HAVE BEEN 
PREVIOUSLY EXPOSED TO TNF INHIBITORS
PROTOCOL NUMBER: GA28950
VERSION NUMBER:
8
EUDRACT NUMBER:
2013-004278-88
IND NUMBER:
100366
TEST PRODUCT:
Etrolizumab (PRO145223, RO5490261)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  12 November 2013
DATES AMENDED:
Version 2:  23 January 2014
Version 3:  11 March 2014
Version 4:  29 May 2014
Version 5:  27 September 2015, 7 December 2015 (VHP)
Version 6: 18 November 2016
Version 7:  2 September 2017
Version 8:  See electronic date stamp below.
 
11-Jul-2018 05:42:19
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Etrolizumab—F. Hoffmann-La Roche Ltd
2/Protocol GA28950, Version 8
PROTOCOL AMENDMENT, VERSION 8:
RATIONALE
Protocol GA28950 has primarily been amended to reflect changes in efficacy endpoints. 
The changes will not impact study conduct at the site level. These changes are as 
follows:

The primary efficacy endpoint for the Maintenance Phase has been changed to 
remission at Week 66 for patients who achieve clinical response (rather than 
remission) at Week 14.  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, 6.4 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).

The study sample size has been reduced from 800 to 605 patients as a result of the 
change in the Maintenance Phase primary efficacy endpoint, which will be powered 
at >90%. The Induction Phase primary efficacy endpoint definition (proportion of 
patients in remission at Week 14) will remain unchanged, but the reduction in 
sample size will lead to a drop in power from >90% to 80% (Sections 3.1.1, 6.1, 9.4, 
and Figure 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 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).


Etrolizumab—F. Hoffmann-La Roche Ltd
3/Protocol GA28950, Version 8

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 4.6.1.4 and Appendix 3).

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 4.6.1.5 and 
Appendix 12).

Language regarding local injection-site reactions has been clarified in Table 5, 
"Guidelines for Managing Specific Adverse Events" (Section 5.1.2).

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 has been add to Section 6.1 to clarify that for the purpose of statistical 
analyses and sample size calculations, the Induction and Maintenance Phases will 
be treated as two independent studies, and as such, no adjustment to alpha is 
required.
Additional minor changes have been made to improve clarity and consistency. 
Substantive new information appears in italics. This amendment represents cumulative 
changes to the original protocol. 


Etrolizumab—F. Hoffmann-La Roche Ltd
4/Protocol GA28950, Version 8
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 29
1.1
Background on Ulcerative Colitis........................................... 29
1.2
Background on Etrolizumab................................................... 30
1.3
Study Rationale and Benefit-Risk Assessment...................... 31
2.
OBJECTIVES.............................................................................................. 34
2.1
Efficacy Objectives ................................................................ 34
2.2
Safety Objectives................................................................... 37
2.3
Pharmacokinetic Objectives .................................................. 37
2.4
Exploratory Pharmacodynamic and Diagnostic 
Objectives.............................................................................. 37
3.
STUDY DESIGN......................................................................................... 38
3.1
Description of Study .............................................................. 38
3.1.1
Overview of Study Design ..................................................... 38
3.1.1.1
Definition of Clinical Relapse................................................. 41
3.1.1.2
Rescue Therapy .................................................................... 41
3.1.2
Data Monitoring Committee................................................... 45
3.2
End of Study and Length of Study......................................... 45
3.3
Rationale for Study Design.................................................... 46
3.3.1
Rationale for Test Product Dosage........................................ 46
3.3.2
Rationale for Patient Population ............................................ 47
3.3.3
Rationale for Control Group................................................... 48
3.3.4
Rationale for Biomarker Assessments................................... 48
3.4
Outcome Measures ............................................................... 50
3.4.1
Efficacy Outcome Measures.................................................. 50
3.4.2
Safety Outcome Measures .................................................... 51
3.4.3
Pharmacokinetic Outcome Measures.................................... 52
3.4.4
Exploratory Biomarker Outcome Measures........................... 52


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4.
MATERIALS AND METHODS .................................................................... 52
4.1
Patients.................................................................................. 52
4.1.1
Inclusion Criteria.................................................................... 52
4.1.2
Exclusion Criteria................................................................... 54
4.2
Method of Treatment Assignment and Blinding..................... 58
4.3
Study Treatment.................................................................... 61
4.3.1
Formulation, Packaging, and Handling.................................. 63
4.3.1.1
Etrolizumab and Placebo....................................................... 63
4.3.1.2
Concomitant Background Treatment for 
Ulcerative Colitis.................................................................... 64
4.3.2
Dosage, Administration, and Compliance.............................. 64
4.3.2.1
Etrolizumab and Placebo....................................................... 64
4.3.2.2
Concomitant Background Treatment and Rescue 
Therapy ................................................................................. 66
4.3.3
Investigational Medicinal Product Accountability ................... 68
4.3.4
Assessment of Compliance ................................................... 69
4.3.5
Destruction of the Investigational Medicinal 
Product/Comparator .............................................................. 70
4.3.6
Reporting of Prefilled Syringe Complaints/Events ................. 70
4.4
Concomitant Therapy ............................................................ 71
4.4.1
Permitted Therapy................................................................. 71
4.4.2
Prohibited Therapy ................................................................ 71
4.5
Clinical Relapse..................................................................... 71
4.5.1
Definition of Clinical Relapse................................................. 71
4.6
Study Assessments ............................................................... 72
4.6.1
Description of Study Assessments ........................................ 72
4.6.1.1
Medical History and Demographic Data ................................ 72
4.6.1.2
Physical Examinations........................................................... 72
4.6.1.3
Vital Signs.............................................................................. 72
4.6.1.4
Ulcerative Colitis Disease Activity Assessments ................... 72
4.6.1.5
Laboratory Assessments ....................................................... 76
4.6.1.6
Chest X-Ray .......................................................................... 79
4.6.1.7
Electrocardiograms................................................................ 79
4.6.1.8
Patient-Reported Outcomes .................................................. 80


Etrolizumab—F. Hoffmann-La Roche Ltd
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4.6.1.9
Medication Use and Compliance........................................... 81
4.6.1.10
Samples for Roche Clinical Repository.................................. 81
4.6.2
Timing of Study Assessments ............................................... 84
4.6.2.1
Screening and Pretreatment Assessments............................ 84
4.6.2.2
Assessments during Treatment............................................. 87
4.6.2.3
Assessments at Study Completion/Early 
Withdrawal from Treatment Visit............................................ 88
4.6.2.4
Safety Follow-Up Assessments............................................. 92
4.6.2.5
Assessments at Unscheduled Visits...................................... 92
4.7
Patient, Study, and Site Discontinuation................................ 93
4.7.1
Patient Discontinuation.......................................................... 93
4.7.1.1
Discontinuation from Study Drug........................................... 93
4.7.1.2
Withdrawal from Study........................................................... 94
4.7.2
Study and Site Discontinuation.............................................. 94
5.
ASSESSMENT OF SAFETY....................................................................... 94
5.1
Safety Plan ............................................................................ 94
5.1.1
Potential Risks for Etrolizumab.............................................. 95
5.1.2
Progressive Multifocal Leukoencephalopathy........................ 95
5.1.2.1
Screening and Patient Selection............................................ 95
5.1.2.2
Monitoring and Management................................................. 96
5.1.3
Monitoring for Other Serious Infections ................................. 97
5.1.4
Monitoring for Hypersensitivity Reactions.............................. 97
5.1.5
Management of Specific Adverse Events .............................. 98
5.2
Safety Parameters and Definitions ...................................... 102
5.2.1
Adverse Events ................................................................... 102
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 102
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 103
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 104
5.3.1
Adverse Event Reporting Period ......................................... 104
5.3.2
Eliciting Adverse Event Information..................................... 104
5.3.3
Assessment of Severity of Adverse Events ......................... 105


Etrolizumab—F. Hoffmann-La Roche Ltd
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5.3.4
Assessment of Causality of Adverse Events ....................... 105
5.3.5
Procedures for Recording Adverse Events.......................... 106
5.3.5.1
Diagnosis versus Signs and Symptoms............................... 106
5.3.5.2
Adverse Events Occurring Secondary to Other 
Events.................................................................................. 107
5.3.5.3
Persistent or Recurrent Adverse Events.............................. 107
5.3.5.4
Abnormal Laboratory Values ............................................... 108
5.3.5.5
Abnormal Vital Sign Values ................................................. 108
5.3.5.6
Abnormal Liver Function Tests............................................ 109
5.3.5.7
Deaths ................................................................................. 109
5.3.5.8
Preexisting Medical Conditions............................................ 110
5.3.5.9
Lack of Efficacy or Worsening of Ulcerative 
Colitis................................................................................... 110
5.3.5.10
Hospitalization or Prolonged Hospitalization........................ 110
5.3.5.11
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 111
5.3.5.12
Patient-Reported Outcome Data ......................................... 111
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 111
5.4.1
Emergency Medical Contacts.............................................. 112
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 112
5.4.3
Reporting Requirements for Pregnancies............................ 113
5.4.3.1
Pregnancies in Female Patients.......................................... 113
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 113
5.4.3.3
Abortions ............................................................................. 113
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 114
5.4.4
Reporting Requirements for Medical Device 
Complaints........................................................................... 114
5.5
Follow-Up of Patients after Adverse Events ........................ 114
5.5.1
Investigator Follow-Up......................................................... 114
5.5.2
Sponsor Follow-Up .............................................................. 114
5.6
Post-Study Adverse Events................................................. 114


Etrolizumab—F. Hoffmann-La Roche Ltd
8/Protocol GA28950, Version 8
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 115
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 116
6.1
Determination of Sample Size ............................................. 116
6.2
Summaries of Conduct of Study.......................................... 117
6.3
Summaries of Treatment Group Comparability ................... 117
6.4
Efficacy Analyses ................................................................ 117
6.4.1
Primary Efficacy Endpoint.................................................... 119
6.4.2
Secondary Efficacy Endpoints............................................. 119
6.4.3
Exploratory Efficacy Endpoints............................................ 120
6.5
Safety Analyses................................................................... 121
6.5.1
Adverse Events ................................................................... 121
6.5.2
Laboratory Tests.................................................................. 122
6.6
Pharmacokinetic, Pharmacodynamic, and 
Biomarker Analyses............................................................. 122
7.
DATA COLLECTION AND MANAGEMENT ............................................. 122
7.1
Data Quality Assurance....................................................... 122
7.2
Electronic Case Report Forms............................................. 123
7.3
Electronic Patient-Reported Outcome Data......................... 123
7.4
Source Data Documentation................................................ 123
7.5
Use of Computerized Systems ............................................ 124
7.6
Retention of Records........................................................... 124
8.
ETHICAL CONSIDERATIONS.................................................................. 125
8.1
Compliance with Laws and Regulations .............................. 125
8.2
Informed Consent................................................................ 125
8.3
Institutional Review Board or Ethics Committee.................. 126
8.4
Confidentiality...................................................................... 126
8.5
Financial Disclosure ............................................................ 127


Etrolizumab—F. Hoffmann-La Roche Ltd
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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 127
9.1
Study Documentation .......................................................... 127
9.2
Protocol Deviations.............................................................. 127
9.3
Site Inspections ................................................................... 128
9.4
Administrative Structure....................................................... 128
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 128
9.6
Protocol Amendments ......................................................... 129
10. REFERENCES ......................................................................................... 130
LIST OF TABLES
Table 1
Efficacy Outcomes Definitions .................................................... 36
Table 2
Population Pharmacokinetic Modeling Predicted Percentage 
of Patients Achieving 1.7 g/mL Steady-State Trough 
Concentration under Different Dosing Scenarios........................ 47
Table 3
Treatment/Concomitant Background Treatments ....................... 61
Table 4
Eligibility for Enrollment into Part 1 (OLE) of Study GA28951 
or Transfer to 12-Week Safety Follow-Up................................... 91
Table 5
Guidelines for Managing Specific Adverse Events...................... 98
Table 6
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 105
Table 7
Causal Attribution Guidance ..................................................... 106
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 44
Figure 2
Effects of High and Low Baseline Expression of the E 
Biomarker in Colon on the Remission Status of Ulcerative 
Colitis Patients Treated with Etrolizumab in EUCALYPTUS 
(Observed Data) ......................................................................... 49
Figure 3
Schedule of Study Drug Administration ...................................... 60
Figure 4
Overview of Screening Activities................................................. 86




Etrolizumab—F. Hoffmann-La Roche Ltd
11/Protocol GA28950, Version 8
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
PHASE III, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER STUDY OF THE EFFICACY AND 
SAFETY OF ETROLIZUMAB DURING INDUCTION AND 
MAINTENANCE IN PATIENTS WITH MODERATE TO 
SEVERE ACTIVE ULCERATIVE COLITIS WHO HAVE 
BEEN PREVIOUSLY EXPOSED TO TNF INHIBITORS
PROTOCOL NUMBER:
GA28950
VERSION NUMBER:
8
EUDRACT NUMBER:
2013-004278-88
IND NUMBER:
100366
TEST PRODUCT:
Etrolizumab (PRO145223, RO5490261)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please return the signed original of this form to a Sponsor representative.  Please retain 
a copy for your study files.


Etrolizumab—F. Hoffmann-La Roche Ltd
12/Protocol GA28950, Version 8
PROTOCOL SYNOPSIS
TITLE:
PHASE III, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER STUDY OF THE EFFICACY AND SAFETY OF 
ETROLIZUMAB DURING INDUCTION AND MAINTENANCE IN 
PATIENTS WITH MODERATE TO SEVERE ACTIVE ULCERATIVE 
COLITIS WHO HAVE BEEN PREVIOUSLY EXPOSED TO TNF 
INHIBITORS
PROTOCOL NUMBER:
GA28950
VERSION NUMBER:
8
EUDRACT NUMBER:
2013-004278-88
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 objectives for this study are as follows:

To evaluate the efficacy of etrolizumab (105 mg subcutaneous [SC] every 4 weeks [Q4W]) 
compared with placebo for the induction of remission, as determined by the Mayo Clinic 
Score (MCS) at Week 14

To evaluate the efficacy of etrolizumab (105 mg SC Q4W) compared with placebo for 
remission at Week 66 among patients with a clinical response at Week 14, as determined 
by the MCS
The secondary efficacy objectives for this study are as follows:
Induction Phase

To evaluate induction of clinical remission at Week 14

To evaluate clinical response at Week 14

To evaluate improvement in endoscopic appearance of the mucosa at Week 14

To evaluate endoscopic remission at Week 14

To evaluate histologic remission at Week 14

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


Etrolizumab—F. Hoffmann-La Roche Ltd
13/Protocol GA28950, Version 8

To evaluate change from baseline in UC bowel movement signs and symptoms at 
Week 14, as assessed by the Ulcerative ColitisPatient-Reported Outcome Signs and 
Symptoms (UC-PRO/SS) measure

To evaluate change from baseline in UC abdominal symptoms at Week 14, as assessed by
the UC-PRO/SS measure

To evaluate change from baseline in patientreported health-related quality of life (QOL) at 
Week 14, as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ)
Maintenance Phase

To evaluate clinical remission at Week 66 in patients in clinical remission at Week 14

To evaluate clinical remission at Week 66

To evaluate remission at Week 66 among patients in remission at Week 14

To evaluate improvement in endoscopic appearance of the mucosa at Week 66

To evaluate histologic remission at Week 66

To evaluate endoscopic remission at Week 66

To evaluate corticosteroid-free clinical remission at Week 66 (off corticosteroid for at least 
24 weeks prior to Week 66) in patients who were receiving corticosteroids at baseline

To evaluate corticosteroid-free remission at Week 66 (off corticosteroid for at least 
24 weeks prior to Week 66) in patients who were receiving corticosteroids at baseline

To evaluate change in UC bowel movement signs and symptoms from baseline to
Week 66, as assessed by the UC-PRO/SS measure

To evaluate change in UC abdominal symptoms from baseline to Week 66, as assessed by 
the UCPRO/SS measure

To evaluate change in patientreported health-related QOL from baseline to Week 66, as 
assessed by the IBDQ
The exploratory efficacy objectives for this study are as follows:

To evaluate clinical response at Week 66 among patients with a clinical response at 
Week 14

To evaluate remission achieved at Week 66 among patients in clinical remission at 
Week 14

To evaluate corticosteroid-free clinical remission at Week 66 (off corticosteroid for at least 
12 weeks prior to Week 66) in patients who were receiving corticosteroids at baseline

To evaluate change in histologic disease activity from baseline to Week 14 and Week 66

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 baseline to Week 14 and Week 14 to Week 66

To evaluate frequency and duration of hospitalizations from Week 14 to Week 66

To evaluate response, remission, and corticosteroid-free endpoints, as determined by the 
modified MCS (mMCS)
Safety Objectives
The safety objectives for this study are as follows:

To evaluate the overall safety and tolerability of etrolizumab compared with placebo during 
induction and maintenance therapy over a period of 66 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)


Etrolizumab—F. Hoffmann-La Roche Ltd
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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 
(Weeks 14 and 66) and at predose time in the steady state during the maintenance dosing 
period

To evaluate the inter-individual 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

To evaluate the PD effects on biomarkers in colonic tissue and/or peripheral blood following 
study drug

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, double-blind, placebo-controlled study evaluating the safety, 
efficacy, and tolerability of etrolizumab during induction and maintenance of remission 
compared with placebo in the treatment of moderately to severely active UC.
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 (see protocol), 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 of 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 of 1), and involvement that 
extends a minimum of 20 cm from the anal verge.
Patients who are on background immunosuppressant therapy (6-mercaptopurine [MP], 
azathioprine [AZA], methotrexate [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 


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Such patients should continue stable doses of their background corticosteroid until Week 14, 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) if the dose has been 
stable for 4 weeks prior to Day 1.  Oral 5-aminosalicylate (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 protocol for list of all prohibited concomitant treatments).  Patients must have
discontinued TNF inhibitor treatment and topical treatments for UC at least 8 weeks and 
2 weeks prior to Day 1, respectively.
The study will be divided into:

Screening period of up to 35 days during which patient eligibility will be determined 

Induction Phase of 14 weeks (Cohort 1: open-label etrolizumab treatment; 
Cohort 2: randomized to etrolizumab or placebo)

Randomization of etrolizumab responders prior to a double-blind Maintenance Phase of 
52 weeks or continued blinded treatment with placebo Q4W for 52 weeks for placebo 
induction responders 

Safety follow-up period of 12 weeks
A total of approximately 605 patients will be recruited from approximately 225 sites via an 
open-label induction arm (Cohort 1, n 130) and a double-blind induction arm (Cohort 2, 
n 475), which will be enrolled sequentially.
Cohort 1 patients will receive open-label etrolizumab 105 mg SC Q4W during the 14-week 
Induction Phase.  Cohort 2 patients will be randomized in a 4:1 ratio to 105 mg etrolizumab SC 
Q4W (n ≈380) or placebo (n ≈95) during the 14-week Induction Phase.  Randomization will be 
stratified by concomitant treatment with corticosteroids (including budesonide) (yes/no), 
concomitant treatment with immunosuppressants (yes/no), and disease activity measured 
during screening (MCS9/MCS10).
Eligibility for entry into the Maintenance Phase will be determined between Weeks 14 and 16.  
Patients in the etrolizumab arm of Cohort 2 who achieved a clinical response at Week 14 
(see protocol for definition of clinical response) and all Week 14 clinical responders in Cohort 1 
will be randomized into the Maintenance Phase and will receive either etrolizumab (105 mg SC
Q4W) or placebo in a 1:1 ratio.  Randomization will be stratified by remission status at Week 14, 
concomitant treatment with corticosteroids (including budesonide) at baseline, disease activity 
measured during screening (MCS9/MCS10), and induction cohort (Cohort 1/Cohort 2).  It is 
estimated that the planned approximately 510 etrolizumab patients from Cohort 1 and Cohort 2 
will provide approximately 154 patients in clinical response for randomization into the 
Maintenance Phase.  Additional patients may be enrolled into Cohort 1, if needed, to achieve a 
sufficient number of patients in the Maintenance Phase.
Patients initially randomized to placebo will also be assessed for clinical response at Week 14.  
Patients achieving a clinical response will continue to receive blinded placebo during the 
Maintenance Phase of the study.  Patients in either Cohort 1 or Cohort 2, who do not achieve 
clinical response at Week 14, patients who have clinical relapse during the Maintenance Phase, 
patients who receive defined rescue treatment, and patients who complete 66 weeks of the 
study may be given the option of enrolling into Part 1 (OLE) of Study GA28951, where they will 
receive open-label etrolizumab treatment, if eligible.  If patients choose not to 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.
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 his or her caregiver in the clinic; if deemed appropriate by the 
HCP, the remaining doses of study drug, starting at Week 16, will be self-administered by the 


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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 the protocol).  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 the 
protocol.
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 14 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 14, patients receiving budesonide who achieve clinical 
response at Week 14 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 corticosteroid 
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.
Clinical relapse is defined as an:

Increase in partial Mayo Clinic Score (pMCS) 3 points compared to induction timepoint  
(Week 14) 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 if eligible.
Rescue Therapy That Can be Given with Study Medication for the Treatment of UC
During the Induction Phase (prior to Week 14)
Patients are required to maintain stable doses of their concomitant medications (oral 
5-aminosalicylate [5-ASA], corticosteroids, immunosuppressants) for UC.
In the Induction Phase, any patient who requires initiation of an immunosuppressant (AZA, 
6-MP, or MTX), 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 14, 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 of 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 14 and may not continue into the Maintenance Phase of the trial.
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 period early to enroll in Part 1 (OLE) of Study GA28951 
should complete the early withdrawal from treatment visit prior to enrollment in Study GA28951.


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Patients must begin the specified corticosteroid taper at Week 14 during the Maintenance 
Phase.  For patients who cannot tolerate the corticosteroid taper without recurrence of clinical 
symptoms of either UC or corticosteroid 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.
Patients who were not receiving corticosteroids at baseline and patients who have completed 
the corticosteroid 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 corticosteroid 
withdrawal 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 period early to 
enroll in Part 1 (OLE) of Study GA28951 should complete the early withdrawal from treatment 
visit prior to enrollment in Study GA28951.
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 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 period 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.
Rescue Therapy That Cannot be Given with Study Medication for the Treatment of UC
At ANY time during the conduct of the trial, 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 the protocol).  These patients will 
also be requested to enroll in Part 2 (SM) of Study GA28951 for 92 weeks of extended PML 
monitoring.
A complete list of study visits and assessments can be found in the Schedule of Assessments 
(see the protocol for further details).  A complete list of eligibility for transfer of patients to 
OLE-SM and 12-week safety follow-up is in the protocol.
Number of Patients
A total of approximately 605 patients will be enrolled from approximately 225 sites via an open-
label induction arm (Cohort 1, n 130) and a double-blind induction arm (Cohort 2, n 475).
Cohort 2 patients will be randomized in a 4:1 ratio to etrolizumab 105 mg SC (n ≈380) or 
placebo (n ≈95) Q4W.  Patients in the etrolizumab arm of Cohort 2 who achieved a clinical 
response at Week 14 (see protocol for definition of clinical response) and all Week 14 clinical 
responders in Cohort 1 will be randomized into the Maintenance Phase and will receive either 
etrolizumab (105 mg SC Q4W) or placebo in a 1:1 ratio.  It is estimated that the planned 
approximately 510 etrolizumab patients from Cohort 1 and Cohort 2 will provide approximately
154 patients in clinical response for randomization into the Maintenance Phase.  Additional 
patients may be enrolled into Cohort 1, if needed, to meet sample size requirements for the 
Maintenance Phase.


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Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Treatment within 5 years prior to screening with one or two induction regimens that contain 
TNF inhibitors (including TNF inhibitor biosimilars), as defined below:

Infliximab:  5 mg/kg IV, 2 doses

Adalimumab:  160 mg SC followed by an 80-mg dose

Golimumab:  200 mg SC followed by a 100-mg dose
Patients will be categorized as TNF inhibitor refractory, TNF inhibitor intolerant, or 
neither refractory nor intolerant to TNF inhibitors.  TNF inhibitor refractory and TNF 
inhibitor intolerant are defined as follows:
TNF inhibitor refractory:  Persistent signs and symptoms of active disease despite 
TNF inhibitor treatment or recurrence of symptoms during maintenance TNF inhibitor 
treatment (i.e., following prior clinical benefit)
TNF inhibitor intolerant:  History of intolerance to TNF inhibitors, (including, but not 
limited to, injection-site reactions, congestive heart failure, or infection)

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:  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 the protocol, a 
rectal bleeding subscore 1, and a stool frequency subscore of 1 during the screening 
period (prior to Day 1).  See the protocol for additional information regarding the time 
window.  

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 the protocol for additional information regarding the time 
window.

Washout of TNF inhibitor therapy for at least 8 weeks preceding Day 1

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 at least 2 weeks immediately prior to Day 1
May be receiving AZA, 6-MP, or MTX, provided that the dose has been stable for at 
least 8 weeks immediately prior to Day 1


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
For women who are not postmenopausal (at least 12 months of nontherapy-induced 
amenorrhea) or surgically sterile (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, a condom, 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 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
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


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
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, except for AZA and 6-MP.  

Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil 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 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 co-morbidity, such as cardiac (e.g., moderate to severe heart failure 
New York Heart Association 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


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
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 , 
high-grade squamous intraepithelial lesions, or cervical intraepithelial neoplasia 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 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 has a known history of HCV 
antibody positivity with history of undetectable HCV RNA for 6 months 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 result is positive, the patient is not eligible for this study.  
In the event HBV DNA test cannot be performed, the patient is not eligible for this 
study. 
If the HBV DNA test result 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 is required during screening evaluation only if clinical suspicion is high 
and to determine the need for CMV treatment.

History of active or latent tuberculosis (TB) regardless of treatment history
Patients with a history of active or latent TB (based on a positive screening assay, 
either purified protein derivative skin test or QuantiFERONTB Gold test, see below) 
are not eligible for this study.
Patients with a chest X-ray (posteroanterior 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 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 Abnormalities (at Screening)

Serum creatinine 2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 66 weeks. Patients who do not achieve a clinical 
response at Week 14, patients who have clinical relapse during the Maintenance Phase, 
patients who receive defined rescue treatment, and patients who complete 66 weeks of the 
study may be given the option of enrolling into 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  monitoring for PML.
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 the Study GA28951 
(OLE-SM), whichever is the 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 transferred to Study GA28951 (OLE-SM), whichever is later.
Outcome Measures
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:
Primary Efficacy Outcome Measures
Induction Phase

Remission at Week 14, as determined by the MCS
Maintenance Phase

Remission at Week 66 among patients with a clinical response at Week 14, as determined 
by the MCS


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Secondary Efficacy Outcome Measures
Induction Phase

Clinical remission at Week 14

Clinical response at Week 14

Improvement in endoscopic appearance of the mucosa at Week 14

Endoscopic remission at Week 14

Histologic remission at Week 14

Change from baseline in rectal bleed subscore at Week 6

Change from baseline in stool frequency subscore at Week 6

Change from baseline in UC bowel movement signs and symptoms as assessed by the 
UC-PRO/SS measure at Week 14

Change from baseline in UC abdominal symptoms as assessed by the UC-PRO/SS 
measure at Week 14

Change from baseline in patients’ health-related QOL at Week 14 as assessed by the 
overall score of the IBDQ
Maintenance Phase

Clinical remission at Week 66 among patients in clinical remission at Week 14

Clinical remission at Week 66

Remission at Week 66 among patients in remission at Week 14

Improvement in endoscopic appearance of the mucosa at Week 66

Histologic remission at Week 66

Endoscopic remission at Week 66

Corticosteroid-free clinical remission at Week 66 (off corticosteroid for at least 24 weeks 
prior to Week 66) in patients who were receiving corticosteroids at baseline

Corticosteroid-free remission at Week 66 (off corticosteroid for at least 24 weeks prior to 
Week 66) in patients who were receiving corticosteroids at baseline

Change from baseline in UC bowel movement signs and symptoms as assessed by the 
UC-PRO/SS measure at Week 66

Change from baseline in UC abdominal symptoms as assessed by the UC-PRO/SS 
measure at Week 66

Change from baseline in patients’ health-related QOL at Week 66 as assessed by the 
overall score of the IBDQ
Exploratory Efficacy Outcome Measures

Clinical response at Week 66 among patients with a clinical response at Week 14

Remission at Week 66 among patients in clinical remission at Week 14

Corticosteroid-free clinical remission at Week 66 (off corticosteroid for at least 12 weeks 
prior to Week 66) in patients who are receiving corticosteroids at baseline

Histologic disease activity change from baseline to Week 14 and Week 66

Improvement in histologic and/or endoscopic disease activity

Change in health utilities, as assessed by the EQ-5D, from baseline to Week 14 and Week 
14 to Week 66

Frequency and duration of hospitalizations from Week 14 to Week 66

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 16 to 
Week 66

Serum concentration at primary endpoint time (Week 14 and  Week 66)
Exploratory Biomarker Outcome Measures
The exploratory biomarker outcome measures for this study are as follows:

Remission at Week 14 and maintenance of remission at Week 66 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 14).  Tapering of corticosteroid (including budesonide) is to 
be attempted during the Maintenance Phase.
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 discontinuing 
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.
Probiotics and oral 5-ASA may be continued at a stable dose throughout the study.


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Occasional use of NSAIDs and acetaminophen (e.g., headache, arthritis, myalgias, 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
For the purpose of statistical analyses, the Induction and Maintenance Phases will be treated as 
two independent studies.  The analysis of the Induction Phase will formally evaluate the efficacy 
and safety of 105 mg etrolizumab SC Q4W versus placebo as an induction therapy.
The analysis of the Maintenance Phase will formally evaluate the efficacy and safety of 
105 mg etrolizumab SC Q4W versus placebo as a maintenance therapy.
The analysis of data from the 66-week treatment period (Induction and Maintenance Phases) 
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 
analyses, patients and study site personnel will remain blinded to individual treatment 
assignment (for Cohort 2 patients and those re-randomized into the Maintenance Phase) until 
after the study is completed (after all patients have either completed the safety follow-up periods 
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 endpoints in the blinded Induction Phase and the Maintenance Phase respectively.  
Approximately 605 patients will be enrolled in the open-label induction arm (Cohort 1, n ≈130) or 
the blinded induction cohort (Cohort 2, n ≈475).
Cohort 2 patients will be randomized in a 4:1 ratio to etrolizumab (n ≈380) or placebo (n ≈95).  
This will provide approximately 80% power to detect a 10% difference in remission rates at 
Week 14 between the etrolizumab and placebo arms, under the assumption of a placebo 
remission rate of 5% and a two-sided 2 test at the 5% significance level.
The primary endpoint for the Maintenance Phase is Week 66 remission among patients with a 
clinical response at Week 14. In total, it is estimated that approximately 154 etrolizumab 
patients will achieve clinical response at the end of the Induction Phase and therefore will be 
randomized in the Maintenance Phase, under the assumption of a Week 14 clinical response 
rate of approximately 30% in the pooled etrolizumab induction group.
A sample size of 154 patients in the Maintenance Phase will provide 90% power to detect a 
30% difference in remission rates between the two maintenance arms, under the assumption of 
a placebo Week 66 remission rate 10% and a Fisher exact test at the 5% significance level.
The planned approximately 510 etrolizumab patients from Cohort 1 and Cohort 2 would provide 
approximately 154 patients with a clinical response at Week 14, under the assumption of a 
Week 14 clinical response rate of at least 30% in the pooled (Cohort 1 and Cohort 2) 
etrolizumab induction group.  Additional patients may be enrolled into Cohort 1, if needed, to 
achieve this target number of approximately 154 patients randomized into the Maintenance 
Phase.
For the purpose of statistical analyses and sample size calculations, the Induction and 
Maintenance Phases will be treated as two independent studies, and as such no adjustment to 
alpha is required.


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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
DCSI
Development Core Safety Information
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
ePRO 
electronic Patient-Reported Outcome
EQ-5D
EuroQoL Five-Dimension Questionnaire
FDA
U.S. Food and Drug Administration
HBsAg
HBV surface antigen
HBV
hepatitis B virus
HCP
health-care professional
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HSIL
high-grade squamous intraepithelial lesions 
IBD
inflammatory bowel disease
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Council for Harmonisation
IDCC
independent data coordinating center 
iDMC
independent Data Monitoring Committee
IHC
immunohistochemistry
IMP
investigational medicinal product


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Abbreviation
Definition
IND
Investigational New Drug
IRB
Institutional Review Board
IV 
intravenous
IxRS
interactive voice/Web-based response system 
JAK
Janus kinase 
JCV
John Cunningham virus
LD
loading dose
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 
NYHA
New York Heart Association 
OLE
open-label extension
OLE-SM
open-label extensionsafety monitoring
PA
posteroanterior
PD
pharmacodynamic
PEG
polyethylene glycol
PFS
prefilled syringe
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


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Abbreviation
Definition
SC
subcutaneous
SM
safety monitoring
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 corticosteroid-free remission), induce mucosal healing, reduce 
hospitalization and surgery, improve quality of life (QOL), and avoid disability.  For mildly 
to moderately active UC, oral and rectal preparations of 5-aminosalicylate (5-ASA) 
medications are used either alone or together and result in remission in approximately 
50% of patients.  Patients whose UC fails to respond to 5-ASA drugs or who have 
moderately to severely active UC often receive conventional therapy, including 
corticosteroids and immunomodulator therapy (e.g., azathioprine [AZA], 
6-mercaptopurine [6-MP], and methotrexate [MTX]).  Corticosteroids achieve remission
in about 70% of patients, but approximately 20% become corticosteroid dependent and 
only half maintain corticosteroid-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 corticosteroid-free remission, but efficacy in 
maintaining corticosteroid-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 corticosteroid 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 corticosteroid-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 IBD patients who have chronic disease (Hanauer et al. 2002; Sandborn et al. 2005; 
Feagan et al. 2013).  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 have 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 and hematologic and cardiovascular systems).  No adverse events 
were observed in the embryo-fetal developmental toxicity studies.
Etrolizumab is a humanized MAb based on the human IgG1 subgroup-III VH, 
subgroup-1 VL consensus sequences and was constructed using standard 
recombinant DNA techniques.  This recombinant antibody consists of two heavy chains 
(446 residues) and two light chains (214 residues) and is produced in Chinese hamster 
ovary (CHO) cells that have been genetically engineered to synthesize the antibody.  
The protein is manufactured in bioreactors and purified using a series of harvest, 
purification, and formulation steps.  The potency of etrolizumab is determined by an 
in vitro assay that measures the inhibition of adhesion of 47-expressing cells to 
mucosal addressin cell adhesion moleculefragment crystallizable region (MAdCAM-Fc).
Safety assessments for etrolizumab have been completed in the adult Phase I, Phase II, 
and Phase II open-label extension (OLE) studies without significant safety concerns.
The following is a summary of the etrolizumab safety experience to date:

There were no observed significant adverse effects in multiple nonclinical toxicity 
studies of up to 6 months’ duration in adult animals or in embryo-fetal 
developmental toxicity studies.  No adverse effects were seen in any organ system 
(including the CNS, 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 Investigator's Brochure for details on nonclinical and clinical studies.
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 


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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 leucocyte/lymphocyte in the 
intestinal mucosa.
No clinically significant safety signals were detected on administration of etrolizumab to 
patients with moderate to severe UC across a dose range of 0.310.0 mg/kg IV/SC in 
the single ascending dose stage and of 0.53.0 mg/kg SC and 4 mg/kg IV monthly for 
3 doses in the multidose stage of the Phase I study or in the Phase II study of 
120 patients.
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 moderate to severely active 
UC patients 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).


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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.  In the inadequate response to anti-tumor necrosis factor
(TNF-IR) subgroup, which represents a refractory population with limited treatment 
options, clinical remission at Week 10 was observed in 4.5% of the 100 mg etrolizumab 
group, 4% of the 300 mgLD group, and in 0% of the placebo group, respectively.  
However, data from SPRUCE (OLE Study GA27927) suggests that with longer duration 
of treatment, gut mucosal-selective anti-trafficking agents do benefit this patient 
population over time (Feagan et al. 2012).  With 4 additional weeks of follow-up in OLE, 
clinically meaningful efficacy was observed:

31% (10 of 32) of TNF-IR patients who had not responded to etrolizumab by 
Week 10 and rolled into the OLE achieved clinical response by partial Mayo Clinic 
Score (pMCS) at 14 weeks

9% (3 of 32) of TNF-IR patients who had not responded to etrolizumab by Week 10 
and rolled into the OLE achieved clinical remission by pMCS at 14 weeks
The present study is powered to detect a 10% difference in induction of remission rates 
between etrolizumab and placebo-treated patients.  Given that patients failing TNF 
inhibitor therapy have very limited treatment options available to them, the TNF-IR 
patient population represent an unmet medical need population.  Consequently, the 
potential benefits of etrolizumab in this population warrant further investigation.
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.


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2.
OBJECTIVES
2.1
EFFICACY OBJECTIVES
The primary efficacy objectives for this study are as follows:

To evaluate the efficacy of etrolizumab (105 mg SC every 4 weeks [Q4W]) 
compared with placebo for the induction of remission, as determined by the MCS at 
Week 14

To evaluate the efficacy of etrolizumab (105 mg SC Q4W) compared with placebo 
for remission at Week 66 among patients with a clinical response at Week 14, as 
determined by the MCS
The secondary efficacy objectives for this study are as follows:
Induction Phase

To evaluate induction of clinical remission at Week 14

To evaluate clinical response at Week 14

To evaluate improvement in endoscopic appearance of the mucosa at Week 14

To evaluate endoscopic remission at Week 14

To evaluate histologic remission at Week 14

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 change from baseline in UC bowel movement signs and symptoms at 
Week 14, as assessed by the Ulcerative ColitisPatient-Reported Outcome Signs 
and Symptoms (UC-PRO/SS) measure

To evaluate change from baseline in UC abdominal symptoms at Week 14, as 
assessed by the UC-PRO/SS measure

To evaluate change from baseline in patientreported health-related QOL at 
Week 14, as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ)
Maintenance Phase

To evaluate clinical remission at Week 66 in patients in clinical remission at Week 
14

To evaluate clinical remission at Week 66

To evaluate remission at Week 66 among patients in remission at Week 14

To evaluate improvement in endoscopic appearance of the mucosa at Week 66

To evaluate histologic remission at Week 66

To evaluate endoscopic remission at Week 66


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
To evaluate corticosteroid-free clinical remission at Week 66 (off corticosteroid for at 
least 24 weeks prior to Week 66) in patients who were receiving corticosteroids at 
baseline

To evaluate corticosteroid-free remission at Week 66 (off corticosteroid for at least 
24 weeks prior to Week 66) in patients who were receiving corticosteroids at 
baseline

To evaluate change in UC bowel movement signs and symptoms from baseline to
Week 66, as assessed by the UC-PRO/SS measure

To evaluate change in UC abdominal symptoms from baseline to Week 66, as 
assessed by the UCPRO/SS measure

To evaluate change in patientreported health-related QOL from baseline to
Week 66, as assessed by the IBDQ
The exploratory efficacy objectives for this study are as follows:

To evaluate clinical response at Week 66 among patients with a clinical response at 
Week 14

To evaluate remission achieved at Week 66 among patients in clinical remission at 
Week 14

To evaluate corticosteroid-free clinical remission at Week 66 (off corticosteroid for at 
least 12 weeks prior to Week 66) in patients who were receiving corticosteroids at 
baseline

To evaluate change in histologic disease activity from baseline to Week 14 and 
Week 66

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 baseline to Week 14 and Week 14 to Week 66

To evaluate frequency and duration of hospitalizations from Week 14 to Week 66

To evaluate response, remission, and corticosteroid-free endpoints, as determined 
by the mMCS
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 PGA
Partial MCS
pMCS is a composite of 3 assessments of the MCS, each rated from 03:  stool 
frequency, rectal bleeding, and PGA
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 14) and maintained at 
the end of the Maintenance Phase (Week 66).
Clinical remission
MCS 2 with individual subscores 1
Maintained clinical remission
Clinical remission achieved at the start of the Maintenance Phase (Week 14) and 
maintained at the end of the Maintenance Phase (Week 66)
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 12 or 24 weeks prior to Week 66
Corticosteroid-free remission
Remission with no corticosteroid use for 24 weeks prior to Week 66
Improvement in endoscopic appearance
of the mucosa
Endoscopic subscore 1
Endoscopic remission
Histologic remission
Endoscopic subscore 0
NHI 1
MCSMayo Clinic Score; mMCS modified Mayo Clinic Score; PGAPhysician’s Global Assessment; pMCSpartial Mayo Clinic 
Score; NHI Nancy histological index.
.


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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 compared with placebo 
during induction and maintenance therapy over a period of 66 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 (Weeks 14 and 66) and at predose time in the steady state during the 
maintenance dosing period

To evaluate the inter-individual 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 drug

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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3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
3.1.1
Overview of Study Design
This is a multicenter, Phase III, double-blind, placebo-controlled study evaluating the 
safety, efficacy, and tolerability of etrolizumab during induction and maintenance of 
remission compared with placebo in the treatment of moderately to severely active UC 
(see Figure 1).
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 (see Appendix 3), 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 
of 612, endoscopy subscore of 2 as determined by the central reading procedure 
described in Section 4.6.1.4, a rectal bleeding subscore 1, and a stool frequency 
subscore of ≥1) and involvement that extends a minimum of 20 cm from the anal verge.
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 14, at which point a corticosteroid taper will be initiated.  


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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) if 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).  Patients must have discontinued TNF inhibitor treatment and topical 
treatments for UC at least 8 weeks and 2 weeks prior to Day 1, respectively.
The study will be divided into:

Screening period of up to 35 days during which patient eligibility will be determined
(for details see Section 4.6.2.1)

Induction Phase of 14 weeks (Cohort 1: open-label etrolizumab treatment; 
Cohort 2: randomized to etrolizumab or placebo)

Randomization of etrolizumab responders prior to a double-blind Maintenance
Phase of 52 weeks or continued blinded treatment with placebo Q4W for 52 weeks 
for placebo induction responders 

Safety follow-up period of 12 weeks
A total of approximately 605 patients will be recruited (see Figure 1) from approximately 
225 sites via an open-label induction arm (Cohort 1, n130) and a double-blind 
induction arm (Cohort 2, n475), which will be enrolled sequentially.
Cohort 1 patients will receive open-label etrolizumab 105 mg SC Q4W during the 
14-week Induction Phase.  Cohort 2 patients will be randomized in a 4:1 ratio to 105 mg 
etrolizumab SC Q4W (n≈380) or placebo (n≈95) during the 14-week Induction Phase.  
Randomization will be stratified by concomitant treatment with corticosteroids (including 
budesonide) (yes/no), concomitant treatment with immunosuppressants (yes/no), and 
disease activity measured during screening (MCS 9/MCS10).
Eligibility for entry into the Maintenance Phase will be determined between Weeks 14 
and 16.  Patients in the etrolizumab arm of Cohort 2 who achieved a clinical response at 
Week 14 (see Table 1 for definition of clinical response) and all Week 14 clinical 
responders in Cohort 1 will be randomized into the Maintenance Phase and will receive 
either etrolizumab (105 mg SC Q4W) or placebo in a 1:1 ratio.  Randomization will be 
stratified by remission status at Week 14, concomitant treatment with corticosteroids
(including budesonide) at baseline, disease activity measured during screening
(MCS 9/MCS 10), and induction cohort (Cohort 1/Cohort 2).  It is estimated that the 
planned approximately 510 etrolizumab patients from Cohort 1 and Cohort 2 will provide 
approximately 154 patients in clinical response for randomization into the Maintenance 
Phase.  Additional patients may be enrolled into Cohort 1, if needed, to achieve a 
sufficient number of patients in the Maintenance Phase.


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Patients initially randomized to placebo will also be assessed for clinical response at 
Week 14.  Patients achieving a clinical response will continue to receive blinded placebo 
during the Maintenance Phase of the study.  Patients in either Cohort 1 or Cohort 2, who 
do not achieve clinical response at Week 14, 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 66 weeks of the study may be given 
the option of enrolling into Part 1 (OLE) of Study GA28951, where they will receive 
open-label etrolizumab treatment, if eligible.  If patients choose not to 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.
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 his or her caregiver in the clinic; 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 14 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 14, patients
receiving budesonide who achieve clinical response at Week 14 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 corticosteroid withdrawal, corticosteroid dose may 
be increased (up to the dose at study entry if required), but tapering must begin again 
within 2 weeks.


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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.
3.1.1.1
Definition of Clinical Relapse
Clinical relapse is defined as an:

Increase in partial Mayo Clinic Score (pMCS) 3 points compared to induction 
timepoint (Week 14) 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
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 14)
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), 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 14, 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 of 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 14 and may not continue 
into the Maintenance Phase of the trial.  
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.


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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 period 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 must begin the specified corticosteroid taper at Week 14 during the 
Maintenance Phase.  For patients who cannot tolerate the corticosteroid taper without 
recurrence of clinical symptoms of either UC or corticosteroid 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.
Patients who were not receiving corticosteroids at baseline and patients who have 
completed the corticosteroid 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 corticosteroid withdrawal 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 period early to enroll in Part 1 (OLE) of 
Study GA28951 should complete the early withdrawal from treatment visit prior to 
enrollment in Study GA28951.
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 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 period 
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.


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Rescue Therapy That Cannot Be Given with Study Medication for the 
Treatment of UC
At ANY time during the conduct of the trial, 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 be requested to 
enroll in Part 2 (SM) of Study GA28951 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).  Eligibility criteria for the transfer of patients to 
Study GA28951 and 12-week safety follow-up can be found in Table 4.


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Figure 1
Study Schema
6-MP6-mercaptopurine; AZAazathioprine; CScorticosteroid; EPendpoint; IS immunosuppressant; MTX methotrexate; 
OLE-SMopen-label extensionsafety monitoring study (Study GA28951); Q4W every 4 weeks; QDonce a day; QODevery other day; 
SCsubcutaneous; wk week.
a Stable budesonide at 9 mg/day.  Taper from Week 14 to QOD for 2 weeks and then discontinue. 


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Number of Patients
A total of approximately 605 patients will be enrolled from approximately 225 sites via an 
open-label induction arm (Cohort 1, n130) and a double-blind induction arm (Cohort 2, 
n475).
Cohort 2 patients will be randomized in a 4:1 ratio to etrolizumab 105 mg SC (n≈380) or 
placebo (n≈95) Q4W.  Patients in the etrolizumab arm of Cohort 2 who achieved a 
clinical response at Week 14 (see Table 1 for definition of clinical response) and all 
Week 14 clinical responders in Cohort 1 will be randomized into the Maintenance Phase 
and will receive either etrolizumab (105 mg SC Q4W) or placebo in a 1:1 ratio.  It is 
estimated that the planned approximately 510 etrolizumab patients from Cohort 1 and 
Cohort 2 will provide approximately 154 patients in clinical response for randomization 
into the Maintenance Phase.  Additional patients may be enrolled into Cohort 1, 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 risk-benefit 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 66 weeks. Patients who do not achieve a 
clinical response at Week 14, 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 66 weeks of the study may be given the option of enrolling into 
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 monitoring for PML.
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 the 
Study GA28951 (OLE-SM), whichever is the 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 transferred to Study GA28951 (OLE-SM), 
whichever is later.
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 nominal 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.

In Phase II, the nominal 100-mg Q4W SC dose (0.7 mL of 150 mg/mL solution via 
vial and syringe, with an actual dose of 105 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 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; 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 1.2), a PFS delivering a dose of 105 mg Q4W is considered the most 
appropriate dosing regimen for this Phase III study.
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, resulting in low rates of 
sustained remission, or being highly invasive (i.e., colectomy; see Section 1.1 for details).  


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The Phase II EUCALYPTUS study provided evidence of efficacy 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 at Week 10, the proportions of 
patients in clinical remission (defined as MCS 2 and all subscores 1) in the overall 
population (both TNF-naive and TNF-IR) were 20.5% in the 100-mg arms compared 
with 0% in the placebo arm.  Data from SPRUCE (the OLE study) suggests that with 
longer duration of treatment, gut-selective anti-trafficking agents do benefit this patient 
population over time (Feagan et al. 2012).  With 4 additional weeks of follow-up in OLE, 
clinically meaningful benefit was observed:

31% (10 of 32) of TNF-IR patients who had not responded to etrolizumab by 
Week 10 and rolled into the OLE achieved clinical response by pMCS at 14 weeks

9% (3 of 32) of TNF-IR patients who had not responded to etrolizumab by Week 10 
and rolled into the OLE achieved clinical remission by pMCS at 14 weeks
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 
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 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 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 the Phase III study to further evaluate whether they may function as 
predictive response biomarkers in the TNF-IR patient population.


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Figure 2
Effects of High and Low Baseline Expression of the E Biomarker in Colon on the Remission Status of 
Ulcerative Colitis Patients Treated with Etrolizumab in EUCALYPTUS (Observed Data)
LDloading dose; SCsubcutaneous.


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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 14 and 66 for potential exploratory PD biomarker analyses that include, but are 
not limited to, E expression.
3.4
OUTCOME MEASURES
3.4.1
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:
Primary Efficacy Outcome Measures
Induction Phase

Remission at Week 14, as determined by the MCS
Maintenance Phase

Remission at Week 66 among patients with a clinical response at Week 14, as 
determined by the MCS
Secondary Efficacy Outcome Measures
Induction Phase

Clinical remission at Week 14

Clinical response at Week 14

Improvement in endoscopic appearance of the mucosa at Week 14

Endoscopic remission at Week 14

Histologic remission at Week 14

Change from baseline in rectal bleed subscore at Week 6

Change from baseline in stool frequency subscore at Week 6  

Change from baseline in UC bowel movement signs and symptoms as assessed by 
the UC-PRO/SS measure at Week 14

Change from baseline in UC abdominal symptoms as assessed by the UC-PRO/SS 
measure at Week 14

Change from baseline in patients’ health-related QOL at Week 14 as assessed by 
the overall score of the IBDQ
Maintenance Phase

Clinical remission at Week 66 among patients in clinical remission at Week 14

Clinical remission at Week 66

Remission at Week 66 among patients in remission at Week 14 

Improvement in endoscopic appearance of the mucosa at Week 66

Histologic remission at Week 66


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
Endoscopic remission at Week 66

Corticosteroid-free clinical remission at Week 66 (off corticosteroid for at least 
24 weeks prior to Week 66) in patients who were receiving corticosteroids at 
baseline

Corticosteroid-free remission at Week 66 (off corticosteroid for at least 24 weeks 
prior to Week 66) in patients who were receiving corticosteroids at baseline

Change from baseline in UC bowel movement signs and symptoms as assessed by 
the UC-PRO/SS measure at Week 66

Change from baseline in UC abdominal symptoms as assessed by the UC-PRO/SS 
measure at Week 66

Change from baseline in patients’ health-related QOL at Week 66 as assessed by 
the overall score of the IBDQ
Exploratory Efficacy Outcome Measures

Clinical response at Week 66 among patients with a clinical response at Week 14

Remission at Week 66 among patients in clinical remission at Week 14

Corticosteroid-free clinical remission at Week 66 (off corticosteroid for at least 
12 weeks prior to Week 66) in patients who are receiving corticosteroids at baseline

Histologic disease activity change from baseline to Week 14 and Week 66

Improvement in histologic and/or endoscopic disease activity

Change in health utilities, as assessed by the EQ-5D, from baseline to Week 14 and 
Week 14 to Week 66

Frequency and duration of hospitalizations from Week 14 to Week 66

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 16 
to Week 66

Serum concentration at primary endpoint time (Week 14 and Week 66)
3.4.4
Exploratory Biomarker Outcome Measures
The exploratory biomarker outcome measures for this study are as follows:

Remission at Week 14 and maintenance of remission at Week 66 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 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 4.6.1.4, a rectal bleeding subscore 1, a stool frequency 
subscore of 1, and colonic involvement extending a minimum of 20 cm from the anal 
verge) and who have been previously exposed to TNF inhibitors.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Treatment within 5 years prior to screening with one or two induction regimens that 
contain TNF inhibitors (including TNF inhibitor biosimilars), as defined below:

Infliximab: 5 mg/kg IV, 2 doses

Adalimumab: 160 mg SC followed by an 80-mg dose

Golimumab: 200 mg SC followed by a 100-mg dose
Patients will be categorized as TNF inhibitor refractory, TNF inhibitor intolerant, 
or neither refractory nor intolerant to TNF inhibitors.  TNF inhibitor refractory 
and TNF inhibitor intolerant are defined as follows:
TNF inhibitor refractory:  Persistent signs and symptoms of active disease 
despite TNF inhibitor treatment or recurrence of symptoms during maintenance 
TNF inhibitor treatment (i.e., following prior clinical benefit)
TNF inhibitor intolerant:  History of intolerance to TNF inhibitors, (including, but 
not limited to, injection-site reactions, congestive heart failure, or infection)


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
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:  
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 4.6.1.4, a rectal bleeding subscore 1, and a stool frequency subscore of
1 during the screening period (prior to Day 1).  See Section 4.6.2.1 for additional 
information regarding the time window)  

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 Section 4.6.2.1 for additional information 
regarding the time window. 

Washout of TNF inhibitor therapy for at least 8 weeks preceding Day 1

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 at least 2 weeks immediately prior 
to Day 1
May be receiving AZA, 6-MP, or MTX provided that the dose has been stable 
for at least 8 weeks immediately prior to Day 1


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
For women who are not postmenopausal (at least 12 months of 
nontherapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or 
uterus): agreement to remain abstinent or use a highly effective method of 
contraception during the treatment period and for at least 24 weeks after the last 
dose of study drug (see Appendix 4).
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, a condom, 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 4.6.1.4)
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 
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


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
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 corticosteroids within 30 days prior to screening with the exception of a 
single administration of IV corticosteroid

Use of agents that deplete B or T cells (e.g., alemtuzumab or visilizumab) within 
12 months prior to Day 1, except for 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 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


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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 co-morbidity, 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 history of undetectable HCV RNA for
6 months and undetectable HCV RNA at screening in the absence of history of 
HCV anti-viral treatment.


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
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 result is positive, the patient is not eligible for this 
study.  
In the event HBV DNA test cannot be performed, the patient is not 
eligible for this study. 
If the HBV DNA test result 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 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 4.6.1.5)
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

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


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
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 within4 weeks prior to Day 1

History of organ transplant
Exclusion Criteria Related to Laboratory Abnormalities (at Screening)

Serum creatinine 2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 
Patients will be randomized into the Induction Phase through an interactive 
voice/Webbased response system (IxRS).  After written informed consent has been 
obtained, all patients will receive a screening number, which will be assigned by the 
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 open-label 
etrolizumab (Cohort 1; see Figure 3) or will be randomized to either placebo or 
etrolizumab (105 mg SC Q4W; Cohort 2).  Randomization for Cohort 2 will be stratified 
by concomitant treatment with corticosteroids (yes/no), concomitant treatment with 
immunosuppressants (yes/no), and disease activity measured during screening 
(MCS 9/MCS 10).  A permuted blocks randomization method will be used to obtain an 
approximately 1:4 ratio between the placebo and etrolizumab arms in Cohort 2.  
At Week 16, following receipt of the endoscopy score, etrolizumab patients from either 
Cohort 1 or from Cohort 2 achieving a clinical response at Week 14 (see Table 1 for 
definition of clinical response) will undergo a second randomization, stratified by 
remission status at Week 14, concomitant treatment with corticosteroids (yes/no), 
disease activity measured during screening (MCS 9/MCS 10), and induction cohort 
(Cohort 1/Cohort 2), to either 105 mg etrolizumab SC or placebo in a 1:1 ratio 
(Maintenance Phase).  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 14 remission status 


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stratification variable will consist of three levels according to whether remission was 
achieved with or without inclusion of the PGA criteria described in Table 1.
For the second randomization, a permuted blocks randomization method will be used to 
obtain an approximately 1:1 ratio between the treatment and placebo arm within each 
stratum.  Study drug will be administered Q4W for a total of 13 doses with the final dose 
given at Week 64 (see Appendix 1 for details of study drug administration schedule).  
Patients achieving a clinical response while receiving placebo in the Induction Phase will 
continue on blinded placebo in the Maintenance Phase.
During the 14-week induction and 52-week maintenance double-blind treatment periods, 
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 2 or 3 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 14-week double-blind (Cohort 2) induction and 
52-week maintenance double-blind treatment periods.  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 66 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 as 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corticosteroid; dday; EPendpoint; HCPhealth care professional; OLEopen-label extension; OLE-SMopen-label extensionsafety monitoring study; 
QODevery other day; TCtelephone call; wkweek.


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4.3
STUDY TREATMENT
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:
5-ASA (oral); 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 IS 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 IS 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 are to taper their dose 
starting from Week 14 from 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 ulcerative colitis or corticosteroid withdrawal, 
corticosteroid dose may be increased (up to the dose at study entry if required), but tapering 
must begin again within 2 weeks.
5-ASA5-aminosalicylic acid; 6-MP6-mercaptopurine; AZAazathioprine; ISimmunosuppressants; MTXmethotrexate; 
NSAIDnonsteroidal anti-inflammatory drug; SCsubcutaneous.


Table 3
Treatment/Concomitant Background Treatments (cont.)
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Treatment/Concomitant Background Treatment
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; ISimmunosuppressants; MTXmethotrexate; 
NSAIDnonsteroidal anti-inflammatory drug; 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 4 dose administrations, study medication is to be administered under close 
supervision of the HCP in a setting where medications and resuscitation facilities are 
available.  The first two treatments (each 0.7 mL delivered via PFS; Week 0 [Day 1] and 
Week 4) will be administered by the HCP and observed by the patient (and/or caregiver).  
The following two treatments (Week 8 and Week 12) will be administered by the patient 
(or caregiver) and observed by the HCP in the clinic setting.  Following the first four 
study treatment administrations, patients will be monitored for acute hypersensitivity 
reactions for at least one 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.


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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 and are 
to enter the 12-week safety follow-up in this study followed by PML monitoring in Part 2
(SM) of Study GA28951.
All adverse events of systemic hypersensitivity reactions or anaphylactoid or anaphylaxis 
reactions must be reported within 24 hours to the Sponsor and the Medical Monitor must 
be informed as soon as is practical (see the Study Manual for contact information).
Following the first four study drug administrations (Weeks 012), and therefore,
completion of this first 3-month period training in a clinical setting, study drug 
administration (Week 16 and then Q4W onwards) 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 by use of 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), 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 two 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)


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(see Section 5.1.5) should be documented on the appropriate adverse event electronic 
Case Report Form (eCRF) page. Patients administering the injection 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 4.7
and 5.1.
4.3.2.2
Concomitant Background Treatment and Rescue Therapy
Patients entering the study may be refractory to, dependent on, or intolerant to
corticosteroids as defined below:

Corticosteroid refractory:  persistent symptoms of active disease despite history of 
at least one 4-week induction regimen that included 30 mg prednisone (oral) daily
(or equivalent) for at least 2 weeks or 30 mg/day of IV prednisone (or equivalent) 
for at least 1 week

Corticosteroid dependent:  two failed attempts to taper corticosteroids below 
10 mg/day of oral prednisone (or equivalent)

Corticosteroid intolerant:  history of intolerance to corticosteroids (including, but not 
limited to, Cushing’s Syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, 
or infection)
All patients are to be defined in the eCRF as refractory, dependent, or intolerant to 
corticosteroids, if appropriate.  
In addition, patients entering the study may be refractory to or intolerant to
immunosuppressants 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)

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

History of intolerance to AZA, 6-MP, or MTX (including, but not limited to,
nausea/vomiting, abdominal pain, pancreatitis, liver function tests abnormalities, 
lymphopenia, TPMT genetic mutation, or infection)
All patients are to be defined in the eCRF as refractory or intolerant to 
immunosuppressants, if appropriate.
Management of Concomitant Medications during the Study
During Induction Phase (prior to Week 14)
Patients are required to maintain stable doses of their concomitant medications (oral 
5-ASA, corticosteroids, immunosuppressants) for UC. 


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During Maintenance Phase (after Week 14)
Corticosteroids
Corticosteroids are to be tapered starting from Week 14 in patients who achieve a 
clinical response (patients not achieving clinical response will be allowed to enroll in
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 corticosteroid 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
(AZA, 6-MP, or MTX), 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 14, 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 14)
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 should also be avoided as 
concomitant medications.  However, if these are clinically required to treat symptoms of 
UC, then the patient may remain in this blinded phase of the study or 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 period early to enroll in Part 1 (OLE) of 
Study GA28951 should complete the early withdrawal from treatment visit prior to 
enrollment in Study GA28951.


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Patients who were not receiving corticosteroids at baseline and patients who have 
completed the corticosteroid 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 UC or corticosteroid withdrawal may remain in this blinded phase of the study or 
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 period 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 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 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 period 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.
Rescue Therapy That Cannot Be Given with Study Medication for the 
Treatment of UC
At ANY time during the conduct of the trial, 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), 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 also be 
requested 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 


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investigational site will acknowledge receipt of IMP (e.g., drug receipt record) and 
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 PFSs will be provided locally to patients for home usage.  
After home injections, the used syringes must be placed into the sharps containers 
immediately.  The sharps containers should be returned to sites.  Sharps containers will 
be discarded by the site staff at the frequency per local schedule.
A Drug Dispensing Log must be kept as described in Section 4.3.3.  The investigator is 
responsible for ensuring that dosing is administered in compliance with the protocol.  
Delegation of this task must be clearly documented and approved by the investigator.  
When the study is completed, the investigator will return all completed Drug Dispensing 
Logs to the Monitors.
Any unused study drug and Drug Return Records should be returned to the Monitor, 
unless alternate destruction has been authorized by Roche or required by local or 


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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/Comparator
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 necessary.
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. If the medical device complaint results in an adverse event to an 
individual other than the study patient, the device complaint must be reported on the 
PD103 IMP Deviation Form and the adverse event must be reported as a spontaneous 
adverse event to the Sponsor via telephone.


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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 entered into safety follow-up within this 
study.
4.5
CLINICAL RELAPSE
4.5.1
Definition of Clinical Relapse
Clinical relapse is defined as an:

Increase in pMCS 3 points compared to induction timepoint (Week 14) 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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4.6
STUDY ASSESSMENTS 
4.6.1
Description of Study Assessments
4.6.1.1
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.  Patients will be categorized as TNF 
inhibitor refractory, TNF inhibitor intolerant, or neither refractory nor intolerant to TNF 
inhibitors at screening (see definitions in Section 4.1.1).
Demographic data, including age, sex, whether the patient is a fraternal or identical twin, 
and self-reported race/ethnicity, will be collected during screening.
4.6.1.2
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.
4.6.1.3
Vital Signs
Vital signs will include measurement 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 before study drug administration at the indicated timepoints in Schedule of 
Assessments (see Appendix 1).
4.6.1.4
Ulcerative Colitis Disease Activity Assessments
Extent and duration of patient’s disease are 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 
range 09, with higher scores indicating more severe disease.  MCS is a composite of 
four assessments, each rated from 03:  stool frequency, rectal bleeding, endoscopy, 
and PGA.  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 4.6.2.1). 
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 visit(s) 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 3.  Appendix 3 also outlines 
procedures to follow in the event of e-diary malfunction or loss.
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 14 and 66 and/or withdrawal from study
(early withdrawal from treatment visit, see Appendix 1).  


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Central reading of endoscopies will be performed throughout this study, and a detailed 
charter will address the standardization of endoscopic procedures, video recordings and 
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 the 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 (performed 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 a 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 biopsies 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.

Five paired biopsy samples (10 samples) from the most inflamed area of the colon 
within 2040 cm from the anal verge (sigmoid colon).  Three pairs (6 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. In UK sites ONLY, one of the latter pair of biopsies (2 samples) will be 
placed in storage solution at 4°C and shipped to the UK laboratory.

ONLY if there is suspicion for 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 
performed locally if possible or can be sent to a central lab if necessary. 


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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 lab if necessary).

If neither CMV testing or histopathologic confirmation of UC is needed, these 
additional 2 biopsy samples should not be obtained.
At Weeks 14 and 66 and/or at early withdrawal from treatment visit 
(see Appendix 1) 

Four paired biopsy samples (8 samples) will be obtained at subsequent visits, as 
specified in Appendix 1.  Four paired biopsy samples (8 samples) are 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 should be 
taken.  Two pairs will go into formalin and two pairs will be placed in stabilization 
buffer (such as RNAlater or a similar buffer) and shipped to a central laboratory for 
storage at 80C (see Appendix 1).  In UK sites ONLY, one of the latter pair of 
biopsies (2 samples) will be placed in storage solution at 4°C and shipped to the 
UK laboratory.  
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 patients will be educated regarding the signs and symptoms of 
PML.  Close monitoring during the course of the study for any new symptoms or signs 
suggestive of PML will be performed, with regular neurologic examinations (including 
evaluation of cranial nerves, motor and sensory function, coordination, and mental status) 
as per the Schedule of Assessments (see Appendix 1).  The PML Subjective Checklist 
(symptom assessment) and the PML Objective Checklist (neurologic evaluation) will be 
administered (Appendix 5) 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 
Evaluation of Progressive Multifocal Leukoencephalopathy [PML]).  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 


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for further work-up, which may include brain magnetic resonance imaging (MRI) 
performed with and without contrast.  If there remains any suspicion for PML, the PML 
adjudication committee may recommend performing a lumbar puncture with 
cerebrospinal fluid (CSF) analysis for John Cunningham virus (JCV) by PCR.  If JCV is 
detected, the patient should be treated as a PML case, permanently discontinue study 
drug, and transfer to safety follow-up. 
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 (PML).
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 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 Part 2 (SM) of Study GA28951, patients will not be 
administered study drug.
The PML extended follow-up period in the Study GA28951 (OLE-SM) will consist of the 
PML assessment interview conducted by telephone at 6-month intervals.
4.6.1.5
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 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 differential count [neutrophils, eosinophils, lymphocytes, monocytes, 
basophils, other cells], mean corpuscular volume, mean corpuscular hemoglobin, 
mean corpuscular hemoglobin concentration, and RBC distribution width)


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
Serum chemistries, including liver function tests (sodium, potassium, chloride, 
bicarbonate, glucose, blood urea nitrogen, creatinine, calcium, phosphorus, 
magnesium, total and direct bilirubin, total protein, albumin, alanine 
aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline 
phosphatase, creatine phosphokinase, and uric acid)

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 
pregnancy test.


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
Viral serology and detection
HBV (HBsAg, total HB core antibody [anti-HBc] and HBV DNA)
HCV antibody
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.
HIV

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 assay.

CMV testing of colonic biopsy, if there is suspicion for clinically significant CMV 
colitis 
Baseline colon biopsy (to be obtained at the base of the ulcer) will be analyzed 
for histologic presence of CMV

Fecal calprotectin

Exploratory diagnostic biomarker assays
Peripheral blood, serum, stool, and colon biopsies will be assessed using 
qualified methods (including but not limited to ELISA, IHC, and/or qPCR) for 
exploratory and diagnostic biomarker analysis.

Histologic activity on colon biopsies using the Nancy histological index.


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
Exploratory PD biomarker assays
Peripheral blood, serum, stool, and colon biopsies 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.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.6.1.10), 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.
4.6.1.6
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.
4.6.1.7
Electrocardiograms
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 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.


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4.6.1.8
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 other 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 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 
(UCPRO/SS) 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.
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.


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Mayo Clinic Score (MCS) and Partial Mayo Clinic Score (pMCS)
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 4.6.1.4.  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 are provided in 
Appendix 3.
EuroQol Five-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.
4.6.1.9
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.
4.6.1.10
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.
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


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
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 
Informed Consent Form).
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 PD; see Appendix 1 for 
specific collection timepoints)

Serum for exploratory PD (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.
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the Reference Manual or Laboratory Manual.
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.


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Confidentiality
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable.
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.
Patient medical information associated with RCR specimens is confidential and may only 
be disclosed to third parties 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.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise.
Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
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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 GA28950 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 GA28950.
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.
4.6.2
Timing of Study Assessments
4.6.2.1
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.
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.


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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 4.6.1.5).  The ECG and chest X-ray can be obtained any time before Day 1
(see Section 4.6.1.6 and 4.6.1.7 for additional details on the chest X-ray and ECG).  
Colon biopsy specimen collection is detailed in Section 4.6.1.4.
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; see Figure 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 4.6.1.4).
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 3.
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 3.


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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.
4.6.2.1.1
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.
4.6.2.1.2
Re-Screening
Re-screening is required if a patient has not met all the eligibility criteria within 35 days 
of 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 the re-screening 
Day 1 visit (day of randomization for 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 4.6.1.5, if a negative TB screening test result has been 
documented within 3 months before screening or rescreen, 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.
4.6.2.2
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.
For induction (Week 14) and maintenance (Week 66) visits that are associated with a 
MCS requiring endoscopy, every effort should be made to schedule the endoscopy on 


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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 3).
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.  Data will be collected as for a clinic visit at this time with the 
exception of blood sample and in clinic PRO assessments.  All patients will be queried 
and closely monitored for any adverse event at all study assessment timepoints 
(every 4 weeks) during both clinic visits and study assessments made over the 
telephone.  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 4.6.2.5).
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.
4.6.2.3
Assessments at Study Completion/Early Withdrawal from 
Treatment Visit
The completion of the study treatment period is defined as the Week 66 visit.  Patients 
who complete the treatment medication will be asked to visit the clinic for Week 66 
assessments. Eligible patients who consent to receive open-label etrolizumab 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 Part 1 (OLE) 
Study GA28951.
If a patient leaves the study prior to Week 66, an early withdrawal from treatment visit is 
to be conducted on 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) Study GA28951 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.


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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. 
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 then enroll in Part 2 (SM) of Study GA28951 for 
extended PML monitoring.
4.6.2.3.1
Eligibility for Entry to Open-Label Extension and Safety 
Monitoring Study
The Study GA28951 (OLE-SM) 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 
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 patient who requires initiation of an immunosuppressant 
(AZA, 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 14 
assessment, if eligible.  

Patients who do not achieve a clinical response at Week 14

Patients who meet the criteria for relapse (see Section 4.5.1 for definition) at any 
time between Week 14 and Week 66 

Patients who were not receiving corticosteroids at baseline and patients who have 
completed the corticosteroid 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 corticosteroid
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 66


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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 14 or do not perform the 
Week 14 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 4.7.1.1), malignancies, 
specific de novo or reactivated serious viral infections, PML, or other life-threatening 
infections during the trial (see Table 5 and Sections 4.7.1.1 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 14 onward)
Must Transfer to 12-Week 
Safety Follow-Up of this study
Day 1 to Week 14
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 
14-week timepoint)
Yes (must transfer to SFU if 
they do not choose OLE)
Week 14
Did not achieve a clinical response at Week 14
Yes
Yes (must transfer to SFU if 
they do not choose OLE)
Week 14 to Week 66 Met criteria for clinical relapse (see Section 4.5.1) at any time between 
Week 14 and Week 66
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 66
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 corticosteroid taper
Yes
Day 1 to Week 66
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 66
End of treatment period (all patients remaining)
Yes
Yes (must transfer to SFU if 
they do not choose OLE)
Day 1 to Week 14
Discontinuation of study treatment prior to Week 14
No
Yes (transfer after dosing 
termination visit)
Day 1 to Week 66
Patients requiring rescue medications that are prohibited 
(see Section 4.3.2.2)
No
Yes (transfer after dosing 
termination visit)
Day 1 to Week 66
Occurrence of severe hypersensitivity reactions (see Section 4.3.2.1), 
malignancies, specific de novo or reactivated serious viral infections , 
PML or other life-threatening infections during the study (see Table 5
and Sections 4.7.1.1 and 5.1.5)
No
Yes (transfer after dosing 
termination visit)
5-ASA 5-aminosalicylic acid; 6-MP 6-mercaptopurine; AZA azathioprine; IV intravenous; MTX methotrexate; OLE open-label extension; 
OLE-SM open-label extensionsafety monitoring; SFU safety follow-up.


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4.6.2.4
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 phone 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 into 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 monitoring 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) of Study GA28951 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 (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.
4.6.2.5
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 and 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 to be performed in case of an unscheduled 
visit. 
4.7
PATIENT, STUDY, AND SITE DISCONTINUATION
4.7.1
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
4.7.1.1
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 specific de novo or reactivated serious viral 
infection, such as HBV, HCV, HIV, should discontinue study medication.
Any patient who develops CMV colitis as defined by colon biopsy samples should 
discontinue study medication, but may be considered to restart study treatment 
only after consultation with the Medical Monitor once the event has resolved and 
treatment with appropriate anti-viral medication has been completed.
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 4.4.2)


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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 completion/early withdrawal from treatment visit 
(see Section 4.6.2.3) 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 4.6.2.4).  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.
4.7.1.2
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.
4.7.2
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 always refer to the Etrolizumab Investigator's Brochure (Section 6) 
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 which 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) as per the Schedule of Assessments 
(see Appendix 1).  The PML Subjective Checklist (symptom assessment) and the PML 
Objective Checklist (neurologic evaluation) will be administered (see Appendix 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 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 DNA by PCR.  If JCV DNA is 
detected, the patient should be treated as a PML case and the patient should 
permanently discontinue study drug and enter safety follow-up.  Dosing with study 
treatments can only be resumed in patients where PML has been ruled out.  Refer to 
Appendix 6 for the Algorithm for Evaluation of Progressive Multifocal 
Leukoencephalopathy (PML).
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
Event
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 specific 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)


Table 5  Guidelines for Managing Specific Adverse Events (cont.)
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Event
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 class drugs that target 4 integrins (natalizumab) and 47 integrins 
(vedolizumab).  Therefore, this potential risk is being monitored in the 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.


Table 5  Guidelines for Managing Specific Adverse Events (cont.)
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Event
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).


Table 5  Guidelines for Managing Specific Adverse Events (cont.)
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Event
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; measurement of 
protocol-specified safety laboratory assessments; measurement of protocol-specified 
vital signs; and other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
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, 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 collections)
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:

Fatal (i.e., the adverse event actually causes or leads to death)

Life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)


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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)

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an adverse event (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 AE 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., invasive 
procedures such as biopsy sample collections, 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, for 
patients who enter the OLE-SM study (Study GA28951), adverse event reporting should 
follow requirements of the OLE-SM study (Study GA28951).
If the patient does not enter the OLE-SM study (Study GA28951), 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 (see Table 7):

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.  Avoid colloquialisms and abbreviations.
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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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 also 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:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Clinically significant in the investigator’s judgment
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5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:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.


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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 (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), 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 
care outside of normal outpatient clinic operating hours


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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 errors in administration of study drug (e.g., dosing outside of 
the allowed window and injection without completion of full volume administration) 
should be noted on the Study Drug Administration eCRF.
All adverse events associated with an overdose or errors in administration of study drug 
(e.g., dosing outside of the allowed window and injection without completion of full 
volume administration) should be recorded on the Adverse Event eCRF.  If the 
associated adverse event fulfills serious criteria, the event should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
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 (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information


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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 and 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.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest 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 event), either by faxing or by scanning and emailing the form with use of 
the fax numbers or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.


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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 last 
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.
In addition, the investigator will submit a paper Clinical Trial Pregnancy Reporting Form 
when updated information on the course and outcome of the pregnancy becomes 
available.
5.4.3.2
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 last dose of study drug.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  When 
permitted by the site, the pregnant partner would need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
If the authorization has been signed, the investigator should submit a paper Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available. An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician.
5.4.3.3
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).


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5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient or 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.
5.6
POST-STUDY ADVERSE EVENTS
For patients who enter the OLE-SM study (Study GA28951), adverse event reporting
should follow the requirements for the OLE-SM study (Study GA28951).
Post-study, if the patient does not enter OLE-SM study (Study GA28951), 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 also 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.


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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 numbers 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 
regulatory reporting to all health authorities, with the exception of the FDA. For the FDA, 
SUSARs will be submitted as 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).


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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
For the purpose of statistical analyses, the Induction and Maintenance Phases will be 
treated as two independent studies.  The analysis of the Induction Phase will formally 
evaluate the efficacy and safety of 105 mg etrolizumab SC Q4W versus placebo as an 
induction therapy.
The analysis of the Maintenance Phase will formally evaluate the efficacy and safety of 
105 mg etrolizumab SC Q4W versus placebo as a maintenance therapy.
The analysis of data from the 66-week treatment period (Induction and Maintenance 
Phases) 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 analyses, patients and study site personnel will remain blinded to individual 
treatment assignment (for Cohort 2 patients and those re-randomized into the 
Maintenance Phase) until after the study is completed (after all patients have either 
completed the safety follow-up periods 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 endpoints in the blinded Induction Phase and the Maintenance Phase 
respectively.  Approximately 605 patients will be enrolled in the open-label induction arm 
(Cohort 1, n≈130) or the blinded induction cohort (Cohort 2, n≈475).
Cohort 2 patients will be randomized in a 4:1 ratio to etrolizumab (n≈380) or placebo 
(n≈95).  This will provide approximately 80% power to detect a 10% difference in 
remission rates at Week 14 between the etrolizumab and placebo arms, under the 
assumption of a placebo remission rate of 5% and a two-sided 2 test at the 
5% significance level.
The primary endpoint for the Maintenance Phase is Week 66 remission among patients
with a clinical response at Week 14. In total, it is estimated that approximately 
154 etrolizumab patients will achieve clinical response at the end of the Induction 
Phase and therefore will be randomized in the Maintenance Phase, under the 
assumption of a Week 14 clinical response rate of approximately 30% in the pooled 
etrolizumab induction group.


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A sample size of 154 patients in the Maintenance Phase will provide 90% power to 
detect a 30% difference in remission rates between the two maintenance arms, under
the assumption of a placebo Week 66 remission rate 10% and a Fisher exact test at 
the 5% significance level.  
The planned approximately 510 etrolizumab patients from Cohort 1 and Cohort 2 would 
provide approximately 154 patients with a clinical response at Week 14, under the 
assumption of a Week 14 clinical response rate of at least 30% in the pooled (Cohort 1 
and Cohort 2) etrolizumab induction group.  Additional patients may be enrolled into 
Cohort 1, if needed, to achieve this target number of approximately 154 patients 
randomized into the Maintenance Phase.
For the purpose of statistical analyses and sample size calculations, the Induction and 
Maintenance Phases will be treated as two independent studies, and as such no 
adjustment to alpha is required.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients randomized and re-randomized will be tabulated by study site 
and treatment arm.  Patient disposition (the number of patients 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 randomized patients by treatment group by use of 
descriptive statistics for both the Induction and Maintenance Phases.  Exposure to study 
drug (number of study treatments and duration of treatment) will be summarized by 
treatment arm.
6.4
EFFICACY ANALYSES

Efficacy analyses for the Induction Phase will be performed using a modified 
intent-to-treat analysis set including all patients randomized in Cohort 2 who 
received at least one dose of study drug with patients grouped according to the 
treatment assigned at randomization.

Efficacy analyses for the Maintenance Phase will be performed using a modified 
intent-to-treat analysis set including patients randomized in the Maintenance Phase 
with patients grouped according to the treatment assigned at randomization.


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
To manage the overall type I error, the primary and secondary endpoints within the 
Induction and Maintenance Phases, respectively, will be tested sequentially.  Within 
each of the Induction and Maintenance Phases, respectively, the primary endpoint 
will be tested first at a two-sided 5% significance level.  A small number of 
secondary endpoints will then be tested, sequentially, conditional on positive results 
for the corresponding primary endpoint and any preceding secondary endpoints.  
The remaining secondary endpoints and all exploratory endpoints will be considered 
to provide supportive information and no adjustments for multiple comparisons will 
be performed.  All endpoints will be assessed at a nominal two-sided 5% 
significance level.
Patients who are non-evaluable for efficacy at a specific timepoint (e.g., due to missing 
data or transfer to Part 1 [OLE] of the OLE-SM protocol [Study GA28951]) 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 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, corticosteroid, or 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.
In addition to the analyses described herein and in Sections 6.4.1 and 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 pre-specified
subgroups (e.g., based on age, sex, race/ethnicity, baseline UC medications, 
baseline CS dose).
Further details, including additional missing data handling rules, will be provided in the 
SAP.


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6.4.1
Primary Efficacy Endpoint
In the Induction Phase, the proportion of patients from Cohort 2 in remission at Week 14 
will be compared between the etrolizumab and placebo arms with use of the 
Cochran-Mantel-Haenszel test statistic stratified by the factors used at randomization:  
concomitant treatment with corticosteroids (yes/no), concomitant treatment with 
immunosuppressants (yes/no), and baseline disease activity (MCS 9/MCS 10).
The primary endpoint for the Maintenance Phase is Week 66 remission among patients 
with a clinical response at Week 14.  Patients who are randomized into the 
maintenance phase (i.e., clinical responders at Week 14) 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 induction cohort 
(1, 2), concomitant treatment with corticosteroids (yes/no), and baseline disease activity 
(MCS9/MCS10).  The Fisher exact test will be used as a sensitivity analysis.
6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints for this Induction Phase are as follows:

Proportion of patients in clinical remission at Week 14

Proportion of patients with clinical response at Week 14

Proportion of patients with improvement in endoscopic appearance of the mucosa at 
Week 14

Proportion of patients in endoscopic remission at Week 14

Proportion of patients with histologic remission at Week 14

Change from baseline in rectal bleed subscore at Week 6

Change from baseline in stool frequency subscore at Week 6  

Change from baseline to Week 14 in UC bowel movement signs and symptoms, as 
assessed by the UC-PRO/SS measure

Change from baseline to Week 14 in UC abdominal symptoms, as assessed by the 
UCPRO/SS measure

Change from baseline to Week 14 in health-related QOL, as assessed by the overall 
IBDQ score
The secondary efficacy endpoints for the Maintenance Phase are as follows:

Proportion of patients in clinical remission at Week 66 among patients in clinical 
remission at Week 14

Proportion of patients in clinical remission at Week 66

Proportion of patients in remission at Week 66 among patients in remission at 
Week 14

Proportion of patients with improvement in endoscopic appearance of the mucosa 
at Week 66


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
Proportion of patients with histologic remission at Week 66

Proportion of patients in endoscopic remission at Week 66

Proportion of patients in corticosteroid-free clinical remission at Week 66 (off 
corticosteroid for at least 24 weeks prior to Week 66) in patients who were receiving 
corticosteroids at baseline

Proportion of patients in corticosteroid-free remission at Week 66 (off corticosteroid 
for at least 24 weeks prior to Week 66) in patients who were receiving 
corticosteroids at baseline

Change from baseline to Week 66 in UC bowel movement signs and symptoms, as 
assessed by the UC-PRO/SS measure

Change from baseline to Week 66 in UC abdominal symptoms, as assessed by the 
UC-PRO/SS measure

Change from baseline to Week 66 in health-related QOL, as assessed by the overall 
IBDQ score
All the responder/remitter 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 the factors used at randomization into the 
Induction/Maintenance Phases as stratification variables and the baseline value of the 
studied measure as a covariate. Baseline is defined here as the last available value 
prior to treatment in the Induction/Maintenance Phases.
Further details regarding the analysis of the secondary endpoints will be provided in the 
SAP.
6.4.3
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints are as follows:

Proportion of patients with a clinical response at Week 66 among patients with a 
clinical response at Week 14

Proportion of patients with remission at Week 66 among patients in clinical 
remission at Week 14 

Proportion of patients with corticosteroid-free clinical remission at Week 66 (off 
corticosteroid for at least 12 weeks prior to Week 66) in patients who were receiving 
corticosteroids at baseline

Proportion of patients with change in histologic disease activity from baseline to 
Week 14 and Week 66

Proportion of patients with improvement in histologic and/or endoscopic disease 
activity

Change in health utilities, as assessed by the EQ-5D, from baseline to Week 14


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
Change in health utilities, as assessed by the EQ-5D, from Week 14 to Week 66

Frequency and duration of hospitalizations from Week 14 to Week 66

Proportion of patients with response, remission and corticosteroid-free endpoints,
as determined by the mMCS
The analysis methods for the exploratory endpoints will be described in the SAP.
6.5
SAFETY ANALYSES
The safety analysis population for the Induction Phase will consist of all patients who 
received at least one dose of study drug during the Induction Phase with patients 
grouped according to the treatment actually received (open-label etrolizumab, blinded 
etrolizumab, or blinded placebo). 
The safety analysis population for the Maintenance Phase will consist of all patients 
randomized into the Maintenance Phase with patients grouped according to the 
treatment actually received during 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 antibodies to etrolizumab.
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.


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
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.
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 positive 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 two 
primary endpoint times (Weeks 14 and 66).  Estimates for these parameters will be 
tabulated and summarized (mean, standard deviation, 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 post-treatment.  Results will be summarized descriptively.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
Sponsor, 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.


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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 Medidata RAVE for appropriate eCRF 
completion.  eCRFs will be submitted electronically to the Sponsor and should be 
handled in accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
Patient-reported data will be collected electronically through use of electronic devices 
provided by an ePRO vendor.  The electronic devices are designed for entry of data in a 
way that is attributable, secure, and accurate, in compliance with U.S. Food and Drug 
Administration (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 tablet device and all the study documentation.
Details regarding patient reported data and the electronic devices 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, 


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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 
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.


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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. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the EU/EEA will comply 
with the EU Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the “Consent Forms”) before IRB/EC 
submission.  The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
The 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.


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


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Patient medical information obtained by this study is confidential and may 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 U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient last visit).
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.


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9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial is sponsored by F. HoffmannLa Roche Ltd.  Approximately 225 international 
study centers will participate in this study to enroll approximately 605 patients.
A contract research organization (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 biopsies as 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 


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country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
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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Dis. 2013; 19:7.
Laharie D, Bourreille A, Branche J, et al. Ciclosporin versus infliximab in patients with 
severe ulcerative colitis refractory to intravenous corticosteroids: a parallel, open-
label randomised controlled trial. Lancet 2012; 380:1909–15.
Lobel EZ, Korelitz BI, Xuereb MA, et al. A search for the optimal duration of treatment 
with 6-mercaptopurine for ulcerative colitis. Am J Gastroenterol 2004; 3:462-5.
Mañosa M, García V, Castro L, et al. Methotrexate in ulcerative colitis: a Spanish 
multicentric study on clinical use and efficacy. J Crohns Colitis 2011;5:397-40.
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.
Molodecky NA, Soon IS,Rabi DM, et al. Increasing incidence and prevalence of the 
inflammatory bowel diseases with time, based on systematic review. 
Gastroenterology 2012;142:4654.
Rabin, R, deCharro, F. EQ-5D: a measure of health status from the EuroQol Group. Ann 
Med 2001;33:337-343.
Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance 
therapy for ulcerative colitis. N Engl J Med 2005;353:246276.
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.
Sandborn WJ, Colombel JF, D’Haens G, et al. One-year maintenance outcomes among 
patients with moderately-to-severely active ulcerative colitis who responded to 
induction therapy with adalimumab: subgroup analyses from ULTRA 2. Aliment 
Pharmacol Ther 2013;37:20413.
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Etrolizumab—F. Hoffmann-La Roche Ltd
132/Protocol GA28950, Version 8
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Etrolizumab—F. Hoffmann-La Roche Ltd
133/Protocol GA28950, Version 8
Appendix 1
Schedule of Assessments
Assessments
Screening
Day a
35 to 1
Treatment Period Study Week (3 days)
Unscheduled 
Visit d
Early 
Withdrawal
from 
Treatment 
Phase
0 b
4
8
12
14
16
20
24
28 c
32
36 c
40 c
44
48 c
52 c
56
60 c
64 c
66
Informed consent
x
Review eligibility criteria e
x
x
Demographic data
x
Pregnancy test f
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs (BP and pulse)
x
x
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
x
x
x
x
x d
x j
Chemistry 
x
x
x
x
x
x
x d
x j
Urinalysis
x
x
x d
TB screen k
x
HIV test
x
Hepatitis B and C serology l
x


Appendix 1
Schedule of Assessments (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
134/Protocol GA28950, Version 8
Assessments
Screening
Day a
35 to 1
Treatment Period Study Week (3 days)
Unscheduled 
Visit d
Early 
Withdrawal
from 
Treatment 
Phase
0 b
4
8
12
14
16
20
24
28 c
32
36 c
40 c
44
48 c
52 c
56
60 c
64 c
66
Hepatitis B DNA m
x
x
x
x
x
x
x
Hepatitis C RNA (Amplicor) n
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
x t
x
x
x d
x j
Partial MCS (pMCS; excludes 
endoscopy) u
x u
x
x
x
x
x
x
x
x
x
x d
x j
Stool sample collection
x v
x w
x w
x w
x d
x w
Colonic biopsy (CMV if required)
x x
x d
Colonic biopsy (histopathological 
confirmation of UC if required)
x y
Colonic biopsies (formalin)
x z
x aa
x aa
x d, aa
x j, aa
Colonic biopsies (for qPCR)
x z
x aa
x aa
x d, aa
x j ,aa
Serum sample (CRP)
x
x
x
x d
x j
Serum sample (future exploratory 
PD) o
x
x
x
x
x
x
Blood sample (RNA Paxgene) o, bb
x
x
x
x
x


Appendix 1
Schedule of Assessments (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
135/Protocol GA28950, Version 8
Assessments
Screening
Day a
35 to 1
Treatment Period Study Week (3 days)
Unscheduled 
Visit d
Early 
Withdrawal
from 
Treatment 
Phase
0 b
4
8
12
14
16
20
24
28 c
32
36 c
40 c
44
48 c
52 c
56
60 c
64 c
66
Whole blood (EDTA Blood) 
optional
x
UC-PRO/SS cc
x
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
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
x
Initial randomization
x
Randomization of responders to 
Maintenance Phase
x ee
Etrolizumab/etrolizumab placebo ff
x
x
x
x
x ff
x ff
x ff
x ff
x ff
x ff
x ff
x ff
x ff
x ff
x ff
x ff
x ff
BPblood pressure; CMVcytomegalovirus; CRPC-reactive protein; ECGelectrocardiogram; eCRFelectronic case report form; EQ-5DEuroQoL Five-Dimension 
Questionnaire; HBVhepatitis B virus; HCVhepatitis C virus; IBDQInflammatory Bowel Disease Questionnaire; IHCimmunohistochemistry; JCVJohn Cunningham virus;
MCSMayo Clinic Score; PDpharmacodynamic; PKpharmacokinetic; PMLprogressive multifocal leukoencephalopathy; qPCRquantitative polymerase chain reaction; 
UC-PRO/SSUlcerative Colitis Patient-Reported Outcome Signs and Symptoms; TBtuberculosis; UCulcerative colitis.


Appendix 1
Schedule of Assessments (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
136/Protocol GA28950, Version 8
Notes:  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.
d
Unscheduled visit represents a visit that is not as per Schedule of Assessments and is required for an adverse event or for potential relapse assessment.  All 
indicated assessments are NOT performed at each unscheduled visit.  Assessments would be symptom-driven (e.g., perform PML neurological examination only 
if patient reports symptoms suspected of PML; and confirmation of clinical relapse is performed by the Mayo Clinic Score assessment).  Assessments 
corresponding to items noted in this column should be recorded on the eCRF.
e
Perform prior to first administration of study drug.
f
Serum test at screening for all female patients except those who are more than 1-year postmenopausal or are surgically sterile.  Urine test at all 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 result via e-diary.  Patients must be instructed at screening and reminded throughout the study that in case of positive 
pregnancy test result 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 exam consists of the PML Subjective Checklist and the PML Objective Checklist. Administer before other assessments, as 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 hepatitis C. This includes testing for HBsAg (HBV surface antigen), anti-HBc total (HBV core antibody total), 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
The PK, ATA, and exploratory PD sample collections will be from all patients during the Induction Phase.  During the Maintenance Phase, PK, ATA, and 
exploratory PD samples will only be collected from patients who were randomized into the Maintenance Phase.


Appendix 1
Schedule of Assessments (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
137/Protocol GA28950, Version 8
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).
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 (PGA).  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
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 PGA will be 
obtained only once, on Day 1 (prior to randomization), and the PGA subscore will be used to calculate both the baseline (screening) MCS and the baseline (Day 
1) pMCS.
u
Partial MCS during screening is defined as the MCS score excluding the endoscopy score (i.e., rectal bleeding assessmentstool frequency 
assessmentPGA).
v
For culture and sensitivity testing; ova, parasites, and Clostridium difficile toxin testing.
w 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).
x
IF REQUIRED:  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 lab if necessary.  Result must be negative for CMV 
prior to dosing on Day 1. 
y
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 and read locally for histopathologic confirmation of UC.
z
In addition to the optional biopsy noted in footnote “x” and “y” above, 5 pairs (10 biopsy samples) will be obtained at screening (all taken from the most inflamed 
area of the colon within 20-40 cm of the anal verge [sigmoid]).  These five biopsy pairs will be sent to the central laboratory for further storage or distribution.  
Two pairs will be placed in a stabilization buffer (such as RNAlater or a similar buffer) and stored at 80C (1 pair for diagnostic qPCR and 1 pair for PD 
biomarkers).  In UK sites ONLY, one of the latter pair of biopsies (2 samples) will be placed in storage solution at 4°C and shipped to the UK laboratory.  The 
other 3 pairs will be placed in formalin and then paraffin embedded; these biopsy samples will be used for exploratory PD biomarkers and/or diagnostic 
biomarkers. Original biopsy location and endoscopic depth should be clearly indicated.


Appendix 1
Schedule of Assessments (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
138/Protocol GA28950, Version 8
aa A total of four pairs (8 biopsy samples) will be obtained from all patients (all taken from the most inflamed area of the colon within 20-40 cm of anal verge 
[sigmoid]).  All will be sent to the central laboratory for further storage or distribution. In UK sites ONLY, one of the latter pair of biopsies (2 samples) will be 
placed in storage solution at 4°C and shipped to the UK laboratory. Two pairs will be placed in a stabilization buffer (such as RNAlater or a similar buffer) and 
stored at 80C for exploratory PD biomarker and/or diagnostic biomarker qPCR.  The other two pairs will be placed in formalin and then paraffin embedded; 
these biopsy samples will be used for exploratory PD biomarkers and/or diagnostic biomarkers. Original biopsy location and endoscopic depth should be clearly 
indicated.
bb Paxgene blood RNA samples must be collected after all other blood and serum samples.
cc 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.
dd With the exception of Week 0, the IBDQ and the EQ-5D will be completed in the 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 14 timepoint.
ff
Where indicated, patients must be instructed to administer study drug at home within 3 days (maximum) after clinic visit.


Etrolizumab—F. Hoffmann-La Roche Ltd
139/Protocol GA28950, Version 8
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 sample; 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 exam consists of the PML Subjective Checklist and the PML Objective 
Checklist.  Administer before other assessments as per Appendix 5.
e At all timepoints indicated and whenever serum sickness is expected.  ATA samples 
may be used for PK and/or exploratory PD assessments.


Etrolizumab—F. Hoffmann-La Roche Ltd
140/Protocol GA28950, Version 8
Appendix 3
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'S GLOBAL ASSESSMENT
0 Normal (Subscores are 0) 
1 Mild disease (Subscores are mostly 1s) 
2 Moderate disease (Subscores are 1 to 2) 
3 Severe disease (Subscores are 2 to 3) 
Subscore 03 


Appendix 3
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
141/Protocol GA28950, Version 8
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 into 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.


Appendix 3
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
142/Protocol GA28950, Version 8
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 that 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). 


Appendix 3
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
143/Protocol GA28950, Version 8
4.
Physician's Global Assessment 
The Physician’s Global Assessment (PGA) 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 examination 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 PGA 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 
1.
Eligibility for Enrollment 

Moderately to severely active ulcerative colitis as determined by a Mayo Clinic 
Score of 612 with an endoscopic subscore 2 and a rectal bleeding subscore 1, 
and a stool frequency subscore 1.  
2.
Achievement of Clinical Response at Week 14 

MCS with 3-point decrease and 30% reduction from baseline as well as 1-point 
decrease in rectal bleeding subscore or an absolute score 0 or 1 
3.
Identification of Clinical Relapse 
Clinical relapse is defined as an increase in pMCS 3 points compared with 
induction timepoint (Week 14) AND absolute pMCS of 5 AND an endoscopy 
subscore of 2


Appendix 3
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
144/Protocol GA28950, Version 8
Figure 1
Derivation of Stool Frequency and Rectal Bleeding Subscores at Screening


Appendix 3
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
145/Protocol GA28950, Version 8
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.


Appendix 3
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
146/Protocol GA28950, Version 8
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 with 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.


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Appendix 4
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). 
Refer to 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 post-menopausal (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 only acceptable 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


Appendix 4
Childbearing Potential, Pregnancy Testing,
and Contraception (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
148/Protocol GA28950, Version 8

Sole sexual partner consisting of surgically sterilized male partner with appropriate 
post-surgical 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 as friction between the two can 
result in either product failing)
Patients may provide verbal confirmation that the partner completed appropriate follow-
up after vasectomy. Sites are not required to obtain partner medical records.
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined 
below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 24 weeks 
after the last dose of study drug.  Men must refrain from donating sperm during this 
same period.
For men and women: The reliability of sexual abstinence should be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception.


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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).


Appendix 5
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
150/Protocol GA28950, Version 8
PML Subjective Checklist
Symptoms
“Compared to 
how you usually
feel, have you 
had a significant 
change in any of
the following?”
If the answer is “Yes”,
obtain a description of
the symptom(s) with 
examples
Applicable Objective 
Test(s): Document result 
on PML Objective 
Checklist Worksheet
YES
NO
1. Have you been 
experiencing any persistent
difficulty with your vision such
as loss of vision or double 
vision? Have you been having
trouble with reading?

Test visual fields and 
ocular motility
2. Have you been 
experiencing any persistent
difficulty speaking or having
your speech understood by 
others?

Casual observation of 
speech output for 
dysarthria or aphasia.
3. Have you been 
experiencing any persistent
weakness in an arm or a leg?

Test for pronator drift 
(Barre maneuver).

Assess gait.

Test muscle strength
(only if indicated).
4. Have you noticed yourself
regularly bumping into things
or having difficulty writing?

Observe tandem gait
and finger to nose.
5. Have you regularly been
experiencing difficulty
understanding others?

Test ability to follow 
serial commands.
6. Have you had persistent
problems with your memory or
thinking?

Recall of 3 objects over 
1 minute with distraction 
(only if indicated).
7. Have you been 
experiencing any persistent
numbness or other loss of
sensation?

Test sensation side to 
side with either pinprick
or cold (only if
indicated).


Appendix 5
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
151/Protocol GA28950, Version 8
PML Objective Checklist
Neurologic function 
being assessed
Instructions 
(bold text indicates parts of exam 
required at each visit, as specified in 
Schedule of Assessments)
Abnormal 
exam?
If the answer is 
“Yes”, describe the 
abnormal objective 
exam finding
YES
NO
1. Visual fields and 
ocular motility

Visual Field Testing 

Ocular Motility Testing
2. Speech

Observe the patient’s speech 
output for dysarthria or aphasia.
3. Strength

Pronator drift test (Barre 
maneuver)

Gait testing (normal, heel and 
toe walk)

ONLY if the patient has any 
subjective complaints of weakness,
test muscle strength of the relevant 
4. Coordination

Observe tandem gait and finger 
to nose
5. Comprehension

Test ability to follow serial 
commands

“Take a piece of paper in your 
hand, fold it in half, and put it on 
the floor.”
6. Memory and thinking

ONLY if the patient has subjective 
complaints about their memory or 
thinking, test the ability of the 
patient to recall 3 objects over 1 
minute with distraction
7. Sensation

ONLY if the patient has subjective 
sensory complaints, evaluate 
relevant areas based on patient’s 
subjective complaints by comparing
left vs. right side sensation to cold
(e.g. alcohol swab or cold
stethoscope) or pinprick (e.g. 
broken Q-tip)


Appendix 5
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
152/Protocol GA28950, Version 8
Please refer to the PML Algorithm in the Protocol Appendix for details.

If there is an abnormal finding on the PML Subjective Checklist, this should be
appropriately documented on the worksheet and in the eCRF.

If there is an abnormal finding on the PML Objective Checklist, this should be
appropriately documented on the worksheet and in the eCRF.

If there are any abnormalities found on the PML Subjective Checklist that are
accompanied by the corresponding abnormality on the PML Objective Checklist, or if
there is high clinical suspicion for PML (in the opinion of the investigator):

This must be reported as an adverse event of special interest (AESI) within 
24 hours

An urgent referral to a neurologist should be made.

Dosing with study drug will be suspended until PML can be ruled out.

Further evaluation will proceed according to the PML Algorithm in the 
Protocol Appendix.

Any confirmed diagnosis of PML should be reported as a serious adverse 
event (SAE).
Please complete the PML eCRF.
Was the PML Subjective Checklist administered? (Yes/No)
If yes, date of administration of PML Subjective Checklist (Date)
If yes, were there any abnormalities on the PML Subjective Checklist? (Yes/No) 
Was the PML Objective Checklist administered? (Yes/No)
If yes, were there any abnormalities on the PML Objective Checklist? (Yes/No) 
Is PML suspected? (Yes/No)


Appendix 5
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
153/Protocol GA28950, Version 8
More detailed instructions for the PML Objective Checklist Neurologic Evaluations
(please refer to the PML Neurologic Exam Video for more information):
1. Visual fields and ocular motility
Visual Field Testing:

Position yourself approximately 3 feet away from the patient, with eyes at the same
level.

Keeping both eyes open, ask the patient to cover one eye and ask if all parts of your
face and head are clear to them. Ask them to repeat, covering the other eye.

Have the patient cover one eye and stare at your nose, and then ask them how
many fingers you are holding up, testing each of the 4 visual quadrants. Repeat with
the other eye covered.
Ocular Motility Testing:

Evaluate the patient for conjugate eye movement.

Starting about 3 feet from center, move in a big “H”, pausing at the center and at 
lateral gaze, and finishing with convergence (finger to their nose). Watch for
nystagmus in lateral gaze, smooth pursuits, and pupillary constriction with
convergence. Note: a couple of beats of nystagmus upon extreme lateral gaze is
considered normal.
2. Speech

Observe the patient’s speech output for dysarthria or aphasia.

Dysarthria is a motor speech disorder. Findings can include “slurred” speech, 
decreased volume, slow rate of speech, limited tongue, lip, and jaw movement,
abnormal rhythm when speaking, changes in vocal quality, and drooling or poor 
control of saliva.

Aphasia is a disorder that results from damage to parts of the brain that control 
language, and can lead to problems with any or all of the following: speaking, 
listening, reading or writing.
3. Strength
Pronator drift test (Barre maneuver):

Ask the patient to stand with their feet together and extend their arms out in front of 
them at 90 degrees (parallel to floor) with palms facing upwards toward the ceiling.

Ask the patient to close their eyes and keep their arms extended for 15 seconds.

If either arm drifts downward, upward, or starts to pronate (i.e. thumb turns up), this
is considered an abnormal exam.


Appendix 5
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
154/Protocol GA28950, Version 8
Gait testing:

Ask the patient to walk across the room (~10 feet).  The patient should have a
normal gait, with their left arm swinging forward when the right foot leads, and vice
versa.  Be certain to note whether there is symmetric arm swinging, because a
slight decrease in arm swinging may be an indicator of upper extremity weakness.

Ask the patient to walk on their heels across the room (~10 feet). Carefully observe
whether they have any difficulty maintaining their toes off the ground or loss of
balance.

Ask the patient to walk on their toes across the room (~10 feet). Carefully observe if
they have any difficulty maintaining their heels off the ground or loss of balance.
Additional strength testing (ONLY if the patient has any subjective complaints of 
weakness):

Test muscle strength of the relevant muscle groups based on the patient’s
subjective complaints.

General guidelines for a basic muscle strength exam:

Upper extremity:
o
Finger grip strength
o
Flexion at elbow
o
Extension at elbow
o
Deltoid strength: Maintain bent arms up (perpendicular to floor) and
resist while investigator pushes down
o
Shoulder shrug against resistance

Lower extremity: (examine while patient is sitting down)
o
Raise thigh (while bent)
o
Straighten leg
o
Flex leg
o
Flex foot
o
Extend foot


Appendix 5
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
155/Protocol GA28950, Version 8
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.”
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


Appendix 7
Patient Daily Diary (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
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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 (EQ-5D) Questionnaire


         
Health Questionnaire
   
(English version for the US)
© 1998 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group
Etrolizumab—F. Hoffmann-La Roche Ltd
182/Protocol GA28950, Version 8


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, Double Blind, Placebo Controlled, Multicenter Study of the 
Efficacy and Safety of Etrolizumab During Induction and Maintenance 
in Patients With Moderate to Severe Active Ulcerative Colitis Who 
Have Been Previously Exposed to TNF Inhibitors 
NCT Number: NCT02100696 
Document Date: SAP Version 3: 04-May-2020 
 
 


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 GA28950
STATISTICAL ANALYSIS PLAN
TITLE:
PHASE III, DOUBLE BLIND, PLACEBO CONTROLLED, 
MULTICENTER STUDY OF THE EFFICACY AND SAFETY 
OF ETROLIZUMAB DURING INDUCTION AND 
MAINTENANCE IN PATIENTS WITH MODERATE TO 
SEVERE ACTIVE ULCERATIVE COLITIS WHO HAVE 
BEEN PREVIOUSLY EXPOSED TO TNF INHIBITORS
PROTOCOL NUMBER:
GA28950 (Hickory)
STUDY DRUG:
Etrolizumab
VERSION NUMBER:
3
IND NUMBER:
100366
EUDRACT NUMBER:
2013-004278-88
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 14:39:16
Company Signatory


Etrolizumab—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan GA28950
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE FOR VERSION 3

Change to Section 4.1.1.3 update the modified Intent to Treat (mITT) Population 
definition to clarify it will not be used for histologic remission analysis

Change to Section 4.4 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 added in sensitivity analysis for key secondary endpoints
as applicable.

Change to Section 4.1.1.5 and 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.


Etrolizumab—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan GA28950
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
2.3
Determination of Sample Size ................................................. 8
2.3.1
Sample Size for the Induction Phase....................................... 8
2.3.2
Sample Size for the Maintenance Phase................................. 9
2.4
Analysis Timing ....................................................................... 9
3.
STUDY CONDUCT....................................................................................... 9
3.1
Randomization......................................................................... 9
3.1.1
Induction Phase..................................................................... 10
3.1.2
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
Modified Intent-to-Treat (mITT) Population............................ 11
4.1.1.4
Pharmacokinetic-Evaluable Population ................................. 11
4.1.1.5
Histology-Evaluable Population............................................. 11
4.1.1.6
Safety Population .................................................................. 11
4.1.2
Maintenance Phase Population............................................. 12
4.1.2.1
Modified Intent-to-Treat (mITT) Population............................ 12
4.1.2.2
Pharmacokinetic (PK)Evaluable Population ........................ 12
4.1.2.3
Histology-Evaluable Population............................................. 12
4.1.2.4
Safety Population .................................................................. 12


Etrolizumab—F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan GA28950
4.2
Analysis of Study Conduct..................................................... 12
4.3
Analysis of Treatment Group Comparability .......................... 12
4.4
Efficacy Analysis.................................................................... 13
4.4.1
Induction Primary Efficacy ..................................................... 14
4.4.1.1
Induction Primary Treatment Effect ....................................... 14
4.4.1.2
Induction Primary Efficacy Endpoint ...................................... 14
4.4.1.3
Remission Definition.............................................................. 14
4.4.2
Maintenance Primary Efficacy ............................................... 14
4.4.2.1
Maintenance Primary Treatment effect.................................. 14
4.4.2.2
Maintenance Primary Efficacy ............................................... 15
4.4.2.3
Remission among Clinical Responders Definition ................. 15
4.4.3
Secondary Efficacy Endpoints............................................... 15
4.4.3.1
Control of Type I Error ........................................................... 15
4.4.3.2
Clinical Response.................................................................. 18
4.4.3.3
Improvement in Endoscopic Appearance of the 
Mucosa.................................................................................. 18
4.4.3.4
Endoscopic Remission .......................................................... 19
4.4.3.5
Rectal Bleed Subscore .......................................................... 19
4.4.3.6
Stool Frequency Subscore .................................................... 19
4.4.3.7
Histological Remission........................................................... 19
4.4.3.8
Remission at Week 66 (Among Patients in 
Remission at Week 14).......................................................... 20
4.4.3.9
Corticosteroid-Free Remission at Week 66 (Off 
Corticosteroid for at Least 24 Weeks Prior to 
Week 66) in Patients who were Receiving 
Corticosteroids at Baseline.................................................... 20
4.4.3.10
Corticosteroid-Free Clinical Remission at Week 
66 (Off Corticosteroid for at Least 24 Weeks prior 
to Week 66) in Patients who were Receiving 
Corticosteroids at Baseline.................................................... 20
4.4.3.11
Clinical Remission at Week 66 (Among Patients 
in Clinical Remission at Week 14) ......................................... 20
4.4.3.12
Clinical Remission ................................................................. 21
4.4.3.13
Ulcerative Colitis Patient-Reported Outcome 
Signs and Symptoms (UC-PRO/SS) ..................................... 21


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4.4.3.14
Inflammatory Bowel Disease Questionnaire 
(IBDQ) ................................................................................... 21
4.4.4
Exploratory Efficacy Endpoints.............................................. 21
4.4.5
Sensitivity Analyses............................................................... 22
4.4.6
Supplementary Analyses....................................................... 23
4.4.7
Subgroup Analyses ............................................................... 23
4.5
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 23
4.6
Safety Analyses..................................................................... 23
4.6.1
Exposure of Study Medication............................................... 24
4.6.2
Adverse Events ..................................................................... 24
4.6.3
Laboratory Data..................................................................... 24
4.6.4
Vital Signs.............................................................................. 24
4.6.5
Concomitant Medications ...................................................... 24
4.6.6
Medical History...................................................................... 24
4.7
Missing Data.......................................................................... 24
4.8
Interim Analyses .................................................................... 24
5.
REFERENCES ........................................................................................... 25
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 8
Figure 2
Multiple Testing Procedure for Induction Endpoints.................... 17
Figure 3
Multiple Testing Procedure for Maintenance Endpoints.............. 18
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 26
Appendix 2
Schedule of Assessments........................................................... 40
Appendix 3
Rescue Therapy.......................................................................... 46


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GLOSSARY OF ABBREVIATIONS
ANCOVA
analysis of covariance
CCOD
clinical cutoff date
CMH
Cochran-Mantel Haenszel
CS
corticosteroids
ES
endoscopic subscore
IBDQ
Inflammatory Bowel Disease Questionnaire
ICE
intercurrent event
IxRS
interactive voice/web based response system
MCS
Mayo Clinic Score
mITT
modified intent to treat
mMSC
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
RB
rectal bleeding
RHI
Robarts Histopathological Index
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 GA28950.  Study GA28950 is part of a large Phase III development program for 
etrolizumab.  Details which are common among Studies GA28950, GA29102, 
GA28948, GA28949, and GA29103 are described in the project SAP.
Study GA28950 is made up of two phases: the Induction Phase and the Maintenance 
Phase.  For the purpose of statistical analyses, the Induction and Maintenance Phases 
will be treated as two independent studies and analyzed separately.  The analysis for 
the Induction Phase and Maintenance Phase will be conducted once data from the 
Week 66 treatment period has been collected in the database and data have been 
cleaned and verified, this will be referred to as the primary analysis.
This SAP details the plans for the primary analysis for Cohort 1 and Cohort 2 during the 
Induction Phase and etrolizumab induction responders who were randomized into the 
Maintenance Phase.  Patients who were placebo responders at the end of the 
Induction Phase and continued to receive placebo during the Maintenance Phase will 
have their data listed and/or summarized separately as appropriate.
2.
STUDY DESIGN
This is a multicenter, Phase III, double-blind, placebo-controlled study evaluating the 
safety, efficacy, and tolerability of etrolizumab during induction and maintenance 
compared with placebo in the treatment of moderate to severe ulcerative colitis (UC) 
patients who have been previously exposed to tumor necrosis factor (TNF) inhibitors 
(see Figure 1).


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Figure 1 Study Schema
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
Details of outcome measures for efficacy, safety, and pharmacokinetic (PK) are 
available in the Protocol Synopsis in Appendix 1.  Baseline throughout this document is 
defined as the last available assessment prior to first receipt of study drug in the 
Induction Phase.
2.3
DETERMINATION OF SAMPLE SIZE
2.3.1
Sample Size for the Induction Phase
The study sample size was selected so that sufficient patients are enrolled to evaluate 
the primary endpoints in the blinded Induction Phase and the Maintenance Phase, 
respectively.  Approximately 605 patients will be enrolled into the open-label induction 
(OLI) arm (Cohort 1, n130) or the blinded Induction Cohort (Cohort 2, n≈475).


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Cohort 2 patients will be randomized in a 4:1 ratio to etrolizumab (n≈380) or placebo 
(n≈95).  This will provide approximately 80% power to detect a 10% difference in 
remission rates at Week 14 between the etrolizumab and placebo arms, under the 
assumption of a placebo remission rate of5% and a two-sided test at the 
5% significance level.
2.3.2
Sample Size for the Maintenance Phase
The primary endpoint for the Maintenance Phase is Week 66 remission among patients
in clinical response at Week 14.  In total, it is estimated approximately 
510 etrolizumab-treated patients from Cohort 1 and Cohort 2 would provide 
approximately 154 patients in clinical response at Week 14, under the assumption of a 
Week 14 clinical response rate of at least 30% in the pooled (Cohort 1 and Cohort 2) 
etrolizumab induction group.
A sample size of 154 patients in the Maintenance Phase will provide90% power to 
detect a 30% difference in remission rates between the two maintenance arms, under 
the assumption of a placebo Week 66 remission rate10% and a Fisher’s exact test at 
the 5% significance level.
2.4
ANALYSIS TIMING
The primary analysis for the Induction and Maintenance Phases will be conducted once 
the last patient has attended a visit to either complete their Week 66 treatment period 
or discontinue 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 treatment assignment (for Cohort 2 patients 
and those re-randomized into the Maintenance Phase) until after the study is 
completed (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-week safety 
follow-up and the database has been locked.  These analyses will report all adverse 
events 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 


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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 3.1.2, however further combining or removal maybe re required to 
ensure the analysis is not invalidated due to zero counts.
3.1.1
Induction Phase
A total of 130 patients were enrolled into Cohort 1 and received OLI treatment of 
etrolizumab 105 mg.
In Cohort 2, a total of 475 patients were randomized using a 4:1 ratio of etrolizumab 
(n≈380) to placebo (n≈95).  Patients were randomized using permuted blocks stratified 
(dynamically generated) randomization.  Patients were stratified using the following 
stratification factors:

Concomitant treatment with corticosteroids at baseline (yes/no)

Concomitant treatment with immunosuppressants at baseline (yes/no)

Disease activity at screening (Mayo Clinic Score [MCS]9/MCS10)
3.1.2
Maintenance Phase
Patients who received etrolizumab treatment during the Induction Phase, and achieved 
a clinical response at Week 14 without receiving (permitted/non-permitted) rescue 
therapy were eligible to be randomized into the Maintenance Phase from the Induction 
Phase.  Patients were randomized to etrolizumab or placebo using a 1:1 ratio and 
permuted blocks stratified randomization (dynamically-generated).  Patients were 
stratified using the following stratification factors:

Concomitant treatment with corticosteroids at baseline (yes/no)

Disease activity at screening (MCS9/MCS10)

Induction Cohort (Cohort 1/Cohort 2)

Remission criteria at Week 14 (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 14’.  This scenario would invalidate the CMH test, the 
Sponsor proposes not to fit ‘Remission Criteria at Week 14’ as a term within the 
analysis models.
All maintenance analysis will be adjusted for using three stratification factors:

Disease activity at screening (MCS9/MCS10)

Concomitant treatment with corticosteroids at baseline (yes/no)

Induction Cohort (Cohort 1/Cohort 2)


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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 Cohort 1 and receive study drug will be reported under the 
OLI population for all efficacy analyses.
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
Modified Intent-to-Treat (mITT) Population
Efficacy analyses for the Induction Phase will be performed using a modified 
intent-to-treat (mITT) analysis population (with the exception of histologic remission) 
including all patients randomized in Cohort 2 who received at least one dose of study 
drug with patients grouped according to the treatment assigned at randomization.
4.1.1.4
PharmacokineticEvaluable Population
The PK-evaluable population includes patients who have received at least one dose of 
etrolizumab and have had at least one quantifiable concentration measured during the 
Induction Phase.
4.1.1.5
Histology-Evaluable Population
The histology-evaluable patients will include all patients in the induction 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.
4.1.1.6
Safety Population
The safety analysis population for the Induction Phase will include all patients who 
received at least one dose of study drug during the Induction Phase.  Patients will be 
grouped by cohort and be included in the treatment arm for the treatment most 
frequently received during the Induction Phase.


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4.1.2
Maintenance Phase Population
4.1.2.1
Modified Intent-to-Treat (mITT) Population
Efficacy analyses for the Maintenance Phase will be performed using a mITT analysis 
population.  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.
4.1.2.2
Pharmacokinetic (PK)Evaluable Population
The PK evaluable population includes patients who have received at least one dose of 
etrolizumab and have at least quantifiable one 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, 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 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 
received study drug during 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 66 visit will be included to evaluate study conduct.  This will include all available 
data from 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 rescue therapy.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Details are included in the project SAP, Section 4.3.


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4.4
EFFICACY ANALYSIS
All statistical hypotheses for the primary and key secondary endpoints at each of the 
Induction and Maintenance Phases 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.
All comparisons between the etrolizumab and placebo arms for binary categorical data 
will use the CMH test statistic stratified by the IxRS stratification factors described in 
Section 3.1.  For all analyses in both the Induction and Maintenance Phases where 
comparison 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 effects 
(estimands) are described for each primary treatment effect in Sections 4.4.1.1 and 
4.4.2.1.  The estimand attributes includes 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 Induction or Maintenance Phases will not be assessed for
any future Week 14 or Week 66 endpoints, respectively.  Therefore, these patients 
will be assumed to be non-responders within the categorical endpoint analyses.
For continuous endpoints (e.g., Inflammatory Bowel Disease Questionnaire [IBDQ], 
Ulcerative Colitis Patient-Reported Outcome Signs and Symptoms [UC-PRO/SS], 
Stool Frequency [SF] subscores and Rectal Bleeding [RB] subscores) 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 therapies 
are described in the protocol and are also summarized in Appendix 3.  All patients 
receiving permitted rescue therapy during the Induction or Maintenance Phases 
will be asked to continue the study through endpoint assessment and safety follow-
up.  All patients receiving prohibited rescue therapy during the induction or 
Maintenance Phases will be asked to enter safety follow-up, with no assessment of 
any future Week 14 or Week 66 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 
timepoints following the time they received rescue therapy.  For continuous 
outcomes (e.g., IBDQ, UC-PRO/SS, SF subscores and RB subscores), 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.


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4.4.1
Induction Primary Efficacy
4.4.1.1
Induction Primary Treatment Effect
The primary efficacy treatment effect (estimand) targeted for the Induction Phase is 
described by the following four attributes:
a)
Population:  Adult Patients with moderate to severe active UC who have been 
previously exposed to TNF inhibitors
b)
Variable:  Remission at Week 14
c)
Intercurrent Event (ICE):

Treatment discontinuation

Use of rescue therapy
Details of the intercurrent events strategy are explained in Section 4.4.
d)
Population-Level Summary:  Difference in proportion of patients between 
etrolizumab and placebo treatment groups in Cohort 2.
4.4.1.2
Induction Primary Efficacy Endpoint 
The primary endpoint for the Induction Phase is the difference in the proportion of 
patients in remission at Week 14 between etrolizumab and placebo patients 
randomized into the induction mITT population.
	
  	
 	
 		
   
#  	
 	
 		
  
#  	
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Null hypothesis H0:  ρ Etro- PBO 0; the proportion of patients achieving remission 
at Week 14 in the placebo arm is the same as the proportion of patients achieving 
remission in the respective etrolizumab arm.
Alternative hypothesis H1:  ρ Etro - PBO ≠0; the proportion of patients achieving 
remission at Week 14 in the placebo arm is not the same as the proportion of patients 
achieving remission in the respective etrolizumab arm.
4.4.1.3
Remission Definition
Details are included in the project SAP, Section 4.4.2.1.4.
4.4.2
Maintenance Primary Efficacy
4.4.2.1
Maintenance Primary Treatment effect
The primary efficacy treatment effect (estimand) targeted for the Maintenance Phase is 
described by the following four attributes:
a)
Population:  Adult patients with moderate to severe active UC who have been 
previously exposed to TNF inhibitors,


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b)
Variable: Remission at Week 66 given the patient is an etrolizumab-induction 
clinical responder at Week 14.
c)
Intercurrent Event (ICE):

Treatment discontinuation 

Use of rescue therapy
Details of the intercurrent events 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.
4.4.2.2
Maintenance Primary Efficacy
The primary endpoint for the Maintenance Phase is the difference in the proportion of 
patients in remission at Week 66 between the etrolizumab and placebo patients who 
achieved clinical response at Week 14.
	
  	
 	
 		
    
 	
	 
   
# 	
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#  	
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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 maintenance 
mITT population who received etrolizumab treatment during the Induction Phase.
Null hypothesis H0: EtroPBO0; the proportion of patients achieving remission 
at Week 66 among clinical responders at Week 14 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 66 among clinical responders at Week 14 in the placebo arm is not 
the same as the proportion of patients achieving remission among clinical responders 
in the respective etrolizumab arm.
4.4.2.3
Remission among Clinical Responders Definition
Details are included in the project SAP, Section 4.4.2.1.4.
4.4.3
Secondary Efficacy Endpoints
4.4.3.1
Control of Type I Error
The primary and key secondary endpoints for the Induction Phase (Figure 2) and the 
Maintenance Phase (Figure 3) will be evaluated separately 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


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Familiy 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 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 1 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 and Figure 3. 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%.


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Figure 2 Multiple Testing Procedure for Induction Endpoints
Hierarchy
Endpoints
Primary

Remission at Week 14
Success on primary endpoint
Key 
Secondary 
(Family 1)

Clinical response at Week 14

Improvement of endoscopic appearance of mucosa at 
Week 14
Success on at least one endpoint
(Family 2)

Histologic remission at Week 14

Change from baseline to Week 6 in RB

Change from baseline to Week 6 in SF
Success on at least one endpoint
(Family 3)

Endoscopic remission at Week 14

Change from baseline to Week 14 in UC-PRO/SS (Bowel) 

Change from baseline to Week 14 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 result from the hypotheses 
tests and not reflective of the endpoints order in Figure 2.


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Figure 3 Multiple Testing Procedure for Maintenance Endpoints
Hierarchy
Endpoints
Primary

Remission at Week 66 among clinical responders at Week 14

Success on primary endpoint
Key 
secondary
(Family 1)

Corticosteroid free remission at Week 66 (off corticosteroid for 
at least 24 weeks prior to Week 66) in patients who were 
receiving corticosteroids at baseline

Improvement of endoscopic appearance of the Mucosa at 
Week 66
Success on at least one endpoint
(Family 2)

Remission at Week 66 among patients in remission at Week 14

Endoscopic remission at Week 66

Histologic remission at Week 66
Success on at least one endpoint
(Family 3)

Change from baseline in UC-PRO/SS (Functional) at Week 66

Change from baseline in UC-PRO/SS(Bowel) at Week 66
UC-PRO/SSUlcerative Colitis Patient-Reported Outcome Signs and Symptoms.
Ordering of endpoints within a family will be based on the p-value result from the hypotheses 
tests and not reflective of the endpoints order in Figure 3.
4.4.3.2
Clinical Response
Definition of clinical response is provided in the project SAP, Section 4.4.2.1.4.  The 
induction endpoint assessing the proportion of patients in clinical response at Week 14 
will be analyzed using the same methods as the primary endpoint.
4.4.3.3
Improvement in Endoscopic Appearance of the Mucosa
The induction endpoint assessing the proportion of patients with improvement in 
endoscopic appearance of the mucosa at Week 14 will be analyzed using the same 
methods as primary endpoint.
The maintenance endpoint assessing the proportion of patients with improvement in 
endoscopic appearance of the mucosa at Week 66 will be analyzed using the same 
methods as the primary endpoint.


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Definition of improvement in the appearance of the endoscopic mucosa is provided in 
the project SAP, Section 4.4.2.
4.4.3.4
Endoscopic Remission
The induction endpoint assessing the proportion of patients with endoscopic remission 
at Week 14 will be analyzed using the same methods as the primary endpoint.  The 
maintenance endpoint assessing the proportion of patients with endoscopic remission 
at Week 66 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.
4.4.3.5
Rectal Bleed Subscore
The difference in the change from baseline in rectal bleed subscore at baseline to 
Week 6 between placebo and etrolizumab will be analyzed using a RANK analysis of 
covariance (ANCOVA) model under the assumption rectal bleed subscore is 
non-parametric.  The Induction Phase stratification factors used at randomization as 
described in Section 3.1 will be adjusted for in the model along with the baseline RB 
score.  Definition of RB subscore is described in the project SAP, Section 4.4.2.1.1.
4.4.3.6
Stool Frequency Subscore
The difference in the change from baseline in stool frequency subscore at baseline to 
Week 6 between placebo and etrolizumab will be will be analyzed using a RANK 
ANCOVA model under the assumption SF subscore is non-parametric.  The Induction 
Phase stratification factors used at randomization as described in Section 3.1 will be 
adjusted for in the model along with the baseline SF subscore.  Definition of SF 
subscore is described in project SAP, Section 4.4.2.1.1.
4.4.3.7
Histological Remission
Proportion of patients with histologic remission at Week 14 will be analyzed using the 
same methods as the primary endpoint, using the induction histology evaluable 
population.  The maintenance endpoint assessing the proportion of patients with 
histologic remission at Week 66 will be analyzed using the same methods as primary 
endpoint using the maintenance histology evaluable population.  Definition of 
histological 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.


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4.4.3.8
Remission at Week 66 (Among Patients in Remission at 
Week 14)
The proportion of patients who achieved remission at Week 66 and given they 
achieved remission at Week 14 will be analyzed using the same model 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 cohort 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, Table 2.
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4.4.3.9
Corticosteroid-Free Remission at Week 66 (Off Corticosteroid 
for at Least 24 Weeks Prior to Week 66) in Patients who were 
Receiving Corticosteroids at Baseline
This analysis will only be conducted on a sub-group of patients who were receiving 
corticosteroids at baseline as per the data collected in electronic Case Report Form 
(e-CRF) database and were randomized 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 corticosteroids (CS) if they have no record of taking CS on the date 
which is twenty four weeks prior to Week 66. This date is defined is the Week 66 visit 
date168 days.
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4.4.3.10
Corticosteroid-Free Clinical Remission at Week 66 (Off 
Corticosteroid for at Least 24 Weeks prior to Week 66) in 
Patients who were Receiving Corticosteroids at Baseline
This endpoint will be analyzed using the same methods as Section 4.4.3.9.  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 4.4.3.1), this endpoint is not included in the multiple testing procedure for 
endpoints.
4.4.3.11
Clinical Remission at Week 66 (Among Patients in Clinical 
Remission at Week 14)
The secondary endpoint will be analyzed using the same methods as Section 4.4.3.8.  
Remission will be substituted with clinical remission.  Clinical remission is determined by 


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the MCS and described in the project SAP, Section 4.4.2.1.4.  As detailed in Figure 2
(Section 4.4.3.1), this endpoint is not included in the multiple testing procedure for 
endpoints.
4.4.3.12
Clinical Remission
Definition of clinical remission is included in the project SAP, Section 4.4.2.1.4.
The induction endpoint assessing the proportion of patients in clinical remission at 
Week 14 will be analyzed using the same methods as the primary endpoint.  The 
maintenance endpoint assessing the proportion of patients in clinical remission at 
Week 66 will be analyzed using the same methods as the primary endpoint. As detailed 
in Figure 2 (Section 4.4.3.1), these endpoints are not included in the multiple testing 
procedure for endpoints.
4.4.3.13
Ulcerative Colitis Patient-Reported Outcome Signs and 
Symptoms (UC-PRO/SS)
Details of UC-PRO/SS endpoints and the analyses are provided in the project SAP, 
Section 4.4.2.3.
For the Induction Phase the change from baseline at Week 14 in both functional domain 
and bowel domain will be analyzed.
For Maintenance Phase the change from baseline at Week 66 in both functional domain 
and bowel domain will be analyzed.
4.4.3.14
Inflammatory Bowel Disease Questionnaire (IBDQ)
Details of the IBDQ endpoint and the analyses are provided in the project SAP, 
Section 4.4.2.4.
For Induction Phase the change from baseline at Week 14 in IBDQ will be analyzed.
For Maintenance Phase the change from baseline at Week 66 in IBDQ will be analyzed.
As detailed in Figure 2 (Section 4.4.3.1), these endpoints are not included in the multiple 
testing procedure for endpoints.
4.4.4
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.


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4.4.5
Sensitivity Analyses
To support the primary analyses, the following sensitivity analyses will be conducted:  
definitions of partial Mayo Clinic Score (pMCS) and modified Mayo Clinic Score (mMCS) 
are included in the project SAP Section 4.4.2.1.4.

Proportion of patients in remission at Week 14 (remission derived using the mMCS
including mild friability in Mayo ES1)

Proportion of patients in remission at Week 14 (remission derived using the pMCS)

Proportion of patients in remission at Week 14 (difference in proportions calculated 
using Fisher’s exact test)

Proportion of patients in remission (mMCS) at Week 14 (exclude friability from 
Mayo ES1)

Proportion of patients in remission at Week 14 (Tipping Point Analysis)

Proportion of patients in remission at Week 66 among clinical responders at 
Week 14 (remission derived using mMCS including mild friability in Mayo ES1)

Proportion of patients in remission at Week 66 among clinical responders at 
Week 14 (remission derived using pMCS)

Proportion of patients in remission at Week 66 among clinical responders at 
Week 14 (difference in proportions calculated using Fisher’s exact test)

Proportion of patients in remission (mMCS) at Week 66 among clinical responders 
at Week 14 (exclude friability from Mayo ES1)

Proportion of patients in remission at Week 66 among clinical responders at 
Week 14 (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 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 populations and are listed 
below:

Proportion of patients in clinical response at Week 14 (clinical response derived 
using the mMCS excluding mild friability in Mayo ES1)

Proportion of patients with Improvement of endoscopic appearance of mucosa at 
Week 14 (endoscopic score excluding mild friability in Mayo ES1)

Proportion of patients corticosteroid free remission at Week 66 (off corticosteroid for 
at least 24 Weeks Prior to Week 66) 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 66 (endoscopic score excluding mild friability in Mayo ES1)


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
Proportion of patients remission at Week 66 among patients in remission at 
Week 14  (remission at Week 14 and week 66 derived using the mMCS excluding 
mild friability in Mayo ES1)
4.4.6
Supplementary Analyses
To support the primary analyses the following supplementary analyses will be conducted:

Proportion of patients in remission at Week 14 (patients who received rescue 
therapy will not be assumed non-responders; they will be assessed based on 
efficacy data)

Proportion of patients in remission at Week 14 (using logistic regression model)

Proportion of patients in remission at Week 66 among clinical responders at 
Week 14 (patients who received rescue therapy will not be assumed to be 
non-responders; they will be assessed based on efficacy data)

Proportion of patients in remission at Week 66 among clinical responders at 
Week 14 (using clinical database derivation of clinical response at Week 14, if 
appropriate)

Proportion of patients in remission at Week 66 among clinical responders at 
Week 14 (using logistic regression model)
Definition of clinical response is included in the project SAP, Section 4.4.2.1.4.
4.4.7
Subgroup Analyses
Subgroup analyses are detailed in the project SAP, Section 4.4.3.  Additional subgroup 
analyses specific to Study GA28950 include TNF status at baseline.
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 will include data for all patients in induction 
safety population, 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 to 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 completes/withdraws from the study.  
For 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 to the primary analyses CCOD will be reported.


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Further details of the safety analyses are provided 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.
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 4.7.8.
4.8
INTERIM ANALYSES
No efficacy interim analyses are planned, or have been undertaken.


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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, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER STUDY OF THE EFFICACY AND SAFETY OF 
ETROLIZUMAB DURING INDUCTION AND MAINTENANCE IN 
PATIENTS WITH MODERATE TO SEVERE ACTIVE ULCERATIVE 
COLITIS WHO HAVE BEEN PREVIOUSLY EXPOSED TO TNF 
INHIBITORS
PROTOCOL NUMBER:
GA28950
VERSION NUMBER:
8
EUDRACT NUMBER:
2013-004278-88
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 objectives for this study are as follows:

To evaluate the efficacy of etrolizumab (105 mg subcutaneous [SC] every 4 weeks [Q4W]) 
compared with placebo for the induction of remission, as determined by the Mayo Clinic 
Score (MCS) at Week 14

To evaluate the efficacy of etrolizumab (105 mg SC Q4W) compared with placebo for 
remission at Week 66 among patients with a clinical response at Week 14, as determined 
by the MCS
The secondary efficacy objectives for this study are as follows:
Induction Phase

To evaluate induction of clinical remission at Week 14

To evaluate clinical response at Week 14

To evaluate improvement in endoscopic appearance of the mucosa at Week 14

To evaluate endoscopic remission at Week 14

To evaluate histologic remission at Week 14

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


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
To evaluate change from baseline in UC bowel movement signs and symptoms at 
Week 14, as assessed by the Ulcerative ColitisPatient-Reported Outcome Signs and 
Symptoms (UC-PRO/SS) measure

To evaluate change from baseline in UC functional symptoms at Week 14, as assessed by
the UC-PRO/SS measure

To evaluate change from baseline in patientreported health-related quality of life (QOL) at 
Week 14, as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ)
Maintenance Phase

To evaluate clinical remission at Week 66 in patients in clinical remission at Week 14

To evaluate clinical remission at Week 66

To evaluate remission at Week 66 among patients in remission at Week 14

To evaluate improvement in endoscopic appearance of the mucosa at Week 66

To evaluate histologic remission at Week 66

To evaluate endoscopic remission at Week 66

To evaluate corticosteroid-free clinical remission at Week 66 (off corticosteroid for at least 
24 weeks prior to Week 66) in patients who were receiving corticosteroids at baseline

To evaluate corticosteroid-free remission at Week 66 (off corticosteroid for at least 
24 weeks prior to Week 66) in patients who were receiving corticosteroids at baseline

To evaluate change in UC bowel movement signs and symptoms from baseline to
Week 66, as assessed by the UC-PRO/SS measure

To evaluate change in UC functional symptoms from baseline to Week 66, as assessed by 
the UCPRO/SS measure

To evaluate change in patientreported health-related QOL from baseline to Week 66, as 
assessed by the IBDQ
The exploratory efficacy objectives for this study are as follows:

To evaluate clinical response at Week 66 among patients with a clinical response at 
Week 14

To evaluate remission achieved at Week 66 among patients in clinical remission at 
Week 14

To evaluate corticosteroid-free clinical remission at Week 66 (off corticosteroid for at least 
12 weeks prior to Week 66) in patients who were receiving corticosteroids at baseline

To evaluate change in histologic disease activity from baseline to Week 14 and Week 66

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 baseline to Week 14 and Week 14 to Week 66

To evaluate frequency and duration of hospitalizations from Week 14 to Week 66

To evaluate response, remission, and corticosteroid-free endpoints, as determined by the 
modified MCS (mMCS)
Safety Objectives
The safety objectives for this study are as follows:

To evaluate the overall safety and tolerability of etrolizumab compared with placebo during 
induction and maintenance therapy over a period of 66 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)


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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 
(Weeks 14 and 66) and at predose time in the steady state during the maintenance dosing 
period

To evaluate the inter-individual 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

To evaluate the PD effects on biomarkers in colonic tissue and/or peripheral blood
following study drug

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, double-blind, placebo-controlled study evaluating the safety, 
efficacy, and tolerability of etrolizumab during induction and maintenance of remission 
compared with placebo in the treatment of moderately to severely active UC.
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 (see protocol), 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 of 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 of 1), and 
involvement that extends a minimum of 20 cm from the anal verge.
Patients who are on background immunosuppressant therapy (6-mercaptopurine [MP], 
azathioprine [AZA], methotrexate [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


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
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 14, 
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) if the dose has been 
stable for 4 weeks prior to Day 1.  Oral 5-aminosalicylate (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 protocol for list of all prohibited concomitant treatments).  Patients must have 
discontinued TNF inhibitor treatment and topical treatments for UC at least 8 weeks and 
2 weeks prior to Day 1, respectively.
The study will be divided into:

Screening period of up to 35 days during which patient eligibility will be determined 

Induction Phase of 14 weeks (Cohort 1: open-label etrolizumab treatment; 
Cohort 2: randomized to etrolizumab or placebo)

Randomization of etrolizumab responders prior to a double-blind Maintenance Phase of 
52 weeks or continued blinded treatment with placebo Q4W for 52 weeks for placebo 
induction responders 

Safety follow-up period of 12 weeks
A total of approximately 605 patients will be recruited from approximately 225 sites via an 
open-label induction arm (Cohort 1, n 130) and a double-blind induction arm (Cohort 2, 
n 475), which will be enrolled sequentially.
Cohort 1 patients will receive open-label etrolizumab 105 mg SC Q4W during the 14-week 
Induction Phase.  Cohort 2 patients will be randomized in a 4:1 ratio to 105 mg etrolizumab SC 
Q4W (n ≈380) or placebo (n ≈95) during the 14-week Induction Phase.  Randomization will 
be stratified by concomitant treatment with corticosteroids (including budesonide) (yes/no), 
concomitant treatment with immunosuppressants (yes/no), and disease activity measured 
during screening (MCS9/MCS10).
Eligibility for entry into the Maintenance Phase will be determined between Weeks 14 and 16.  
Patients in the etrolizumab arm of Cohort 2 who achieved a clinical response at Week 14 
(see protocol for definition of clinical response) and all Week 14 clinical responders in Cohort 1 
will be randomized into the Maintenance Phase and will receive either etrolizumab (105 mg 
SC Q4W) or placebo in a 1:1 ratio.  Randomization will be stratified by remission status at 
Week 14, concomitant treatment with corticosteroids (including budesonide) at baseline, 
disease activity measured during screening (MCS9/MCS10), and induction cohort 
(Cohort 1/Cohort 2).  It is estimated that the planned approximately 510 etrolizumab patients 
from Cohort 1 and Cohort 2 will provide approximately 154 patients in clinical response for 
randomization into the Maintenance Phase.  Additional patients may be enrolled into Cohort 1, 
if needed, to achieve a sufficient number of patients in the Maintenance Phase.
Patients initially randomized to placebo will also be assessed for clinical response at Week 14.  
Patients achieving a clinical response will continue to receive blinded placebo during the 
Maintenance Phase of the study.  Patients in either Cohort 1 or Cohort 2, who do not achieve 
clinical response at Week 14, patients who have clinical relapse during the Maintenance 
Phase, patients who receive defined rescue treatment, and patients who complete 66 weeks 
of the study may be given the option of enrolling into Part 1 (OLE) of Study GA28951, where 
they will receive open-label etrolizumab treatment, if eligible.  If patients choose not to 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.
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 


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self-administered by the patient or his or her caregiver in the clinic; 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 the protocol).  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 the protocol.
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 14 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 14, patients receiving budesonide who achieve 
clinical response at Week 14 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 corticosteroid 
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.
Clinical relapse is defined as an:

Increase in partial Mayo Clinic Score (pMCS) 3 points compared to induction timepoint  
(Week 14) 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 if eligible.
Rescue Therapy That Can be Given with Study Medication for the Treatment of UC
During the Induction Phase (prior to Week 14)
Patients are required to maintain stable doses of their concomitant medications (oral
5-aminosalicylate [5-ASA], corticosteroids, immunosuppressants) for UC.
In the Induction Phase, any patient who requires initiation of an immunosuppressant (AZA, 
6-MP, or MTX), 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 14, 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 of 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 14 and may not continue into the Maintenance Phase of the trial.
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 


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discretion.  Patients who leave the treatment period 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 must begin the specified corticosteroid taper at Week 14 during the Maintenance 
Phase.  For patients who cannot tolerate the corticosteroid taper without recurrence of clinical 
symptoms of either UC or corticosteroid 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.
Patients who were not receiving corticosteroids at baseline and patients who have completed 
the corticosteroid 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 corticosteroid 
withdrawal 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 period early 
to enroll in Part 1 (OLE) of Study GA28951 should complete the early withdrawal from 
treatment visit prior to enrollment in Study GA28951.
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 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 period 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.
Rescue Therapy That Cannot be Given with Study Medication for the Treatment of UC
At ANY time during the conduct of the trial, 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 the protocol).  These 
patients will also be requested to enroll in Part 2 (SM) of Study GA28951 for 92 weeks of 
extended PML monitoring.
A complete list of study visits and assessments can be found in the Schedule of Assessments 
(see the protocol for further details).  A complete list of eligibility for transfer of patients to 
OLE-SM and 12-week safety follow-up is in the protocol.
Number of Patients
A total of approximately 605 patients will be enrolled from approximately 225 sites via an open-
label induction arm (Cohort 1, n 130) and a double-blind induction arm (Cohort 2, n 475).
Cohort 2 patients will be randomized in a 4:1 ratio to etrolizumab 105 mg SC (n ≈380) or 
placebo (n ≈95) Q4W.  Patients in the etrolizumab arm of Cohort 2 who achieved a clinical 
response at Week 14 (see protocol for definition of clinical response) and all Week 14 clinical 
responders in Cohort 1 will be randomized into the Maintenance Phase and will receive either 
etrolizumab (105 mg SC Q4W) or placebo in a 1:1 ratio.  It is estimated that the planned 
approximately 510 etrolizumab patients from Cohort 1 and Cohort 2 will provide approximately 
154 patients in clinical response for randomization into the Maintenance Phase.  Additional 
patients may be enrolled into Cohort 1, if needed, to meet sample size requirements for the 
Maintenance Phase.


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32/Statistical Analysis Plan GA28950
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Treatment within 5 years prior to screening with one or two induction regimens that contain 
TNF inhibitors (including TNF inhibitor biosimilars), as defined below:

Infliximab:  5 mg/kg IV, 2 doses

Adalimumab:  160 mg SC followed by an 80-mg dose

Golimumab:  200 mg SC followed by a 100-mg dose
Patients will be categorized as TNF inhibitor refractory, TNF inhibitor intolerant, or neither 
refractory nor intolerant to TNF inhibitors.  TNF inhibitor refractory and TNF inhibitor intolerant 
are defined as follows:
TNF inhibitor refractory:  Persistent signs and symptoms of active disease despite TNF inhibitor 
treatment or recurrence of symptoms during maintenance TNF inhibitor treatment (i.e., following 
prior clinical benefit)
TNF inhibitor intolerant:  History of intolerance to TNF inhibitors, (including, but not limited to, 
injection-site reactions, congestive heart failure, or infection)

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:  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 the protocol, a 
rectal bleeding subscore 1, and a stool frequency subscore of 1 during the screening 
period (prior to Day 1).  See the protocol for additional information regarding the time 
window.  

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 the protocol for additional information regarding the time 
window.

Washout of TNF inhibitor therapy for at least 8 weeks preceding Day 1

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 at least 2 weeks immediately prior to Day 1
May be receiving AZA, 6-MP, or MTX, provided that the dose has been stable for at 
least 8 weeks immediately prior to Day 1


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
For women who are not postmenopausal (at least 12 months of nontherapy-induced 
amenorrhea) or surgically sterile (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, a condom, 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 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
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


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34/Statistical Analysis Plan GA28950

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, except for AZA and 6-MP.  

Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil 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 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 co-morbidity, such as cardiac (e.g., moderate to severe heart failure 
New York Heart Association 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


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
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 ,
high-grade squamous intraepithelial lesions, or cervical intraepithelial neoplasia 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 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 has a known history of 
HCV antibody positivity with history of undetectable HCV RNA for 6 months 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 result is positive, the patient is not eligible for this study.  
In the event HBV DNA test cannot be performed, the patient is not eligible for this 
study. 
If the HBV DNA test result 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 is required during screening evaluation only if clinical suspicion is high 
and to determine the need for CMV treatment.

History of active or latent tuberculosis (TB) regardless of treatment history
Patients with a history of active or latent TB (based on a positive screening assay, 
either purified protein derivative skin test or QuantiFERONTB Gold test, see below) 
are not eligible for this study.
Patients with a chest X-ray (posteroanterior 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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36/Statistical Analysis Plan GA28950

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 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 Abnormalities (at Screening)

Serum creatinine 2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 66 weeks.  Patients who do not achieve a clinical 
response at Week 14, patients who have clinical relapse during the Maintenance Phase, 
patients who receive defined rescue treatment, and patients who complete 66 weeks of the 
study may be given the option of enrolling into 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  monitoring for PML.
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 the Study GA28951 
(OLE-SM), whichever is the 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 transferred to Study GA28951 (OLE-SM), whichever is later.
Outcome Measures
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:
Primary Efficacy Outcome Measures
Induction Phase

Remission at Week 14, as determined by the MCS
Maintenance Phase

Remission at Week 66 among patients with a clinical response at Week 14, as determined 
by the MCS


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Secondary Efficacy Outcome Measures
Induction Phase

Clinical remission at Week 14

Clinical response at Week 14

Improvement in endoscopic appearance of the mucosa at Week 14

Endoscopic remission at Week 14

Histologic remission at Week 14

Change from baseline in rectal bleed subscore at Week 6

Change from baseline in stool frequency subscore at Week 6

Change from baseline in UC bowel movement signs and symptoms as assessed by the 
UC-PRO/SS measure at Week 14

Change from baseline in UC functional symptoms as assessed by the UC-PRO/SS 
measure at Week 14

Change from baseline in patients’ health-related QOL at Week 14 as assessed by the 
overall score of the IBDQ
Maintenance Phase

Clinical remission at Week 66 among patients in clinical remission at Week 14

Clinical remission at Week 66

Remission at Week 66 among patients in remission at Week 14

Improvement in endoscopic appearance of the mucosa at Week 66

Histologic remission at Week 66

Endoscopic remission at Week 66

Corticosteroid-free clinical remission at Week 66 (off corticosteroid for at least 24 weeks 
prior to Week 66) in patients who were receiving corticosteroids at baseline

Corticosteroid-free remission at Week 66 (off corticosteroid for at least 24 weeks prior to 
Week 66) in patients who were receiving corticosteroids at baseline

Change from baseline in UC bowel movement signs and symptoms as assessed by the 
UC-PRO/SS measure at Week 66

Change from baseline in UC functional symptoms as assessed by the UC-PRO/SS 
measure at Week 66

Change from baseline in patients’ health-related QOL at Week 66 as assessed by the 
overall score of the IBDQ
Exploratory Efficacy Outcome Measures

Clinical response at Week 66 among patients with a clinical response at Week 14

Remission at Week 66 among patients in clinical remission at Week 14

Corticosteroid-free clinical remission at Week 66 (off corticosteroid for at least 12 weeks 
prior to Week 66) in patients who are receiving corticosteroids at baseline

Histologic disease activity change from baseline to Week 14 and Week 66

Improvement in histologic and/or endoscopic disease activity

Change in health utilities, as assessed by the EQ-5D, from baseline to Week 14 and Week 
14 to Week 66

Frequency and duration of hospitalizations from Week 14 to Week 66

Response, remission and corticosteroid-free endpoints as determined by the mMCS


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38/Statistical Analysis Plan GA28950
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 16 to 
Week 66

Serum concentration at primary endpoint time (Week 14 and  Week 66)
Exploratory Biomarker Outcome Measures
The exploratory biomarker outcome measures for this study are as follows:

Remission at Week 14 and maintenance of remission at Week 66 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 14).  Tapering of corticosteroid (including budesonide) is to 
be attempted during the Maintenance Phase.
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 discontinuing 
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.
Probiotics and oral 5-ASA may be continued at a stable dose throughout the study.


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39/Statistical Analysis Plan GA28950
Occasional use of NSAIDs and acetaminophen (e.g., headache, arthritis, myalgias, 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
For the purpose of statistical analyses, the Induction and Maintenance Phases will be treated as 
two independent studies.  The analysis of the Induction Phase will formally evaluate the efficacy 
and safety of 105 mg etrolizumab SC Q4W versus placebo as an induction therapy.
The analysis of the Maintenance Phase will formally evaluate the efficacy and safety of 
105 mg etrolizumab SC Q4W versus placebo as a maintenance therapy.
The analysis of data from the 66-week treatment period (Induction and Maintenance Phases) 
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 
analyses, patients and study site personnel will remain blinded to individual treatment 
assignment (for Cohort 2 patients and those re-randomized into the Maintenance Phase) until 
after the study is completed (after all patients have either completed the safety follow-up periods 
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 endpoints in the blinded Induction Phase and the Maintenance Phase respectively.  
Approximately 605 patients will be enrolled in the open-label induction arm (Cohort 1, n ≈130) or 
the blinded induction cohort (Cohort 2, n ≈475).
Cohort 2 patients will be randomized in a 4:1 ratio to etrolizumab (n ≈380) or placebo (n ≈95).  
This will provide approximately 80% power to detect a 10% difference in remission rates at 
Week 14 between the etrolizumab and placebo arms, under the assumption of a placebo 
remission rate of 5% and a two-sided 2 test at the 5% significance level.
The primary endpoint for the Maintenance Phase is Week 66 remission among patients with a 
clinical response at Week 14.  In total, it is estimated that approximately 154 etrolizumab 
patients will achieve clinical response at the end of the Induction Phase and therefore will be 
randomized in the Maintenance Phase, under the assumption of a Week 14 clinical response 
rate of approximately 30% in the pooled etrolizumab induction group.
A sample size of 154 patients in the Maintenance Phase will provide 90% power to detect a 
30% difference in remission rates between the two maintenance arms, under the assumption of 
a placebo Week 66 remission rate 10% and a Fisher exact test at the 5% significance level.
The planned approximately 510 etrolizumab patients from Cohort 1 and Cohort 2 would provide 
approximately 154 patients with a clinical response at Week 14, under the assumption of a 
Week 14 clinical response rate of at least 30% in the pooled (Cohort 1 and Cohort 2) 
etrolizumab induction group.  Additional patients may be enrolled into Cohort 1, if needed, to 
achieve this target number of approximately 154 patients randomized into the Maintenance 
Phase.
For the purpose of statistical analyses and sample size calculations, the Induction and 
Maintenance Phases will be treated as two independent studies, and as such no adjustment to 
alpha is required.


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Appendix 2
Schedule of Assessments
Assessments
Screening 
Day a
35 to 1
Treatment Period Study Week (3 days)
Unscheduled 
Visit d
Early 
Withdrawal
from 
Treatment 
Phase
0 b
4
8
12
14
16
20
24
28 c
32
36 c
40 c
44
48 c
52 c
56
60 c
64 c
66
Informed consent
x
Review eligibility criteria e
x
x
Demographic data
x
Pregnancy test f
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs (BP and pulse)
x
x
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
x
x
x
x
x d
x j
Chemistry 
x
x
x
x
x
x
x d
x j
Urinalysis
x
x
x d
TB screen k
x
HIV test
x
Hepatitis B and C serology l
x


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Appendix 2
Schedule of Assessments (cont.)
Assessments
Screening 
Day a
35 to 1
Treatment Period Study Week (3 days)
Unscheduled 
Visit d
Early 
Withdrawal
from 
Treatment 
Phase
0 b
4
8
12
14
16
20
24
28 c
32
36 c
40 c
44
48 c
52 c
56
60
c
64 c
66
Hepatitis B DNA m
x
x
x
x
x
x
x
Hepatitis C RNA (Amplicor) n
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
x t
x
x
x d
x j
Partial MCS (pMCS; excludes 
endoscopy)  u
x u
x
x
x
x
x
x
x
x
x
x d
x j
Stool sample collection
x v
x w
x w
x w
x d
x w
Colonic biopsy (CMV if 
required)
x x
x d
Colonic biopsy 
(histopathological confirmation 
of UC if required)
x y
Colonic biopsies (formalin)
x z
x
aa
x aa
x d, aa
x j, aa
Colonic biopsies (for qPCR)
x z
x
aa
x aa
x d, aa
x j ,aa
Serum sample (CRP)
x
x
x
x d
x j


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42/Statistical Analysis Plan GA28950
Appendix 2
Schedule of Assessments (cont.)
Assessments
Screening 
Day a
35 to 1
Treatment Period Study Week (3 days)
Unschedule
d Visit d
Early 
Withdrawal
from 
Treatment 
Phase
0 b
4
8
12
14
16
20
24
28 c
32
36 c
40
c
44
48 c
52 c
56
60 c
64 c
66
Serum sample (future 
exploratory PD) o
x
x
x
x
x
x
Blood sample (RNA Paxgene) o, 
bb
x
x
x
x
x
Whole blood (EDTA Blood) 
optional
x
UC-PRO/SS cc 
x
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
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
x
Initial randomization
x
Randomization of responders to 
Maintenance Phase
x
ee
Etrolizumab/etrolizumab 
placebo ff
x
x
x
x
x ff
x ff
x ff
x ff
x ff
x ff
x ff
x ff
x ff
x ff
x ff
x ff
x ff
BPblood pressure; CMVcytomegalovirus; CRPC-reactive protein; ECGelectrocardiogram; eCRFelectronic case report form; 
EQ-5DEuroQoL Five-Dimension Questionnaire; HBVhepatitis B virus; HCVhepatitis C virus; IBDQInflammatory Bowel Disease Questionnaire; 
IHCimmunohistochemistry; JCVJohn Cunningham virus; MCSMayo Clinic Score; PDpharmacodynamic; PKpharmacokinetic; PMLprogressive multifocal 
leukoencephalopathy; qPCRquantitative polymerase chain reaction; UC-PRO/SSUlcerative Colitis Patient-Reported Outcome Signs and Symptoms; 
TBtuberculosis; UCulcerative colitis.


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43/Statistical Analysis Plan GA28950
Appendix 2
Schedule of Assessments (cont.)
Notes:  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.
d
Unscheduled visit represents a visit that is not as per Schedule of Assessments and is required for an adverse event or for potential relapse assessment.  All 
indicated assessments are NOT performed at each unscheduled visit.  Assessments would be symptom-driven (e.g., perform PML neurological examination only 
if patient reports symptoms suspected of PML; and confirmation of clinical relapse is performed by the Mayo Clinic Score assessment).  Assessments 
corresponding to items noted in this column should be recorded on the eCRF.
e
Perform prior to first administration of study drug.
f
Serum test at screening for all female patients except those who are more than 1-year postmenopausal or are surgically sterile.  Urine test at all 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 result via e-diary.  Patients must be instructed at screening and reminded throughout the study that in case of positive 
pregnancy test result 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 exam consists of the PML Subjective Checklist and the PML Objective Checklist. Administer before other assessments, as 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 hepatitis C.  This includes testing for HBsAg (HBV surface antigen), anti-HBc total (HBV core antibody total), 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
The PK, ATA, and exploratory PD sample collections will be from all patients during the Induction Phase.  During the Maintenance Phase, PK, ATA, and 
exploratory PD samples will only be collected from patients who were randomized into the Maintenance Phase.


Etrolizumab—F. Hoffmann-La Roche Ltd
44/Statistical Analysis Plan GA28950
Appendix 2
Schedule of Assessments (cont.)
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).
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 (PGA).  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
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 PGA will be 
obtained only once, on Day 1 (prior to randomization), and the PGA subscore will be used to calculate both the baseline (screening) MCS and the baseline (Day 
1) pMCS.
u
Partial MCS during screening is defined as the MCS score excluding the endoscopy score (i.e., rectal bleeding assessmentstool frequency 
assessmentPGA).
v
For culture and sensitivity testing; ova, parasites, and Clostridium difficile toxin testing.
w 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).
x
IF REQUIRED:  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 lab if necessary.  Result must be negative for CMV 
prior to dosing on Day 1. 
y
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 and read locally for histopathologic confirmation of UC.
z
In addition to the optional biopsy noted in footnote “x” and “y” above, 5 pairs (10 biopsy samples) will be obtained at screening (all taken from the most inflamed 
area of the colon within 20-40 cm of the anal verge [sigmoid]).  These five biopsy pairs will be sent to the central laboratory for further storage or distribution.  
Two pairs will be placed in a stabilization buffer (such as RNAlater or a similar buffer) and stored at 80C (1 pair for diagnostic qPCR and 1 pair for PD 
biomarkers).  In UK sites ONLY, one of the latter pair of biopsies (2 samples) will be placed in storage solution at 4°C and shipped to the UK laboratory.  The 
other 3 pairs will be placed in formalin and then paraffin embedded; these biopsy samples will be used for exploratory PD biomarkers and/or diagnostic 
biomarkers. Original biopsy location and endoscopic depth should be clearly indicated.


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45/Statistical Analysis Plan GA28950
Appendix 2
Schedule of Assessments (cont.)
aa A total of four pairs (8 biopsy samples) will be obtained from all patients (all taken from the most inflamed area of the colon within 20-40 cm of anal verge 
[sigmoid]).  All will be sent to the central laboratory for further storage or distribution.  In UK sites ONLY, one of the latter pair of biopsies (2 samples) will be 
placed in storage solution at 4°C and shipped to the UK laboratory. Two pairs will be placed in a stabilization buffer (such as RNAlater or a similar buffer) and 
stored at 80C for exploratory PD biomarker and/or diagnostic biomarker qPCR.  The other two pairs will be placed in formalin and then paraffin embedded; 
these biopsy samples will be used for exploratory PD biomarkers and/or diagnostic biomarkers.  Original biopsy location and endoscopic depth should be clearly 
indicated.
bb Paxgene blood RNA samples must be collected after all other blood and serum samples.
cc 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.
dd With the exception of Week 0, the IBDQ and the EQ-5D will be completed in the 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 14 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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46/Statistical Analysis Plan GA28950
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 JAK inhibitors, vaccines (e.g., MAP or ChAdOx2 HAV)
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


Etrolizumab — F. Hoffmann-La Roche Ltd
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.


Etrolizumab — F. Hoffmann-La Roche Ltd
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


Etrolizumab — F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan Project SAP
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


Etrolizumab — F. Hoffmann-La Roche Ltd
5/Statistical Analysis Plan Project SAP
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


Etrolizumab — F. Hoffmann-La Roche Ltd
6/Statistical Analysis Plan Project SAP
GLOSSARY OF ABBREVIATIONS
WOCF Worse Observation Carried Forward


Etrolizumab — F. Hoffmann-La Roche Ltd
7/Statistical Analysis Plan Project SAP
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.


Etrolizumab — F. Hoffmann-La Roche Ltd
8/Statistical Analysis Plan Project SAP
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 


Etrolizumab — F. Hoffmann-La Roche Ltd
9/Statistical Analysis Plan Project SAP
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 


Etrolizumab — F. Hoffmann-La Roche Ltd
10/Statistical Analysis Plan Project SAP
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.


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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


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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


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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