Conditions: Ulcerative Colitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 358
Healthy volunteers: no

Brief summary:
This Phase III, double-blind, placebo and active-comparator controlled, multicenter study will investigate the efficacy and safety of etrolizumab in induction of remission in participants with moderately to severely active ulcerative colitis (UC) who are naIve to tumor necrosis factor (TNF) inhibitors and refractory to or intolerant of prior immunosuppressant and/or corticosteroid treatment. In addition to this study, a second Phase III trial with identical study design (GA28948; NCT02163759) was independently conducted.

Detailed description:

Arms:
arm 1: Participants will receive placebo matching to etrolizumab up to Week 12 and placebo matching to adalimumab up to Week 8. arm 2: Participants will receive adalimumab up to Week 8 and placebo matching to etrolizumab up to Week 12. arm 3: Participants will receive etrolizumab up to Week 12 and placebo matching to adalimumab up to Week 8.

Interventions: intervention 1: Adalimumab intervention 2: Adalimumab Placebo intervention 3: Etrolizumab intervention 4: Etrolizumab Placebo
Intervention descriptions: intervention 1: Adalimumab 160 milligrams (mg) will be administered subcutaneously (SC) at Week 0; 80 mg SC at Week 2; 40 mg SC at Weeks 4, 6 and 8. intervention 2: Placebo matching to adalimumab will be administered SC at Weeks 0, 2, 4, 6, and 8. intervention 3: Etrolizumab 105 mg will be administered SC every 4 weeks (Q4W) up to Week 12 (at Weeks 0 \[Day 1\], 4, 8, and 12 \[clinical remitters only\]). intervention 4: Placebo matching to etrolizumab will be administered SC once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 \[Day 1\], 4, 8, and 12 \[clinical remitters only\]).

Protocol document:
Prot_002.pdf: 
 
Official Title: Phase III, Randomized, Double-Blind, Double-Dummy, Placebo-
Controlled, Multicenter Study to Evaluate the Efficacy (Induction of 
Remission) and Safety of Etrolizumab Compared With Adalimumab 
and Placebo in Patients With Moderate to Severe Ulcerative Colitis 
who are Naive to TNF Inhibitors 
NCT Number: NCT02171429 
Document Date: Protocol Version 8: 15-March-2019 
 
 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, 
especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) 
and therefore is provided to you in confidence as an investigator, potential investigator, or 
consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional 
Review Board.  It is understood that this information will not be disclosed to others without written 
authorization from Roche except to the extent necessary to obtain informed consent from persons 
to whom the drug may be administered.
Etrolizumab—F. Hoffmann-La Roche Ltd
Protocol GA28949, Version 8
PROTOCOL
TITLE:
PHASE III, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY,
PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
EVALUATE THE EFFICACY (INDUCTION OF REMISSION) AND 
SAFETY OF ETROLIZUMAB COMPARED WITH ADALIMUMAB 
AND PLACEBO IN PATIENTS WITH MODERATE TO SEVERE 
ULCERATIVE COLITIS WHO ARE NAIVE TO TNF INHIBITORS
PROTOCOL NUMBER:
GA28949
VERSION NUMBER:
8
EUDRACT NUMBER:
2013-004277-27
IND NUMBER:
100366
TEST PRODUCT:
Etrolizumab (PRO145223, RO5490261)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  9 April 2014
DATES AMENDED:
Version 2:  25 June 2014
Version 3:  19 July 2014
Version 4:  18 September 2015
Version 5:  18 December 2016
Version 6:  30 August 2017
Version 7:  30 October 2018
Version 8:  See electronic date stamp below.
 
15-Mar-2019 15:20:14
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Etrolizumab—F. Hoffmann-La Roche Ltd
2/Protocol GA28949, Version 8
PROTOCOL AMENDMENT, VERSION 8:
RATIONALE
Protocol GA28949 has been amended to provide further clarification. Changes to the 
protocol, along with a rationale for each change, are summarized below:

Exploratory efficacy objectives have been modified as follows (Sections 2.1, 3.4.1, 
and 6.4.3):
–
Evaluation of response at Week 10, in subgroups by baseline expression levels 
of colonic tissue and/or peripheral blood biomarkers, has been added to predict 
patient subgroups with a greater likelihood of responding to etrolizumab.
–
Evaluation of corticosteroid-free response and remission as determined by the 
modified Mayo Clinic Score has been removed.  This endpoint is applicable 
only to studies with a maintenance phase.

Language in Section 6.4 has been updated to clarify that the efficacy analyses will 
be performed using a modified intent-to-treat analysis set including all patients 
randomized who received at least one dose of study drug, with patients grouped 
according to the treatment assigned at randomization.

The partial Mayo Clinic Score (pMCS) assessment indicated in the Schedule of 
Assessments for the 12-Week Safety Follow-Up (Appendix 2) has been removed.  
This assessment was added in 2014, but a recent review concluded that the value 
of the data from this assessment is minimal and removing it would not impact 
patient safety or the analysis of any efficacy endpoints of the study.  This change 
also accounts for the inability of patients to record data to calculate pMCS during 
this time period.
Additional minor changes have been made to improve clarity and consistency. 
Substantive new information appears in italics. This amendment represents cumulative 
changes to the original protocol.


Etrolizumab—F. Hoffmann-La Roche Ltd
3/Protocol GA28949, Version 8
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10
PROTOCOL SYNOPSIS .................................................................................... 11
1.
BACKGROUND .......................................................................................... 26
1.1
Background on Ulcerative Colitis........................................... 26
1.2
Background on Etrolizumab................................................... 27
1.3
Study Rationale and Benefit-Risk Assessment...................... 28
2.
OBJECTIVES.............................................................................................. 31
2.1
Efficacy Objectives ................................................................ 31
2.2
Safety Objectives................................................................... 34
2.3
Pharmacokinetic Objectives .................................................. 34
2.4
Exploratory Pharmacodynamic, Predictive, and 
Prognostic Objectives............................................................ 34
3.
STUDY DESIGN......................................................................................... 34
3.1
Description of Study .............................................................. 34
3.1.1
Overview of Study Design ..................................................... 34
3.1.1.1
Rescue Therapy .................................................................... 38
3.1.1.2
Number of Patients................................................................ 41
3.1.2
Data Monitoring Committee................................................... 41
3.2
End of Study and Length of Study......................................... 41
3.3
Rationale for Study Design.................................................... 42
3.3.1
Rationale for Test Product Dosage........................................ 42
3.3.2
Rationale for Patient Population ............................................ 43
3.3.3
Rationale for Control Group................................................... 44
3.3.4
Rationale for Active Comparator............................................ 44
3.3.5
Rationale for Biomarker Assessments................................... 44
3.4
Outcome Measures ............................................................... 45
3.4.1
Efficacy Outcome Measures.................................................. 45
3.4.2
Safety Outcome Measures .................................................... 46
3.4.3
Pharmacokinetic Outcome Measures.................................... 46
3.4.4
Exploratory Biomarker Outcome Measures........................... 47


Etrolizumab—F. Hoffmann-La Roche Ltd
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4.
MATERIALS AND METHODS .................................................................... 47
4.1
Patients.................................................................................. 47
4.1.1
Inclusion Criteria.................................................................... 47
4.1.2
Exclusion Criteria................................................................... 49
4.2
Method of Treatment Assignment and Blinding..................... 53
4.3
Study Treatment.................................................................... 57
4.3.1
Formulation, Packaging, and Handling.................................. 58
4.3.1.1
Etrolizumab and Placebo....................................................... 58
4.3.1.2
Adalimumab and Placebo...................................................... 59
4.3.1.3
Concomitant Background Treatment for 
Ulcerative Colitis.................................................................... 59
4.3.2
Dosage, Administration, and Compliance.............................. 59
4.3.2.1
Etrolizumab and Etrolizumab Placebo................................... 60
4.3.2.2
Adalimumab and Adalimumab Placebo................................. 61
4.3.2.3
Concomitant Background Treatment and Rescue 
Therapy ................................................................................. 62
4.3.3
Investigational Medicinal Product Accountability ................... 64
4.3.4
Assessment of Compliance ................................................... 65
4.3.5
Destruction of the Investigational Medicinal 
Product/Comparator .............................................................. 65
4.3.6
Reporting of Prefilled Syringe Complaints/Events ................. 65
4.4
Concomitant Therapy ............................................................ 66
4.4.1
Permitted Therapy................................................................. 66
4.4.2
Prohibited Therapy ................................................................ 66
4.5
Study Assessments ............................................................... 67
4.5.1
Description of Study Assessments ........................................ 67
4.5.1.1
Medical History and Demographic Data ................................ 67
4.5.1.2
Physical Examinations........................................................... 67
4.5.1.3
Vital Signs.............................................................................. 67
4.5.1.4
Ulcerative Colitis Disease Activity Assessments ................... 67
4.5.1.5
Laboratory Assessments ....................................................... 71
4.5.1.6
Chest X-ray............................................................................ 74
4.5.1.7
Electrocardiograms................................................................ 74
4.5.1.8
Patient-Reported Outcomes .................................................. 75


Etrolizumab—F. Hoffmann-La Roche Ltd
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4.5.1.9
Medication Use and Compliance........................................... 76
4.5.1.10
Samples for Roche Clinical Repository.................................. 76
4.5.2
Timing of Study Assessments ............................................... 79
4.5.2.1
Screening and Pretreatment Assessments............................ 79
4.5.2.2
Assessments during Treatment............................................. 82
4.5.2.3
Assessments at Study Completion/Early 
Withdrawal from Treatment Visit............................................ 82
4.5.2.4
Safety Follow-Up Assessments............................................. 84
4.5.2.5
Assessments at Unscheduled Visits...................................... 85
4.6
Patient, Study, and Site Discontinuation................................ 85
4.6.1
Patient Discontinuation.......................................................... 85
4.6.1.1
Discontinuation from Study Drug........................................... 86
4.6.1.2
Withdrawal from Study........................................................... 86
4.6.2
Study and Site Discontinuation.............................................. 86
5.
ASSESSMENT OF SAFETY....................................................................... 87
5.1
Safety Plan ............................................................................ 87
5.1.1
Potential Risks for Etrolizumab.............................................. 87
5.1.1.1
Serious Infections.................................................................. 88
5.1.1.2
Hypersensitivity Reactions..................................................... 91
5.1.1.3
Local Injection-Site Reactions ............................................... 92
5.1.1.4
Hepatic Effects ...................................................................... 92
5.1.1.5
Malignancies.......................................................................... 93
5.1.1.6
Immunogenicity ..................................................................... 93
5.1.1.7
Decreased Effectiveness of Immunizations........................... 94
5.1.2
Risks Associated with Adalimumab....................................... 94
5.1.3
Risks Associated with Worsening of Ulcerative 
Colitis..................................................................................... 94
5.2
Safety Parameters and Definitions ........................................ 95
5.2.1
Adverse Events ..................................................................... 95
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 95
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 96


Etrolizumab—F. Hoffmann-La Roche Ltd
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5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 97
5.3.1
Adverse Event Reporting Period ........................................... 97
5.3.2
Eliciting Adverse Event Information....................................... 97
5.3.3
Assessment of Severity of Adverse Events ........................... 98
5.3.4
Assessment of Causality of Adverse Events ......................... 98
5.3.5
Procedures for Recording Adverse Events............................ 99
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 99
5.3.5.2
Adverse Events Occurring Secondary to Other 
Events.................................................................................. 100
5.3.5.3
Persistent or Recurrent Adverse Events.............................. 100
5.3.5.4
Abnormal Laboratory Values ............................................... 101
5.3.5.5
Abnormal Vital Sign Values ................................................. 101
5.3.5.6
Abnormal Liver Function Tests............................................ 102
5.3.5.7
Deaths ................................................................................. 102
5.3.5.8
Preexisting Medical Conditions............................................ 103
5.3.5.9
Lack of Efficacy or Worsening of Ulcerative 
Colitis................................................................................... 103
5.3.5.10
Hospitalization or Prolonged Hospitalization........................ 103
5.3.5.11
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 104
5.3.5.12
Patient-Reported Outcome Data ......................................... 104
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 104
5.4.1
Emergency Medical Contacts.............................................. 105
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 105
5.4.3
Reporting Requirements for Pregnancies............................ 106
5.4.3.1
Pregnancies in Female Patients.......................................... 106
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 106
5.4.3.3
Abortions ............................................................................. 107
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 107
5.4.4
Reporting Requirements for Medical Device 
Complaints........................................................................... 107
5.5
Follow-Up of Patients after Adverse Events ........................ 107


Etrolizumab—F. Hoffmann-La Roche Ltd
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5.5.1
Investigator Follow-Up......................................................... 107
5.5.2
Sponsor Follow-Up .............................................................. 107
5.6
Post-Study Adverse Events................................................. 108
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 108
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 109
6.1
Determination of Sample Size ............................................. 109
6.2
Summaries of Conduct of Study.......................................... 110
6.3
Summaries of Treatment Group Comparability ................... 110
6.4
Efficacy Analyses ................................................................ 110
6.4.1
Primary Efficacy Endpoint.................................................... 111
6.4.2
Secondary Efficacy Endpoints............................................. 111
6.4.3
Exploratory Efficacy Endpoints............................................ 112
6.5
Safety Analyses................................................................... 112
6.5.1
Adverse Events ................................................................... 113
6.5.2
Laboratory Tests.................................................................. 113
6.6
Pharmacokinetic, Pharmacodynamic, and 
Biomarker Analyses............................................................. 114
7.
DATA COLLECTION AND MANAGEMENT ............................................. 114
7.1
Data Quality Assurance....................................................... 114
7.2
Electronic Case Report Forms............................................. 114
7.3
Electronic Patient-Reported Outcome Data......................... 115
7.4
Source Data Documentation................................................ 115
7.5
Use of Computerized Systems ............................................ 116
7.6
Retention of Records........................................................... 116
8.
ETHICAL CONSIDERATIONS.................................................................. 116
8.1
Compliance with Laws and Regulations .............................. 116
8.2
Informed Consent................................................................ 117
8.3
Institutional Review Board or Ethics Committee.................. 118
8.4
Confidentiality...................................................................... 118
8.5
Financial Disclosure ............................................................ 119


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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 119
9.1
Study Documentation .......................................................... 119
9.2
Protocol Deviations.............................................................. 119
9.3
Site Inspections ................................................................... 119
9.4
Administrative Structure....................................................... 119
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 120
9.6
Protocol Amendments ......................................................... 121
10. REFERENCES ......................................................................................... 122




Etrolizumab—F. Hoffmann-La Roche Ltd
10/Protocol GA28949, Version 8
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
PHASE III, RANDOMIZED, DOUBLE-BLIND, 
DOUBLE-DUMMY, PLACEBO-CONTROLLED, 
MULTICENTER STUDY TO EVALUATE 
THE EFFICACY (INDUCTION OF REMISSION) AND 
SAFETY OF ETROLIZUMAB COMPARED WITH 
ADALIMUMAB AND PLACEBO IN PATIENTS WITH 
MODERATE TO SEVERE ULCERATIVE COLITIS 
WHO ARE NAIVE TO TNF INHIBITORS
PROTOCOL NUMBER:
GA28949
VERSION NUMBER:
8
EUDRACT NUMBER:
2013-004277-27
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
11/Protocol GA28949, Version 8
PROTOCOL SYNOPSIS
TITLE:
PHASE III, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY,
PLACEBO-CONTROLLED, MULTICENTER STUDY TO EVALUATE 
THE EFFICACY (INDUCTION OF REMISSION) AND SAFETY OF 
ETROLIZUMAB COMPARED WITH ADALIMUMAB AND 
PLACEBO IN PATIENTS WITH MODERATE TO SEVERE 
ULCERATIVE COLITIS WHO ARE NAIVE TO TNF INHIBITORS
PROTOCOL NUMBER:
GA28949
VERSION NUMBER:
8
EUDRACT NUMBER:
2013-004277-27
IND NUMBER:
100366
TEST PRODUCT:
Etrolizumab (PRO145223, RO5490261)
PHASE:
III
INDICATION:
Ulcerative colitis
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Efficacy Objectives
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of etrolizumab (105 mg subcutaneous [SC] every 4 weeks [Q4W]) 
compared with placebo for the induction of remission in tumor necrosis factor (TNF)naive 
(i.e., naive to tumor necrosis factor inhibitor) patients with ulcerative colitis (UC) as 
determined by the Mayo Clinic Score (MCS) at Week 10
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of etrolizumab compared with adalimumab for the induction of 
remission at Week 10

To evaluate the efficacy of etrolizumab for the induction of clinical remission at Week 10

To evaluate the efficacy of etrolizumab for clinical response at Week 10

To evaluate the efficacy of etrolizumab for improvement in endoscopic appearance of the 
mucosa at Week 10

To evaluate the efficacy of etrolizumab for endoscopic remission at Week 10

To evaluate the efficacy of etrolizumab compared with placebo in achieving remission at 
Week 10 and maintaining it to Week 14 

To evaluate the efficacy of etrolizumab for histologic remission at Week 10

To evaluate the efficacy of etrolizumab for onset of action, defined as change from baseline 
in MCS rectal bleeding subscore at Week 6

To evaluate the efficacy of etrolizumab for onset of action, defined as change from baseline 
in MCS stool frequency subscore at Week 6


Etrolizumab—F. Hoffmann-La Roche Ltd
12/Protocol GA28949, Version 8

To evaluate the efficacy of etrolizumab for UC bowel movement signs and symptoms at 
Week 10 as assessed by the Ulcerative Colitis Patient-Reported Outcome Signs and 
Symptoms (UC-PRO/SS) measure

To evaluate the efficacy of etrolizumab for UC abdominal symptoms at Week 10 as 
assessed by the UC-PRO/SS measure

To evaluate the efficacy of etrolizumab for patient-reported health-related QOL at Week 10 
as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ)
The exploratory efficacy objectives for this study are as follows:

To evaluate the impact of etrolizumab on remission at Week 14 in patients who achieved 
clinical remission at Week 10 compared with placebo

To evaluate the efficacy of etrolizumab compared with placebo in achieving clinical 
remission at Week 10 and maintaining it to Week 14

To evaluate change in histologic disease activity from baseline to Week 10 as measured by 
the Nancy Histological Index 

To evaluate improvement in histologic and/or endoscopic disease activity

To evaluate change in health utilities at Week 10, as assessed by the EuroQoL 
Five-Dimension Questionnaire (EQ-5D)

To evaluate response and remission at Week 10 in subgroups by baseline expression levels 
of colonic tissue and/or peripheral blood biomarkers (including, but not limited to, 
E integrin) to predict patient subgroups with a greater likelihood of responding to 
etrolizumab

To evaluate response and remission 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 during induction of remission 
of UC 

To evaluate the incidence and severity of infection-related adverse events

To evaluate the incidence and severity of hypersensitivity reactions

To evaluate the incidence and the clinical significance of anti-therapeutic antibodies (ATAs)
to etrolizumab, or if required, adalimumab
Pharmacokinetic Objectives
The pharmacokinetic (PK) objectives for this study are as follows:

To evaluate the etrolizumab serum concentration at the time of primary and secondary 
endpoints (Weeks 10 and 14) and during drug washout at the time of safety follow-up

To evaluate the interindividual variability and potential covariate effects on etrolizumab 
serum exposure
Exploratory Pharmacodynamic, Predictive, and Prognostic Objectives
The exploratory pharmacodynamic (PD), predictive, and prognostic objectives for this study are 
as follows:

To evaluate the expression levels of biomarkers including, but not limited to, E integrin, in 
colonic tissue and/or peripheral blood and/or serum at baseline, during, or end of the 
treatment period

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


Etrolizumab—F. Hoffmann-La Roche Ltd
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Study Design
Description of Study
This is a multicenter, Phase III, randomized, double-blind, double-dummy, placebo and active 
comparator controlled study to evaluate the safety, efficacy, and tolerability of etrolizumab 
(105 mg SC Q4W) in the induction of remission for patients naive to TNF inhibitors.  
Comparisons will be made against placebo and adalimumab (160 mg SC Week 0, 80 mg SC 
Week 2, 40 mg SC Weeks 4, 6, and 8).
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 study population 
consists of TNF-naive 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 1) and involvement 
that extends to a minimum of 20 cm from the anal verge.
Patients must have had an inadequate response, loss of response, or intolerance to prior 
immunosuppressant and/or corticosteroid treatment.
Patients who are on background immunosuppressant therapy (6-MP, AZA, MTX) may be 
enrolled if they have received a stable dose for at least 8 weeks prior to randomization (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 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 the 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 randomization

If corticosteroids are being tapered, the dose has to be stable for at least 2 weeks 
immediately prior to randomization
Such patients should continue stable doses of their background corticosteroid until Week 10, at 
which point a corticosteroid taper will be initiated for clinical remitters. Initiation of corticosteroid 
or an increase in corticosteroid dose above the patient's entry dose (up to a maximum of 
30 mg/day) prednisone [or equivalent]) will not be permitted during screening.  Use of 
budesonide will be allowed at stable doses (9 mg) provided that the dose has been stable for 
4 weeks prior to randomization.  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 randomization.  Certain concomitant treatments are prohibited 
(see protocol for list of all prohibited concomitant treatments).  
A total of approximately 350 patients from approximately 115 global sites will be randomized in 
a 2:2:1 ratio (etrolizumab:adalimumab:placebo).  Patients will be stratified by concomitant 
treatment with corticosteroids (yes/no) at randomization, concomitant treatment with 
immunosuppressants (yes/no) at randomization, and disease activity measured during 
screening (MCS 9/MCS 10).
The study will be divided into:

Screening period of up to 35 days

Double-blind treatment period of up to 14 weeks, which consists of a 10-week induction 
period and an additional 4-week treatment period for patients who meet the definition of 
clinical remission at Week 10

Safety follow-up period of 12 weeks.




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Oral Corticosteroids during the Study
During the Induction Phase, patients are to maintain their stable baseline corticosteroid dose.  
For patients who achieve clinical remission and remain in the study for an additional 4 weeks 
beyond the Week 10 Induction Phase, corticosteroids are to be tapered starting from Week 10.  
Patients who were 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.  
Patients receiving budesonide should taper their dose starting from Week 10 from 9 mg every 
day to 9 mg every other day for 2 weeks and then discontinue budesonide treatment.
Number of Patients
A total of approximately 350 patients are to be randomized into one of three study treatment 
groups in a 2:2:1 ratio as follows:

Treatment Group A:  etrolizumab SC plus adalimumab placebo SC 

Treatment Group B:  adalimumab SC plus etrolizumab placebo SC 

Treatment Group C:  etrolizumab placebo SC plus adalimumab placebo SC 
Target Population
Patients must meet the following criteria for study entry:

Able and willing to provide written informed consent

1880 years of age, inclusive

Diagnosis of UC established at least 3 months prior to randomization (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 1 during the screening 
period (prior to day of randomization)..  See 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 randomization.  See protocol for additional information regarding the time 
window.

Naive to treatment with TNF inhibitor therapy

Patients must have had an inadequate response, loss of response, or intolerance to prior 
immunosuppressant and/or corticosteroid treatment.
Inadequate response to, loss of response to, or intolerance to prior immunosuppressant 
treatment is defined as one or more of the following: 
Persistent signs and symptoms of active disease despite a history of at least one 
12-week regimen of oral AZA (1.5 mg/kg) or 6-MP (0.75 mg/kg) and/or 
MTX (15 mg/week) within the previous 5 years
Persistent signs and symptoms of active disease despite a 6TG level of 
230 pmol/8 108 RBCs during at least one 12-week regimen of oral AZA or 
6mercaptopurine (6MP) at a stable or increasing dose within the previous 5 years.
History of intolerance to AZA, 6-MP, or MTX (including, but not limited to, 
nausea/vomiting, abdominal pain, pancreatitis, LFT abnormalities, lymphopenia, 
TPMT genetic mutation, infection) within the previous 5 years


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Inadequate response, loss of response, or intolerance to corticosteroid treatment is defined 
as one or more of the following: 
Steroid refractory:  persistent symptoms of active disease despite treatment with at 
least one 4-week induction regimen that included a dose of 30 mg prednisone (oral) 
daily, or equivalent, for at least 2 weeks or IV for at least 1 week within the previous 
5 years
Steroid dependent:  two failed attempts to taper steroids below a dose equivalent to 
10 mg prednisone (oral) daily
Steroid intolerant:  history of intolerance to corticosteroids (including, but not limited to, 
Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, infection) 
within the previous 5 years 

Any ongoing UC therapy must be at stable doses:
May be receiving oral 5-ASA compounds provided that the dose has been stable 
for 4 weeks immediately prior to randomization
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 randomization.  
If corticosteroids are being tapered, the dose has to be stable for at least 2 weeks 
immediately prior to randomization.
May be receiving budesonide therapy at a stable dose of up to 9 mg a day provided 
that the dose has been stable for 4 weeks prior to randomization
May be receiving probiotics (e.g., Culturelle, Saccharomyces boulardii), provided that 
the dose has been stable for the 2 weeks immediately prior to randomization
May be receiving AZA, 6-MP, or MTX, provided that the dose has been stable for the 
8 weeks immediately prior to randomization

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 for the duration of the study 
[i.e., 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 study and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 
24 weeks after the last dose of study drug to avoid exposing the embryo to study drug.  
Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical study 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)
Include removal of any adenomatous polyps 
Document evidence of surveillance for dysplasia for all patients with left-sided colitis 
of 12 years’ duration and total/extensive colitis of 8 years duration


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


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Exclusion Criteria Related to General Safety

Pregnant or lactating

Lack of peripheral venous access

Hospitalized (other than for elective reasons) during the screening period

Inability to comply with study protocol, in the opinion of the investigator

Significant uncontrolled comorbidity, such as cardiac (e.g., moderate to severe heart failure 
New York Heart Association Class III/IV), pulmonary, renal, hepatic, endocrine, or 
gastrointestinal disorders

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:
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.
Local basal cell or squamous cell carcinoma of the skin that has been excised and is 
considered cured is not exclusionary 
Exclusion Criteria Related to Infection Risk

Congenital or acquired immune deficiency

Patients must undergo screening for HIV and test positive for preliminary and confirmatory 
tests

Positive hepatitis C virus (HCV) antibody test result, unless the patient (1) has undetectable 
HCV RNA levels for 6 months after completing a successful course of HCV anti-viral 
treatment and an undetectable HCV RNA at screening or (2) has a known history of HCV 
antibody positivity with a history of undetectable HCV RNA 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 is positive, the patient is not eligible for this study.  
In the event the HBV DNA test cannot be performed, the patient is not eligible for 
this study. 
If the HBV DNA test is negative, the patient is eligible for this study.  These 
patients will undergo periodic monitoring for HBV DNA during the study.

Evidence of or treatment for Clostridium difficile (as assessed by C. difficile toxin testing) 
within 60 days prior to randomization or other intestinal pathogens (as assessed by stool 
culture and ova and parasite evaluation) within 30 days prior to randomization.


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
Evidence of or treatment for clinically significant cytomegalovirus (CMV) colitis (based on 
the investigator’s judgment) within 60 days prior to randomization.  Laboratory confirmation 
of CMV from colon biopsy sample is required during screening evaluation only if clinical 
suspicion is high and to determine the need for CMV treatment.

History of active or latent TB (regardless of treatment history)
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 
randomization suspicious for pulmonary TB are not eligible for this study.
Any immunosuppressed patient with a strong suspicion of TB exposure and no prior 
vaccination with bacille Calmette-Guérin (BCG) should be considered at risk for having 
latent TB infection.  Patients at risk for TB exposure include:
Patients who have household contact with a person with active TB 
Patients living in areas with high incidence of TB
Patients who frequently visit areas with high prevalence of active TB
Patients who meet these criteria should be evaluated per local practice to exclude 
latent TB.

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 prior to screening

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 randomization
Fungal infections of the nail beds
Oral or vaginal candidiasis that has resolved with or without treatment prior to 
randomization

Any major episode of infection requiring treatment with IV antibiotics within 8 weeks prior to 
screening or oral antibiotics within 4 weeks prior to screening
Treatment with antibiotics as adjunctive therapy for UC in the absence of documented 
infection is not exclusionary.

Received a live attenuated vaccine within 4 weeks prior to randomization

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 maximum length of the treatment period will be 14 weeks.  Patients who do not achieve 
clinical remission at Week 10, patients who receive defined rescue treatment, and all patients 
who complete the 14-week treatment period of the study will be given the option of enrolling into 
Part 1 (OLE) of Study GA28951 after Week 12, if eligible, where they will receive open-label 
etrolizumab treatment.


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Patients not enrolling in Part 1 (OLE) of Study GA28951 to receive open-label etrolizumab will 
have a 12-week safety follow-up after the last dose of study medication in this study.  These 
patients will then be requested to enroll into Part 2 (SM) of Study GA28951 only for an 
additional 92 weeks of extended PML follow-up.
The total length of the study is expected to last from the first patient screened to either the last 
patient last follow-up visit in this protocol or last patient enrolled into Study GA28951, whichever 
is later.
End of Study
The end of the study is defined as the last patient last safety follow-up visit in this protocol or 
last patient in this protocol enrolled into Study GA28951 (OLESM), whichever is later.
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:
Primary Outcome Measure:

Remission at Week 10
Secondary Outcome Measures:

Clinical remission at Week 10

Clinical response at Week 10

Improvement in endoscopic appearance of the mucosa at Week 10

Endoscopic remission at Week 10

Remission at Week 10 and Week 14

Histologic remission at Week 10

Change from baseline in MCS rectal bleeding subscore at Week 6

Change from baseline in MCS stool frequency subscore at Week 6

Change from baseline to Week 10 in UC bowel movement signs and symptoms as 
assessed by the UC-PRO/SS

Change from baseline to Week 10 in UC abdominal symptoms as assessed by the 
UC-PRO/SS

Change from baseline to Week 10 in patient's health-related QOL as assessed by the 
overall score of the IBDQ
Exploratory Efficacy Outcome Measures:

Clinical remission at Week 10 and remission at Week 14

Clinical remission at Weeks 10 and 14

Change from baseline to Week 10 in histologic disease activity 

Improvement in histologic and/or endoscopic disease activity from baseline

Change in health utilities, as assessed by the EQ-5D, from baseline to Week 10

Response and remission at Week 10 in patient subgroups by baseline expression levels of 
colonic tissue and/or peripheral blood biomarkers, including, but not limited to, E integrin

Response and remission endpoints, as determined by the mMCS 
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence and severity of adverse events

Incidence of serious adverse events

Incidence and severity of infection-related adverse events

Incidence of serious infection-related adverse events

Incidence and severity of injection-site reactions 


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
Incidence of adverse events leading to study drug discontinuation

Incidence of laboratory abnormalities

Incidence and severity of hypersensitivity reaction events

Incidence of ATAs to etrolizumab, or if required, adalimumab
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:

Serum concentration during drug washout (through end of safety follow-up)

Serum concentration at primary and secondary endpoints Weeks 10 and 14
Exploratory Biomarker Outcome Measures
The exploratory biomarker outcome measures for this study are as follows:

Relationship between baseline levels of exploratory colonic tissue and/or peripheral blood 
and/or serum biomarkers and changes in response to treatment or disease progression

Relationship between baseline levels of stool biomarkers, which may include, but are not 
limited to, those in the microbiota and bacterial cultures

Changes from baseline in stool biomarkers in response to treatment or disease progression
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
Adalimumab (Humira) is supplied for single-use as a 1-mL glass PFS with a fixed 27-gauge 
½-inch needle, providing 40 mg (0.8 mL) of adalimumab administered as an SC injection, or as 
a single-use, 1-mL, glass PFS with a fixed 29-gauge ½-inch needle, providing 40 mg (0.4 mL) of 
adalimumab.
Adalimumab placebo will be supplied by the Sponsor as a liquid formulation in PFSs and is 
administered as an SC injection. Each 1-mL PFS will contain 0.7 mL of a solution of 20 mM 
histidine, 0.2 M arginine succinate, and 0.04% polysorbate 20, pH 5.8.
Non-Investigational Medicinal Products
Patients are to continue on their baseline dose of corticosteroid (including budesonide) to the 
end of the Induction Phase (Week 10).  Tapering of corticosteroid (including budesonide) is to 
be attempted from Week 10 in clinical remitters.
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.
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


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Statistical Methods
Primary Analysis
The primary analysis will be performed when all data through Week 14 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 who were blinded during the study will remain 
blinded to individual treatment assignment until after the study is completed (after all patients 
have either completed the safety follow-up period or discontinued early from the study) and the 
database is locked.
Detailed specifications of the statistical methods will be described in the Statistical Analysis 
Plan (SAP).
Determination of Sample Size  
A total of approximately 350 patients will be randomized in a 2:2:1 ratio: etrolizumab (n140), 
adalimumab (n140), and placebo (n70), respectively.
Under the assumption of a difference in remission rates between the etrolizumab and placebo 
arms of 25% (35% vs. 10%), the sample size of 140 patients receiving etrolizumab and 70 
patients receiving placebo will provide 90% power to detect a difference with use of a 2 test at 
the two-sided 5% significance level. The assumption is based on the observed Week 10 
remission results in the Phase II etrolizumab study for the TNF-naive subgroup. In addition, 
under the assumption of a remission rate of 20% in the adalimumab arm (based on the clinical 
remission induction results achieved in the Phase III adalimumab ULTRA2 trial), the planned 
size of 140 patients/active treatment arm will provide approximately 80% power to detect a 
15% absolute difference between the remission rates in the etrolizumab and adalimumab arms 
(35% vs. 20%), with use of a 2 test at the two-sided 5% significance level.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
5-ASA
5-aminosalicylate
6-MP
6-mercaptopurine
AIS
adenocarcinoma in situ
ATA
anti-therapeutic antibody
AZA
azathioprine
BCG 
bacille Calmette-Guérin 
CD
Crohn’s disease
CHO
Chinese hamster ovary
CIN
cervical intraepithelial neoplasia 
CMV
cytomegalovirus
CRO
contract research organization
CRP
C-reactive protein
CSF
cerebrospinal fluid
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
ePRO 
electronic patient-reported outcomes
EQ-5D
EuroQoL Five-Dimension Questionnaire
FDA
U.S. Food and Drug Administration
GI
gastrointestinal
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B 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
iDMC
independent Data Monitoring Committee
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug


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Abbreviation
Definition
IRB
Institutional Review Board
IV 
intravenous
IxRS
interactive voice/Web-based response system 
JAK
Janus kinase 
JCV
John Cunningham virus
LD
loading dose
LFT
liver function test
MAb
monoclonal antibody
MAdCAM-Fc
mucosal addressin cell adhesion molecule-fragment 
crystallizable region
MCS
Mayo Clinic Score
mMCS
modified Mayo Clinic Score
MMF
mycophenolate mofetil
MP
mercaptopurine
MRI
magnetic resonance imaging
MTX
methotrexate
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
NSAID
nonsteroidal anti-inflammatory drug 
OLE
open-label extension
OLE-SM
open-label extensionsafety monitoring
PA
posteroanterior
PCR
polymerase chain reaction
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
TNF-naive
naive to tumor necrosis factor inhibitor
UC
ulcerative colitis
UC-PRO/SS
Ulcerative Colitis Patient-Reported Outcome Signs and 
Symptoms
ULN
upper limit of normal


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


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More recently, monoclonal antibodies (MAbs) targeting tumor necrosis factoralpha 
(TNF-), such as infliximab and adalimumab, have been used to induce and maintain 
remission in patients whose immunomodulatory therapy fails, are steroid dependent or 
refractory, and have moderately to severely active UC.  These biologic agents induce 
remission in up to 40% of patients, but sustained remission is seen in only 10%20% of 
patients over 1 year (Rutgeerts et al. 2005; Sandborn et al. 2013).  Importantly, TNF
inhibitor therapies are associated with serious adverse events, such as bacterial 
infection, including tuberculosis (TB), disseminated fungal infections, lymphoma, and 
demyelination (Chang and Lichtenstein 2006).  In fulminant steroid-unresponsive colitis, 
infliximab and (less commonly) cyclosporine are utilized as bridging agents to avoid 
urgent colectomy.  With either therapy, however, treatment failure occurs in 
approximately 55%60% of patients (Laharie et al. 2012).
In short, a large proportion of patients with moderately to severely active UC do not 
maintain a durable response to therapy.  Available therapies are associated with 
significant adverse events and at best achieve sustained remission in only 10%30% of 
patients with IBD who have chronic disease (Hanauer et al. 2002; Sandborn et al. 2005).  
Patients whose disease fails to respond to medical therapy may be treated with total 
proctocolectomy with an ileal pouch-anal anastomosis.  Although surgical intervention 
may be curative, complications such as chronic pouchitis, fecal incontinence, or 
decreased female fertility can occur (Bradley and Oliva-Hemker 2012).  The current 
treatments are associated with significant adverse events, resulting in low rates of 
sustained remission, or are highly invasive.
Consequently, there continues to be a high unmet medical need in moderately to 
severely active UC.  Targeted therapy with an improved safety profile and ability to 
sustain remission and prevent long-term complications would provide a valuable 
therapeutic option for these patients.
1.2
BACKGROUND ON ETROLIZUMAB
A new class of molecules targeting the integrin receptors that regulate leukocyte 
trafficking to specific tissues in the body has been developed for treatment of IBD.  
Clinical studies have shown evidence of efficacy for these agents, including natalizumab 
(anti-4) for Crohn’s disease (CD) (Sandborn et al. 2005) and vedolizumab (anti-47) 
for UC and CD (Feagan et al. 2005, 2008); both agents have been approved for their 
respective indications.  Natalizumab and vedolizumab require IV administration, but only 
vedolizumab is gut-selective.  Natalizumab is not gut-selective and is associated with the 
risk of progressive multifocal leukoencephalopathy (PML). Etrolizumab distinguishes 
itself from these molecules by specifically binding the integrin 7 subunit, found in both 
47 (Holzmann et al. 1989; Hu et al. 1992) and E7 (Cepek et al. 1993), which 
regulate trafficking and retention of leukocyte/lymphocyte subsets, respectively, in the 
intestinal mucosa.


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It is important to note that etrolizumab does not bind to 41 (target for natalizumab), 
which regulates trafficking to both mucosal and non-mucosal tissues, including the CNS.  
Etrolizumab, therefore, represents a novel gut mucosalselective anti-trafficking agent 
whose selectivity may enhance efficacy in UC and eliminate generalized 
immunosuppression by preferentially targeting trafficking to the gut rather than to other 
organs and tissues.  Data from multiple nonclinical toxicology studies of up to 6 months’ 
duration in adult animals demonstrated no adverse effects in any organ system 
(including the CNS and hematologic and cardiovascular systems).  No adverse events 
were observed in the embryo-fetal developmental toxicity studies.
Etrolizumab is a humanized MAb based on the human IgG1 subgroup-III VH, 
subgroup-1 VL consensus sequences and was constructed using standard 
recombinant DNA techniques.  This recombinant antibody consists of two heavy chains 
(446 residues) and two light chains (214 residues) and is produced in Chinese hamster 
ovary (CHO) cells that have been genetically engineered to synthesize the antibody.  
The protein is manufactured in bioreactors and purified using a series of harvest, 
purification, and formulation steps.  The potency of etrolizumab is determined by an 
in vitro assay that measures the inhibition of adhesion of 47-expressing cells to 
mucosal addressin cell adhesion moleculefragment crystallizable region (MAdCAM-Fc).
Safety assessments for etrolizumab have been completed in the adult Phase I, Phase II, 
and Phase II open-label extension (OLE) studies without significant safety concerns.
The following is a summary of the etrolizumab safety experience to date:

There were no observed significant adverse effects in multiple nonclinical toxicity 
studies of up to 6 months’ duration in adult animals or in embryo-fetal 
developmental toxicity studies.  No adverse effects were seen in any organ system 
(including the CNS and hematologic and cardiovascular systems), no effects were 
seen in embryo-fetal development, and there was no evidence of increased rates of 
infection.

No significant adverse safety signal, including any evidence of increased rates of 
serious or opportunistic infections, was associated with etrolizumab treatment in the 
Phase I or Phase II trials in adult patients with moderately to severely active UC who 
received either single or multiple doses of intravenous (IV) or subcutaneous (SC) 
etrolizumab.

No events of PML have been reported in etrolizumab-treated patients.
See the most recent Etrolizumab Investigator's Brochure for details on nonclinical and 
clinical studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Although effective therapeutic options, including TNF inhibitors, are available to help 
patients with moderate to severe UC to reduce the acute symptomatic flares in disease 
activity, no currently available therapy, including approved anti-integrins (natalizumab for 


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CD and vedolizumab for UC and CD), achieves sustained remission in more than 
10%30% of patients with IBD (Hanauer et al. 2002; Sandborn et al. 2005;
Feagan et al. 2013).  Furthermore, TNF inhibitors are associated with elevated rates of 
serious bacterial infection, including TB, and (more rarely) lymphoma and demyelination 
(Chang and Lichtenstein 2006).  Adalimumab has been very commonly associated with 
respiratory tract infections, neutropenia, injection-site reactions, rash, musculoskeletal 
pain, headache, elevated liver enzymes, abdominal pain, and nausea.  Adalimumab has 
been commonly associated with intestinal, skin, soft tissue, genitourinary tract, and 
systemic infections (including sepsis); skin cancers (excluding melanoma); 
hypersensitivity; mood alterations; tachycardia; and vascular disorders (Humira
Summary of Product Characteristics [SmPC]).  Consequently, patients and investigators 
carefully weigh these benefit-risk tradeoffs both before embarking and while managing 
long-term treatment with TNF inhibitors.
The recent availability of the gut-selective anti-integrin class of monoclonal antibody 
treatments may provide potential treatment alternatives to TNF inhibitors and may 
exhibit a more tolerable safety profile.
Etrolizumab distinguishes itself from other anti-integrins on the basis of gut selectivity 
combined with a dual mechanism of action.  It binds E7 in addition to 47 and so 
regulates retention as well as trafficking of leukocytes/lymphocytes in the intestinal 
mucosa.
No clinically significant safety signals have been detected on administration of 
etrolizumab to patients with moderate to severe UC across a dose range of 0.310.0 
mg/kg IV/SC in the single-ascending-dose stage and of 0.53.0 mg/kg SC and 4 mg/kg 
IV monthly for three doses in the multidose stage of the Phase I study.
A global Phase II multicenter study (Study ABS4986g; EUCALYPTUS) designed to 
determine the exposure-response relationship and to further characterize the safety and 
tolerability of etrolizumab in treatment of adult patients with moderately to severely active 
UC has been completed.  Patients whose treatment with standard therapy and/or TNF 
inhibitors has failed 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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Compared with patients assigned to receive placebo, patients who received etrolizumab 
showed clinically meaningful efficacy for both doses:  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.  No new safety signals were observed and etrolizumab was 
well tolerated in the Phase II EUCALYPTUS study and in the OLE study (SPRUCE), and 
no events of PML have been reported to date. 
Given the efficacy and safety profile demonstrated in the Phase II studies, further 
investigation is warranted to compare sustained clinical remission with etrolizumab 
against adalimumab in a previously TNF-naive population. 
The present double-blinded, placebo-controlled and active-comparator study employs a 
robust design that uses independent and centrally read endoscopy to confirm patient 
eligibility and endpoint determination.  The study is powered to detect a clinically 
meaningful difference of 25% in the proportion of patients achieving induction of 
remission at Week 10 between etrolizumab-treated patients and placebo-treated 
patients.  The study is also powered to detect a clinically meaningful difference of 15% in 
the proportion of patients achieving induction of remission between etrolizumab-treated 
patients and placebo-treated patients with the TNF inhibitor adalimumab 10 weeks after 
initiation of treatment.  All patients will be allowed to receive rescue therapy at any time.  
Non-remitters at Week 10, patients requiring use of rescue medications who complete 
the Week 10 assessment, and all patients at Week 14 will be allowed to enroll in an OLE 
study beginning at Week 12 to receive open-label etrolizumab therapy, if eligible.  
There is no known safety risk identified for etrolizumab at this time, but as an 
investigational medicinal product with limited Phase II data, the full safety profile for 
etrolizumab will be further characterized as Phase III clinical development progresses.  A 
safety plan is provided in Section 5.1 that describes potential risks for etrolizumab and 
the risk-mitigation strategies to minimize risks for the patients in this trial.  
Refer to the most recent Etrolizumab Investigator’s Brochure for additional details on 
clinical and nonclinical studies and additional safety information.


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2.
OBJECTIVES
The study will assess the efficacy of etrolizumab compared with placebo for induction of 
remission and will also carry out a comparative assessment of etrolizumab and 
adalimumab in inducing remission.
2.1
EFFICACY OBJECTIVES
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of etrolizumab (105 mg SC every 4 weeks [Q4W]) 
compared with placebo for the induction of remission in TNF-naive patients with UC 
as determined by the MCS at Week 10
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of etrolizumab compared with adalimumab for the induction 
of remission at Week 10

To evaluate the efficacy of etrolizumab for the induction of clinical remission at 
Week 10

To evaluate the efficacy of etrolizumab for clinical response at Week 10

To evaluate the efficacy of etrolizumab for improvement in endoscopic appearance 
of the mucosa at Week 10

To evaluate the efficacy of etrolizumab for endoscopic remission at Week 10

To evaluate the efficacy of etrolizumab compared with placebo in achieving 
remission at Week 10 and maintaining it to Week 14 

To evaluate the efficacy of etrolizumab for histologic remission at Week 10

To evaluate the efficacy of etrolizumab for onset of action, defined as change from 
baseline in MCS rectal bleeding subscore at Week 6

To evaluate the efficacy of etrolizumab for onset of action, defined as change from 
baseline in MCS stool frequency subscore at Week 6

To evaluate the efficacy of etrolizumab for UC bowel movement signs and 
symptoms at Week 10 as assessed by the Ulcerative Colitis Patient-Reported 
Outcome Signs and Symptoms (UC-PRO/SS) measure

To evaluate the efficacy of etrolizumab for UC abdominal symptoms at Week 10 as 
assessed by the UC-PRO/SS measure

To evaluate the efficacy of etrolizumab for patient-reported health-related QOL at 
Week 10 as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ)
The exploratory efficacy objectives for this study are as follows:

To evaluate the impact of etrolizumab on remission at Week 14 in patients who 
achieved clinical remission at Week 10 compared with placebo

To evaluate the efficacy of etrolizumab compared with placebo in achieving clinical 
remission at Week 10 and maintaining it to Week 14


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
To evaluate change in histologic disease activity from baseline to Week 10 as 
measured by the Nancy Histological Index 

To evaluate improvement in histologic and/or endoscopic disease activity

To evaluate change in health utilities at Week 10, as assessed by the EuroQoL 
Five-Dimension Questionnaire (EQ-5D)

To evaluate response and remission at Week 10 in subgroups by baseline 
expression levels of colonic tissue and/or peripheral blood biomarkers (including, 
but not limited to, E integrin) to predict patient subgroups with a greater likelihood 
of responding to etrolizumab

To evaluate response and remission endpoints, as determined by the modified MCS
(mMCS)
The efficacy outcomes definitions are given in Table 1.


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Table 1
Efficacy Outcomes Definitions
Outcome Measure
Outcome Measure Definition
Mayo Clinic Score
MCS is a composite of 4 assessments, each rated from 03:  stool frequency, rectal 
bleeding, endoscopy, and physician’s global assessment
Partial Mayo Clinic Score
pMCS is a composite of 3 assessments, each rated from 03:  stool frequency, rectal 
bleeding, and physician’s global assessment
Modified MCS
mMCS is a composite of 3 assessments of the MCS, each rated from 03:  stool 
frequency, rectal bleeding, and endoscopy
Remission
MCS 2 with individual subscores 1 and a rectal bleeding subscore of 0
Clinical remission
MCS 2 with individual subscores 1
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
Improvement in endoscopic appearance 
of the mucosa
Endoscopic subscore 1
Endoscopic remission
Endoscopic subscore0
Histologic remission
NHI 1 a
MCS Mayo Clinic Score; mMCS modified Mayo Clinic Score; pMCS partial Mayo Clinic Score; NHI Nancy histological index.
a See Appendix 12


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2.2
SAFETY OBJECTIVES
The safety objectives for this study are as follows:

To evaluate the overall safety and tolerability of etrolizumab during induction of 
remission of UC 

To evaluate the incidence and severity of infection-related adverse events

To evaluate the incidence and severity of hypersensitivity reactions

To evaluate the incidence and the clinical significance of anti-therapeutic 
antibodies (ATAs) to etrolizumab, or if required, adalimumab
2.3
PHARMACOKINETIC OBJECTIVES
The pharmacokinetic (PK) objectives for this study are as follows:

To evaluate the etrolizumab serum concentration at the time of primary and 
secondary endpoints (Weeks 10 and 14) and during drug washout at the time of 
safety follow-up.

To evaluate the interindividual variability and potential covariate effects on 
etrolizumab serum exposure
2.4
EXPLORATORY PHARMACODYNAMIC, PREDICTIVE, AND 
PROGNOSTIC OBJECTIVES
The exploratory pharmacodynamic (PD), predictive, and prognostic objectives for this 
study are as follows:

To evaluate the expression levels of biomarkers including, but not limited to, E 
integrin, in colonic tissue and/or peripheral blood and/or serum at baseline, during,
or end of the treatment period

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
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
3.1.1
Overview of Study Design
This is a multicenter, Phase III, randomized, double-blind, double-dummy, placebo 
and active comparator controlled study to evaluate the safety, efficacy, and tolerability 
of etrolizumab (105 mg SC Q4W) in the induction of remission for patients naive to 
TNF inhibitors.  Comparisons will be made against placebo and adalimumab 
(160 mg SC Week 0, 80 mg SC Week 2, 40 mg SC Weeks 4, 6, and 8).
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]). 


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Disease severity will be measured using the MCS (see Appendix 4), which is the current 
outcome measure accepted by regulatory authorities for drug development in UC.  The 
study population consists of TNF-naive 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 4.5.1.4, a rectal bleeding subscore 1, and a 
stool frequency subscore 1) and involvement that extends to a minimum of 20 cm from 
the anal verge.
Patients must have had an inadequate response, loss of response, or intolerance to 
prior immunosuppressant and/or corticosteroid treatment.
Patients who are on background immunosuppressant therapy (6-MP, AZA, MTX) may 
be enrolled if they have received a stable dose for at least 8 weeks prior to 
randomization (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 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 the 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 randomization

If corticosteroids are being tapered, the dose has to be stable for at least 2 weeks 
immediately prior to randomization
Such patients should continue stable doses of their background corticosteroid until 
Week 10, at which point a corticosteroid taper will be initiated for clinical remitters.
Initiation of corticosteroid or an increase in corticosteroid dose above the patient's entry 
dose (up to a maximum of 30 mg/day prednisone [or equivalent]) will not be permitted 
during screening.  Use of budesonide will be allowed at stable doses (9 mg) provided 
that the dose has been stable for 4 weeks prior to randomization.  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 
randomization.  Certain concomitant treatments are prohibited (see Section 4.1.2 for list 
of all prohibited concomitant treatments).  


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A total of approximately 350 patients (see Figure 1) from approximately 115 global sites
will be randomized in a 2:2:1 ratio (etrolizumab:adalimumab:placebo).  Patients will be 
stratified by concomitant treatment with corticosteroids (yes/no) at randomization, 
concomitant treatment with immunosuppressants (yes/no) at randomization, and disease 
activity measured during screening (MCS 9/MCS 10). 
The study will be divided into:

Screening period of up to 35 days (for details see Section 4.5.2.1)

Double-blind treatment period of up to 14 weeks, which consists of a 10-week 
induction period and an additional 4-week treatment period for patients who meet 
the definition of clinical remission at Week 10 

Safety follow-up period of 12 weeks
An extended safety-monitoring period of an additional 92 weeks (after 12-week safety 
follow-up) for PML will be conducted in an OLE and safety monitoring (OLE-SM) study 
(GA28951) under a separate protocol.
The study design is double-blind, double-dummy, placebo-controlled so all patients will 
receive two study treatments:  active etrolizumabadalimumab placebo, 
active adalimumabetrolizumab placebo, or etrolizumab placeboadalimumab placebo. 
Study Drug Administration
Etrolizumab/etrolizumab placebo and adalimumab/adalimumab placebo will be 
administered SC via a prefilled syringe (PFS) in the clinic by an unblinded health care 
professional (HCP) because the adalimumab syringe is not visually identical to the 
adalimumab placebo syringe.  Unblinded HCPs will not be involved in performing patient 
assessments and will have no further interaction with blinded site staff or patients.  Study 
site personnel involved in performing patient assessments and the patients must remain 
blinded to study treatment. 
 
Patients randomized to an active treatment arm will receive one active drug and one 
placebo according to the randomization code to achieve blinding.  Patients randomized 
to the placebo arm will receive no active treatment but will receive etrolizumab placebo 
SC and adalimumab placebo SC.  The injections are not required to be administered 
in any specific order.  Patients will be monitored for 1 hour in the clinic following the 
injections.
A detailed guide to the injections required at each study visit is provided in Section 4.2
and Table 3.


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Patients are to visit the clinic every 2 weeks from Day 1 to Week 10 and at Weeks 12 
and 14 only for patients who achieve clinical remission at Week 10. 
The last dose of adalimumab/adalimumab placebo will be given at Week 8, after which 
patients will begin a 4-week washout period from adalimumab.  Patients who achieve 
clinical remission at Week 10 (without use of rescue medications) will continue in the 
study.  Patients continuing beyond Week 10 will receive etrolizumab/etrolizumab 
placebo at Week 12.  The patient’s clinical remission status will be assessed again at 
Week 14 by MCS. 
Patients not achieving clinical remission at Week 10 and patients who achieve clinical 
remission at Week 10 but required the use of rescue medications prior to Week 10 
should remain in the blinded study until Week 12.  They will not receive any more study 
medication in this study after Week 10.  These patients may enroll in Part 1 (OLE) of
Study GA28951 at Week 12 (Day 1 OLE), if eligible, where they will receive open-label 
etrolizumab (see Section 4.5.2.3).  Clinical remitters at Week 10 (who did not use rescue 
medications prior to Week 10) should remain in the blinded study until Week 14, at 
which time they may enroll in the Part 1 (OLE) of Study GA28951, if eligible.  The first 
dose of open-label etrolizumab will be given upon enrollment into Part 1 (OLE) of Study 
GA28951.  If patients are not eligible to enroll in Part 1 (OLE) of Study GA28951, they 
will enter the 12-week safety follow-up period of this study and will then be requested to 
enroll in Part 2 (SM) of Study GA28951 for 92 weeks of extended PML monitoring.
Concomitant Drugs for Ulcerative Colitis during the Study
Throughout the treatment phase of the study, patients are to maintain their stable 
baseline doses of their concomitant medications (5-ASA, corticosteroids, 
immunosuppressants) for UC except that all patients receiving corticosteroids who 
achieve clinical remission and who continue in this study past Week 10 must begin a 
corticosteroid taper at Week 10.
Immunosuppressants during 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 
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.


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Oral Corticosteroids during the Study
During the Induction Phase, patients are to maintain their stable baseline corticosteroid 
dose.  For patients who achieve clinical remission and remain in the study for an 
additional 4 weeks beyond the Week 10 Induction Phase, corticosteroids are to be 
tapered starting from Week 10.  Patients who were 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.  Patients receiving budesonide should 
taper their dose starting from Week 10 from 9 mg every day to 9 mg every other day for 
2 weeks and then discontinue budesonide treatment.
3.1.1.1
Rescue Therapy
Rescue Therapy That Can Be Given with Study Medication for the 
Treatment of Ulcerative Colitis
Prior to Week 10, any patient who requires initiation of an immunosuppressant (AZA, 
6-MP, or MTX), corticosteroid, or oral or topical 5-ASA, or who requires an increase in 
dose over baseline levels for treatment of worsening disease symptoms should stay in 
the study until Week 12 after performing the Week 10 assessment.  Patients not 
achieving clinical remission at the Week 10 assessment and patients who achieve 
clinical remission at Week 10 but required the use of rescue medications prior to 
Week 10 can enroll in Part 1 (OLE) of Study GA28951 to receive open-label etrolizumab, 
if eligible, at Week 12 (a 2-week delay to allow for adalimumab washout).  Alternatively, 
they can enter the 12-week safety follow-up and then enroll in Part 2 (SM) of Study 
GA28951 for extended PML monitoring. 
After Week 10, any patient who requires initiation of an immunosuppressant, 
corticosteroid, or oral or topical 5-ASA or increase in dose over baseline levels for 
treatment of worsening disease symptoms should remain in the study to perform the 
Week 14 assessment and can then enroll in Part 1 (OLE) of Study GA28951 to receive 
open-label etrolizumab, if eligible, or enter the 12-week safety follow-up and then enroll 
in Part 2 (SM) of Study GA28951 for extended PML monitoring.
Endoscopy to document disease activity for patients exiting the treatment period early 
for any reason may be performed at the discretion of the investigator.


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Rescue Therapy That Cannot Be Given with Study Medication for the 
Treatment of Ulcerative Colitis
At ANY time during the conduct of the study, use of other immunosuppressive agents 
including, but not limited to, anakinra, abatacept, anti-integrins, T- or B-cell depleters 
(except AZA and 6-MP), TNF inhibitors (including TNF inhibitor biosimilars), cyclosporine, 
tacrolimus, anti-adhesion molecules, Janus kinase (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 the 12-week safety 
follow-up period of this study.  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 and Appendix 2).


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Figure 1
Study Schema
6-MP6-mercaptopurine; AZAazathioprine; CScorticosteroid; dday; EPendpoint; MCSMayo Clinic Score; 
OLEopen--label extension; OLE-SMopen-label extensionsafety monitoring study; MTX methotrexate; Q2W every 2 
weeks; Q4W every 4 weeks; QDonce a day; QODevery other day; Rxstudy treatment; SCsubcutaneous; SMsafety 
monitoring; TNF-naivenaive to tumor necrosis factor inhibitor; UCulcerative colitis; wk week.


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3.1.1.2
Number of Patients
A total of approximately 350 patients are to be randomized into one of three study 
treatment groups in a 2:2:1 ratio as follows:

Treatment Group A:  etrolizumab SC plus adalimumab placebo SC 

Treatment Group B:  adalimumab SC plus etrolizumab placebo SC 

Treatment Group C:  etrolizumab placebo SC plus adalimumab placebo SC 
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.  If the iDMC deems a benefit-risk assessment necessary, the iDMC may also 
review unblinded efficacy data.  The iDMC may recommend stopping the study early for 
safety reasons.  However, the iDMC may not recommend stopping the trial early for 
positive efficacy or solely for futility.
3.2
END OF STUDY AND LENGTH OF STUDY
Length of Study
The maximum length of the treatment period will be 14 weeks. Patients who do not 
achieve clinical remission at Week 10, patients who receive defined rescue treatment 
(see Section 3.1.1.1), and all patients who complete the 14week treatment period of the 
study will be given the option of enrolling into Part 1 (OLE) of Study GA28951 after 
Week 12, if eligible, where they will receive open-label etrolizumab treatment.
Patients not enrolling in Part 1 (OLE) of Study GA28951 to receive open-label 
etrolizumab will have a 12-week safety follow-up after the last dose of study medication 
in this study.  These patients will then be requested to enroll into Part 2 (SM) of 
Study GA28951 only for an additional 92 weeks of extended PML follow-up.
The total length of the study is expected to last from the first patient screened to either 
the last patient last follow-up visit in this protocol or last patient enrolled into 
Study GA28951, whichever is later.
End of Study
The end of the study is defined as the last patient last safety follow-up visit in this 
protocol or last patient in this protocol enrolled into Study GA28951 (OLESM), 
whichever is later.


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


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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 for patients with moderately to severely active UC 
who have failed to achieve sufficient benefit from immunosuppressants.  Current 
therapies (TNF inhibitors) achieve clinical remission at induction in only approximately 
15%40% of patients (Reinisch et al. 2011; Rutgeerts et al. 2005) and can be 
associated with significant adverse events.
The Phase II EUCALYPTUS study provided evidence of efficacy, including induction of 
remission at Week 10, in patients with moderately to severely active UC refractory to or 
intolerant of conventional and/or TNF inhibitor therapies.  Results from this study 
showed that at Week 10, the proportions of patients in clinical remission (defined as 
MCS 2 and all subscores 1) in the overall population were 20.5% in the 100-mg arm 


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compared with 0% in the placebo arm.  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, suggesting substantial efficacy in the TNF-naive population at 
Week 10.
In summary, because of the limitations of the currently available therapies for the 
treatment of moderately to severely active UC and the favorable benefit-risk observed in 
the TNF-naive population in EUCALYPTUS, this Phase III study is designed to test the 
efficacy and safety of etrolizumab in this patient population. 
3.3.3
Rationale for Control Group
Patients in the placebo-treated control group will enter the study while on their stable 
background UC treatment.
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 their stable 
background UC therapy compared with patients who receive placebo plus their stable 
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 Active Comparator 
Adalimumab is a biologic licensed for the induction of clinical remission in UC.  
Adalimumab was successful at achieving induction of clinical remission at Week 8 in 
approximately 16.5%18.5% (Reinisch et al. 2011) of patients with moderately to 
severely active UC, indicating that a substantial proportion of treated patients were 
unable to achieve induction of clinical remission. 
The active-treated control group will be used in this study to assess the differences in 
efficacy, safety, and tolerability in patients who receive etrolizumab plus their stable 
background UC therapy compared with patients who receive adalimumab plus their 
stable background UC therapy. 
3.3.5
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 (described in 
Section 1.3), TNF-naive patients with higher baseline biopsy E gene expression by 
quantitative polymerase chain reaction (qPCR) and Ecell counts by 
immunohistochemistry (IHC) have 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 determine whether they may function as predictive response biomarkers.


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Figure 2
Effects of High and Low Baseline Expression of the E Biomarker in 
Colon on the Remission Status of Ulcerative Colitis Patients Treated 
with Etrolizumab in EUCALYPTUS (Observed Data)
LDloading dose; SCsubcutaneous.
All patients enrolled in the current study will have mandatory colonic mucosal sampling 
at the screening visit to analyze the relationship of E levels (and other biomarkers) with 
response to treatment.  In addition, samples will be collected at Week 10 for potential 
exploratory PD biomarker analyses.
Additional biomarkers, including, but not limited to, protein biomarkers or mRNA gene 
expression will be assessed at baseline and after treatment to increase the knowledge 
and understanding of disease biology, patient populations, etrolizumab mechanism of 
action and relationships to exposure, and inform biomarkers predictive of response to 
treatment.
3.4
OUTCOME MEASURES
3.4.1
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:
Primary Outcome Measure:

Remission at Week 10
Secondary Outcome Measures:

Clinical remission at Week 10

Clinical response at Week 10

Improvement in endoscopic appearance of the mucosa at Week 10

Endoscopic remission at Week 10

Remission at Week 10 and Week 14

Histologic remission at Week 10

Change from baseline in MCS rectal bleeding subscore at Week 6


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
Change from baseline in MCS stool frequency subscore at Week 6

Change from baseline to Week 10 in UC bowel movement signs and symptoms as 
assessed by the UC-PRO/SS

Change from baseline to Week 10 in UC abdominal symptoms as assessed by the 
UC-PRO/SS

Change from baseline to Week 10 in patient's health-related QOL as assessed by 
the overall score of the IBDQ
Exploratory Efficacy Outcome Measures:

Clinical remission at Week 10 and remission at Week 14 

Clinical remission at Weeks 10 and 14

Change from baseline to Week 10 in histologic disease activity 

Improvement in histologic and/or endoscopic disease activity from baseline

Change in health utilities, as assessed by the EQ-5D, from baseline to Week 10

Response and remission at Week 10 in patient subgroups by baseline expression 
levels of colonic tissue and/or peripheral blood biomarkers, including, but not limited 
to, E integrin

Response and remission 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 and severity of hypersensitivity reaction events

Incidence of anti-therapeutic antibodies (ATAs) to etrolizumab, or if required, 
adalimumab
3.4.3
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:

Serum concentration during drug washout (through end of safety follow-up)

Serum concentration at primary and secondary endpoints Weeks 10 and 14


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3.4.4
Exploratory Biomarker Outcome Measures
The exploratory biomarker outcome measures for this study are as follows:

Relationship between baseline levels of exploratory colonic tissue and/or peripheral 
blood and/or serum biomarkers and changes in response to treatment or disease 
progression

Relationship between baseline levels of stool biomarkers, which may include, but 
are not limited to, those in the microbiota and bacterial cultures

Changes from baseline in stool biomarkers in response to treatment or disease 
progression
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 4.5.1.4, a rectal bleeding subscore 1, and a stool 
frequency subscore 1) and colonic involvement extending a minimum of 20 cm from 
the anal verge who have had inadequate response or intolerance to conventional 
therapy and are naive to TNF inhibitor therapy.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Able and willing to provide written informed consent

1880 years of age, inclusive

Diagnosis of UC established at least 3 months prior to randomization (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 4.5.1.4 , a rectal bleeding subscore 1, and a stool frequency 
subscore 1 during the screening period (prior to day of randomization).  See also 
Section 4.5.2.1 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 randomization.  See also Section 4.5.2.1 for additional 
information regarding the time window.

Naive to treatment with TNF inhibitor therapy


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
Patients must have had an inadequate response, loss of response, or intolerance to 
prior immunosuppressant and/or corticosteroid treatment.
Inadequate response to, loss of response to, or intolerance to prior 
immunosuppressant treatment is defined as one or more of the following: 
Persistent signs and symptoms of active disease despite a history of at least 
one 12-week regimen of oral AZA (1.5 mg/kg) or 6-mercaptopurin (6MP; 
0.75 mg/kg) and/or MTX (15 mg/week) within the previous 5 years
Persistent signs and symptoms of active disease despite a 6TG level of 
230 pmol/8 108 RBCs during at least one 12-week regimen of oral AZA or 
6mercaptopurine (6MP) at a stable or increasing dose within the previous 
5 years.
History of intolerance to AZA, 6-MP, or MTX (including, but not limited to,
nausea/vomiting, abdominal pain, pancreatitis, LFT abnormalities, 
lymphopenia, TPMT genetic mutation, infection) within the previous 5 years
Inadequate response, loss of response, or intolerance to corticosteroid treatment is 
defined as one or more of the following: 
Steroid refractory:  persistent symptoms of active disease despite treatment 
with at least one 4-week induction regimen that included a dose of 30 mg 
prednisone (oral) daily, or equivalent, for at least 2 weeks or IV for at least 
1 week within the previous 5 years
Steroid dependent:  two failed attempts to taper steroids below a dose 
equivalent to 10 mg prednisone (oral) daily
Steroid intolerant:  history of intolerance to corticosteroids (including, but not 
limited to, Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, 
insomnia, infection) within the previous 5 years

Any ongoing UC therapy must be at stable doses:
May be receiving oral 5-ASA compounds provided that the dose has been 
stable for 4 weeks immediately prior to randomization
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 randomization.  
If corticosteroids are being tapered, the dose has to be stable for at least 
2 weeks immediately prior to randomization.
May be receiving budesonide therapy at a stable dose of up to 9 mg a day 
provided that the dose has been stable for 4 weeks prior to randomization
May be receiving probiotics (e.g., Culturelle, Saccharomyces boulardii), 
provided that the dose has been stable for 2 weeks immediately prior to 
randomization
May be receiving AZA, 6-MP, or MTX, provided that the dose has been stable 
for the 8 weeks immediately prior to randomization


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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 for the duration of the study [i.e., during the treatment period and for 
at least 24 weeks after the last dose of study drug (see Appendix 3)].
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical study and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:  
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at 
least 24 weeks after the last dose of study drug to avoid exposing the embryo 
to study drug.  Men must refrain from donating sperm during this same period.  
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical study and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 

Must have received a colonoscopy within the past year or be willing to undergo a 
colonoscopy in lieu of a flexible sigmoidoscopy at screening.  This colonoscopy 
must:
Confirm disease extent (defined as 1) left-sided colitis [up to the splenic 
flexure], 2) extensive colitis [beyond the splenic flexure but not involving the 
entire colon], and 3) pancolitis; see Section 4.5.1.4)
Include removal of any adenomatous polyps 
Document evidence of surveillance for dysplasia for all patients with left-sided 
colitis of 12 years’ duration and total/extensive colitis of 8 years duration 
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


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
Any diagnosis of Crohn’s disease

Past or present fistula or abdominal abscess

A history or current evidence of colonic mucosal dysplasia

Patients with any stricture (stenosis) of the colon

Patients with history or evidence of adenomatous colonic polyps that have not been 
removed
Exclusion Criteria Related to Prior or Concomitant Therapy

Prior treatment with TNF-antagonists

Any prior treatment with etrolizumab or other anti-integrin agents (including 
natalizumab, vedolizumab, and efalizumab)

Any prior treatment with rituximab

Any treatment with tofacitinib during screening

Any prior treatment with anti-adhesion molecules (e.g., anti-MAdCAM-1)

Use of IV steroids within 30 days prior to screening with the exception of a single 
administration of IV steroid

Use of agents that deplete B or T cells (e.g., alemtuzumab or visilizumab) within 
12 months prior to randomization, with the exception of AZA and 6-MP

Use of anakinra, abatacept, cyclosporine, sirolimus, or mycophenolate mofetil (MMF) 
within 4 weeks prior to randomization

Chronic nonsteroidal anti-inflammatory drug (NSAID) use (Note that occasional use 
of NSAIDs and acetaminophen [e.g., headache, arthritis, myalgias, or menstrual 
cramps] and aspirin up to 325 mg daily is permitted.)

Patients who are currently using anticoagulants including, but not limited to,
warfarin, heparin, enoxaparin, dabigatran, apixaban, rivaroxaban (Note that 
antiplatelet agents such as aspirin up to 325 mg daily or clopidogrel are permitted.)

Patients who have received treatment with corticosteroid enemas/suppositories 
and/or topical (rectal) 5-ASA preparations within 2 weeks prior to randomization

Apheresis (i.e., Adacolumn apheresis) within 2 weeks prior to randomization

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 randomization

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 
randomization


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Exclusion Criteria Related to General Safety

Pregnant or lactating

Lack of peripheral venous access

Hospitalized (other than for elective reasons) during the screening period

Inability to comply with study protocol, in the opinion of the investigator

Significant uncontrolled comorbidity, such as cardiac (e.g., moderate to severe heart 
failure New York Heart Association Class III/IV), pulmonary, renal, hepatic, 
endocrine, or gastrointestinal disorders

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:
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.
Local basal cell or squamous cell carcinoma of the skin that has been excised 
and is considered cured is not exclusionary 
Exclusion Criteria Related to Infection Risk

Congenital or acquired immune deficiency

Patients must undergo screening for HIV and test positive for preliminary and 
confirmatory tests

Positive hepatitis C virus (HCV) antibody test result, unless the patient (1) has 
undetectable HCV RNA levels for 6 months after completing a successful course 
of HCV anti-viral treatment and an undetectable HCV RNA at screening or (2) has a 
known history of HCV antibody positivity with a history of undetectable HCV RNA 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 is positive, the patient is not eligible for this study.  
In the event the HBV DNA test cannot be performed, the patient is not 
eligible for this study. 
If the HBV DNA test is negative, the patient is eligible for this study.  These 
patients will undergo periodic monitoring for HBV DNA during the study.

Evidence of or treatment for Clostridium difficile (as assessed by C. difficile toxin 
testing) within 60 days prior to randomization or other intestinal pathogens (as 
assessed by stool culture and ova and parasite evaluation) within 30 days prior 
to randomization

Evidence of or treatment for clinically significant cytomegalovirus (CMV) colitis 
(based on the investigator’s judgment) within 60 days prior to randomization.  
Laboratory confirmation of CMV from colon biopsy sample is required during 
screening evaluation only if clinical suspicion is high and to determine the need for 
CMV treatment.

History of active or latent TB (regardless of treatment history; see Section 4.5.1.5)
Patients with a history of active or latent TB (based on a positive screening 
assay, either purified protein derivative [PPD] skin test or QuantiFERON-TB 
Gold test, see Section 4.5.1.5) are not eligible for this study.
Patients with a chest X-ray (posteroanterior [PA] and lateral) within 3 months of 
randomization suspicious for pulmonary TB are not eligible for this study.
Any immunosuppressed patient with a strong suspicion of TB exposure and no 
prior vaccination with bacille Calmette-Guérin (BCG) should be considered at 
risk for having latent TB infection.  Patients at risk for TB exposure include:
Patients who have household contact with a person with active TB 
Patients living in areas with high incidence of TB
Patients who frequently visit areas with high prevalence of active TB
Patients who meet these criteria should be evaluated per local practice to 
exclude latent TB.

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 prior to screening


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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 randomization
Fungal infections of the nail beds
Oral or vaginal candidiasis that has resolved with or without treatment prior to 
randomization

Any major episode of infection requiring treatment with IV antibiotics within8 weeks 
prior to screening or oral antibiotics within4 weeks prior to screening
Treatment with antibiotics as adjunctive therapy for UC in the absence of 
documented infection is not exclusionary.

Received a live attenuated vaccine within 4 weeks prior to randomization

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 
After written informed consent has been obtained, all patients will receive a screening 
number, which will be assigned by an interactive voice/Web-based response system 
(IxRS).  Following completion of the screening period and after all patient eligibility 
requirements are confirmed, patients will be assigned a patient number (a different 
number from the screening number) on Day 1 and will undergo randomization in a 
2:2:1 ratio stratified by concomitant treatment with corticosteroids at randomization 
(yes/no), concomitant treatment with immunosuppressants at randomization (yes/no), 
and disease activity measured during screening (MCS 9/MCS 10).  All patients will 
receive two study treatments of active etrolizumabadalimumab placebo, 
active adalimumabetrolizumab placebo, or etrolizumab placeboadalimumab placebo.  
A permuted blocks randomization method will be used to obtain an approximate 
2:2:1 ratio between the two treatments and placebo arm within each stratum. 


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During the 14-week double-blind treatment period, the IxRS will make active 
etrolizumab/etrolizumab placebo study treatment kit assignments at Week 0 (Day 1) and 
Weeks 4 and 8 for all patients and Week 12 for clinical remitters.  Each kit will consist of 
one 1-mL PFS (0.7 mL nominal volume). At each monthly dosing visit (every 4 weeks) 
during the blinded treatment period, one study drug kit will be assigned for administration 
to each patient. 
The placebo for etrolizumab will be matched SC placebo in PFS.  The placebo and 
active kits are filled and packaged to look identical.
The IxRS will also make active adalimumab/adalimumab placebo study treatment kit 
assignments at Week 0 (Day 1) and Weeks 2, 4, 6, and 8.  Adalimumab will be supplied 
for use as a single-use 1-mL glass PFS with a fixed 27-gauge ½-inch needle, providing 
40 mg (0.8 mL) of adalimumab, or as a single-use, 1-mL, glass PFS with a fixed 
29-gauge ½-inch needle, providing 40 mg (0.4 mL) of adalimumab.  
The placebo for adalimumab will be an SC placebo.  This will not be visually identical to 
the adalimumab PFS.  Each adalimumab placebo kit will consist of one 1-mL PFS 
(0.7 mL nominal volume). 
Despite the fact that the volume of the placebo (0.7 mL) differs from the active 
adalimumab (either 0.8 mL or 0.4 mL), this difference is considered acceptable, based 
on the observation that a patient’s sensorial perception of such a small volume of liquid 
is minimal.
A detailed dosing schema for the study is provided in Table 3. 
Patients, all study site personnel, and the Sponsor and its agents (with the exception 
of the IxRS service provider and the unblinded HCPs involved in adalimumab 
administration) will be blinded to treatment assignment throughout the 14-week 
double-blind treatment period.  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, in order to analyze the data, treatment assignment will be 
unblinded to the Sponsor personnel performing the analysis when all data through 
Week 14 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. 


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Given that preparation of an identical adalimumab placebo is not possible, all study 
drugs will be administered by an unblinded HCP.  The unblinded HCP will not be 
involved in safety and efficacy assessments, they will have no further study-related 
interactions with blinded site staff or patients, and will not be involved with or have 
access to patient data.  
 
 
  For 
further details on drug administration see Section 4.3.2.
If unblinding is necessary for patient management (e.g., 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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Table 3
Study Drug Administration Schema
Study Treatment 
Group
Week 0 (Day 1)
Week 2
Week 4
Week 6
Week 8
Week 12 a
Active etrolizumab
and placebo 
adalimumab
1 injection with 
active 
etrolizumab
4 injections with 
adalimumab 
placebo 
2 injections 
with 
adalimumab 
placebo 
1 injection 
with active 
etrolizumab
1 injection 
with 
adalimumab 
placebo
1 injection 
with 
adalimumab 
placebo 
1 injection 
with active 
etrolizumab
1 injection 
with 
adalimumab 
placebo
1 injection 
with active 
etrolizumab
Active adalimumab
and placebo 
etrolizumab
4 injections with 
active 
adalimumab
1 injection with 
etrolizumab 
placebo
2 injections 
with active 
adalimumab
1 injection 
with active 
adalimumab
1 injection 
with 
etrolizumab 
placebo
1 injection 
with active 
adalimumab
1 injection 
with active 
adalimumab
1 injection 
with 
etrolizumab 
placebo
1 injection 
with 
etrolizumab 
placebo
Placebo etrolizumab 
and placebo 
adalimumab
1 injection with 
etrolizumab 
placebo
4 injections with 
adalimumab 
placebo
2 injections 
with 
adalimumab 
placebo
1 injection 
with 
etrolizumab 
placebo
1 injection 
with 
adalimumab 
placebo
1 injection 
with 
adalimumab 
placebo
1 injection 
with 
etrolizumab 
placebo
1 injection 
with 
adalimumab 
placebo
1 injection 
with 
etrolizumab 
placebo
a Only for patients who were determined to be clinical remitters at Week 10.


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4.3
STUDY TREATMENT
Table 4
Treatment/Concomitant Background Treatments
Treatment/Concomitant Background Treatment
Investigational medicinal product
Etrolizumab, 105 mg SC Q4W (Weeks 0 [Day 1], 4, 8 [all patients], and 12 [clinical remitters only])
Comparators
Adalimumab (160 mg Week 0 [Day 1], 80 mg SC Week 2, 40 mg SC Weeks 4, 6, and 8)
Placebo etrolizumab SC Q4W (Weeks 0 [Day 1], 4, 8 [all patients], and 12 [clinical remitters only])
Placebo adalimumab SC (Weeks 0 [Day 1], 2, 4, 6, and 8)
Non-investigational medicinal products
Induction Phase
Continuation of stable baseline doses of the following:
oral 5-ASA; AZA; 6-MP; MTX
Corticosteroids up to 30 mg/day of prednisone (or equivalent)
Budesonide up to 9 mg/day
Week 10 to Week 14
Patients who achieve clinical remission at Week 10 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 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 the dose or discontinue immunosuppressants due to toxicity remains at the discretion of the investigator.
During the Induction Phase, patients are to maintain a stable corticosteroid dose.  For patients staying in the study, corticosteroids are to 
be tapered starting from Week 10 in patients who achieve clinical remission.  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.  Patients receiving budesonide at study entry who achieve clinical remission at Week 10 should taper their dose 
starting from Week 10 from 9 mg every day to 9 mg every other day for 2 weeks and then discontinue budesonide 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, menstrual cramps) and aspirin up to 325 mg daily are 
permitted throughout the study.
Antidiarrheals (e.g., loperamide, diphenoxylate with atropine) for control of chronic diarrhea are permitted.
5-ASA5-aminosalicylic acid; 6-MP6-mercaptopurine; AZAazathioprine; MTXmethotrexate; Q4W every 4 weeks; NSAIDnonsteroidal anti-inflammatory drug; 
SCsubcutaneous.


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4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Etrolizumab and Placebo
Etrolizumab will be supplied by the Sponsor as a liquid formulation in PFSs and is 
administered as an SC injection.  Each 1-mL PFS will contain 150 mg/mL of etrolizumab 
(0.7 mL nominal volume).  Etrolizumab is formulated as 150 mg/mL in 20 mM histidine, 
0.2 M arginine succinate, and 0.04% polysorbate 20, pH 5.8.  Each syringe is for 
single-dose parenteral administration and contains no preservatives.
Etrolizumab placebo will be supplied by the Sponsor as a liquid formulation in PFSs 
(0.7 mL nominal volume) and is administered as an SC injection.  Drug product 
composition for the placebo is exactly the same as that of active drug product without 
the presence of etrolizumab.
Study drug packaging will be overseen by the Sponsor’s Clinical Trial Supplies 
Department and will be labeled with the identification required by local law, the protocol 
number, drug identification, and dosage.  The packaging and labeling of the study 
medication will be in accordance with Sponsor’s standards and local regulations.
Upon arrival of investigational products at the site, the pharmacist or medication nurse 
should check them for damage and verify proper identity, quantity, integrity of seals, and 
temperature conditions and report any deviations or product complaints to the monitor 
upon discovery.
The study drug must be stored according to the details on the product label.  The drug 
label indicates the storage temperature.  
 
 
Used PFSs with study drug will be stored at room temperature in designated sharps 
containers and returned to the site for disposal per local schedule.
Under no circumstances is the investigator to allow study medication to be used other 
than as directed by the protocol.
Details about the packaging and labeling of the study drug will be provided in the 
protocol-supporting documents.
For further details, see the current Etrolizumab Investigator's Brochure.


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4.3.1.2
Adalimumab and Placebo
Adalimumab (Humira) is supplied by the Sponsor for use as a single-use 1-mL glass 
PFS with a fixed 27-gauge ½-inch needle, providing 40 mg (0.8 mL) of adalimumab, or a 
single-use, 1-mL, glass PFS with a fixed 29-gauge ½-inch needle, providing 40 mg 
(0.4 mL) of adalimumab.  Adalimumab is supplied as a preservative-free, sterile solution 
for SC administration. 
Adalimumab placebo will be supplied by the Sponsor as a liquid formulation in PFSs and 
is administered as an SC injection. Each 1-mL PFS will contain 0.7 mL of a solution 
of 20 mM histidine, 0.2 M arginine succinate, and 0.04% polysorbate 20, pH 5.8. Each 
syringe is for single dose SC administration and contains no preservatives.
Study drug packaging will be overseen by the Sponsor’s Clinical Trial Supplies 
Department and bear a label with the identification required by local law, the protocol 
number, drug identification, and dosage.  The packaging and labeling of the study 
medication will be in accordance with the Sponsor’s standards and local regulations.
Upon arrival of investigational products at the site, the unblinded HCP should check 
for damage and verify proper identity, quantity, integrity of seals, and temperature 
conditions and report any deviations or product complaints to the monitor upon 
discovery.
The study drug must be stored according to the details on the product label.  The drug 
label indicates the storage temperature.  PFSs of study medication should be 
refrigerated at 2C8C and protected from excessive light and heat.  PFSs should not 
be frozen, shaken, or stored at room temperature.
For further details, see the adalimumab SmPC or United States Package Insert (USPI).
4.3.1.3
Concomitant Background Treatment for Ulcerative Colitis
For concomitant background treatment for UC see Table 4.
For further details, please refer to respective 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
For detailed guidance to drug administration at each visit see the Study Drug 
Administration Schema (Table 3 in Section 4.2).
In this study, the adalimumab and adalimumab placebo are not visually identical.  
To maintain the adalimumab blind, all study drug administration, including 
etrolizumab/etrolizumab placebo, will be administered by the unblinded HCP 
 
 


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  The unblinded HCP will not be involved in safety and efficacy assessments 
and will not be involved with or have access to patient data.  
The recommended injection sites for etrolizumab and etrolizumab dummy drug are the 
front of the middle thighs, the lower part of the abdomen below the navel except for the 
2-inch area directly around the navel, and the upper arm.
The recommended injection sites for adalimumab are the front of the middle thighs and 
the lower part of the abdomen below the navel except for the 2-inch area directly around 
the navel.
4.3.2.1
Etrolizumab and Etrolizumab 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. 
For all administrations, the study medication is to be administered by an HCP in a setting 
where medications and resuscitation facilities are available.  To maintain the 
adalimumab blind, all study drug administration, including etrolizumab/etrolizumab 
placebo, will be administered by the unblinded HCP 
 
 
  All etrolizumab/etrolizumab placebo (each 0.7 mL delivered via 
PFS; Week 0 [Day 1], Weeks 4, 8, and 12) will be administered by an HCP.  Following 
each study treatment administration, patients will be monitored for acute hypersensitivity 
reactions for at least 1 hour after the end of the injection.  Epinephrine must be readily 
available for immediate use if required to treat anaphylaxis. Adjunctive medications 
such as parenteral diphenhydramine and inhaled bronchodilators may be used IN 
ADDITION TO epinephrine if necessary.  Resuscitation equipment should also be 
available. Site personnel must be able to detect and treat such reactions.
Patients with severe hypersensitivity reactions (e.g., stridor, angioedema, life-threatening 
change in vital signs) must be withdrawn from study treatment and complete the 
12-week safety follow-up phase in this study.  These patients will not be eligible to 
receive open-label etrolizumab in Part 1 (OLE) of Study GA28951 and will be asked to 
enroll in Part 2 (SM) of Study GA28951 for 92 weeks of extended PML monitoring.


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All adverse events of systemic hypersensitivity reactions or anaphylactoid or anaphylaxis 
reactions must be reported within 24 hours to the Sponsor and the Medical Monitor must 
be informed as soon as is practical (see the Study Manual for contact information).
Injections should never be given into areas where the skin is not intact or is tender, 
bruised, red, or hard.  The injection sites will be inspected by the site personnel at each 
clinic visit.  Any injection-site reactions (see Section 5.1.1.3) should be documented on 
the appropriate adverse event page(s).
If the HCP cannot administer study medication on the scheduled dosing day, study 
medication is to be administered within a window of +3 days from the scheduled dosing 
date.  If the patient experiences a minor illness (e.g., minor infection), at the discretion of 
the investigator, study medication may be delayed for a maximum period of 2 weeks.  
Following the delay, study medication dosing is to be resumed in accordance with the 
original dosing schedule.  Any potential deviation from this window is to be discussed 
with the Medical Monitor for the study.
Guidelines for treatment interruption or discontinuation are provided in Sections 4.6
and 5.1.
4.3.2.2
Adalimumab and Adalimumab Placebo
During this study, adalimumab is intended for use under the guidance and supervision 
of a physician.  Adalimumab will be administered by the unblinded HCP using the 
commercially available Humira PFS (40 mg/0.8 mL or 40 mg/0.4 mL).  Prior to use, 
the solution in the Humira PFS must be carefully inspected for particulate matter and 
discoloration.  If particulates and discolorations are noted, the product should not 
be used. 
Adalimumab is to be administered at a dose of 160 mg at Week 0 (Day 1; 4 injections), 
80 mg at Week 2 (2 injections), and 40 mg (1 injection) at Weeks 4, 6, and 8. 
When using the Humira PFS (40 mg/0.8 mL or 40 mg/0.4 mL), the full amount in the 
Humira PFS must be injected in order to provide 40 mg of adalimumab.  Rotate injection 
sites and do not give injections into areas where the skin is tender, bruised, red, or hard.
The adalimumab placebo is described in Section 4.3.1.2.  Details of the number of 
injections to administer at each visit with adalimumab or adalimumab placebo are 
provided in Table 3.  The adalimumab placebo will also be administered by the 
unblinded HCP.


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As noted previously, to maintain the adalimumab blind, all study drug administration will 
be administered by the unblinded HCP 
 
 
4.3.2.3
Concomitant Background Treatment and Rescue Therapy
Patients must have had an inadequate response, loss of response, or intolerance to 
prior immunosuppressant and/or corticosteroid treatment, as described in Section 4.1.1
and as described below.
Inadequate response to, loss of response to, or intolerance to prior immunosuppressant 
treatment is defined as one or more of the following: 

Persistent signs and symptoms of active disease despite a history of at least one 
12-week regimen of oral AZA (1.5 mg/kg) or 6-MP (0.75 mg/kg) and/or 
MTX (15 mg/week) within the previous 5 years

Persistent signs and symptoms of active disease despite a 6TG level of 
230 pmol/8108 RBCs during at least one 12-week regimen of oral AZA or 6-MP 
at a stable or increasing dose within the previous 5 years

History of intolerance to AZA, 6-MP, or MTX (including, but not limited to,
nausea/vomiting, abdominal pain, pancreatitis, LFT abnormalities, lymphopenia, 
TPMT genetic mutation, infection) within the previous 5 years
Inadequate response, loss of response, or intolerance to corticosteroid treatment is 
defined as one or more of the following:

Steroid refractory:  persistent symptoms of active disease despite treatment with at 
least one 4-week induction regimen that included a dose of 30 mg prednisone 
(oral) daily, or equivalent, for at least 2 weeks or IV for at least 1 week within the 
previous 5 years

Steroid dependent:  two failed attempts to taper steroids below a dose equivalent to 
10 mg prednisone (oral) daily

Steroid intolerant:  history of intolerance to corticosteroids (including, but not limited 
to, Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, 
infection) within the previous 5 years
Patients are to be defined as refractory, dependent, or intolerant in the electronic Case 
Report Form (eCRF), if appropriate, irrespective of whether corticosteroid inadequate 
response forms part of the eligibility criteria. 


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Management of Concomitant Medications during the Study
Throughout the treatment phase of the study, patients are required to maintain stable 
doses of their concomitant medications (5-ASA, corticosteroids, immunosuppressants) 
for UC except that all Week 10 clinical remitters receiving corticosteroids must begin a 
taper at Week 10.
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).
Corticosteroids
During the Induction Phase, patients are to maintain a stable corticosteroid dose.  For 
patients achieving clinical remission and who will remain in the study after the Week 10 
induction timepoint, corticosteroids are to be tapered starting from Week 10.  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.  Patients receiving budesonide should taper their dose starting from Week 
10 from 9 mg every day to 9 mg every other day for 2 weeks and then discontinue 
budesonide treatment.
Rescue Therapy That Can Be Given with Study Medication for the 
Treatment of Ulcerative Colitis
Prior to Week 10, any patient who requires initiation of an immunosuppressant (AZA, 
6-MP, or MTX), corticosteroid, or oral or topical 5-ASA, or who requires an increase in 
dose over baseline levels for treatment of worsening disease symptoms should stay in 
the study until Week 12 after performing the Week 10 assessment.  Patients not 
achieving clinical remission at the Week 10 assessment and patients who achieve 
clinical remission at Week 10 but required the use of rescue medications prior to 
Week 10 can enroll in Part 1 (OLE) of Study GA28951 to receive open-label etrolizumab, 
if eligible, at Week 12 (a 2-week delay to allow for adalimumab washout).  Alternatively, 
they can enter the 12-week safety follow-up and then enroll in Part 2 (SM) of Study 
GA28951 for extended PML monitoring.
After Week 10, any patient who achieved clinical remission at Week 10 (without the use 
of rescue medications) who requires initiation of an immunosuppressant, corticosteroid, 
or oral or topical 5-ASA or an increase in dose over baseline levels for treatment of 
worsening disease symptoms should remain in the study to perform Week 14 
assessment and can then enroll in Part 1 (OLE) of Study GA28951 to receive open-label 
etrolizumab, if eligible, or enter the 12-week safety follow-up and then enroll in Part 2 
(SM) of Study GA28951 for extended PML monitoring.


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Endoscopy to document disease activity for patients exiting the treatment period early 
for any reason may be performed at the discretion of the investigator.
Rescue Therapy That Cannot Be Given with Study Medication for the 
Treatment of UC
At ANY time during the conduct of the study, use of other immunosuppressive agents 
including, but not limited to, anakinra, abatacept, 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 the 12-week safety 
follow-up, these patients will 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, etrolizumab placebo, adalimumab, and adalimumab placebo, 
will be provided by the Sponsor.  The investigator is responsible for the control of the 
drugs under investigation.  The investigational site will acknowledge receipt of IMP 
(e.g., drug receipt record) and 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.  Note that 
adalimumab accountability and storage will be conducted by an unblinded study staff 
member.  Adalimumab study drug will not be available to blinded study staff.
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 
All records and drug supplies must be available for inspection by the study monitor.


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4.3.4
Assessment of Compliance
Patient compliance will be assessed by maintaining adequate drug dispensing logs and 
return records.
A Drug Dispensing Log must be kept as described in Section 4.3.3.  The investigator is 
responsible for ensuring that dosing is administered in compliance with the protocol.  
Delegation of this task must be clearly documented and approved by the investigator.  
When the study is completed, the investigator will return all completed Drug Dispensing 
Logs to the Monitors.
Any unused study drug and Drug Return Records should be returned to the Monitor, 
unless alternate destruction has been authorized by Roche or required by local or 
institutional regulations (Section 4.3.3).  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 (etrolizumab, etrolizumab placebo, adalimumab, or adalimumab placebo)
will be placed into sharps containers immediately after SC injections.  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 patient 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 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.


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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 (e.g., nurse at the site), the device complaint must 
be reported on the PD103 IMP Deviation Form.  The adverse event must be reported to 
the Sponsor as a spontaneous adverse event (see Section 5.3.5).
4.4
CONCOMITANT THERAPY
4.4.1
Permitted Therapy
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal/homeopathic remedies, preventative vaccines, vitamins, nutritional 
supplements) used by a patient from 8 weeks prior to randomization to the patient’s last 
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 4.3.2.3.
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, or rituximab 

Use of TNF inhibitors (including TNF inhibitor biosimilars)

Use of anakinra or abatacept and/or other biological therapeutics

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 discontinued from study drug and 
moved to safety follow-up within this study.


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4.5
STUDY ASSESSMENTS 
4.5.1
Description of Study Assessments
4.5.1.1
Medical History and Demographic Data
Medical history includes clinically significant diseases and procedures.  All medication 
taken in the last 8 weeks prior to randomization (including prescription, over-the-counter, 
and herbal/homeopathic remedies and therapies) are to be recorded.  A detailed history 
of medication used for UC is required for the past 5 years.
Demographic data, including age, sex, whether the patient is a fraternal or identical twin, 
and self-reported race/ethnicity will be collected during screening.
4.5.1.2
Physical Examinations
A complete physical examination should include the evaluation of head, eye, ear, nose, 
and throat and cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal (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.
4.5.1.3
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 at the indicated timepoints in Schedule of Assessments (see Appendix 1), 
before study drug administration.
4.5.1.4
Ulcerative Colitis Disease Activity Assessments
Extent and duration of patient’s disease is to be recorded on the eCRF from the patient 
medical records and should include therapies from the past 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 partial Mayo Clinic Score (pMCS).  The MCS has a range of 
012, whereas pMCS has a range of 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 physician’s global assessment (PGA).  
pMCS is a composite of three assessments, each rated from 03:  stool frequency, 
rectal bleeding, and PGA.
During screening, patients will be instructed on how to appropriately complete an e-diary.  
The patient's normal number of stools is to be recorded.  This is defined as the number 


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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 randomization (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 randomization.  Note that the total 
screening period is up to 35 days (see Section 4.5.2.1).
The symptoms of UC must be recorded throughout the study, including the screening 
period.  The e-diary entries will be reviewed by site personnel during screening (prior to 
dosing, if applicable) and during study visits including the early withdrawal from 
treatment visit and any unscheduled visits due to disease exacerbation.  Because the 
colonoscopy/flexible sigmoidoscopy and bowel cleansing preparations can interfere with 
the assessment of patient-reported symptoms, e-diary entries used to calculate the 
complete MCS should not correspond to days of bowel preparation or endoscopy or the 
day following the endoscopy.  Further details and examples of stool frequency and rectal 
bleeding subscore derivation are provided in Appendix 4.
Colonoscopy/Flexible Sigmoidoscopy with Colonic Biopsies
Patients are to prepare their bowel prior to the colonoscopy/flexible sigmoidoscopy 
procedures. Medications used for bowel preparation should be recorded on concomitant 
medications pages of eCRF.
Stool samples for analysis of fecal calprotectin and other exploratory biomarkers (such 
as analyses of the microbiota and bacterial cultures) are to be collected prior to bowel 
preparation (polyethylene glycol [PEG]-based preparation or enema).
Full colonoscopy within a year of screening is required to ensure against enrollment of 
patients with colonic carcinoma and dysplasia.  If full colonoscopy has not been 
performed within the year before screening, it should be conducted in place of the 
flexible sigmoidoscopy at screening. For patients not requiring a colonoscopy, a flexible 
sigmoidoscopy will be performed for inclusion in the study.  Endoscopy will be performed 
during screening between 416 days prior to randomization.
Endoscopy will be also performed at Week 10 or at withdrawal from study (early 
withdrawal from treatment visit; see Appendix 1).  In patients who are clinical remitters at 
Week 10, an additional endoscopy will be performed at Week 14.
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 


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recording of the entire endoscopic procedure will be performed as specified in the Video 
Submission Guidelines.  All video recordings will be edited by central read vendor to 
produce video clips that are representative of each segment of the colon visualized up to 
the splenic flexure only (rectum, sigmoid, and descending colon).  The video clips will be 
read centrally for mucosal lesions and endoscopic severity by an independent 
gastroenterologist experienced in IBD who is blind to the patient’s clinical activity and 
treatment allocation.  The MCS endoscopic subscore is to be determined both locally (at 
the investigator site) and centrally as described above.  Each segment of the colon up to 
the splenic flexure (rectum, sigmoid, and descending colon) will be assigned an 
endoscopic subscore. The score from the worst affected segment up to the splenic 
flexure is to be used for the MCS calculation for study conduct, except at post-baseline 
time points, when the sigmoid colon MCS endoscopic subscore will be used if the 
baseline sigmoid colon MCS endoscopic subscore is 23.
In the event that there is a discrepancy between the endoscopic subscore obtained by 
the local versus the central reader, a third read (second central reader) is to be 
conducted. From these three endoscopic MCS subscores, the score with which two 
readers agree will be reported as the final overall MCS endoscopic subscore.  If no two 
readers agree on an MCS endoscopic subscore, the median score of the three 
completed reads (i.e., local read, central read #1, and central read #2) will be chosen as 
the final reported overall MCS endoscopic subscore.
In all cases the video recordings are to be taken prior to biopsy.
Each patient entered into the study will have colonic biopsy samples obtained during 
flexible sigmoidoscopy/full colonoscopy as follows: 
At Screening
A total of five to six paired biopsy samples (10-12 samples) will be taken at screening.

Four paired biopsy samples (8 samples) from the most inflamed area of the colon 
within 2040 cm from the anal verge (sigmoid colon).  Two pairs (4 samples) will go 
into formalin and two pairs (4 samples) will be placed in stabilization buffer (such as 
RNAlater or a similar buffer) and be shipped to a central laboratory for storage 
at 80C. 

One paired biopsy sample (2 samples) from the most inflamed area of the worst 
affected segment (descending, sigmoid, or rectum).  This biopsy pair (2 samples) 
will go into formalin.

ONLY if there is suspicion for clinically significant CMV colitis, one biopsy sample 
from this pair should be taken from the base of an ulcer to evaluate for histological 
presence of CMV; otherwise, it is not necessary for inclusion in the study.  Analysis 
should be performed locally if possible, or can be sent to a central laboratory, 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 laboratory, if necessary).

If neither CMV testing or histopathologic confirmation of UC is needed, these 
additional 2 biopsy samples should not be obtained.
At Week 10, Week 14, and/or at early withdrawal from treatment visit 
(see Appendix 1)
A total of four paired biopsy samples will be taken at each of these timepoints as 
specified in Appendix 1.

Two paired biopsy samples (4 samples) to be taken from the most inflamed area of 
the colon within 2040 cm from the anal verge (sigmoid colon, at the same 
endoscopic depth of the original screening endoscopy).  If there is no clearly 
inflamed area, a blind biopsy sample should be taken.  One pair (2 samples) will go 
into formalin, and one pair (2 samples) will be placed in stabilization buffer (such as 
RNAlater or a similar buffer) and shipped to a central laboratory for storage 
at 80 C.

One paired biopsy sample (2 samples) to be taken from the most inflamed area of 
the rectum.  If there is no clearly inflamed area, a blind biopsy sample should be 
taken.  This paired biopsy sample will go into formalin.

One paired biopsy sample (2 samples) to be taken from the most inflamed area of 
the descending colonic segment.  If there is no clearly inflamed area, a blind biopsy 
sample should be taken.  This paired biopsy sample will go into formalin. 
Necrotic areas of ulcerated mucosa should be avoided during biopsy.  Original location 
(colonic segment and endoscopic depth) of biopsy specimen should be clearly indicated. 
Samples will all initially be sent to the laboratory vendor (unless analysis is to be 
performed locally, as indicated).
Progressive Multifocal Leukoencephalopathy Assessment
Study site personnel and patient will be educated regarding the signs and symptoms of 
PML.  Close monitoring during the course of the study for any new symptoms or signs 
suggestive of PML will be performed with regular neurologic examinations (including 
evaluation of cranial nerves, motor and sensory function, coordination, and mental status) 
as per the Schedule of Assessments (see Appendix 1).  The PML Subjective Checklist
(symptom assessment) and the PML Objective Checklist (neurologic evaluation) will be 
administered by a qualified HCP and will be performed 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 


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for PML, the event should be expeditiously reported as an adverse event of special 
interest within 24 hours (see Section 5.1.1 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 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.
After completing the treatment phase of 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 phase 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 the 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 Study GA28951 will consist of the PML 
assessment interview conducted by telephone at 6-month intervals (see Appendix 5).
4.5.1.5
Laboratory Assessments
Laboratory assessments will be performed as indicated on the Schedule of 
Assessments; see the Study Flowchart in Appendix 1.  All laboratory assessments will 
be sent to one or more central laboratories for analysis with the exception of CMV.  If 
there is suspicion for clinically significant CMV colitis, a colonic biopsy sample should be 
sent for CMV evaluation, which may be conducted locally depending on local 
requirements for the timing of the test result.  Urine pregnancy testing will be conducted 
locally.  If a full colonoscopy is required at screening, laboratory samples should be 
drawn prior to the initiation of bowel preparation.


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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)

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.

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.

C-reactive protein (CRP)


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
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.

Viral serology and detection
HBV (HBsAg, total HB core antibody [anti-HBc] and HBV DNA)
HCV antibody
HCV RNA:  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 detection and characterization of antibodies 
against etrolizumab, or if required, adalimumab.  Samples will be analyzed 
using a validated assay.  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.

PK assays
Serum samples will be collected for determination of etrolizumab, or if required, 
adalimumab, concentrations in all patients.  Samples will be analyzed using a 
validated assay.

CMV testing of colonic biopsy sample, if there is suspicion for clinically significant 
CMV colitis
Baseline colon biopsy sample (to be obtained at the base of the ulcer) will be 
analyzed for histologic presence of CMV.

Fecal calprotectin testing

Exploratory predictive and prognostic biomarker assays
Peripheral blood, serum, and colon biopsy samples will be assessed using 
qualified methods (including, but not limited to, ELISA, IHC, and/or qPCR, RNA 
sequencing) for exploratory predictive and prognostic biomarker analysis.


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
Exploratory PD biomarker assays
Peripheral blood, serum, stool, and colon biopsy samples will be collected and 
qualified methods (including, but not limited to, ELISA, IHC, bacterial culture, 
RNA sequencing, and/or qPCR) will be utilized for exploratory PD biomarker 
analysis for samples that are assessed.  Biopsy tissue may also be used for 
exploratory determination of drug concentration.  Stool samples may be used 
for assessments that include, but are not limited to, analyses of the microbiota 
and bacterial cultures.

Histology
Colon biopsy samples will be collected and evaluated for histologic changes.  
Histologic activity on colon biopsies will be categorized using the Nancy 
histological index. 
Unless the patient gives specific consent for his or her leftover samples to be stored 
for optional exploratory research (see Section 4.5.1.10), biological samples will be 
destroyed when the final Clinical Study Report has been completed, with the following 
exceptions:

Serum samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization and for PK or immunogenicity assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed.

Blood or blood-derived samples (RNA Paxgene, serum for exploratory PD) and 
stool samples collected for biomarker research will be destroyed no later than 
5 years after the final Clinical Study Report has been completed.

Colon biopsy samples (formalin and RNA later) will be destroyed no later than 
5 years after the final Clinical Study Report has been completed.
4.5.1.6
Chest X-ray
A chest X-ray will be performed at screening.  If a chest X-ray has been documented 
within the previous 3 months and has shown no clinically significant abnormalities, no 
additional chest X-ray is required.
4.5.1.7
Electrocardiograms
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.


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For safety monitoring purposes, the investigator or designee must review, sign, and date 
all ECG tracings.  Paper copies will be kept as part of the patient's permanent study file 
at the site.  ECG outputs will be stored at site.
4.5.1.8
Patient-Reported Outcomes
Patient-reported outcomes (IBDQ, UC-PRO/SS, EQ-5D, and the stool frequency and 
rectal bleeding components of the MCS and pMCS) and physician-reported outcomes 
(PGA component of the MCS and pMCS) and the endoscopic component of MCS data 
will be collected to help characterize the clinical profile of etrolizumab.  The instruments 
will be translated as required in the local language.
In order to ensure instrument validity and that data standards meet health authority 
requirements, the PROs completed at the sites (IBDQ, EQ-5D, and the stool frequency 
and rectal bleeding components of the MCS and pMCS) should be administered at the 
investigational site prior to the completion of non-PRO assessments and before the 
patient receives any disease-status information or study drug during that visit. At Week 0 
(Day 1), however, IBDQ and EQ-5D do not have to be performed prior to nonPRO 
assessments.   Patients will complete the UC-PRO/SS measure for at least 912 
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 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 has a recall specification of 24 hours.  A copy of the 
UC PRO/SS measure is provided in Appendix 9.
Inflammatory Bowel Disease Questionnaire (IBDQ)
The IBDQ will be used to assess patient's 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 4.5.1.4.  The pMCS is a 
composite of three assessments, each rated from 03:  stool frequency, rectal bleeding, 
and PGA.  The MCS has a range of 012 and the pMCS has a range of 09.  Higher 
scores indicate more severe disease.  Copies of the MCS and pMCS are provided in 
Appendix 4.
EuroQol Five-Dimension Questionnaire (EQ-5D)
The EQ-5D is a generic preference-based health-related QOL questionnaire that 
provides a single index value for health status (Rabin and deCharro 2001).  This tool 
includes questions about mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression that are used to build a composite of the patient’s health status.  The 
EQ-5D questionnaire will be utilized in this study for economic modeling.  A copy of the 
assessment is provided in Appendix 11.
4.5.1.9
Medication Use and Compliance
The details of the study medication administration are to be entered directly into the 
eCRF following clinic administrations.
4.5.1.10
Samples for Roche Clinical Repository
Overview of the Roche Clinical Repository
The Roche Clinical Repository (RCR) is a centrally administered group of facilities for 
the long-term storage of human biologic specimens, including body fluids, solid tissues, 
and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future.
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  In addition, any residual colonic biopsy and blood 
samples for biomarkers left over at the end of the study and analyses will be transferred 
to the RCR in consenting patients.  RCR specimens will be used to achieve the following 
objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
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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.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF.


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In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes using the RCR Subject Withdrawal Form and, if 
the trial is ongoing, must enter the date of withdrawal on the RCR Research Sample 
Withdrawal of Informed Consent eCRF.  The patient will be provided with instructions on 
how to withdraw consent after the trial is closed.  A patient's withdrawal from 
Study GA28949 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 GA28949.
Monitoring and Oversight
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples.
4.5.2
Timing of Study Assessments
4.5.2.1
Screening and Pretreatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.
All screening tests and evaluations will be performed within 35 days prior to 
randomization (Day 1), except for flexible sigmoidoscopy/colonoscopy, which should be 
performed 416 days prior to randomization (see Figure 3). The screening period will 
not exceed 35 calendar days.
Laboratory samples should be collected from the patient early in the screening period to 
allow time for the laboratory results to be available for review by the site for eligibility
(see Section 4.5.1.4).  However, the ECG and chest X-ray can be obtained any time 
before randomization to study medication (see Section 4.5.1.6 and Section 4.5.1.8 for 
additional details on the chest X-ray and ECG).  Colon biopsy specimen collection is 
detailed in Section 4.5.1.4.


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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.
The screening endoscopy for MCS should be performed 416 days prior to Day 1
(randomization) (i.e., Day 16 to Day 4). The endoscopy score from the worst affected 
segment up to the splenic flexure (rectum, sigmoid, and descending colon) is to be used 
for the MCS calculation (see Section 4.5.1.4).
The symptoms of UC must be recorded during the screening period.  The e-diary entries 
will be reviewed by site personnel during screening.  Because the colonoscopy/flexible 
sigmoidoscopy and bowel cleansing preparations can interfere with the assessment of 
patient-reported symptoms, e-diary entries used to calculate the complete MCS should 
not correspond to days of bowel preparation or endoscopy or the day following the 
endoscopy.  Further details and examples of stool frequency and rectal bleeding 
subscore derivation are provided in Appendix 4.
The endoscopy and the stool frequency and rectal bleeding subscores will be 
considered, along with other PGA components, when determining the PGA for the MCS 
calculation at Day 1 (i.e., prior to initiation of study drug), as described in detail in 
Appendix 4.
Figure 3
Overview of Screening Activities
Note:  Endoscopy should be performed 416 days prior to randomization (Day 1).


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All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2.1.1
Re-Testing for Laboratory Inclusion and Exclusion Criteria
Two re-tests are permitted for laboratory inclusion and exclusion criteria.  If a patient 
does not meet laboratory criteria for a third time, he or she will be considered a 
screen failure.
Laboratory testing that is repeated because of administrative or technical issues 
(e.g., breakage of a sample vial during transit to the central laboratory or degradation of 
a sample during transportation) is not considered to be re-screening.
4.5.2.1.2
Re-Screening
Re-screening is required if a patient has not met all the eligibility criteria within 35 days 
of the original screening visit.  Patients who are found to be ineligible for entry into the 
study may be re-screened once only (except for the laboratory tests mentioned 
above)for example, if the patient develops additional manifestations of UC, a 
worsening of existing manifestations at a later time, if patient’s 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.
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 4.5.1.5, if a negative TB screening test result has been 
documented within 3 months before screening, or re-screen, no repeat test is required.
The screening endoscopy and colonic biopsies do not need to be repeated during 
re-screening provided that all of the following criteria are met:

All endoscopy-related inclusion criteria have been met

The initial endoscopy has been performed within 28 days prior to the day of 
randomization for second screening

Colon biopsies as specified by the protocol have been obtained


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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 
randomization (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 
samples is required during re-screening evaluation to rule out CMV infection.
See Appendix 1 for the schedule of screening and pretreatment assessments.
4.5.2.2
Assessments during Treatment
All assessments will be performed on the day of the specified visit, except where a time 
window is specified.  Assessments scheduled on the day of study drug administration 
should be performed prior to dosing, unless otherwise noted (see Schedule of 
Assessments; Appendix 1). 
For the Week 10 and Week 14 visits that are associated with an MCS requiring 
endoscopy, every effort should be made to schedule the endoscopy on the same day as 
the clinic visit.  If this is not possible, endoscopy should be performed as close to the 
clinic visit as possible, with a maximal window of 3 days prior to and 5 days after the visit.  
The endoscopy score should be considered when determining the PGA (as applicable), 
a component of the MCS (see Appendix 4).  All patients will be queried and closely 
monitored for any adverse event at all study assessment timepoints (every 2 weeks) 
during both clinic visits and study assessments made over the telephone.
An unscheduled visit is to be conducted as required (see Section 4.5.2.5).
All patients will receive hands-on training in use of the e-diary and tablet.  Patients will 
also be instructed to contact the site promptly if they have any questions about the use 
of the e-diary during screening or at any time during the study.
See Appendix 1 for the schedule of assessments performed during the treatment period.
4.5.2.3
Assessments at Study Completion/Early Withdrawal from 
Treatment Visit
Clinical remitters who proceed beyond Week 10 and who complete the treatment phase 
until Week 14 will be asked to visit the clinic for Week 14 assessments.  These patients 
will be given the option of enrolling in Part 1 (OLE) of Study GA28951, if eligible, at 
Week 14.  If patients choose not to enroll into Part 1 (OLE) of the study, they should 
perform the safety follow-up assessments (one telephone call at 6 weeks and one clinic 
visit at 12 weeks after the Week 14 visit; see Appendix 2). 


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Patients who complete the 10-week treatment phase but do not continue into the 
additional 4-week treatment phase (i.e., patients who are not clinical remitters at 
Week 10) will be given the option of enrolling in Part 1 (OLE) of Study GA28951, if 
eligible, at Week 12.  If the patient does not enroll in Part 1 (OLE) of the study, he or she
will undergo two safety follow-up assessments (see Appendix 2). 
Patients not eligible for or who choose not to enroll in Part 1 (OLE) of Study GA28951
are to enroll in Part 2 (SM) of the study for extended PML monitoring after completion of 
the 12-week safety follow-up in this study.
If a patient leaves the study prior to Week 10 or if a clinical remitter (who proceeds 
beyond Week 10) leaves the study prior to Week 14, an early withdrawal from treatment 
visit is to be conducted, including for those patients who will enroll in Study GA28951.  
Otherwise, the Week 10 visit is the last visit in the study for patients who are not eligible 
to be dosed at Week 12 and enroll in Part 1 (OLE) of Study GA28951 at Week 12.  
Assessments are specified in the Schedule of Assessments in Appendix 1.
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.
4.5.2.3.1
Eligibility for Entry to Open-Label Extension-Safety Monitoring 
Study
Study GA28951 will be conducted under a separate protocol and eligible patients as 
described below will need to be willing and able to provide separate informed consent to 
enter this study.
Patients not achieving clinical remission at Week 10 who are eligible for and choose to 
enroll in Part 1 (OLE) of Study GA28951 should not receive their first dose of open-label 
etrolizumab until Week 12 (e.g., 2 weeks after the Week 10 timepoint to allow the active 
comparator washout period of 4 weeks to be completed).  Patients who achieve clinical 
remission at Week 10 should complete the study to Week 14, at which time they may 
enroll in Part 1 (OLE) of Study GA28951, if eligible, and receive their first dose of open-
label etrolizumab at Week 14.
Note:  Patients 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 the study) after completing the 12-week safety follow-up in this study.


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The following patients may be eligible to enroll in the open-label treatment portion 
(Part 1) of the OLESM study at Week 12 (for nonclinical remitters at Week 10) or 
Week 14 (for clinical remitters at Week 10):

In the Induction Phase, any patient who requires initiation of an immunosuppressant 
(ASA, 6-MP, MTX), corticosteroid, or oral or topical 5-ASA, or increase in dose of 
these medications over baseline levels for treatment of worsening disease 
symptoms may enroll in Part 1(OLE) of Study GA28951 after the Week 10 
assessment, if eligible.

Patients who do not achieve clinical remission at Week 10

All remaining patients who complete the Week 14 assessment
The following patients are NOT eligible to enroll in Part 1 (OLE) of Study GA28951
and should complete the 12-week safety follow-up in this protocol:

Patients who discontinue study treatment prior to Week 10

Patients who require rescue medications that are prohibited in conjunction with 
etrolizumab (see Section 4.3.2.3)

Patients with severe hypersensitivity reactions (see Section 4.6.1.1), malignancies, 
specific de novo or reactivated serious viral infections, PML, or other life-threatening 
infections during the study (see Sections 4.6.1.1, 5.1.1.1, and 5.1.1.2)
4.5.2.4
Safety Follow-Up Assessments
Safety follow-up will be conducted in this study for a period of 12 weeks for patients not 
enrolling in Part 1(OLE) of the OLE-SM study (see Section 4.5.2.3 for patients who 
should enter the 12-week safety follow-up phase within this protocol).  Patients will be 
assessed at 6-week intervals during this period, one assessment by telephone and one 
in-person clinic visit (see Appendix 2).  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 safety follow-up period in this study.  Adverse events 
should be followed as outlined in Section 5.2.1.  
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 in Part 2 (SM) of the study for the extended PML monitoring will NOT receive 
treatment with open-label etrolizumab.  During Part 2 (SM) of 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 withdrawal from treatment visit 
(see Appendix 2).


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See Appendix 1 for the schedule of assessments performed at the study 
completion/early withdrawal from treatment visit.
After the study completion/early termination visit, adverse events should be followed as 
outlined in Sections 5.5 and 5.6.
See Appendix 2 for the schedule of 12-week safety follow-up assessments.
4.5.2.5
Assessments at Unscheduled Visits
An unscheduled visit may occur at any time during the study, (i.e., due to relapse of 
disease or an adverse event).  Patients who are seen by the investigator or site staff at a 
timepoint not required by the protocol because of assessment of potential relapse will 
undergo the following:

Symptom-directed physical examination

Review of e-diary data

Recording of concomitant medications and procedures

Collection of adverse events and serious adverse events

Clinical chemistry, hematology, and CRP, if indicated

Stool sample collection, if indicated

Partial or complete MCS, if indicated

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 may be performed in case of an unscheduled visit. 
4.6
PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
The investigator has the right to discontinue a patient from study drug or withdraw a 
patient from the study at any time.  In addition, patients have the right to voluntarily 
discontinue study drug or withdraw from the study at any time for any reason.  Reasons 
for discontinuation of study drug or withdrawal from the study may include, but are not 
limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance, specifically defined as missing scheduled visits or 
non-adherence with background medications


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4.6.1.1
Discontinuation from Study Drug
Patients must discontinue study drug if they experience any of the following:

Pregnancy

Anaphylaxis or other severe hypersensitivity reaction

Develop colonic mucosal dysplasia

Malignancy (with the exception of local and resected basal or squamous cell 
carcinoma of the skin) or cervical Pap test with AIS, HSIL, or CIN of Grade 1

Specific serious infection (see Section 5.1.1.1 for details on serious infection):
Any patient who experiences a specific de novo or reactivated serious viral 
infection, such as HBV, HCV, HIV, should discontinue study medication.
Any patient who develops life-threatening infections during the study should 
discontinue study medication.

Any medication for rescue outside defined limits of the protocol (see Section 4.4.2)
Patients who discontinue study drug prematurely for the reasons listed above will be 
asked to return to the clinic for an early withdrawal from treatment visit 
(see Section 4.5.2.3) followed by 12 weeks of safety follow-up within this study.  Patients 
should then enroll in Part 2 (SM) of Study GA28951 for 92 weeks of monitoring for PML 
(see Section 4.5.2.4).  Patients not eligible to receive study drug at Week 12 (i.e., 
patients who did not achieve clinical remission at Week 10) should be considered to 
have discontinued study drug early.  The primary reason for premature study drug 
discontinuation (e.g., lack of efficacy) must be documented on the appropriate eCRF.  
Patients who discontinue study drug prematurely will not be replaced.
4.6.1.2
Withdrawal from Study
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study must be documented on the 
appropriate eCRF. Patients will not be followed for any reason after consent has been 
withdrawn.  Patients who withdraw from the study will not be replaced.
4.6.2
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the study is placed on hold, or if the Sponsor 
decides to discontinue the study or development program.


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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.  
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.
Important potential risks for etrolizumab include the following:

Infections, in particular, serious or life-threatening infections, such as:
PML 
Other serious infections (e.g., gastrointestinal, opportunistic)

Hypersensitivity reactions, in particular:
Anaphylactic, anaphylactoid reactions 
Other systemic hypersensitivity reactions

Local injection-site reactions


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
Hepatic effects

Malignancies

Immunogenicity

Decreased effectiveness of immunization
5.1.1.1
Serious Infections 
5.1.1.1.1
Progressive Multifocal Leukoencephalopathy 
Background
PML is a potentially fatal neurological condition linked to reactivation of a polyomavirus 
(JCV) and active viral replication in the brain.  Cases of PML have been reported in 
patients with CD and multiple sclerosis who received concomitant treatment with the 
anti-4 integrin natalizumab and immunosuppressives.  Integrin 41, which is inhibited 
by natalizumab, is a pleiotropic integrin that is believed to facilitate T cell migration into 
the CNS.  Inhibition of integrin 41 is thought to reduce (CNS) immune surveillance 
and facilitate development of PML.
PML has not been attributed to vedolizumab, which selectively impedes lymphocyte 
trafficking into gut tissue by specifically blocking only the 47 integrin and not the 41 
integrin, despite extensive treatment exposure (Dotan 2017).
Etrolizumab targets cells expressing the 7 integrin (47 and E7 cells) and not 
41 cells.  Despite the lack of theoretical or experimental evidence for a specific role of 
7 integrins in leukocyte homing to the CNS and given the observation of PML risk with 
natalizumab, the Sponsor will continue to conduct extensive risk-monitoring procedures 
during the Phase III trials.  There have been no cases of PML in patients treated with 
etrolizumab to date.
Screening, Patient Selection, and PML Education
No known interventions can reliably prevent PML or adequately treat PML if it occurs; 
therefore, it is important to exclude patients with a perceived higher baseline risk for 
PML, such as patients who have received natalizumab, efalizumab, or rituximab and 
patients with a history of demyelinating disease or PML.  Patients with neurologic 
disease conditions that may interfere with monitoring for PML, such as clinically 
significant abnormalities noted at the screening neurologic examination (subjective or 
objective checklists), should be excluded.
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.


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Study site personnel and patient participants should be educated regarding the signs 
and symptoms of PML.  Patients and partners/caregivers should be issued with alert 
cards to remind them of these and to advise them to contact the investigator right away if 
they notice any new or worsening neurological abnormalities.  
See Appendix 1 for details of assessments regarding PML.  
PML Monitoring
During the study, patients should be closely monitored for any signs and symptoms of 
PML via regular (approximately once every 12 weeks) subjective and objective tests 
employing the use of checklists to assess the patient’s mental and neurological status.  
These will comprise regular neurologic examinations (including evaluation of cranial 
nerves, motor and sensory function, coordination, and mental status) as per the 
Schedule of Assessments (see Appendix 1).  The PML Subjective Checklist (symptom 
assessment) and the PML Objective Checklist (neurologic evaluation) will be 
administered (see Appendix 5; Worksheet for PML Neurologic Examination) 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 5.1.1 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 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 JCV DNA by PCR.  If JCV
DNA 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.  Refer to Appendix 6 for the Algorithm for Evaluation of Progressive Multifocal 
Leukoencephalopathy.


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PML Treatment
There is no known effective treatment for PML.  Plasmapheresis has been employed in 
some patients where the event has been thought to be due to administration of a drug 
(Tan et al. 2011).  If an event of PML occurs, subsequent management of PML will be at 
the direction of the consulting neurologist. 
Additional information for the management of this potential risk is provided in Appendix 5
(Worksheet for the PML Neurologic Examination) and Appendix 6 (Algorithm for the 
Evaluation of Progressive Multifocal Leukoencephalopathy).
5.1.1.1.2
Other Serious Infections
Background
Clinical data to date have not shown an increased risk of serious infections with 
etrolizumab.  In the Phase II EUCALYPTUS study, serious infections were reported in 
2.3% of placebo-treated patients versus none in the etrolizumab-treated patients.  
Nonetheless, serious infections are a potential risk due to the mechanism of action of 
etrolizumab, which blocks trafficking of gut-selective lymphocytes.
Patient Selection
Patients with congenital or acquired immune deficiency are excluded from the study.  
Patients with specific and/or recent infections, such as CMV colitis, C. difficile, and other 
intestinal pathogens, are excluded from the study (see Section 4.1.2 for Exclusion 
Criteria Related to Infection Risk).  Patients with a history of recurrent opportunistic 
infections and/or severe disseminated viral infections or any serious opportunistic 
infection within the past 6 months are excluded from the study.  
Patients with hepatitis B infection who test positive only for core antibody (anti-HBc) 
and test negative for HBV DNA test are eligible for the study; however, these patients 
must undergo periodic monitoring for HBV DNA during the study.  
Patients with a history of active or latent treated TB, regardless of treatment history, are 
excluded from the study.  Investigators are reminded of the risk of false-negative 
tuberculin skin test results, especially in patients who are severely ill or 
immunocompromised. 
Patients at risk for TB exposure are noted below.  Patients who meet these criteria 
should be evaluated per local practice to exclude latent TB infection.

Patients who have household contact with a person with active TB

Patients living in areas with high incidence of TB

Patients who frequently visit areas with high prevalence of active TB, etc.


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Apart from their colitis, patients must be in reasonably good health with no significant 
uncontrolled comorbidity or clinically significant laboratory results (see Section 4.1.2 for 
Exclusion Criteria Related to General Safety and Exclusion Criteria Related to 
Laboratory Values [at Screening]).
Education, Monitoring, and Management
Patients should be monitored closely for other serious infections during the study.  
Patients and study staff should be informed of the possibility of increased susceptibility 
to infectious pathogens.  Investigators will be encouraged to promptly evaluate and 
aggressively treat any signs and symptoms consistent with an infection.  
Patients who experience a serious infection event should not receive further study drug 
until the event has completely resolved and treatment with anti-infective medications has 
been completed. All effort should be made to identify the infectious agent.  For those 
patients who recover from a serious infection, study medication may be restarted 
following consultation with the Medical Monitor.  
Patients who develop life-threatening infections including specific de novo or reactivated 
serious viral infections, such as HBV, HCV, and HIV, during the study should discontinue 
study drug.  Any patient who develops CMV colitis should not receive further study drug 
until the event has resolved and treatment with appropriate anti-viral medication has 
been completed.  Re-initiation of therapy requires consultation with the Medical Monitor.
5.1.1.2
Hypersensitivity Reactions
Background
In completed Phase I/II clinical trials of etrolizumab, one serious adverse event of 
hypersensitivity (Grade 2) has been reported.  No anaphylactic, anaphylactoid, or severe 
hypersensitivity reactions were observed; however, anaphylaxis and hypersensitivity 
reactions will be closely monitored during the study. 
Patient Selection
Patients with a 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 or any of the excipients (L-histidine, 
L-arginine, succinic acid, polysorbate 20) are excluded from study participation.
Education, Monitoring, and Management
All injections in this study need to be administered in the clinic.  Following all injections, 
the patient must be monitored for 60 minutes.  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 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 are to be provided with alert cards to 
remind them and a caregiver or partner of the above.
If the patient develops any systemic hypersensitivity or anaphylactic or anaphylactoid 
reaction, the event should be expeditiously reported to the Sponsor as an adverse event 
of special interest or serious adverse event, as appropriate, within 24 hours.
If a patient has symptoms of anaphylaxis or severe hypersensitivity, the administration of 
etrolizumab must be discontinued permanently. 
Refer to Appendix 8 (Clinical Criteria for Diagnosis Anaphylaxis).
5.1.1.3
Local Injection-Site Reactions
Background
A local injection-site reaction is any local reaction occurring at the site of injection 
following study drug administration.  In completed Phase I/II trials in patients with UC, 
injection-site reactions were reported at a rate of 10%, all of which were of mild 
intensity.
Monitoring
In the clinic setting, patients should be monitored for signs of injection-site reactions in 
the period immediately following injections. Patients will be given guidance on reporting 
injection-site reactions after patient leaves clinic.
5.1.1.4
Hepatic Effects
Background
Liver toxicity has been reported with other drugs that target 4 integrins (natalizumab) 
and 47 integrins (vedolizumab).  Therefore, this potential risk is being monitored in all 
etrolizumab studies.  In nonclinical chronic toxicology studies, no abnormalities 
indicating liver toxicity with etrolizumab were observed.  The risk in humans is currently 
unknown.
Patient Selection
Patients with significant liver function test abnormalities should be excluded from the 
etrolizumab clinical studies (see Section 4.1.2).
Education, Monitoring, and Management
Patients should receive guidance on reporting liver problems if they occur.  Liver function 
tests should continue to be monitored according to the schedule of assessments and as 
clinically indicated.  Significant hepatic events should be evaluated promptly and 
managed accordingly.


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5.1.1.5
Malignancies
Background
There have been no reports of malignancy nor evidence for increased incidence of 
malignancy in completed Phase I/II trials and nonclinical studies to date.  Nonetheless, 
given the elevated risk of malignancy in this patient population a priori, the trial includes 
selection criteria and additional information to minimize any hypothetical risk.
Patient Selection
Patients with a history of cancer, including hematologic malignancy, solid tumors, and 
carcinoma in situ, within 5 years before screening should be excluded from the study 
with the exception of local basal or squamous cell carcinoma of the skin that has been 
excised and is considered cured (see Section 4.1.2 for Exclusion Criteria Related to 
General History).  A history of chronic myelogenous leukemia, hairy cell leukemia, 
melanoma, renal cell carcinoma, Kaposi sarcoma, or AIS, HSIL, or CIN of Grade 1 is 
considered exclusionary irrespective of the length of time before screening. 
Monitoring and Management
Investigators should remain vigilant for signs or symptoms of cancer in scheduled study 
assessments, including those of potential lymphoma.
Any signs or symptoms that could be suggestive of malignancy should be promptly and 
aggressively evaluated and reported to the Sponsor.  Incident hematologic abnormalities 
(e.g., new or worsening neutropenia, anemia, thrombocytopenia, macrocytosis, or 
atypical cells in the WBC differential) should be carefully evaluated.
Patients who develop a malignancy (with the exception of local and resected basal or 
squamous cell carcinoma of the skin) or who develop AIS, HSIL, or CIN of Grade 1 on 
cervical Pap smear or who develop colonic dysplasia during the study should be 
withdrawn from study drug and must not receive additional doses of study drug.
5.1.1.6
Immunogenicity
Background
As with administration of any exogenous protein, a potential exists for the development 
of ATAs.  Such antibodies can be neutralizing, with potential for reducing therapeutic 
effect of the drug and/or sensitizing, producing the potential for allergic reactions.  On 
the basis of the clinical experience to date, approximately 5% of patients develop ATAs 
to etrolizumab; however, this has not been correlated with any efficacy or safety 
sequelae.
Monitoring
To assess for the potential development of immunogenicity, antibody samples will be 
obtained at baseline, at regular intervals during treatment, and during the safety 
follow-up period (see Appendix 1; Schedule of Assessments) and stored appropriately 
for further evaluation as needed.


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5.1.1.7
Decreased Effectiveness of Immunizations
Background
The effect of etrolizumab upon the efficacy of vaccinations is unknown. 
Patient Selection and Risk Mitigation
Patients who received a live attenuated vaccine within 4 weeks prior to randomization 
are excluded from the study.  Patients should not receive live attenuated vaccines during 
the study and for approximately 5 half-lives after final study drug administration.
5.1.2
Risks Associated with Adalimumab
Investigators should be aware of the risks associated with adalimumab and their 
management (see Humira [40 mg/0.8 mL or 40 mg/0.4 mL] SmPC).
5.1.3
Risks Associated with Worsening of Ulcerative Colitis
The worsening of UC may result in the use of rescue medications.  In severe 
cases, worsening of UC may lead to hospitalization and, at worst, colectomy.  
See Section 4.5.2.5 and Appendix 1 for the schedule of assessments to be performed 
in the event of worsening of UC, which may lead to an unscheduled visit.  At any time 
during the study, patients who have worsening of their UC will be permitted to have 
rescue therapy with steroids (IV, oral, or topical).  Addition of or increases in doses of 
5 ASA (oral or topical) and/or immunosuppressants (i.e., AZA, 6-MP, or MTX) will also 
be allowed if clinically indicated by the Principal Investigator.  Rescue therapy with TNF 
inhibitors (including TNF inhibitor biosimilars), cyclosporine, tacrolimus, sirolimus, MMF, 
natalizumab, vedolizumab, rituximab, other lymphocyte depleting agents (with the 
exception of AZA and 6-MP), anakinra, abatacept, anti-adhesion molecules, or other 
biological or investigational therapeutics will not be allowed in conjunction with study 
drug because of the level of immunosuppression anticipated with the use of these 
agents.  Patients who receive any of these prohibited rescue medications are not to 
receive further treatment with study drug or open-label treatment and are to enter into 
safety follow-up within this study, followed by enrollment in Part 2 (SM) of Study 
GA28951.  All patients will be allowed to receive rescue therapy at any time.  Patients 
who are not clinical remitters at Week 10 will be allowed to enroll in Part 1 (OLE) of
Study GA28951 at Week 12 to receive open-label etrolizumab therapy, if eligible.  All 
Week 10 clinical remitters who complete the Week 14 assessment will be allowed to 
enroll in Part 1 (OLE) of the Study GA28951 at Week 14, if eligible.  Patients who do not 
enter Part 1 (OLE) of Study GA28951 will be requested to continue in safety follow-up, 
followed by enrollment into Part 2 (SM) of Study GA28951.


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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 defined as 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 5.1.1.2 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 5 and Section 5.1.1.1.1)


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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 collection, discontinuation of medications) should be 
reported (see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events, regardless of relationship to study drug, 
will be reported until the patient completes his or her last study visit.  After this period, 
patients who enter Study GA28951 should follow the adverse event reporting 
requirements of that study.
If the patient does not enter 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 5 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 5
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in the NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study


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
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event
Table 6
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) and symptoms (e.g., pain, pruritus at 
injection site) rather than a diagnosis of allergic reaction or injection-site reaction.
Other Adverse Events 
For adverse events other than injection-site reactions, a diagnosis (if known) should be 
recorded on the Adverse Event eCRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the Adverse Event eCRF.  If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 


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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.  However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe 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 should 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 be recorded only 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 be recorded only 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").


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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.
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.


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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.11
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 error in administration (e.g., dosing outside 
of the allowed window and injection without completion of full volume administration) of 
study drug is not an adverse event unless it results in untoward medical effects.
Any study drug overdose or error in administration (e.g., dosing outside of the allowed 
window and injection without completion of full volume administration) of study drug 
should be noted on the Study Drug Administration eCRF.
All adverse events associated with an overdose or error in administration (e.g., dosing 
outside of the allowed window and injection without completion of full volume 
administration) of study drug 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)


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The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
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 IQVIA 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 (see "Protocol Administrative and Contact 
Information & List of 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.


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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 provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form with use of the fax number or email address provided to investigators.  Once 
the EDC system is available, all information will need to be entered and submitted via 
the EDC system.
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 
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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). 
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 
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5.6
POST-STUDY ADVERSE EVENTS
Patients who enter Study GA28951 should follow the adverse event reporting 
requirements for that study. 
Post-study, if the patient does not enter 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.
The investigator should report these events directly to Roche or its designee either by 
faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form with use of the fax number or 
email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events for etrolizumab using the following reference 
document:

Etrolizumab Investigator's Brochure:
Within the Investigator’s Brochure, the reference safety information is provided 
in Section 6.4 (Identified Risks and Adverse Drug Reactions [Reference Safety 
Information]).
To determine reporting requirements for single adverse event cases for adalimumab, the 
Sponsor will assess the expectedness of these events using the reference safety 
information in the E.U. SmPC for adalimumab.
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.


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All serious related (as assessed by the investigator and/or sponsor) adverse events 
occurring in a patient administered etrolizumab at any time during the trial and assessed 
as unexpected per the reference safety information will be considered Suspected 
Unexpected Serious Adverse Reactions (SUSARs) for the purpose of regulatory 
reporting to all health authorities, with the exception of the 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).
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The primary analysis will be performed when all data through Week 14 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 who were blinded during the study 
will remain blinded to individual treatment assignment until after the study is completed 
(after all patients have either completed the safety follow-up period or discontinued early 
from the study) and the database is locked.
Detailed specifications of the statistical methods will be described in the Statistical 
Analysis Plan (SAP).
6.1
DETERMINATION OF SAMPLE SIZE
A total of approximately 350 patients will be randomized in a 2:2:1 ratio:  
etrolizumab (n140), adalimumab (n140), and placebo (n70), respectively.
Under the assumption of a difference in remission rates between the etrolizumab and 
placebo arms of 25% (35% vs. 10%), the sample size of 140 patients receiving 
etrolizumab and 70 patients receiving placebo will provide 90% power to detect a 
difference with use of a 2 test at the two-sided 5% significance level. The assumption 
is based on the observed Week 10 remission results in the Phase II etrolizumab study 
for the TNF-naive subgroup. In addition, under the assumption of a remission rate of
20% in the adalimumab arm (based on the clinical remission induction results achieved 
in the Phase III adalimumab ULTRA2 trial [Sandborn et al. 2012]), the planned size of 
140 patients/active treatment arm will provide approximately 80% power to detect a 


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15% absolute difference between the remission rates in the etrolizumab and 
adalimumab arms (35% vs. 20%), with use of a 2 test at the two-sided 5% significance 
level.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients randomized will be tabulated by study site and treatment arm.  
Patient disposition (the number of patients randomized, treated, and completing the 
treatment period/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.  Exposure to study drug (number of study treatments and duration 
of treatment) will be summarized by treatment arm.
6.4
EFFICACY ANALYSES
Efficacy analyses will be performed using a modified intent-to-treat analysis set 
including all patients randomized who received at least one dose of study drug, with
patients grouped according to the treatment assigned at randomization.
Patients who are non-evaluable for efficacy at a specific timepoint (e.g., due to missing 
data or enrollment in Part 1 [OLE] of the OLE-SM protocol between Week 10 and 
Week 14) will be considered non-responders for all response/remission type endpoints.  
In addition, 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 in Section 6.4 and Section 6.4.2, the following 
analyses will be performed for the primary efficacy endpoint and key secondary efficacy 
endpoints.  Details of these analyses will be described in the SAP:

Sensitivity analyses to evaluate the robustness of results to the primary analysis 
methods (e.g., handling of dropouts)

Subgroup analyses to evaluate the consistency of results across prespecified 
subgroups (e.g., based on age, sex, race/ethnicity, baseline UC medications, 
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To manage the overall type I error, the hypotheses will be tested sequentially.  The first 
hypothesis to be tested will compare the primary endpoint between the etrolizumab and 
the placebo arms (primary efficacy objective).  If this test result is not statistically 
significant, further hypothesis tests will be considered exploratory and no claims of 
statistical significance will be made.  The testing hierarchy for the secondary hypotheses 
will be described in the SAP.  All endpoints will be assessed at a nominal two-sided 5% 
significance level.
6.4.1
Primary Efficacy Endpoint
The difference in remission rates between the etrolizumab and placebo arms at Week 10 
will be compared (at the two-sided 5% significance level) with use of the 
Cochran-Mantel-Haenszel test statistic stratified by concomitant treatment with 
corticosteroids at randomization (yes/no), concomitant treatment with 
immunosuppressants at randomization (yes/no), and disease activity measured during 
screening (MCS 9, MCS 10).  The absolute difference in remission rates and 
95% CIs for the point estimate will be calculated.
6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints for this study are as follows:

Proportion of patients in remission at Week 10 (compared with adalimumab only)

Proportion of patients in clinical remission at Week 10

Proportion of patients with clinical response at Week 10

Proportion of patients with improvement in endoscopic appearance of the mucosa at 
Week 10

Proportion of patients in endoscopic remission at Week 10

Proportion of patients who achieve remission at Weeks 10 and 14 

Proportion of patients in histologic remission at Week 10

Change from baseline in MCS rectal bleeding subscore at Week 6

Change from baseline in MCS stool frequency subscore at Week 6

Change from baseline to Week 10 in UC bowel movement signs and symptoms, as 
assessed by the UC-PRO/SS 

Change from baseline to Week 10 in UC abdominal symptoms, as assessed by the 
UC-PRO/SS

Change from baseline to Week 10 in health-related QOL, as assessed by the overall 
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The analysis of the responder type secondary endpoints will be performed in the same 
fashion as for the primary endpoint.  Change from baseline continuous endpoints will be 
analyzed using an analysis of covariance model with concomitant treatment with 
corticosteroids, concomitant treatment with immunosuppressants, baseline disease 
activity (MCS 9, MCS 10) as stratification variables, and the baseline value of the 
studied measure as a covariate.
Further details on secondary endpoint analyses and a description of additional 
exploratory analyses will be provided in the SAP.
6.4.3
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints are as follows:

Proportion of patients who achieved clinical remission at Week 10 and remission at 
Week 14

Proportion of patients who achieved clinical remission at Weeks 10 and 14

Proportion of patients with change in histologic disease activity from baseline to 
Week 10 

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 10

Proportion of patients in response and remission at Week 10 in subgroups by 
baseline expression levels of colonic tissue and/or peripheral blood biomarkers, 
including, but not limited to, E integrin

Proportion of patients with response and remission, as determined by the mMCS
The derivation of the E or other biomarker subsets used to define the subgroups will be 
described prior to the unblinding of the study.
6.5
SAFETY ANALYSES
The safety analyses will include all randomized patients who received at least one dose 
of study drug, with patients grouped according to the treatment actually received.
Safety will be assessed through descriptive summaries of adverse events, laboratory 
test results (serum chemistry and hematology including complete blood count with 
differential and platelet counts), and antibodies to etrolizumab.
Additional details will be provided in the SAP.


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6.5.1
Adverse Events
Verbatim descriptions of treatment-emergent adverse events will be coded and their 
incidence will be summarized by treatment arm, as appropriate.  A treatment-emergent 
adverse event is defined as any new adverse event reported or any worsening of an 
existing condition on or after the first dose of study drug.  In addition, separate 
summaries will be generated for serious adverse events, deaths, and adverse events 
leading to discontinuation of study drug.  Adverse events will be summarized by mapped 
term, appropriate thesaurus level, and toxicity grade.
Analyses will be performed for:

Systemic hypersensitivity events
Specific analyses will be performed for anaphylactic reactions using the 
anaphylactic reaction Sampson’s criteria (see Appendix 8).

Serious infections
The frequency of serious infections, in particular GI infections, will be 
summarized for each treatment arm.

Opportunistic infections
The occurrence of opportunistic infections will be summarized for each 
treatment arm.

Malignancies
Events that occur in the Neoplasms, Benign, Malignant, and Unspecified 
(Including Cysts and Polyps) System Organ Class will also be summarized for 
each treatment arm.

Injection-site reactions
The frequency of injection-site reactions will be summarized for each 
treatment arm.
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.


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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 concentrations of etrolizumab will be 
summarized at Week 10 and Week 14.  Estimates for these parameters will be tabulated 
and summarized (mean, standard deviation, coefficient of variation, median, minimum, 
and maximum).
Additional PK or exposure-response analyses may be conducted as appropriate.
PD and biomarker analyses will include examination of baseline associations with 
response and other biomarkers and changes over time in exploratory biomarkers 
post-treatment relative to baseline.  Results will be summarized descriptively.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
Sponsor, contract research organization (CRO), and Data Management vendor will be 
responsible for the data management of this study, including quality checking of the data.  
Sites will be responsible for data entry into an eCRF via the EDC system.  In the event of 
discrepant data, data queries will be issued to the sites and resolved by the sites via the 
EDC system.  The Sponsor will produce an EDC Study Specification document that 
describes the quality checking to be performed on the data.  In addition, eCRF Help Text 
will be provided to the sites through the EDC system.  eCRFs and correction 
documentation will be maintained in the EDC system’s audit trail.
Central laboratory data will be transferred directly to the Sponsor, with use of the 
Sponsor’s standard procedures to handle and process the electronic transfer of 
these data.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and have access to the Help Text in the Medidata RAVE for appropriate eCRF 
completion.  eCRFs will be submitted electronically to the Sponsor and should be 
handled in accordance with instructions from the Sponsor.
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.


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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, 
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.


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To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The investigational site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research.  An acceptable computerized data collection system allows 
preservation of the original entry of data.  If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, patient data (including PRO), Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 
study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
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).


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8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the “Consent Forms”) before IRB/EC 
submission.  The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  
A separate, specific signature will be required to document a patient's agreement to 
allow any remaining specimens to be used for exploratory research.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
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 


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utilizes a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the 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.


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8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient last visit).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, which include an audit trail containing a complete record of all changes 
to data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study is sponsored by F. HoffmannLa Roche Ltd.  Approximately 350 patients will 
participate in this global study.
A CRO will be contracted to manage the study and perform monitoring activities.
Centralized facilities (vendors) will be used to collect QOL data and endoscopy reading 
and interpretation; however, the investigator or a designee will also read the endoscopy 
if required for clinically indicated safety reasons.


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A central laboratory (i.e., Roche or a vendor) will be used for most laboratory 
assessments, including histologic grading of colonic biopsy samples 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 congresses.  For all clinical 
trials in patients involving an IMP for which a marketing authorization application has 
been filed or approved in any country, the Sponsor aims to submit a journal manuscript 
reporting primary clinical trial results within 6 months after the availability of the 
respective clinical study report.  In addition, for all clinical trials in patients involving an 
IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.  
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
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.


Etrolizumab—F. Hoffmann-La Roche Ltd
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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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Dotan, I. Early use of gut-selective therapy in Crohn’s disease for long-term remission. 
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Crohn's and Colitis Organization, 17 February 2017 (unpublished).
Faubion WA Jr, Loftus EV Jr, Harmsen WS, et al. The natural history of corticosteroid 
therapy for inflammatory bowel disease: a population-based study. 
Gastroenterology 2001;121:25560.
Feagan BG, Greenberg GR, Wild G, et al. Treatment of active Crohn's disease with 
MLN0002, a humanized antibody to the alpha4beta7 integrin. Clin Gastroenterol 
Hepatol 2008;6:13707.
Feagan BG, Greenberg GR, Wild G, et al. Treatment of ulcerative colitis with a 
humanized antibody to the α47 integrin. N Engl J Med 2005;352:2499507.
Feagan BG, Rutgeerts PG, Sand BE, et al. Vedolizumab as induction and maintenance 
therapy for ulcerative colitis. N Engl J Med 2013;369:699710.
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inflammatory bowel disease. Gastroenterology 1989;96:80410.
Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s 
disease: the ACCENT I randomised trial. Lancet 2002;359:154149.
Holzmann B, McIntyre BW, Weissman IL. Identification of a murine Peyer’s 
patchspecific lymphocyte homing receptor as an integrin molecule with an 
-chain homologous to human VLA-4-α. Cell 1989;56:3746.
Hu M, Crowe DT, Weissman IL, et al. Cloning and expression of mouse integrin p(7): 
a functional role in Peyer's patch–specific lymphocyte homing. Proc Natl Acad Sci 
USA 1992;89:82548.
Irvine EJ. Development and subsequent refinement of the inflammatory bowel disease 
questionnaire: a quality-of-life instrument for adult patients with inflammatory bowel 
disease. J Pediatr Gastroenterol Nutr 1999;28:S237.


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Khan N, Abbas AM, Moehlen M, et al. Methotrexate in ulcerative colitis: a nationwide 
retrospective cohort from the Veterans Affairs Health Care System. Inflamm Bowel 
Dis. 2013; 19:7.
Laharie D, Bourreille A, Branche J, et al. Ciclosporin versus infliximab in patients with 
severe ulcerative colitis refractory to intravenous steroids: 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 
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Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the 
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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43.
Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for induction of clinical 
remission in moderately to severely active ulcerative colitis: results of a 
randomised controlled trial. GUT 2011;60:7807.
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 
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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.
Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance 
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Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction and maintenance therapy 
for ulcerative colitis. N Engl J Med 2017;376:172336.


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Sandborn WJ, van Assche G, Reinisch W, et al. Adalimumab induces and maintains 
clinical remission in patients with moderate-to-severe ulcerative colitis. J Gastro 
2012;142:25765.
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 
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Tan IL, McArthur JC, Clifford DB, et al. Immune reconstitution inflammatory syndrome in 
natalizumab-associated PML. Neurology 2011;77:106177.


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Appendix 1
Schedule of Assessments
Assessment
Screening
Day a
35 to 1
Study Week (3 days)
Early 
Withdrawal from 
Treatment 
Phase ee
0 b
2
4
6
8
10
12 c
14 c
Unscheduled 
Visit d
Informed consent
x
Review eligibility criteria e
x
x b
Demographic data
x
Pregnancy test f
x
x b
x
x
x
x
Vital signs  (BP and pulse)
x
x b
x
x
x
x
ECG
x
x
Chest X-ray g
x
Height
x
Weight
x
Medical history
x
Physical examination h
x
x
x
x
PML neurologic examination i
x
x
x
x d
x
Hematology
x
x b
x
x d
x j
Chemistry
x
x b
x
x d
x j
Urinalysis
x
x b
x d
TB screen k
x
HIV test
x
Hepatitis B and C serology l
x
Hepatitis B DNA m
x
x


Appendix 1
Schedule of Assessments (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
126/Protocol GA28949, Version 8
Assessment
Screening
Day a
35 to 1
Study Week (3 days)
Early 
Withdrawal from 
Treatment 
Phase ee
0 b
2
4
6
8
10
12 c
14 c
Unscheduled 
Visit d
Hepatitis C RNA (Amplicor) n
x
PK sampling (serum)
x o
x
x
x d
x j
Anti-therapeutic antibody sample (serum) o,p
x o
x o
x
x q
x d
x j, q
Plasma sample (storage for JCV antibody 
testing) r
x
MCS (includes endoscopy) s
x
x
x
x d
x j, ff
Partial MCS (pMCS, excludes endoscopy)t,u
x
x
x
x d
x j
Stool sample collection
x v
x w
x w
x d
xw
Colonic biopsy (CMV, if required)
x x
x d
Colonic biopsy (histopathological confirmation 
of UC if required) 
x y
Colonic biopsy (formalin)
x z
x aa
x aa
x d, x
x j, x, ff
Colonic biopsy (RNAlater)
x z
x aa
x aa
x d, y
x j, aa, ff
Serum sample (CRP)
x o
x
x d
x j
Serum sample (future exploratory PD) m
x
x
x
x
Blood sample (RNA Paxgene) bb
x o
x
Blood sample for genetic analysis (DNA) 
optional
x
UC-PRO/SS cc
x
x
x
x
IBDQ dd
x
x


Appendix 1
Schedule of Assessments (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
127/Protocol GA28949, Version 8
Assessment
Screening
Day a
35 to 1
Study Week (3 days)
Early 
Withdrawal from 
Treatment 
Phase ee
0 b
2
4
6
8
10
12 c
14 c
Unscheduled 
Visit d
EQ-5D dd
x
x
Concomitant medications
x
x
x
x
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
Adalimumab/adalimumab placebo 
administration
x
x
x
x
x
Etrolizumab/etrolizumab placebo 
administration
x
x
x
x
BPblood pressure; CMVcytomegalovirus; ECGelectrocardiogram; EQ-5DEuroQoL Five-Dimension Questionnaire; 
HBVhepatitis B virus; CRPC-reactive protein; IBDQ Inflammatory Bowel Disease Questionnaire.; JCVJohn Cunningham 
virus; MCSMayo Clinic Score; PDpharmacodynamics; PGAphysician’s global assessment; PKpharmacokinetic; 
pMCSpartial Mayo Clinic Score; PMLprogressive multifocal leukoencephalopathy; qPCR quantitative polymerase chain 
reactions; TBtuberculosis, UC-PRO/SSUlcerative Colitis Patient-Reported Outcome Signs and Symptoms.
Notes:  All study assessments and blood draws are to be conducted prior to study drug administration.
All colonic biopsy samples will be taken during flexible sigmoidoscopy/colonoscopy procedure. 
a All assessments must be performed after obtaining informed consent.  Endoscopy should be performed 416 days prior to 
randomization (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 Only patients who achieve clinical remission, as assessed at Week 10, will attend Week 12 and Week 14 visits


Appendix 1
Schedule of Assessments (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
128/Protocol GA28949, Version 8
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., only perform PML neurologic examination if patient reports symptoms suspected of PML; for 
disease worsening, infectious etiologies may be investigated if clinically indicated; and confirmation of clinical relapse is 
performed by the MCS).  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 visits other than screening; if urine test result is positive, perform a confirmatory serum test.  Do not 
administer etrolizumab unless the serum pregnancy test result is negative.
g Not required if normal chest X–ray result within 3 months prior to screening.
h Full physical examination required at screening; symptom-driven physical examination at all other timepoints indicated.
i PML neurologic examination consists of the PML Subjective Checklist and the PML Objective Checklist.  Administer before 
other assessments 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.
o All samples to be collected prior to administration of study drug.  The PK, ATA, and exploratory PD sample collections will be 
from all patients.
p If serum sickness or a clinically significant allergic drug reaction is suspected, Sponsor should be notified, and serum for the 
analysis of study drug 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).


Appendix 1
Schedule of Assessments (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
129/Protocol GA28949, Version 8
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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 Partial MCS during screening is defined as the MCS score excluding the endoscopy score.  Physician's Global Assessment 
component of MCS/partial MCS will be conducted prior to randomization on Day 1.
u 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 not limited to, analysis 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 laboratory, 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 samples noted in footnote “x” and “y” above, 5 pairs (10 samples) will also be obtained at 
screening.  All will be sent to the central laboratory for further storage or distribution.  Two pairs (taken from the most inflamed 
are of colon within 2040 cm of anal verge [sigmoid]) 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 qPCR).  Two pairs from the most 
inflamed area of colon within 2040 cm of anal verge (sigmoid) will be placed in formalin and then paraffin embedded (1 pair 
will be used for exploratory PD biomarkers and the other pair will be used for diagnostic).  The last pair will be taken from the 
most inflamed area of the worst affected segment and will be placed in formalin and then paraffin embedded (this sample will 
be used for histopathology and exploratory PD biomarkers).  Original biopsy location and endoscopic depth should be clearly 
indicated.


Appendix 1
Schedule of Assessments (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
130/Protocol GA28949, Version 8
aa A total of 4 pairs (8 samples) will be obtained.  All will be sent to the central laboratory for further storage or distribution.  One 
pair will be placed in stabilization buffer (such as RNAlater or a similar buffer) and stored at 80C for exploratory PD or 
diagnostic biomarker qPCR.  The other 3 pairs, representing 3 different segments (rectum, sigmoid, descending colon), will be 
placed in formalin and then paraffin embedded; these biopsies will be used for histopathology, exploratory PD biomarkers 
and/or diagnostic biomarker.  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 
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 If clinical remission is not achieved at Week 10, the patient will be given the option to participate in Part 1 (OLE) of 
Study GA28951, if eligible, to receive open-label etrolizumab at Week 12 (which will correspond to Day 1 in Study GA28951).  
In this case, an early withdrawal from treatment visit is not required (i.e., the Week 10 visit will be the patient's last visit in this 
study).  An early withdrawal from treatment visit is to be conducted if the patient withdraws at any other timepoint in the study.
ff For patients exiting the treatment period early for any reason, an endoscopy to document disease activity may be performed 
at the discretion of the investigator.


Etrolizumab—F. Hoffmann-La Roche Ltd
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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 examination 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 suspected.  ATA samples 
may be used for determination of drug concentrations or exploratory PD assessments.


Etrolizumab—F. Hoffmann-La Roche Ltd
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Appendix 3
Childbearing Potential, Pregnancy Testing, and Contraception
All women of childbearing potential (including those who have had a tubal ligation) will 
have a serum pregnancy test at screening and a urine pregnancy test prior to 
administration of study drug at subsequent visits.  If a urine pregnancy test result is 
positive, study drug will not be administered until pregnancy is ruled out.  The result 
must be confirmed by a serum pregnancy test (conducted by the central laboratory). 
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 postmenopausal (nontherapy-induced amenorrhea) for at 
least 12 months

The patient had a surgical bilateral oophorectomy (with or without hysterectomy) 
more than 6 weeks prior to enrollment

The patient had a hysterectomy
Female patients of reproductive or childbearing potential who are unwilling to use a 
highly effective method of contraception or remain abstinent during the treatment period 
and for at least 24 weeks after the last dose of study drug will be excluded from study 
participation.  
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle 
of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception.
Examples of highly effective contraception include the following:

Combined oral contraceptive pill 

Contraceptive transdermal patch

Intrauterine device

Implants for contraception

Injections for contraception (with prolonged release)

Hormonal vaginal device

Sterilization, surgical tubal ligation


Appendix 3
Childbearing Potential, Pregnancy Testing,
and Contraception (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
133/Protocol GA28949, Version 8

Sole sexual partner consisting of surgically sterilized male partner with appropriate 
postsurgical verification of the absence of spermatozoa in the ejaculate

Double-barrier methods: condom and occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository (Note: a female condom 
and male condom should not be used together because friction between the two 
can result in either product failing)
Patients may provide verbal confirmation that the partner completed appropriate 
follow-up after vasectomy.  Sites are not required to obtain partner medical records.
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined 
below:  
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at least 
24 weeks after the last dose of study drug.  Men must refrain from donating sperm 
during this same period.  
For men and women:  The reliability of sexual abstinence should be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, and postovulation 
methods) and withdrawal are not acceptable methods of contraception.  


Etrolizumab—F. Hoffmann-La Roche Ltd
134/Protocol GA28949, Version 8
Appendix 4
Mayo Clinic Score Measurement
Mayo Clinic Score is a composite endpoint with four components. The score ranges from
0 to 12 with higher scores indicating more severe disease.
The Mayo Clinic components are as follows:
1.
STOOL FREQUENCY
0 Normal number of stools for this patient
11 to 2 stools more than normal
23 to 4 more stools than normal
35 or more stools than normal
Subscore 03
2.
RECTAL BLEEDING
0 No blood in stool
1Streaks of blood with stool less than half the time
2Obvious blood with stool most of the time
3Blood alone passed
Subscore 03
3.
ENDOSCOPY
0 Normal or inactive disease
1Mild disease (erythema, decreased vascular pattern, mild friability)
2Moderate disease (marked erythema, lack of vascular pattern, friability, 
erosions)
3Severe disease (spontaneous bleeding, ulceration) 
Subscore 03
4.
PHYSICIAN'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 4
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
135/Protocol GA28949, 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 onto the
e-diary by the patient and excluded from the MCS calculation)
1.
Stool frequency

Stool frequency is to be recorded daily from start of screening to the end of the study
in the e-diary.

The stool frequency is to be compared to 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.  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 4
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
136/Protocol GA28949, Version 8

For patients undergoing re-screening who meet the criteria to waive the endoscopy 
(see Section 4.5.2.1.2), the stool frequency subscore will be derived from the 
3 consecutive days prior to the new enrollment day (i.e., Days -1, -2, and -3). Any 
missing day or days will be supplemented with the immediate next day or days 
recorded up to 22 days prior to the new enrollment day (e.g., if Day -2 is missing, 
Days -1, -3, and -4 will be used).

The post-baseline stool frequency value for endpoint assessment will be calculated 
as the average (rounded to the nearest integer) from the three most recent stool 
frequency scores that were entered in the e-diary within the 7 days prior to the clinic 
visit and prior to the days devoted to  bowel preparation and endoscopy. 
2.
Rectal bleeding

Rectal bleeding is to be recorded daily from screening to the end of the study in the
e-diary.

The rectal bleeding score is to be categorized from 03 according to the definition
given in 2 above.

Patients are to be instructed to ignore any blood which is caused by menstruation or
hemorrhoids.

The baseline value for the rectal bleeding score will be taken from patient e-diary 
recordings that are entered between Day 22 (inclusive and bowel preparation for 
the screening endoscopy, and will be determined by the worst recording from the 
three most recent scores that were entered just prior to the day of bowel preparation. 
However, up to three post-endoscopy scores, starting with the score recorded 2 
days after the endoscopy, may be used to calculate baseline rectal bleeding, but 
ONLY when fewer than three scores are available between Day 22 and bowel 
preparation (see Figure 1 below). The days selected for this calculation are 
intended to prevent the use of rectal bleeding recordings during the screening 
period that are impacted by bowel preparation and endoscopy, including the day 
immediately following the endoscopy.

For patients undergoing re-screening who meet the criteria to waive the endoscopy 
(see Section 4.5.2.1.2), the rectal bleeding subscore will be derived from the 
3 consecutive days prior to the new enrollment day (i.e., Days -1, -2, and -3). Any 
missing day or days will be supplemented with the immediate next day or days 
recorded up to 22 days prior to the new enrollment day (e.g., if Day -2 is missing, 
Days -1, -3, and -4 will be used).

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. 


Appendix 4
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
137/Protocol GA28949, Version 8
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 randomization (Day 1) (i.e., Day 16 to Day4).
4.
Physician's Global Assessment
The physician’s global assessment WILL:

Be based on the patient’s overall status

Reflect how the patient is doing at present.  Assessment SHOULD NOT reflect past
disease severity or complexity or the number/kinds of medicines the patient is 
receiving

Be based on the:
Rectal bleeding score, stool frequency score, and endoscopic evaluation
Patient’s recollection of abdominal discomfort and general sense of well-being
Patient’s performance status, fecal incontinence and mood
Physician’s observations and physical 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 physician’s global assessment will be provided by the Investigator as a score of 0 to 
3 and entered into the tablet.
CALCULATION OF THE MAYO CLINIC SCORE
Timepoints for MCS assessments can be found in the protocol Schedule of Assessments.
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, a rectal bleeding subscore 1, 
and a stool frequency subscore 1


Appendix 4
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
138/Protocol GA28949, Version 8
2.
Achievement of clinical response at Week 10
MCS with 3-point decrease and 30% reduction from baseline as well as 
1-point decrease in rectal bleeding subscore or an absolute score of 0 or 1
3.
Identification of Clinical Relapse
Clinical relapse is defined as an increase in pMCS 3 points compared to 
induction timepoint (Week 10) AND absolute pMCS of 5 AND an endoscopy
subscore of 2


Appendix 4
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
139/Protocol GA28949, Version 8
Figure 1
Derivation of Stool Frequency and Rectal Bleeding Subscores at Screening
MCS Mayo Clinic Score; RNDrandomization; RBrectal bleeding; SFstool frequency.


Appendix 4
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
140/Protocol GA28949, Version 8
Figure 1
Derivation of Stool Frequency and Rectal Bleeding Subscores at Screening (cont.)
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.
Derivation of stool frequency and rectal bleeding subscores at re-screening in circumstances where a second endoscopy is 
not required:

For patients undergoing re-screening who meet the criteria to waive the endoscopy (see Section 4.5.2.1.2), the stool frequency 
and rectal bleeding subscores will be derived from the 3 consecutive days prior to the new enrollment day (i.e., Days -1, -2, and -
3).  Any missing day or days will be supplemented with the immediate next day or days recorded up to 22 days prior to the new
enrollment day (e.g., if Day -2 is missing, Days -1, -3, and -4 will be used).


Appendix 4
Mayo Clinic Score Measurement (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
141/Protocol GA28949, 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 to induction timepoint AND absolute partial MCS 5 an endoscopy
would be conducted and endoscopy subscore and full MCS calculated
E-DIARY MALFUNCTION OR LOSS
The help desk for the e-diary vendor (CRF Health) should be contacted in the event of 
e-diary malfunction or loss.  Until a working e-diary can be provided to the patient, site 
staff should, after the e-diary malfunction or loss, retrospectively collect the previous 
day's stool frequency and rectal bleeding subscores from the patient via telephone 
interview within the next working day following the e-diary failure or loss.  These data will 
then be transcribed into a data clarification form within CRF Health’s TrialManager 
system for approval.
Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for
mildly to moderately active ulcerative colitis: a randomized study. N Engl J Med
1987;317:1625–9)


Etrolizumab—F. Hoffmann-La Roche Ltd
142/Protocol GA28949, Version 8
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
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 schedule of assessments (see Appendix 1). 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
143/Protocol GA28949, 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
144/Protocol GA28949, 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
145/Protocol GA28949, 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)
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.


Appendix 5
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
146/Protocol GA28949, Version 8

Have the patient cover one eye and stare at your nose, and then ask them how
many fingers you are holding up, testing each of the 4 visual quadrants. Repeat with
the other eye covered.
Ocular Motility Testing:

Evaluate the patient for conjugate eye movement.

Starting about 3 feet from center, move in a big “H”, pausing at the center and at 
lateral gaze, and finishing with convergence (finger to their nose). Watch for
nystagmus in lateral gaze, smooth pursuits, and pupillary constriction with
convergence. Note: a couple of beats of nystagmus upon extreme lateral gaze is
considered normal.
2. Speech

Observe the patient’s speech output for dysarthria or aphasia.

Dysarthria is a motor speech disorder. Findings can include “slurred” speech, 
decreased volume, slow rate of speech, limited tongue, lip, and jaw movement,
abnormal rhythm when speaking, changes in vocal quality, and drooling or poor 
control of saliva.

Aphasia is a disorder that results from damage to parts of the brain that control 
language, and can lead to problems with any or all of the following: speaking, 
listening, reading or writing.
3. Strength
Pronator drift test (Barre maneuver):

Ask the patient to stand with their feet together and extend their arms out in front of 
them at 90 degrees (parallel to floor) with palms facing upwards toward the ceiling.

Ask the patient to close their eyes and keep their arms extended for 15 seconds.

If either arm drifts downward, upward, or starts to pronate (i.e. thumb turns up), this
is considered an abnormal exam.
Gait testing:

Ask the patient to walk across the room (~10 feet).  The patient should have a
normal gait, with their left arm swinging forward when the right foot leads, and vice
versa.  Be certain to note whether there is symmetric arm swinging, because a
slight decrease in arm swinging may be an indicator of upper extremity weakness.

Ask the patient to walk on their heels across the room (~10 feet). Carefully observe
whether they have any difficulty maintaining their toes off the ground or loss of
balance.

Ask the patient to walk on their toes across the room (~10 feet). Carefully observe if
they have any difficulty maintaining their heels off the ground or loss of balance.


Appendix 5
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
147/Protocol GA28949, Version 8
Additional strength testing (ONLY if the patient has any subjective complaints of 
weakness):

Test muscle strength of the relevant muscle groups based on the patient’s
subjective complaints.

General guidelines for a basic muscle strength exam:

Upper extremity:
o
Finger grip strength
o
Flexion at elbow
o
Extension at elbow
o
Deltoid strength: Maintain bent arms up (perpendicular to floor) and
resist while investigator pushes down
o
Shoulder shrug against resistance

Lower extremity: (examine while patient is sitting down)
o
Raise thigh (while bent)
o
Straighten leg
o
Flex leg
o
Flex foot
o
Extend foot
4. Coordination
Tandem gait:

As the patient is looking at his feet, ask them to walk 8 steps with one foot touching
in front of the other (demonstrate for them).
Finger to nose:

Hold your finger out so they need to reach out and lean. Start near the center, and
move your finger slowly so that they reach across their body. Make sure they
alternate touching your finger and their nose at a good speed. Inability to perform 
this accurately is considered an abnormal test.
5. Comprehension

Test ability to follow serial commands

“Take a piece of paper in your hand, fold it in half, and put it on the floor.”


Appendix 5
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
148/Protocol GA28949, Version 8
6. Memory and Thinking

(ONLY if the patient has subjective complaints about their memory or thinking) test
the ability of the patient to recall 3 objects over 1 minute with distraction.
7. Sensation

(ONLY if the patient has subjective sensory complaints) evaluate relevant areas
based on the patient’s subjective complaints by comparing left vs. right side
sensation to cold (e.g. alcohol swab or cold stethoscope) or pinprick (e.g. broken
Q-tip). Confirm that the patient is able to feel the sensation symmetrically.




Etrolizumab—F. Hoffmann-La Roche Ltd
150/Protocol GA28949, Version 8
Appendix 7
Patient Daily Diary


Etrolizumab—F. Hoffmann-La Roche Ltd
151/Protocol GA28949, Version 8
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
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By placing a checkmark in one box in each group below, please indicate which 
statements best describe your own health state today.
Mobility
I have no problems in walking about
q
I have some problems in walking about
q
I am confined to bed
q
Self-Care
I have no problems with self-care
q
I have some problems washing or dressing myself
q
I am unable to wash or dress myself
q
Usual Activities (e.g. work, study, housework, family or
leisure activities)
I have no problems with performing my usual activities
q
I have some problems with performing my usual activities
q
I am unable to perform my usual activities
q
Pain/Discomfort
I have no pain or discomfort
q
I have moderate pain or discomfort
q
I have extreme pain or discomfort
q
Anxiety/Depression
I am not anxious or depressed
q
I am moderately anxious or depressed
q
I am extremely anxious or depressed
q
© 1998 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group
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Appendix 12
Nancy Histological Index
Histologic activity on colon biopsies will be measured using the Nancy histological index 
(below).  Histologic remission is defined as a Nancy histological index of 01 based on 
consensus guidelines recommending that histologic remission should be defined by the 
absence of neutrophils in the crypts and lamina propria.
Nancy Histological Index (NHI)
Marker
Assessment
NHI Grade
Erosion or ulceration
Present
4: Severely active disease
Acute inflammatory 
infiltrate
Moderate to severe
3: Moderately active disease
Mild
2: Mildly active disease
Chronic inflammatory 
infiltrate
Moderate or marked 
increase
1: Chronic inflammatory infiltrate with no acute 
inflammatory infiltrate
No or mild increase
0: No histologically significant disease
Histologic remission: NHI 1
References
Marchal-Bressenot A, Salleron J, Boulagnon-Rombi C, et al. Development and validation 
of the Nancy histological index for UC. Gut 2017;66:43–9.
Marchal-Bressenot A, Scherl A, Salleron J, et al. A practical guide to assess the Nancy 
histological index for UC. Gut 2016;65:1919–20.

SAP_001.pdf: 
 
Official Title: Phase III, Randomized, Double-Blind, Double-Dummy, Placebo-
Controlled, Multicenter Study to Evaluate the Efficacy (Induction of 
Remission) and Safety of Etrolizumab Compared With Adalimumab 
and Placebo in Patients With Moderate to Severe Ulcerative Colitis 
who are Naive to TNF Inhibitors 
NCT Number: NCT02163759, NCT02171429 
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 GA28948/GA28949
STATISTICAL ANALYSIS PLAN
TITLE:
PHASE III, RANDOMIZED, DOUBLE-BLIND, 
DOUBLE-DUMMY, PLACEBO-CONTROLLED, 
MULTICENTER STUDY TO EVALUATE THE EFFICACY 
(INDUCTION OF REMISSION) AND SAFETY OF 
ETROLIZUMAB COMPARED WITH ADALIMUMAB AND 
PLACEBO IN PATIENTS WITH MODERATE TO SEVERE 
ULCERATIVE COLITIS WHO ARE NAIVE TO 
TNF INHIBITORS
PROTOCOL NUMBER(S):
GA28948 (Hibiscus I) and GA28949 (Hibiscus II)
STUDY DRUG:
Etrolizumab
VERSION NUMBER:
3
IND NUMBER:
100366
EUDRACT NUMBER:
2013-004279-11 (GA28948)
2013-004277-27 (GA28949)
SPONSOR:
F. Hoffmann-La Roche Ltd.
PLAN PREPARED BY:
, M.Sc.
DATE FINAL:
Version 1: 15 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 14:50:06
Company Signatory


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2/Statistical Analysis Plan GA28948/GA28949
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE FOR VERSION 3

Changes to Section 4.1.1 (Modified Intent-to-Treat (mITT) Population) were made to 
clarify that it will not be used for histologic remission analysis.

Changes to Section 4.1.3 (Histology-Evaluable Population) were made to clarify 
main analysis and sensitivity analysis populations.

Changes to Section 4.4 (Efficacy Analysis) were made to update the methodology for 
handling of treatment discontinuation intercurrent events to be set to missing for 
continuous endpoints and remove single imputation of worst observation carried 
forward.

Changes to Section 4.4.2.1 (Control of Type I Error) and removal of Appendix 4, to 
simplify and align the multiple testing strategy with other Phase III studies.

Changes to Section 4.4.4 (Sensitivity Analyses) to add additional sensitivity 
analyses for key secondary endpoints as applicable.
Additional minor changes have been made to improve clarity and consistency.


Etrolizumab—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan GA28948/GA28949
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 ................................................. 9
2.4
Analysis Timing ....................................................................... 9
3.
STUDY CONDUCT....................................................................................... 9
3.1
Randomization......................................................................... 9
3.2
Independent Review Facility.................................................. 10
3.3
Data Monitoring ..................................................................... 10
4.
STATISTICAL METHODS .......................................................................... 10
4.1
Analysis Populations ............................................................. 10
4.1.1
Modified Intent-to-Treat (mITT) Population............................ 10
4.1.2
Pharmacokinetic (PK)-Evaluable Population ......................... 10
4.1.3
Histology-Evaluable Population............................................. 10
4.1.4
Safety Population .................................................................. 11
4.2
Analysis of Study Conduct..................................................... 11
4.3
Analysis of Treatment Group Comparability .......................... 11
4.4
Efficacy Analysis.................................................................... 11
4.4.1
Primary Efficacy..................................................................... 12
4.4.1.1
Primary Treatment Effect....................................................... 12
4.4.1.2
Primary Efficacy Endpoint...................................................... 12
4.4.1.3
Remission Definition.............................................................. 13
4.4.2
Secondary Efficacy Endpoints............................................... 13
4.4.2.1
Control of Type I Error ........................................................... 13
4.4.2.2
Pooling of Studies GA28948 and GA28949........................... 15
4.4.2.3
Remission: Adalimumab Treatment Comparison .................. 15
4.4.2.4
Clinical Response.................................................................. 16


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4.4.2.5
Improvement in Endoscopic Appearance of the 
Mucosa.................................................................................. 16
4.4.2.6
Endoscopic Remission .......................................................... 16
4.4.2.7
Rectal Bleed Subscore .......................................................... 16
4.4.2.8
Stool Frequency Subscore .................................................... 17
4.4.2.9
Histologic Remission ............................................................. 17
4.4.2.10
Ulcerative Colitis Patient-Reported Outcome 
Signs and Symptoms (UC-PRO/SS) ..................................... 17
4.4.2.11
Clinical Remission ................................................................. 17
4.4.2.12
Remission at Week 10 and Week 14..................................... 18
4.4.2.13
Inflammatory Bowel Disease Questionnaire 
(IBDQ) ................................................................................... 18
4.4.3
Exploratory Efficacy Endpoints.............................................. 18
4.4.4
Sensitivity Analyses............................................................... 18
4.4.5
Supplementary Analyses....................................................... 19
4.4.6
Subgroup Analyses ............................................................... 19
4.5
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 19
4.6
Safety Analyses..................................................................... 19
4.6.1
Exposure of Study Medication............................................... 19
4.6.2
Adverse Events ..................................................................... 19
4.6.3
Laboratory Data..................................................................... 20
4.6.4
Vital Signs.............................................................................. 20
4.6.5
Concomitant Medications ...................................................... 20
4.6.6
Medical History...................................................................... 20
4.7
Missing Data.......................................................................... 20
4.8
Interim Analyses .................................................................... 20
5.
REFERENCES ........................................................................................... 20
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 8
Figure 2
Multiple Testing Procedure for Induction Endpoints.................... 15


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5/Statistical Analysis Plan GA28948/GA28949
LIST OF APPENDICES
Appendix 1
Protocol Synopsis (Identical to Study GA28949) ........................ 21
Appendix 2
Schedule of Assessments........................................................... 33
Appendix 3
Rescue Therapy.......................................................................... 39


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GLOSSARY OF ABBREVIATIONS
AE adverse event
ANCOVA analysis of covariance
aTNF anti-tumor necrosis factor
CCOD clinical cutoff date
CMH Cochran-Mantel-Haenszel
ES Endoscopic Subscore
Etro etrolizumab
HRQOL health-related quality of life
IBDQ Inflammatory Bowel Disease Questionnaire
ICE intercurrent event
IxRS interactive voice/web based response system
MCS Mayo Clinic Score
mITT modified intent-to-treat
mMCS modified Mayo Clinic Score
NHI Nancy Histology Index
OLE open-label extension
PK pharmacokinetic
PBO placebo
pMCS partial Mayo Clinic Score
Q4W every 4 weeks
RB rectal bleeding
SAP Statistical Analysis Plan
SC subcutaneous
SF stool frequency
SM safety monitoring
TNF tumor necrosis factor
UC ulcerative colitis
UC-PRO/SS Ulcerative Colitis Patient-Reported Outcome Signs 
and Symptoms
VHP Voluntary Harmonisation Procedure


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7/Statistical Analysis Plan GA28948/GA28949
1.
BACKGROUND
Studies GA28948 and GA28949 are two Phase III trials with identical study design.  
This Statistical Analysis Plan (SAP) describes both the analyses that will be performed 
for each study independently and the analyses of some secondary efficacy endpoints for 
which the data from both studies will be pooled.  Only one SAP has been written as the 
analyses conducted in the individual studies will be the same and will be applied to both 
studies.  Studies GA28948 and GA28949 are part of a large Phase III development 
program for etrolizumab.  Details which are common among Studies GA28948, 
GA28949, GA28950, GA29102, and GA29103 are described in the project SAP.
Studies GA28948 and GA28949 are Induction Phase studies.  There is a difference in 
treatment period length between the global protocols for Studies GA28948 and 
GA28949, and the Estonia protocol for Study GA28948 and the Voluntary Harmonisation 
Procedure (VHP) protocol for Study GA28949.  The global protocols have a 14-week 
treatment period whereas the Estonia and VHP protocols have a treatment period of 
16 weeks.  This is to provide a 2-week delay to the first dose in the open-label extension 
and safety monitoring (OLE-SM) study (Study GA28951) for patients achieving clinical 
remission in order to maintain the 4 weekly dosing schedule; however, this does not 
impact the analysis described in this SAP as no additional study drug is administered 
and no efficacy data are collected in this time.
Analyses will be conducted once data up to Week 14 has been collected in the database 
and data have been cleaned and verified.  This will be referred to as the primary analysis.  
Additional safety data collected at Week 16 will be reported along with the safety 
follow-up data as detailed in Section 2.4.
2.
STUDY DESIGN
Studies GA28948 and GA28949 are multicenter, Phase III, randomized, double-blind, 
double-dummy, placebo and active comparator controlled studies to evaluate the safety, 
efficacy, and tolerability of etrolizumab (105 mg subcutaneous [SC] every 4 weeks 
[Q4W]) in the induction of remission for patients with moderate to severe ulcerative 
colitis (UC) naive to tumor necrosis factor (TNF) inhibitors (see Figure 1).  Comparisons 
will be made against placebo and adalimumab (160 mg SC Week 0, 80 mg SC Week 2, 
40 mg SC Weeks 4, 6, and 8).


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Figure 1
Study Schema
6-MP6-mercaptopurine; AZAazathioprine; CScorticosteroid; dday; EPendpoint; MCSMayo 
Clinic Score; OLEopen--label extension; OLE-SMopen-label extensionsafety monitoring study; 
MTXmethotrexate; Q2Wevery 2 weeks; Q4Wevery 4 weeks; QDonce a day; QODevery 
other day; Rxstudy treatment; SCsubcutaneous; SMsafety monitoring; 
TNF-naivenaive to tumor necrosis factor inhibitor; UCulcerative colitis; wkweek.
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
As the Studies GA28948 and GA28949 are independent studies with identical study 
designs, the Protocol Synopsis for only one study (Study GA28948) 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 pharmacokinetics 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.


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2.3
DETERMINATION OF SAMPLE SIZE
For each study, it was planned that a total of approximately 350 patients would be 
randomized in a 2:2:1 ratio:  etrolizumab (n≈140), adalimumab (n≈140), and placebo 
(n≈70), respectively.
Under the assumption of a difference in remission rates between the etrolizumab and 
placebo arms of 25% (35% vs. 10%), the sample size of 140 patients receiving 
etrolizumab and 70 patients receiving placebo was expected to provide 90% power to 
detect a difference with use of a 2 test at the two-sided 5% significance level.  
This assumption was based on the observed Week 10 remission results in the 
Phase II etrolizumab study (Study ABS4986g; EUCALYPTUS) for the aTNF-naive 
(referred to in the protocol as TNF naive) subgroup.  In addition, under the assumption of 
a remission rate of 20% in the adalimumab arm (based on the clinical remission 
induction results achieved in the Phase III adalimumab ULTRA2 trial) 
(Sandborn et al. 2012), the planned size of 140 patients/active treatment arm was 
expected to provide up to 80% power to detect a 15% absolute difference between the 
remission rates in the etrolizumab and adalimumab arms (35% vs. 20%), with use of a 
2 test at the two-sided 5% significance level.
2.4
ANALYSIS TIMING
The primary analysis will be conducted once the last patient has either attended a visit to 
withdraw from the treatment period or complete their Week 14 visit.  The date associated 
with this visit will be termed the clinical cutoff date (CCOD) for the primary analysis, and 
the 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 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.  This will also include the additional 
Week 16 safety data from country-specific protocols.  These analyses will report all 
adverse events (AEs) including the data collected at Week 16 in country-specific 
protocols and 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 analysis 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 


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10/Statistical Analysis Plan GA28948/GA28949
stratification data collected in IxRS at randomization.  Due to low or zero counts in any 
one stratum, the stratification factors may need to be combined or removed in the 
primary analysis to ensure the Cochran-Mantel-Haenszel (CMH) test is not invalidated.
In each study, a total of approximately 350 patients will be randomized in a 2:2:1 ratio of 
etrolizumab (n≈140) to adalimumab (n≈140) to placebo (n≈70).  Patients were 
randomized using permuted blocks stratified (dynamically generated) randomization.  
Patients are stratified by 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)
3.2
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
Modified Intent-to-Treat (mITT) Population
Efficacy analyses will be performed using a modified intent-to-treat (mITT) analysis 
population (with the exception of histologic remission) including all patients randomized 
who received at least one dose of study drug with patients grouped according to the 
treatment assigned at randomization.
4.1.2
Pharmacokinetic (PK)-Evaluable Population 
The PKevaluable population includes patients who have received at least one dose of 
study drug and have had at least one quantifiable concentration measured post baseline.
4.1.3
Histology-Evaluable Population
The histology-evaluable patients will include all patients in the mITT population who 
have documented neutrophilic inflammation at baseline.  This excludes patients in the 
mITT population who have no baseline histology assessment at baseline or have no 
indication of neutrophilic inflammation at baseline.  For the main analysis based on 
Nancy Histological Index (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 
project SAP, Table 3.


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4.1.4
Safety Population
The safety analysis population will include all patients who received at least one dose of 
study drug, with patients grouped according to the treatment of the treatment arm most 
frequently received.
4.2
ANALYSIS OF STUDY CONDUCT
All data available in the database at the time of cutoff for the primary analysis will be 
included to evaluate study conduct.  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.
4.4
EFFICACY ANALYSIS
All statistical hypotheses for the primary and key secondary endpoints will be evaluated 
under a multiple testing procedure to ensure an overall type I error no greater than 5%.  
Details on this testing procedure are included in Section 4.4.2.
All comparisons between the etrolizumab and placebo arms and the etrolizumab and 
adalimumab 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 where 
comparison back to baseline is made, the baseline is defined as the last available 
assessment prior to first receipt of study drug.
In alignment with the addendum to ICH E9, the primary efficacy treatment effects 
(estimands) are described for each primary treatment effect in Section 4.4.1.1.  
The estimand attributes include the following two intercurrent events:  treatment 
discontinuation and use of rescue medication as described below:

Treatment discontinuation:  All patients who discontinue study drug during the 
treatment period will not be assessed for any future efficacy time points (Week 10 
and/or Week 14) past the study day they discontinued study drug.  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 bleed [RB] 
subscores), these patients’ data will be set to missing.  Handling of missing data is 
described in the project SAP, Section 4.8.


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12/Statistical Analysis Plan GA28948/GA28949

Use of rescue therapy:  Increased or new background medications compared to 
baseline for the treatment of UC is considered rescue therapy.  Rescue therapy use 
is described in the protocol and is also summarized in Appendix 3.  All patients 
receiving permitted rescue therapy during the treatment period will be asked to 
continue the study through endpoint assessment and safety follow-up.  All patients 
receiving prohibited rescue therapy during the treatment period will be asked to 
enter safety follow-up, with no assessment of any future Week 10 or Week 14 
endpoints.  Patients who receive (permitted or prohibited) rescue medication will be 
considered non-responders for all time points 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.
4.4.1
Primary Efficacy
4.4.1.1
Primary Treatment Effect
The primary treatment effect (estimand) targeted is described by the following four 
attributes:
a)
Population:  Adult patients with moderate to severe active UC who are naive to 
TNF inhibitors
b)
Variable: Remission at Week 10
c)
Intercurrent Event (ICE):

Treatment discontinuation

Use of rescue therapy
Details of the ICE strategy are explained in Section 4.4.
d)
Population-Level Summary: Difference in proportion of patients between 
etrolizumab and placebo treatment groups.
4.4.1.2
Primary Efficacy Endpoint
The primary efficacy endpoint is the difference in the proportion of patients in remission 
at Week 10 between etrolizumab and placebo patients randomized into the mITT 
population.
	
  	
 	
 		
   
#  	
 	
 		
   
#  	
 	
 
The calculation will be done within treatment groups.


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13/Statistical Analysis Plan GA28948/GA28949
Null hypothesis H0:  EtroPBO 0; the proportion of patients achieving remission at 
Week 10 in the placebo arm is the same as the proportion of patients achieving 
remission in the respective etrolizumab arm.
Alternative hypothesis H1:  EtroPBO≠0; the proportion of patients achieving 
remission at Week 10 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
Secondary Efficacy Endpoints
Secondary efficacy endpoints may include more than one hypotheses test to allow for 
comparisons between etrolizumab and placebo treatment arms, and etrolizumab and 
adalimumab treatment arms.
4.4.2.1
Control of Type I Error
The primary and key secondary endpoints (Figure 2) will be evaluated in a hierarchical 
manner with a component-wise multistage gatekeeping procedure. The multistage 
gatekeeping procedure (Dmitrienko et al. 2008) will be applied to three components of 
tests:
1.
Etrolizumab versus placebo comparisons for primary and key secondary endpoints 
in Families 1 and 2 (Figure 2) using data from Study GA28948.
2.
Etrolizumab versus placebo comparisons for primary and key secondary endpoints 
in Families 1 and 2 (Figure 2) using data from Study GA28949.
3.
Comparisons for key secondary endpoints in Families 3 to 6 (Figure 2) using data 
from Studies GA28948 and GA28949, pooled together.  Comparisons examine 
either etrolizumab versus adalimumab (in Families 3, 5, and 6) or etrolizumab 
versus placebo (in Family 4).
A significance level of 5% will be allocated to testing components 1 and 2 separately.  
Multiplicity in each of Families 1 and 2 will be controlled using the truncated Holm testing 
procedure.  Application of a truncated test in Family 2 enables propagation of any 
remaining significance level to testing in component 3.  In particular let αj,2 be the level 
allocated to Family 2 of component j, Aj,2 be the number tests not rejected in Family 2 of 
component j (on the basis of the multiplicity-adjusted p-value), and e* be the error rate 
function (Dmitrienko et al. 2008, Section 3.1).  The significance level allocated to testing 
component 3 is
3 (α1,2 −e*( A1,2) + α2,2 −e*( A2,2)) / 2.
If α3 0, then all multiplicity-adjusted p-values in Families 3 to 6 will be set to 1 (100%).  
Within Families 3 to 6, the truncated Holm testing procedure will also be applied.


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From repeated application of Proposition 4.1 of Dmitrienko et al. (2008), strong overall 
type I error control is ensured in the following aspects:

The overall type I error is no larger than α5% among the primary endpoint and key 
secondary endpoints in Families 1 and 2 for Study GA28948.

The overall type I error is no larger than 5% among the primary endpoint and 
key secondary endpoints in Families 1 and 2 for Study GA28949.

The overall type I error is no larger than 5% among the key secondary endpoints in 
Families 3 to 6 for Studies GA28948 and GA28949, pooled together, since 
3 ≤5%.  Moreover:
–
Overall type I error is controlled at strictly less than 5%, if at least one endpoint 
in the primary and each key secondary endpoint.  Families 1 and 2 is not 
rejected in Study GA28948 or GA28949.
–
In particular, if success is achieved on the primary endpoint and at least one 
key secondary endpoint in both Families 1 and 2 for only one study, the overall 
type I error on testing Families 3 to 6 is no larger than 2.5%, since (under this 
scenario) 3 αj,2/2 α/2 2.5%.
Throughout all families, the truncated Holm multiple testing procedure with the same
truncation parameter value of 0.5 will be applied.  The truncation parameter 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 ensures overall type I error control 
(Dmitrienko et al. 2009).  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.


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Figure 2
Multiple Testing Procedure for Induction Endpoints
RBrectal bleeding; SFstool frequency; UC-PRO/SSUlcerative Colitis Patient-Reported 
Outcome Signs and Symptoms.
Ordering of endpoints within a family will be based on the p-value results from the hypotheses 
tests and not reflective of the endpoints order in Figure 2.
4.4.2.2
Pooling of Studies GA28948 and GA28949
As described in Section 4.4.2.1, some secondary endpoint comparisons will be 
evaluated by pooling data from both studies.
All etrolizumab versus adalimumab endpoint comparisons and one family of etrolizumab
versus placebo endpoint comparisons (Family 4) will be evaluated on pooled data from 
the two studies following the statistical analysis methods described for each endpoint 
with the addition of study as a further stratification variable.
The summaries for disposition, demographics, and baseline characteristics will be 
reproduced for the pooled population.
4.4.2.3
Remission: Adalimumab Treatment Comparison
The secondary efficacy objective assessing the difference in the proportion of patients in 
remission at Week 10 between etrolizumab and adalimumab patients will be analyzed


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using the same methods as the primary endpoint.  The comparison will be based on 
pooled data from the two studies.
Null hypothesis H0:  EtroAda0; the proportion of patients achieving remission at 
Week 10 in the adalimumab arm is the same as the proportion of patients achieving 
remission in the respective etrolizumab arm.
Alternative hypothesis H1:  EtroAda≠0; the proportion of patients achieving 
remission at Week 10 in the adalimumab arm is not the same as the proportion of 
patients achieving remission in the respective etrolizumab arm.
4.4.2.4
Clinical Response
The endpoint assessing the proportion of patients in clinical response at Week 10 will be 
analyzed using the same methods as the primary endpoint for the two treatment 
comparisons:  etrolizumab versus placebo, and etrolizumab versus adalimumab.  As 
described in Section 4.4.2.1 the adalimumab comparison will be based on pooled data 
from the two studies.  Definition of clinical response is included in the project SAP, 
Section 4.4.2.1.4.
4.4.2.5
Improvement in Endoscopic Appearance of the Mucosa
The endpoint assessing the proportion of patients with improvement in endoscopic 
appearance of the mucosa at Week 10 will be analyzed using the same methods as the 
primary endpoint for the two treatment comparisons:  etrolizumab versus placebo, and 
etrolizumab versus adalimumab.  As described in Section 4.4.2.1, the adalimumab 
comparison will be based on pooled data from the two studies.
Definition of improvement in the appearance of the endoscopic mucosa is included in the 
project SAP, Section 4.4.2.
4.4.2.6
Endoscopic Remission
The endpoint assessing the proportion of patients with endoscopic remission at Week 10 
will be analyzed using the same methods as the primary endpoint for the two treatment 
comparisons: etrolizumab versus placebo, and etrolizumab versus adalimumab.  As 
described in Section 4.4.2.1, the adalimumab comparison will be based on pooled data 
from the two studies.  Definition of endoscopic remission is included in the project SAP, 
Section 4.4.2.1.4.
4.4.2.7
Rectal Bleed Subscore
The difference in the change from baseline in rectal bleed subscore at baseline to 
Week 6 will be analyzed for the two treatment comparisons:  etrolizumab versus 
placebo, and etrolizumab versus adalimumab using a rank analysis of covariance 
(ANCOVA) model under the assumption that RB subscore is non-parametric.  
As described in Section 4.4.2.1, the adalimumab comparison will be based on pooled 
data from the two studies.  The stratification factors used at randomization as described 


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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.
4.4.2.8
Stool Frequency Subscore
The difference in the change from baseline in SF subscore at baseline to Week 6 will be 
analyzed for the two treatment comparisons:  etrolizumab versus placebo, and 
etrolizumab versus adalimumab using a rank ANCOVA model under the assumption that 
SF subscore is non-parametric.  As described in Section 4.4.2.1, the adalimumab 
comparison will be based on pooled data from the two studies.  The 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 the 
project SAP, Section 4.4.2.1.1.
4.4.2.9
Histologic Remission
The endpoint assessing the proportion of patients with histologic remission at Week 10 
will be analyzed using the same methods as the primary endpoint for the two treatment 
comparisons:  etrolizumab versus placebo, and etrolizumab versus adalimumab, using 
the histology evaluable population.  As described in Section 4.4.2.1, the adalimumab 
comparison will be based on pooled data from the two studies.  Definition of histologic 
remission is described in the project SAP, Section 4.4.2.2.  Further details of additional 
analysis to support this endpoint using different scoring systems are detailed in the 
project SAP, Section 4.4.2.2.
4.4.2.10
Ulcerative Colitis Patient-Reported Outcome Signs and 
Symptoms (UC-PRO/SS)
The change from baseline at Week 10 in both functional domain and bowel domain will 
be analyzed for the two treatment comparisons:  etrolizumab versus placebo, and 
etrolizumab versus adalimumab.  As described in Section 4.4.2.1, both the placebo 
comparison and the adalimumab comparison will be based on pooled data from the two 
studies.  Details of UC-PRO/SS endpoints and the analyses are included in the 
project SAP, Section 4.4.2.3.
4.4.2.11
Clinical Remission
The endpoint assessing the proportion of patients in clinical remission at Week 10 will be 
analyzed using the same methods as the primary endpoint for the two treatment 
comparisons: etrolizumab versus placebo, and etrolizumab versus adalimumab.  
As detailed in Figure 2, this endpoint is not included in the multiple testing procedure for 
endpoints.  Definition of clinical remission is included in the project SAP, 
Section 4.4.2.1.4.


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4.4.2.12
Remission at Week 10 and Week 14
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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    
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The endpoint will be analyzed using the same methods as the primary endpoint for the 
treatment comparison of etrolizumab versus placebo, and etrolizumab versus 
adalimumab.  As detailed in Figure 2, this endpoint is not included in the multiple testing 
procedure for endpoints.
4.4.2.13
Inflammatory Bowel Disease Questionnaire (IBDQ)
The change from baseline at Week 10 in IBDQ will be analyzed for the two treatment 
comparisons: etrolizumab versus placebo, and etrolizumab versus adalimumab.  As 
detailed in Figure 2, this endpoint is not included in the multiple testing procedure for 
endpoints.  Details of the IBDQ endpoint and the analyses are included in the project 
SAP, Section 4.4.2.4.
4.4.3
Exploratory Efficacy Endpoints
Exploratory endpoints detailed in the protocol will also be analyzed for the two treatment 
comparisons:  etrolizumab versus placebo, and etrolizumab versus adalimumab.  Binary 
endpoints will use the same statistical methods used for the primary endpoint.  
Continuous endpoints will use the same statistical methods used for the change from 
baseline key secondary endpoints.
4.4.4
Sensitivity Analyses
To support the primary endpoint 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 10 (remission derived using mMCS
including mild friability in ES1)

Proportion of patients in remission at Week 10 (remission derived using pMCS)

Proportion of patients in remission at Week 10 (remission derived using mMCS 
excluding friability from ES1)

Proportion of patients in remission at Week 10 (tipping point analysis)
All key secondary endpoints included in Figure 2 which are calculated using MCS or the 
endoscopic subscore will be re analyzed as a sensitivity analyses using the modified 
Mayo Clinic Score (mMCS) excluding friability from ES1 or the endoscopic subscore 
excluding friability from ES1 if applicable. These analyses will be conducted on the 
mITT population and they will be conducted for the two treatment comparisons.  


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Etrolizumab versus placebo, and etrolizumab versus adalimumab.  As described in 
Section 4.4.2.1, the adalimumab comparison will be based on pooled data from the two 
studies. The analyses are listed below:

Proportion of patients in clinical response at Week 10 (clinical response derived 
using mMCS excluding friability from ES1)

Proportion of patients with improvement in endoscopic appearance of the mucosa at 
Week 10 (excluding friability from ES1)

Proportion of patients in remission at Week 10 (remission derived using mMCS 
excluding friability from ES1) [Comparison of etrolizumab versus adalimumab only 
as the etrolizumab versus placebo comparison is included in the sensitivity of the 
primary endpoint analyses]
4.4.5
Supplementary Analyses
To support the primary endpoint analyses, the following supplementary analyses will be 
conducted:

Proportion of patients in remission at Week 10 (including data collected whilst 
patients received rescue therapy)

Proportion of patients in remission at Week 10 (difference in proportions calculated 
using Fisher’s exact test)

Proportion of patients in remission at Week 10 (using logistic regression model)
4.4.6
Subgroup Analyses
Subgroup analyses are detailed in the project SAP, Section 4.4.3.
4.5
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Details are included in the project SAP, Section 4.5.
4.6
SAFETY ANALYSES
Data reported will include data for all patients in the safety population up until the patient 
completes/withdraws from the study.  If a patient is ongoing in the safety follow-up at the 
time of the primary data analyses, all available to the primary analysis CCOD will be 
reported.  Baseline is defined as the last available assessment prior to first receipt of 
study drug at the beginning of the study.
Further details of the safety analyses are included in the project SAP, Section 4.7.
4.6.1
Exposure of Study Medication
The number of doses of etrolizumab, adalimumab, and placebo injected will be 
summarized using descriptive statistics.
4.6.2
Adverse Events
Details are included in the project SAP, Section 4.7.1.


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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 4.8.
4.8
INTERIM ANALYSES
No efficacy interim analyses are planned or have been undertaken.
5.
REFERENCES
Bretz F, Maurer W, Brannath W, et al. A graphical approach to sequentially rejective 
multiple test procedures. Stat.Med. 2009;28(4):586604.
Bretz F, Posch M, Glimm E, et al. Graphical approaches for multiple comparison
procedures using weighted Bonferroni, Simes, or parametric tests. Biom. J. 2011 
Nov;53(6):894913.
Dmitrienko A, Tamhane AC, Bretz F, editors. Multiple testing problems in pharmaceutical 
statistics. CRC Press 2009;16591.
Dmitrienko A, Tamhane AC, Wiens BL. General multistage gatekeeping procedures. 
Biom J. 2008;50(5):66777.
Sandborn WJ, Van Assche G, Reinisch W, et.al. Adalimumab induces and maintains 
clinical remission in patients with moderate-to-severe ulcerative colitis. 
Gastroenterology. 2012;142(2):25765.


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Appendix 1
Protocol Synopsis (Identical to Study GA28949)
TITLE:
PHASE III, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY,
PLACEBO-CONTROLLED, MULTICENTER STUDY TO EVALUATE 
THE EFFICACY (INDUCTION OF REMISSION) AND SAFETY OF 
ETROLIZUMAB COMPARED WITH ADALIMUMAB AND 
PLACEBO IN PATIENTS WITH MODERATE TO SEVERE 
ULCERATIVE COLITIS WHO ARE NAIVE TO TNF INHIBITORS
PROTOCOL NUMBER:
GA28948
VERSION NUMBER:
8
EUDRACT NUMBER:
2013-004279-11
IND NUMBER:
100366
TEST PRODUCT:
Etrolizumab (PRO145223, RO5490261)
PHASE:
III
INDICATION:
Ulcerative colitis
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Efficacy Objectives
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of etrolizumab (105 mg subcutaneous [SC] every 4 weeks [Q4W]) 
compared with placebo for the induction of remission in tumor necrosis factor (TNF)naive 
(i.e., naive to tumor necrosis factor inhibitor) patients with ulcerative colitis (UC) as 
determined by the Mayo Clinic Score (MCS) at Week 10
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of etrolizumab compared with adalimumab for the induction of 
remission at Week 10

To evaluate the efficacy of etrolizumab for the induction of clinical remission at Week 10

To evaluate the efficacy of etrolizumab for clinical response at Week 10

To evaluate the efficacy of etrolizumab for improvement in endoscopic appearance of the 
mucosa at Week 10

To evaluate the efficacy of etrolizumab for endoscopic remission at Week 10

To evaluate the efficacy of etrolizumab compared with placebo in achieving remission at 
Week 10 and maintaining it to Week 14 

To evaluate the efficacy of etrolizumab for histologic remission at Week 10

To evaluate the efficacy of etrolizumab for onset of action, defined as change from baseline 
in MCS rectal bleeding subscore at Week 6

To evaluate the efficacy of etrolizumab for onset of action, defined as change from baseline 
in MCS stool frequency subscore at Week 6


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
To evaluate the efficacy of etrolizumab for UC bowel movement signs and symptoms at 
Week 10 as assessed by the Ulcerative Colitis Patient-Reported Outcome Signs and 
Symptoms (UC-PRO/SS) measure

To evaluate the efficacy of etrolizumab for UC abdominal symptoms at Week 10 as 
assessed by the UC-PRO/SS measure

To evaluate the efficacy of etrolizumab for patient-reported health-related QOL at Week 10 
as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ)
The exploratory efficacy objectives for this study are as follows:

To evaluate the impact of etrolizumab on remission at Week 14 in patients who achieved 
clinical remission at Week 10 compared with placebo

To evaluate the efficacy of etrolizumab compared with placebo in achieving clinical 
remission at Week 10 and maintaining it to Week 14

To evaluate change in histologic disease activity from baseline to Week 10 as measured by 
the Nancy Histological Index 

To evaluate improvement in histologic and/or endoscopic disease activity

To evaluate change in health utilities at Week 10, as assessed by the EuroQoL 
Five-Dimension Questionnaire (EQ-5D)

To evaluate response and remission at Week 10 in subgroups by baseline expression levels 
of colonic tissue and/or peripheral blood biomarkers (including, but not limited to, 
E integrin) to predict patient subgroups with a greater likelihood of responding to 
etrolizumab

To evaluate response and remission 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 during induction of remission 
of UC 

To evaluate the incidence and severity of infection-related adverse events

To evaluate the incidence and severity of hypersensitivity reactions

To evaluate the incidence and the clinical significance of anti-therapeutic antibodies (ATAs) 
to etrolizumab, or if required, adalimumab
Pharmacokinetic Objectives
The pharmacokinetic (PK) objectives for this study are as follows:

To evaluate the etrolizumab serum concentration at the time of primary and secondary 
endpoints (Weeks 10 and 14) and during drug washout at the time of safety follow-up

To evaluate the interindividual variability and potential covariate effects on etrolizumab 
serum exposure
Exploratory Pharmacodynamic, Predictive, and Prognostic Objectives
The exploratory pharmacodynamic (PD), predictive, and prognostic objectives for this study are 
as follows:

To evaluate the expression levels of biomarkers including, but not limited to, E integrin, in 
colonic tissue and/or peripheral blood and/or serum at baseline, during, or end of the 
treatment period

To evaluate biomarkers in stool at baseline and during the treatment period through 
assessments that may include, but are not limited to, analyses of the microbiota and 
bacterial cultures


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Study Design
Description of Study
This is a multicenter, Phase III, randomized, double-blind, double-dummy, placebo and active 
comparator controlled study to evaluate the safety, efficacy, and tolerability of etrolizumab 
(105 mg SC Q4W) in the induction of remission for patients naive to TNF inhibitors.  
Comparisons will be made against placebo and adalimumab (160 mg SC Week 0, 80 mg SC 
Week 2, 40 mg SC Weeks 4, 6, and 8).
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 study population 
consists of TNF-naive 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 1) and involvement 
that extends to a minimum of 20 cm from the anal verge.
Patients must have had an inadequate response, loss of response, or intolerance to prior 
immunosuppressant and/or corticosteroid treatment.
Patients who are on background immunosuppressant therapy (6-MP, AZA, MTX) may be 
enrolled if they have received a stable dose for at least 8 weeks prior to randomization (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 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 the 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 randomization

If corticosteroids are being tapered, the dose has to be stable for at least 2 weeks 
immediately prior to randomization
Such patients should continue stable doses of their background corticosteroid until Week 10, at 
which point a corticosteroid taper will be initiated for clinical remitters. Initiation of corticosteroid 
or an increase in corticosteroid dose above the patient's entry dose (up to a maximum of 
30 mg/day) prednisone [or equivalent]) will not be permitted during screening.  Use of 
budesonide will be allowed at stable doses (9 mg) provided that the dose has been stable for 
4 weeks prior to randomization.  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 randomization.  Certain concomitant treatments are prohibited 
(see protocol for list of all prohibited concomitant treatments).  
A total of approximately 350 patients from approximately 115 global sites will be randomized in 
a 2:2:1 ratio (etrolizumab:adalimumab:placebo).  Patients will be stratified by concomitant 
treatment with corticosteroids (yes/no) at randomization, concomitant treatment with 
immunosuppressants (yes/no) at randomization, and disease activity measured during 
screening (MCS 9/MCS 10).
The study will be divided into:

Screening period of up to 35 days

Double-blind treatment period of up to 14 weeks, which consists of a 10-week induction 
period and an additional 4-week treatment period for patients who meet the definition of 
clinical remission at Week 10

Safety follow-up period of 12 weeks.




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Oral Corticosteroids during the Study
During the Induction Phase, patients are to maintain their stable baseline corticosteroid dose.  
For patients who achieve clinical remission and remain in the study for an additional 4 weeks 
beyond the Week 10 Induction Phase, corticosteroids are to be tapered starting from Week 10.  
Patients who were 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.  
Patients receiving budesonide should taper their dose starting from Week 10 from 9 mg every 
day to 9 mg every other day for 2 weeks and then discontinue budesonide treatment.
Number of Patients
A total of approximately 350 patients are to be randomized into one of three study treatment 
groups in a 2:2:1 ratio as follows:

Treatment Group A:  etrolizumab SC plus adalimumab placebo SC 

Treatment Group B:  adalimumab SC plus etrolizumab placebo SC 

Treatment Group C:  etrolizumab placebo SC plus adalimumab placebo SC 
Target Population
Patients must meet the following criteria for study entry:

Able and willing to provide written informed consent

1880 years of age, inclusive

Diagnosis of UC established at least 3 months prior to randomization (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 1 during the screening 
period (prior to day of randomization)..  See 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 randomization.  See protocol for additional information regarding the time 
window.

Naive to treatment with TNF inhibitor therapy

Patients must have had an inadequate response, loss of response, or intolerance to prior 
immunosuppressant and/or corticosteroid treatment.
Inadequate response to, loss of response to, or intolerance to prior immunosuppressant 
treatment is defined as one or more of the following: 
Persistent signs and symptoms of active disease despite a history of at least one 
12-week regimen of oral AZA (1.5 mg/kg) or 6-MP (0.75 mg/kg) and/or 
MTX (15 mg/week) within the previous 5 years
Persistent signs and symptoms of active disease despite a 6TG level of 
230 pmol/8 108 RBCs during at least one 12-week regimen of oral AZA or 
6mercaptopurine (6MP) at a stable or increasing dose within the previous 5 years.
History of intolerance to AZA, 6-MP, or MTX (including, but not limited to, 
nausea/vomiting, abdominal pain, pancreatitis, LFT abnormalities, lymphopenia, 
TPMT genetic mutation, infection) within the previous 5 years


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Inadequate response, loss of response, or intolerance to corticosteroid treatment is defined 
as one or more of the following: 
Steroid refractory:  persistent symptoms of active disease despite treatment with at 
least one 4-week induction regimen that included a dose of 30 mg prednisone (oral) 
daily, or equivalent, for at least 2 weeks or IV for at least 1 week within the previous 
5 years
Steroid dependent:  two failed attempts to taper steroids below a dose equivalent to 
10 mg prednisone (oral) daily
Steroid intolerant:  history of intolerance to corticosteroids (including, but not limited to, 
Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, infection) 
within the previous 5 years 

Any ongoing UC therapy must be at stable doses:
May be receiving oral 5-ASA compounds provided that the dose has been stable 
for 4 weeks immediately prior to randomization
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 randomization.  
If corticosteroids are being tapered, the dose has to be stable for at least 2 weeks 
immediately prior to randomization.
May be receiving budesonide therapy at a stable dose of up to 9 mg a day provided 
that the dose has been stable for 4 weeks prior to randomization
May be receiving probiotics (e.g., Culturelle, Saccharomyces boulardii), provided that 
the dose has been stable for the 2 weeks immediately prior to randomization
May be receiving AZA, 6-MP, or MTX, provided that the dose has been stable for the 
8 weeks immediately prior to randomization

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 for the duration of the study 
[i.e., 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 study and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 
24 weeks after the last dose of study drug to avoid exposing the embryo to study drug.  
Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical study 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)
Include removal of any adenomatous polyps 
Document evidence of surveillance for dysplasia for all patients with left-sided colitis 
of 12 years’ duration and total/extensive colitis of 8 years duration


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27/Statistical Analysis Plan GA28948/GA28949
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

Prior treatment with TNF-antagonists

Any prior treatment with etrolizumab or other anti-integrin agents (including natalizumab, 
vedolizumab, and efalizumab)

Any prior treatment with rituximab

Any treatment with tofacitinib during screening

Any prior treatment with anti-adhesion molecules (e.g., anti-MAdCAM-1)

Use of IV steroids within 30 days prior to screening with the exception of a single 
administration of IV steroid

Use of agents that deplete B or T cells (e.g., alemtuzumab or visilizumab) within 12 months 
prior to randomization, with the exception of AZA and 6-MP

Use of anakinra, abatacept, cyclosporine,  sirolimus, or mycophenolate mofetil (MMF) within 
4 weeks prior to randomization

Chronic nonsteroidal anti-inflammatory drug (NSAID) use (Note that occasional use of 
NSAIDs and acetaminophen [e.g., headache, arthritis, myalgias, or menstrual cramps] and 
aspirin up to 325 mg daily is permitted.)

Patients who are currently using anticoagulants including, but not limited to, warfarin, 
heparin, enoxaparin, dabigatran, apixaban, rivaroxaban. (Note that antiplatelet agents such 
as aspirin up to 325 mg daily or clopidogrel are permitted.)

Patients who have received treatment with corticosteroid enemas/suppositories and/or 
topical (rectal) 5-ASA preparations within 2 weeks prior to randomization

Apheresis (i.e., Adacolumn apheresis) within 2 weeks prior to randomization

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 
randomization

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 
randomization


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28/Statistical Analysis Plan GA28948/GA28949
Exclusion Criteria Related to General Safety

Pregnant or lactating

Lack of peripheral venous access

Hospitalized (other than for elective reasons) during the screening period

Inability to comply with study protocol, in the opinion of the investigator

Significant uncontrolled comorbidity, such as cardiac (e.g., moderate to severe heart failure 
New York Heart Association Class III/IV), pulmonary, renal, hepatic, endocrine, or 
gastrointestinal disorders

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:
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.
Local basal cell or squamous cell carcinoma of the skin that has been excised and is 
considered cured is not exclusionary 
Exclusion Criteria Related to Infection Risk

Congenital or acquired immune deficiency

Patients must undergo screening for HIV and test positive for preliminary and confirmatory 
tests

Positive hepatitis C virus (HCV) antibody test result, unless the patient (1) has undetectable 
HCV RNA levels for 6 months after completing a successful course of HCV anti-viral 
treatment and an undetectable HCV RNA at screening or (2) has a known history of HCV 
antibody positivity with a history of undetectable HCV RNA 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 is positive, the patient is not eligible for this study.  
In the event the HBV DNA test cannot be performed, the patient is not eligible for 
this study. 
If the HBV DNA test is negative, the patient is eligible for this study.  These 
patients will undergo periodic monitoring for HBV DNA during the study.

Evidence of or treatment for Clostridium difficile (as assessed by C. difficile toxin testing) 
within 60 days prior to randomization or other intestinal pathogens (as assessed by stool 
culture and ova and parasite evaluation) within 30 days prior to randomization.


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29/Statistical Analysis Plan GA28948/GA28949

Evidence of or treatment for clinically significant cytomegalovirus (CMV) colitis (based on 
the investigator’s judgment) within 60 days prior to randomization.  Laboratory confirmation 
of CMV from colon biopsy sample is required during screening evaluation only if clinical 
suspicion is high and to determine the need for CMV treatment.

History of active or latent TB (regardless of treatment history)
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 
randomization suspicious for pulmonary TB are not eligible for this study.
Any immunosuppressed patient with a strong suspicion of TB exposure and no prior 
vaccination with bacille Calmette-Guérin (BCG) should be considered at risk for having 
latent TB infection.  Patients at risk for TB exposure include:
Patients who have household contact with a person with active TB 
Patients living in areas with high incidence of TB
Patients who frequently visit areas with high prevalence of active TB
Patients who meet these criteria should be evaluated per local practice to exclude 
latent TB.

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 prior to screening

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 randomization
Fungal infections of the nail beds
Oral or vaginal candidiasis that has resolved with or without treatment prior to 
randomization

Any major episode of infection requiring treatment with IV antibiotics within 8 weeks prior to 
screening or oral antibiotics within 4 weeks prior to screening
Treatment with antibiotics as adjunctive therapy for UC in the absence of documented 
infection is not exclusionary.

Received a live attenuated vaccine within 4 weeks prior to randomization

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 maximum length of the treatment period will be 14 weeks.  Patients who do not achieve 
clinical remission at Week 10, patients who receive defined rescue treatment, and all patients 
who complete the 14-week treatment period of the study will be given the option of enrolling into 
Part 1 (OLE) of Study GA28951 after Week 12, if eligible, where they will receive open-label 
etrolizumab treatment.


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30/Statistical Analysis Plan GA28948/GA28949
Patients not enrolling in Part 1 (OLE) of Study GA28951 to receive open-label etrolizumab will 
have a 12-week safety follow-up after the last dose of study medication in this study.  These 
patients will then be requested to enroll into Part 2 (SM) of Study GA28951 only for an 
additional 92 weeks of extended PML follow-up.
The total length of the study is expected to last from the first patient screened to either the last 
patient last follow-up visit in this protocol or last patient enrolled into Study GA28951, whichever 
is later.
End of Study
The end of the study is defined as the last patient last safety follow-up visit in this protocol or 
last patient in this protocol enrolled into Study GA28951 (OLESM), whichever is later.
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:
Primary Outcome Measure:

Remission at Week 10
Secondary Outcome Measures:

Clinical remission at Week 10

Clinical response at Week 10

Improvement in endoscopic appearance of the mucosa at Week 10

Endoscopic remission at Week 10

Remission at Week 10 and Week 14

Histologic remission at Week 10

Change from baseline in MCS rectal bleeding subscore at Week 6

Change from baseline in MCS stool frequency subscore at Week 6

Change from baseline to Week 10 in UC bowel movement signs and symptoms as 
assessed by the UC-PRO/SS

Change from baseline to Week 10 in UC abdominal symptoms as assessed by the 
UC-PRO/SS

Change from baseline to Week 10 in patient's health-related QOL as assessed by the 
overall score of the IBDQ
Exploratory Efficacy Outcome Measures:

Clinical remission at Week 10 and remission at Week 14

Clinical remission at Weeks 10 and 14

Change from baseline to Week 10 in histologic disease activity 

Improvement in histologic and/or endoscopic disease activity from baseline

Change in health utilities, as assessed by the EQ-5D, from baseline to Week 10

Response and remission at Week 10 in patient subgroups by baseline expression levels of 
colonic tissue and/or peripheral blood biomarkers, including, but not limited to, E integrin

Response and remission endpoints, as determined by the mMCS 
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence and severity of adverse events

Incidence of serious adverse events

Incidence and severity of infection-related adverse events

Incidence of serious infection-related adverse events

Incidence and severity of injection-site reactions 


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31/Statistical Analysis Plan GA28948/GA28949

Incidence of adverse events leading to study drug discontinuation

Incidence of laboratory abnormalities

Incidence and severity of hypersensitivity reaction events

Incidence of ATAs to etrolizumab, or if required, adalimumab
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:

Serum concentration during drug washout (through end of safety follow-up)

Serum concentration at primary and secondary endpoints Weeks 10 and 14
Exploratory Biomarker Outcome Measures
The exploratory biomarker outcome measures for this study are as follows:

Relationship between baseline levels of exploratory colonic tissue and/or peripheral blood 
and/or serum biomarkers and changes in response to treatment or disease progression

Relationship between baseline levels of stool biomarkers, which may include, but are not 
limited to, those in the microbiota and bacterial cultures

Changes from baseline in stool biomarkers in response to treatment or disease progression
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
Adalimumab (Humira) is supplied for single-use as a 1-mL glass PFS with a fixed 27-gauge 
½-inch needle, providing 40 mg (0.8 mL) of adalimumab administered as an SC injection, or as 
a single-use, 1-mL, glass PFS with a fixed 29-gauge ½-inch needle, providing 40 mg (0.4 mL) of 
adalimumab.
Adalimumab placebo will be supplied by the Sponsor as a liquid formulation in PFSs and is 
administered as an SC injection. Each 1-mL PFS will contain 0.7 mL of a solution of 20 mM 
histidine, 0.2 M arginine succinate, and 0.04% polysorbate 20, pH 5.8.
Non-Investigational Medicinal Products
Patients are to continue on their baseline dose of corticosteroid (including budesonide) to the 
end of the Induction Phase (Week 10).  Tapering of corticosteroid (including budesonide) is to 
be attempted from Week 10 in clinical remitters.
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.
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


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32/Statistical Analysis Plan GA28948/GA28949
Statistical Methods
Primary Analysis
The primary analysis will be performed when all data through Week 14 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 who were blinded during the study will remain 
blinded to individual treatment assignment until after the study is completed (after all patients 
have either completed the safety follow-up period or discontinued early from the study) and the 
database is locked.
Detailed specifications of the statistical methods will be described in the Statistical Analysis 
Plan (SAP).
Determination of Sample Size  
A total of approximately 350 patients will be randomized in a 2:2:1 ratio: etrolizumab (n140), 
adalimumab (n140), and placebo (n70), respectively.
Under the assumption of a difference in remission rates between the etrolizumab and placebo 
arms of 25% (35% vs. 10%), the sample size of 140 patients receiving etrolizumab and 70 
patients receiving placebo will provide 90% power to detect a difference with use of a 2 test at 
the two-sided 5% significance level. The assumption is based on the observed Week 10 
remission results in the Phase II etrolizumab study for the TNF-naive subgroup. In addition, 
under the assumption of a remission rate of 20% in the adalimumab arm (based on the clinical 
remission induction results achieved in the Phase III adalimumab ULTRA2 trial), the planned 
size of 140 patients/active treatment arm will provide approximately 80% power to detect a 
15% absolute difference between the remission rates in the etrolizumab and adalimumab arms 
(35% vs. 20%), with use of a 2 test at the two-sided 5% significance level.


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33/Statistical Analysis Plan GA28948/GA28949
Appendix 2 Schedule of Assessments
Assessment
Screening
Day a
35 to 1
Study Week (3 days)
Early 
Withdrawal from 
Treatment 
Phase ee
0 b
2
4
6
8
10
12 c
14 c
Unscheduled 
Visit d
Informed consent
x
Review eligibility criteria e
x
x b
Demographic data
x
Pregnancy test f
x
x b
x
x
x
x
Vital signs  (BP and pulse)
x
x b
x
x
x
x
ECG
x
x
Chest X-ray g
x
Height
x
Weight
x
Medical history
x
Physical examination h
x
x
x
x
PML neurologic examination i
x
x
x
x d
x
Hematology
x
x b
x
x d
x j
Chemistry
x
x b
x
x d
x j
Urinalysis
x
x b
x d
TB screen k
x
HIV test
x
Hepatitis B and C serology l
x
Hepatitis B DNA m
x
x


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34/Statistical Analysis Plan GA28948/GA28949
Appendix 2 Schedule of Assessments (cont.)
Assessment
Screening 
Day a
35 to 1
Study Week (3 days)
Early Withdrawal 
from Treatment 
Phase
0 b
2
4
6
8
10
12 c
14 c
Unscheduled 
Visit d
Hepatitis C RNA (Amplicor) n
x
PK sampling (serum) 
x o
x
x
x d
x j
Anti-therapeutic antibody sample (serum) o,p
x o
x o
x
x q
x d
x j, q
Plasma sample (storage for JCV antibody 
testing) r
x
MCS (includes endoscopy) s
x
x
x
x d
x j, ff
Partial MCS (pMCS, excludes endoscopy) t,u
x
x
x
x d
x j
Stool sample collection
x v
x w
x w
x d
xw
Colonic biopsy (CMV, if required)
x x
x d
Colonic biopsy (histopathological confirmation of 
UC if required) 
x y
Colonic biopsy (formalin)
x z
x aa
x aa
x d, x
x j, x, ff
Colonic biopsy (RNAlater)
x z
x aa
x aa
x d, y
x j, aa, ff
Serum sample (CRP) 
x o
x
x d
x j
Serum sample (future exploratory PD) m
x
x
x
x
Blood sample (RNA Paxgene) bb
x o
x
Blood sample for genetic analysis (DNA) optional
x
UC-PRO/SS cc
x
x
x
x


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35/Statistical Analysis Plan GA28948/GA28949
Appendix 2 Schedule of Assessments (cont.)
Assessment
Screening 
Day a
35 to 1
Study Week (3 days)
Early 
Withdrawal 
from Treatment 
Phase
0 b
2
4
6
8
10
12 c
14 c
Unscheduled 
Visit d
IBDQ dd
x
x
EQ-5D dd
x
x
Concomitant medications
x
x
x
x
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
Adalimumab/adalimumab placebo administration
x
x
x
x
x
Etrolizumab/etrolizumab placebo administration
x
x
x
x
BPblood pressure; CMVcytomegalovirus; ECGelectrocardiogram; EQ-5DEuroQoL Five-Dimension Questionnaire; HBVhepatitis B virus; 
CRPC-reactive protein; IBDQ Inflammatory Bowel Disease Questionnaire.; JCVJohn Cunningham virus; MCSMayo Clinic Score; 
PDpharmacodynamics; PGAphysician’s global assessment; PKpharmacokinetic; pMCSpartial Mayo Clinic Score; PMLprogressive 
multifocal leukoencephalopathy; qPCRquantitative polymerase chain reactions; TBtuberculosis, 
UC-PRO/SSUlcerative Colitis Patient-Reported Outcome Signs and Symptoms.
Notes:  All study assessments and blood draws are to be conducted prior to study drug administration.
All colonic biopsy samples will be taken during flexible sigmoidoscopy/colonoscopy procedure. 
a All assessments must be performed after obtaining informed consent.  Endoscopy should be performed 416 days prior to randomization (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 Only patients who achieve clinical remission, as assessed at Week 10, will attend Week 12 and Week 14 visits


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36/Statistical Analysis Plan GA28948/GA28949
Appendix 2 Schedule of Assessments (cont.)
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., only 
perform PML neurologic examination if patient reports symptoms suspected of PML; for disease worsening, infectious etiologies may be 
investigated if clinically indicated; and confirmation of clinical relapse is performed by the MCS).  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 
visits other than screening; if urine test result is positive, perform a confirmatory serum test.  Do not administer etrolizumab unless the serum 
pregnancy test result is negative.
g Not required if normal chest X–ray result within 3 months prior to screening.
h Full physical examination required at screening; symptom-driven physical examination at all other timepoints indicated.
i PML neurologic examination consists of the PML Subjective Checklist and the PML Objective Checklist.  Administer before other assessments 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 treatment. Patients with newly 
diagnosed HCV antibody positivity are not eligible for this study, and, therefore, do not require measurement of HCV. All samples to be collected 
prior to administration of study drug.  The PK, ATA, and exploratory PD sample collections will be from all patients.
p If serum sickness or a clinically significant allergic drug reaction is suspected, Sponsor should be notified, and serum for the analysis of study 
drug 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).


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37/Statistical Analysis Plan GA28948/GA28949
Appendix 2 Schedule of Assessments (cont.)
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 ∗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 Partial MCS during screening is defined as the MCS score excluding the endoscopy score.  Physician's Global Assessment component of 
MCS/partial MCS will be conducted prior to randomization on Day 1.
u 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 not limited to, analysis 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 laboratory, 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 samples noted in footnote “x” and “y” above, 5 pairs (10 samples) will also be obtained at screening.  All will be 
sent to the central laboratory for further storage or distribution.  Two pairs (taken from the most inflamed are of colon within 2040 cm of anal 
verge [sigmoid]) will be placed in a stabilization buffer (such as RNAlater or a similar buffer) and stored at 80C (1 pair for diagnostic qPCR 
and 1 pair for PD biomarkers qPCR).  Two pairs from the most inflamed area of colon within 2040 cm of anal verge (sigmoid) will be placed in 
formalin and then paraffin embedded (1 pair will be used for exploratory PD biomarkers and the other pair will be used for diagnostic).  The last 
pair will be taken from the most inflamed area of the worst affected segment and will be placed in formalin and then paraffin embedded (this 
sample will be used for histopathology and exploratory PD biomarkers).  Original biopsy location and endoscopic depth should be clearly 
indicated.
aa A total of 4 pairs (8 samples) will be obtained.  All will be sent to the central laboratory for further storage or distribution.  One pair will be placed in 
stabilization buffer (such as RNAlater or a similar buffer) and stored at #801C for exploratory PD or diagnostic biomarker qPCR.  The other 3 pairs, 
representing 3 different segments (rectum, sigmoid, descending colon), will be placed in formalin and then paraffin embedded; these biopsies will 
be used for histopathology, exploratory PD biomarkers and/or diagnostic biomarker.  Original biopsy location and endoscopic depth should be 
clearly indicated.


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38/Statistical Analysis Plan GA28948/GA28949
Appendix 2 Schedule of Assessments (cont.)
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 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 If clinical remission is not achieved at Week 10, the patient will be given the option to participate in Part 1 (OLE) of Study GA28951, if eligible, to 
receive open-label etrolizumab at Week 12 (which will correspond to Day 1 in Study GA28951).  In this case, an early withdrawal from treatment 
visit is not required (i.e., the Week 10 visit will be the patient's last visit in this study).  An early withdrawal from treatment visit is to be conducted if 
the patient withdraws at any other timepoint in the study.
ff For patients exiting the treatment period early for any reason, an endoscopy to document disease activity may be performed at the discretion of 
the investigator.


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39/Statistical Analysis Plan GA28948/GA28949
Appendix 3 Rescue Therapy
Type
Description
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, 
anakinra, abatacept and rituximab

Other investigational agents, including JAK inhibitors, vaccines (e.g., 
MAP or ChAdOx2 HAV)
5-ASA5-aminosalicylic acid; 6-MP6-mercaptopurine ; AZAazathioprine; ChAdOx2 
HAVchimpanzee adenovirus Oxford 2 Hepatitis A vaccine; JAKJanus kinase; 
MAPMycobacterium avium subspecies paratuberculosis; MMFmycophenolate mofetil; 
MTXmethotrexate; TNFtumor necrosis factor; UCulcerative colitis.


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Etrolizumab — F. Hoffmann-La Roche Ltd
Statistical Analysis Plan Project SAP
STATISTICAL ANALYSIS PLAN
TITLE:
DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER 
STUDIES OF THE EFFICACY AND SAFETY OF ETROLIZUMAB 
DURING INDUCTION AND/OR MAINTENANCE PHASES IN 
PATIENTS WITH MODERATE TO SEVERE ACTIVE ULCERATIVE 
COLITIS WHO HAVE BEEN PREVIOUSLY EXPOSED TO TNF
INHIBITORS OR PATIENTS WHO ARE aTNF NAÏVE
PROTOCOL NUMBER(S): RO5490261 (GA28948, GA28949, GA29102, 
GA29103, GA28950)
STUDY DRUG:
Etrolizumab
VERSION NUMBER:
3
IND NUMBER:
100366
EUDRACT NUMBER:
2013-004278-88, 2013-004280-31, 2013-004279-11, 
2013 004277-27, 2013-004282-14
SPONSOR:
F. Hoffmann-La Roche Ltd.
PLAN PREPARED BY:
, M.Sc.
DATE FINAL:
Version 1: 14 May 2019
DATE AMENDED:
Version 2: 17 December 2019
Version 3: See electronic date stamp below.
Date and Time(UTC)        Reason for Signing                              Name
04-May-2020 14:40:20
Company Signatory


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


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


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


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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


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GLOSSARY OF ABBREVIATIONS
WOCF Worse Observation Carried Forward


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


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


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


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


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


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


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4.4.2.1
Mayo Clinic Score
The MCS is a composite endpoint made up of four components.  The score ranges from 
0 to 12 with higher scores indicating more severe disease.
The MCS is used to determine a number of efficacy endpoints as described in Table 3.
MCSStool Frequency subscoreRectal Bleeding subscoreEndoscopy 
subscore PGA subscore
4.4.2.1.1
Stool Frequency and Rectal Bleeding
Stool frequency (SF) and rectal bleeding (RB) data are collected daily via patient’s 
diaries and each day a patient provides a score between 0-3 for each component.
Stool Frequency Subscore 03

0Normal number of stools for this patient

11 to 2 stools more than normal

23 to 4 more stools than normal

35 or more stools than normal
Rectal Bleeding Subscore 03

0No blood in stool

1Streaks of blood with stool less than half the time

2Obvious blood with stool most of the time

3Blood alone passed
–
Stool Frequency (SF) subscoreAverage of 3 days daily diary scores
–
Rectal Bleeding (RB) subscoreWorst value of 3 days daily diary scores
Table 2 summarizes the different scenarios for calculating SF/RB sub score in the 
analyses. The three days of daily diary data used to calculate the subscores described 
above are selected from the days most recent to, (but not including) a pre specified date, 
and this is called the ‘anchor date’. 


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


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


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4.4.2.1.4
Outcome Measures Derived from the MCS
The outcome measures calculated using the MCS or a selection of components from the 
MCS are detailed in Table 3.
Table 3
Outcome Measures
Outcome Measure
Definition
Mayo Clinic Score (MCS)
MCS (012) is a composite of 4 assessments, each rated from 
03: stool frequency, rectal bleeding, endoscopy, and PGA
Partial Mayo Clinic Score 
(pMCS)
pMCS (09) is a composite of 3 assessments, each rated from 
03: stool frequency, rectal bleeding, and PGA
Modified Mayo Clinic Score 
(mMCS)
mMCS (09) is a composite of 3 assessments, each rated from 
03: stool frequency, rectal bleeding, and endoscopy
MCS Remission
MCS 2 with individual subscores 1 and a rectal bleeding 
subscore of 0
MCS Clinical Remission
MCS 2 with individual subscores 1
MCS Clinical Response
MCS with 3-point decrease and 30% reduction from baseline as 
well as 1-point decrease in rectal bleeding subscore or an 
absolute rectal bleeding score of 0 or 1
pMCS Remission
pMCS 2, with, rectal bleeding score of 0, PGA 01 and stool 
frequency subscore 01
mMCS Remission 
(excluding friability from 
ES1)
mMCS 2, with, rectal bleeding score of 0, endoscopy 01 and 
stool frequency subscore 01
(Friability must be Absent for ES1)
mMCS Remission
(including friability in ES1)
mMCS 2, with, rectal bleeding score of 0, endoscopy 01 and 
stool frequency subscore 01
pMCS Clinical Remission
pMCS 2, with, rectal bleeding score of 01, PGA 01 and stool 
frequency subscore 01
mMCS Clinical Remission
(excluding friability from 
ES1)
mMCS 2, with, rectal bleeding score of 01, endoscopy 01 and 
stool frequency subscore 01
(Friability must be Absent for ES1)
mMCS Clinical Remission
(including friability in ES1)
mMCS 2, with, rectal bleeding score of 01, endoscopy 01 and 
stool frequency subscore 01
pMCS Clinical Response
A decrease in the pMCS of at least 2 points and at least 30% 
improvement from baseline, with an accompanying decrease in 
the rectal bleeding score by at least one point or an absolute rectal 
bleeding score of 0 or 1.
mMCS Clinical Response
(excluding friability from 
ES1)
A decrease in the mMCS of at least 2 points and at least 30% 
decrease (improvement) from baseline, with an accompanying 
decrease in the rectal bleeding score by at least one point or an 
absolute rectal bleeding score of 0 or 1.
(Friability must be Absent for ES1)
mMCS Clinical Response
(including friability in ES1)
A decrease in the mMCS of at least 2 points and at least 30% 
decrease (improvement) from baseline, with an accompanying 
decrease in the rectal bleeding score by at least one point or an 
absolute rectal bleeding score of 0 or 1.
Improvement in endoscopic 
appearance of the mucosa
(including friability in ES1)
Endoscopy subscore1


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


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


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


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


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be generated for SAEs, deaths, AEs leading to discontinuation of study drug, and 
adverse events of special interest (AESIs).  In addition to summaries or listings, 
narratives will be provided for all deaths, SAE’s, AE’s leading to treatment 
discontinuation and pregnancies as well as for all serious infections, opportunistic 
infections and malignancies in the individual CSRs.
For the etrolizumab Phase III program, the AESIs (identified by the investigator using the 
eCRF tick box) are the following:

Systemic hypersensitivity reactions and anaphylactic and anaphylactoid reaction. 
These will be further described using the MedDRA anaphylactic reaction SMQ 
(Standard MedDRA Query) algorithmic and Hypersensitivity SMQ narrow.

Neurological signs, symptoms, and AEs that may suggest possible progressive 
multifocal leukoencephalopathy (PML) (see Appendices 5 and 6 of Protocol)

Suspected transmission of an infectious agent by the study drug

Cases of potential drug-induced liver injury that include an elevated alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with 
either an elevated bilirubin or clinical jaundice, as defined by Hy’s Law
Specific AEs listed below will also be reported:

Serious infections (including GI) – Events occurred in the MedDRA Infections and 
Infestations System Organ Class (SOC) using the primary coding events

Opportunistic infections – Events occurred in the Sponsor-defined Adverse Event 
Group Terms

Malignancies Events that occur in the MedDRA Malignant and Unspecified 
Tumours SMQ (narrow).

Injection site reactions – Events identified using the eCRF tick box indicating an 
Injection site reaction AND/OR events occurred in the MedDRA Injection Site 
Reaction High Level Term (HLT) using both primary and secondary coding.
Outputs will be summarized using the safety population split by treatment arm and 
cohort as appropriate.
Summaries of AEs will be generated to summarize the incidence of treatment-emergent 
AEs only.  Treatment-emergent events are defined as any new AE reported or any 
worsening of an existing condition on or after the first dose of study drug.  If the onset 
date of the AE is prior to the day of first dose, the AE will be considered 
treatment-emergent only if the most extreme intensity is greater than the initial intensity 
(i.e., the intensity for a given AE increases and its end date is on or after the date of the 
first dose). Non-treatment emergent AE’s collected in the database will also be reported 
separately, for each individual CSRs. 
For each treatment group, the incidence count for each AE preferred term will be defined 
as the number of patients reporting at least one treatment-emergent occurrence of the


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


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


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


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


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


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


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


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


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


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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


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


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