Clinical trial NCT02136069
Conditions: Ulcerative Colitis
Sponsor: Hoffmann-La Roche
Start date: 2014-12-24; Completion date: 2020-06-23
Enrollment: 397 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, Phase III, randomized, double-blind, double-dummy, parallel-group study to evaluate the safety, efficacy, and tolerability of etrolizumab compared with infliximab in treating participants with moderate to severe ulcerative colitis (UC) who are naive to tumor necrosis factor (TNF) inhibitors. Participants will be randomized in a 1:1 ratio to receive either etrolizumab 105 milligrams (mg) by subcutaneous (SC) injection once every 4 weeks (Q4W) + placebo (intravenous \[IV\] infusion at Weeks 0, 2, and 6, then once every 8 weeks \[Q8W\]) or infliximab 5 milligrams/kilogram (mg/kg) IV at Weeks 0, 2, and 6, then Q8W) + placebo (SC Q4W). Time on treatment is 54 weeks.

Detailed description:

Arms: arm 1: Participants will receive ertolizumab (SC) Q4W until Week 52 along with placebo matched to infliximab as IV infusion until Week 46. arm 2: Participants will receive IV infusion of infliximab at Weeks 0,2, and 6, then every 8 weeks until Week 46 partnered with placebo matched to etrolizumab by SC injection Q4W until Week 52.
Interventions: intervention 1: Etrolizumab intervention 2: Infliximab intervention 3: Placebo (IV) intervention 4: Placebo (Injection)
Intervention descriptions: intervention 1: 105 mg administered by subcutaneous (SC) injection once every 4 weeks (Q4W) until Week 52. intervention 2: 5 mg/kg of infliximab will be administered by intravenous (IV) infusion at Weeks 0, 2, and 6 and then every 8 weeks until Week 46. intervention 3: Administered by (IV) infusion at Weeks 0, 2, and 6 and then every 8 weeks until Week 46. intervention 4: Administered by SC injection Q4W until Week 52

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
Phase III, Randomized, Multicenter Double-Blind, Double Dummy 
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 
NCT Number: 
NCT02136069 
Document Date: 
Protocol Amendment Version 7: 22-October-2018 
 
 
 


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 GA29103, Version 7 
PROTOCOL 
TITLE: 
PHASE III, RANDOMIZED, MULTICENTER, 
DOUBLE-BLIND, DOUBLE-DUMMY 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 
PROTOCOL NUMBER: GA29103  
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
2013-004282-14 
IND NUMBER: 
100366 
TEST PRODUCT: 
Etrolizumab (PRO145223, RO5490261) 
MEDICAL MONITOR: 
, M.D.  
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  21 January 2014 
DATES AMENDED: 
Version 2:  26 March 2014 
Version 3:  9 July 2014 
Version 4:  5 October 2015 
Version 5:  2 November 2016 
Version 6:  25 January 2018 
Version 7:  See electronic date stamp below. 
 
22-Oct-2018 19:15:38
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Etrolizumab—F. Hoffmann-La Roche Ltd 
2/Protocol GA29103, Version 7 
PROTOCOL AMENDMENT, VERSION 7: 
RATIONALE 
Protocol GA29103 has been amended primarily to reflect an increase in the assumed 
difference in treatment effect between etrolizumab and infliximab; as such, the study 
sample size has been reduced.  This and other changes to the protocol, along with a 
rationale for each change, are summarized below: 
•
The difference in treatment effect between etrolizumab and infliximab is considered
to be higher than previously assumed.  As a result, the estimated sample size for
this study has been reduced from 600 to 390 patients.  Patients will continue to be
randomized in the same 1:1 ratio. (Sections 3.1.1, 3.1.1.4, 6.1, and 9.4, and
Figure 1).
Additional changes are as follows: 
•
Language in the Background section has been amended to align with the other
ulcerative colitis studies in the Etrolizumab Phase III Program (Sections 1.1, 1.2,
and 1.3).
•
A secondary efficacy endpoint, to evaluate clinical remission at Week 54 among
patients with a clinical response at Week 10, has been added (Sections 2.1, 3.4.1,
6.4.2).
•
Language has been amended to clarify exploratory biomarker analyses
(Sections 2.4, 3.3.4, 3.4.4, 4.7.1.5, and 6.6).
•
Language has been added to clarify that an endoscopy for the documentation of
disease activity may be performed at the discretion of the investigator for patients
exiting the treatment period early for any reason (Sections 3.1.1.2 and 4.4.2.3, and
Appendix 1).
•
Janus kinase inhibitors have been added to the list of rescue therapies prohibited at
any time during the study (Sections 3.1.1.2, 4.4.2.3, and 4.5.2).
•
Language has been updated to indicate that 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
(Section 3.3.4).
•
Exclusion criteria have been amended to include any treatment with tofacitinib
during screening as this drug has been approved for use in the United States and
European Union and is no longer an investigational product (Section 4.1.2).
•
Information regarding the reporting of adverse events related to medical device
complaints in individuals other than the study patient has been added in
Section 4.4.6.


Etrolizumab—F. Hoffmann-La Roche Ltd 
3/Protocol GA29103, Version 7 
• 
Procedures for adverse event reporting have been updated to clarify that adverse 
event reports will not be derived from patient-reported outcome (PRO) data and 
safety analyses will not be performed using PRO data. Sites are not expected to 
review the PRO data for adverse events (Section 5.3.5.12). 
• 
Appendix 4 has been updated to clarify that for patients undergoing re-screening 
who meet the criteria to waive the endoscopy, the MCS rectal bleeding and stool 
frequency subscores will be derived from the 3 consecutive days prior to the new 
enrollment day. 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.  


Etrolizumab—F. Hoffmann-La Roche Ltd 
4/Protocol GA29103, Version 7 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11 
PROTOCOL SYNOPSIS .................................................................................... 12 
1. 
BACKGROUND .......................................................................................... 27 
1.1 
Background on Ulcerative Colitis ........................................... 27 
1.2 
Background on Etrolizumab ................................................... 28 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 30 
2. 
OBJECTIVES .............................................................................................. 32 
2.1 
Efficacy Objectives ................................................................ 32 
2.2 
Safety Objectives ................................................................... 34 
2.3 
Pharmacokinetic Objectives .................................................. 34 
2.4 
Exploratory Pharmacodynamic and Diagnostic 
Objectives .............................................................................. 34 
3. 
STUDY DESIGN ......................................................................................... 34 
3.1 
Description of Study .............................................................. 34 
3.1.1 
Overview of Study Design ..................................................... 34 
3.1.1.1 
Disease Worsening ............................................................... 38 
3.1.1.2 
Rescue Therapy .................................................................... 38 
3.1.1.3 
Infliximab Washout Period ..................................................... 40 
3.1.1.4 
Number of Patients ................................................................ 42 
3.1.2 
Data Monitoring Committee ................................................... 42 
3.2 
End of Study and Length of Study ......................................... 42 
3.3 
Rationale for Study Design .................................................... 43 
3.3.1 
Rationale for Test Product Dosage ........................................ 43 
3.3.2 
Rationale for Patient Population ............................................ 44 
3.3.3 
Rationale for Active Comparator ............................................ 45 
3.3.4 
Rationale for Biomarker Assessments ................................... 45 
3.4 
Outcome Measures ............................................................... 46 
3.4.1 
Efficacy Outcome Measures .................................................. 46 


Etrolizumab—F. Hoffmann-La Roche Ltd 
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3.4.2 
Safety Outcome Measures .................................................... 47 
3.4.3 
Pharmacokinetic Outcome Measures .................................... 48 
3.4.4 
Exploratory Biomarker Outcome Measures ........................... 48 
4. 
MATERIALS AND METHODS .................................................................... 48 
4.1 
Patients .................................................................................. 48 
4.1.1 
Inclusion Criteria .................................................................... 48 
4.1.2 
Exclusion Criteria ................................................................... 51 
4.2 
Method of Treatment Assignment and Blinding ..................... 54 
4.3 
Study Medication Blinded Washout of Infliximab ................... 58 
4.4 
Study Treatment .................................................................... 61 
4.4.1 
Formulation, Packaging, and Handling .................................. 63 
4.4.1.1 
Etrolizumab and Etrolizumab Dummy.................................... 63 
4.4.1.2 
Infliximab and Infliximab Dummy ........................................... 64 
4.4.1.3 
Concomitant Background Treatment for 
Ulcerative Colitis .................................................................... 64 
4.4.2 
Dosage, Administration, and Compliance .............................. 64 
4.4.2.1 
Etrolizumab and Etrolizumab Dummy.................................... 65 
4.4.2.2 
Infliximab and Infliximab Dummy ........................................... 67 
4.4.2.3 
Concomitant Background Treatment and Rescue 
Therapy ................................................................................. 68 
4.4.3 
Investigational Medicinal Product Accountability ................... 71 
4.4.4 
Assessment of Compliance ................................................... 71 
4.4.5 
Destruction of the Investigational Medicinal 
Product .................................................................................. 72 
4.4. 
Reporting of Prefilled Syringe Complaints/Events ................. 73 
4.5 
Concomitant Therapy ............................................................ 73 
4.5.1 
Permitted Therapy ................................................................. 73 
4.5.2 
Prohibited Therapy ................................................................ 73 
4.6 
Disease Worsening ............................................................... 74 
4.6.1 
Definition of Disease Worsening ............................................ 74 
4.7 
Study Assessments ............................................................... 74 
4.7.1 
Description of Study Assessments ........................................ 74 
4.7.1.1 
Medical History and Demographic Data ................................ 74 
4.7.1.2 
Physical Examinations ........................................................... 74 


Etrolizumab—F. Hoffmann-La Roche Ltd 
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4.7.1.3 
Vital Signs .............................................................................. 75 
4.7.1.4 
Ulcerative Colitis Disease Activity Assessments ................... 75 
4.7.1.5 
Laboratory Assessments ....................................................... 79 
4.7.1.6 
Chest X-Ray .......................................................................... 82 
4.7.1.7 
Electrocardiograms ................................................................ 82 
4.7.1.8 
Patient-Reported Outcomes .................................................. 82 
4.7.1.9 
Medication Use and Compliance ........................................... 83 
4.7.1.10 
Samples for Roche Clinical Repository.................................. 84 
4.7.2 
Timing of Study Assessments ............................................... 87 
4.7.2.1 
Screening and Pretreatment Assessments............................ 87 
4.7.2.2 
Assessments during Treatment ............................................. 90 
4.7.2.3 
Assessments at Study Completion/Early 
Withdrawal/End of Washout Visit ........................................... 90 
4.7.2.4 
Safety Follow-Up Assessments ............................................. 93 
4.7.2.5 
Assessments at Unscheduled Visits ...................................... 93 
4.8 
Patient, Study, and Site Discontinuation ................................ 94 
4.8.1 
Patient Discontinuation .......................................................... 94 
4.8.1.1 
Discontinuation from Study Drug ........................................... 94 
4.8.1.2 
Withdrawal from Study........................................................... 95 
4.8.2 
Study and Site Discontinuation .............................................. 95 
5. 
ASSESSMENT OF SAFETY ....................................................................... 95 
5.1 
Safety Plan ............................................................................ 95 
5.1.1 
Potential Risks for Etrolizumab .............................................. 96 
5.1.1.1 
Serious Infections .................................................................. 96 
5.1.1.2 
Hypersensitivity Reactions ..................................................... 99 
5.1.1.3 
Local Injection-Site Reactions ............................................. 100 
5.1.1.4 
Hepatic Effects .................................................................... 100 
5.1.1.5 
Malignancies ........................................................................ 101 
5.1.1.6 
Immunogenicity ................................................................... 101 
5.1.1.7 
Decreased Effectiveness of Immunizations ......................... 102 
5.1.2 
Risks Associated with Infliximab .......................................... 102 
5.1.3 
Risks Associated with Worsening of Ulcerative 
Colitis ................................................................................... 102 


Etrolizumab—F. Hoffmann-La Roche Ltd 
7/Protocol GA29103, Version 7 
5.2 
Safety Parameters and Definitions ...................................... 103 
5.2.1 
Adverse Events ................................................................... 103 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) .................................................................... 103 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................. 104 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters .............................................. 105 
5.3.1 
Adverse Event Reporting Period ......................................... 105 
5.3.2 
Eliciting Adverse Event Information ..................................... 106 
5.3.3 
Assessment of Severity of Adverse Events ......................... 106 
5.3.4 
Assessment of Causality of Adverse Events ....................... 107 
5.3.5 
Procedures for Recording Adverse Events .......................... 107 
5.3.5.1 
Diagnosis versus Signs and Symptoms............................... 108 
5.3.5.2 
Adverse Events Occurring Secondary to Other 
Events.................................................................................. 108 
5.3.5.3 
Persistent or Recurrent Adverse Events .............................. 108 
5.3.5.4 
Abnormal Laboratory Values ............................................... 109 
5.3.5.5 
Abnormal Vital Sign Values ................................................. 110 
5.3.5.6 
Abnormal Liver Function Tests ............................................ 110 
5.3.5.7 
Deaths ................................................................................. 110 
5.3.5.8 
Preexisting Medical Conditions ............................................ 111 
5.3.5.9 
Lack of Efficacy or Worsening of Ulcerative 
Colitis ................................................................................... 111 
5.3.5.10 
Hospitalization or Prolonged Hospitalization ........................ 111 
5.3.5.11 
Adverse Events Associated with an Overdose or 
Error in Study Drug Administration ...................................... 112 
5.3.5.12 
Electronic Patient-Reported Outcome Data ......................... 112 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor ........................................................ 113 
5.4.1 
Emergency Medical Contacts .............................................. 113 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ................... 114 
5.4.3 
Reporting Requirements for Pregnancies ............................ 114 
5.4.3.1 
Pregnancies in Female Patients .......................................... 114 


Etrolizumab—F. Hoffmann-La Roche Ltd 
8/Protocol GA29103, Version 7 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ............... 115 
5.4.3.3 
Abortions ............................................................................. 115 
5.4.3.4 
Congenital Anomalies/Birth Defects .................................... 115 
5.4.4 
Reporting Requirements for Medical Device 
Complaints ........................................................................... 115 
5.5 
Follow-Up of Patients after Adverse Events ........................ 116 
5.5.1 
Investigator Follow-Up ......................................................... 116 
5.5.2 
Sponsor Follow-Up .............................................................. 116 
5.6 
Post-Study Adverse Events ................................................. 116 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ............................................................... 117 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ..................... 118 
6.1 
Determination of Sample Size ............................................. 118 
6.2 
Summaries of Conduct of Study .......................................... 118 
6.3 
Summaries of Treatment Group Comparability ................... 118 
6.4 
Efficacy Analyses ................................................................ 118 
6.4.1 
Primary Efficacy Endpoints .................................................. 119 
6.4.2 
Secondary Efficacy Endpoints ............................................. 120 
6.4.3 
Exploratory Efficacy Endpoints ............................................ 121 
6.5 
Safety Analyses ................................................................... 121 
6.5.1 
Laboratory Tests .................................................................. 121 
6.5.2 
Adverse Events ................................................................... 121 
6.6 
Pharmacokinetic, Pharmacodynamic, and 
Biomarker Analyses ............................................................. 122 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 122 
7.1 
Data Quality Assurance ....................................................... 122 
7.2 
Electronic Case Report Forms ............................................. 122 
7.3 
Electronic Patient-Reported Outcome Data ......................... 123 
7.4 
Source Data Documentation ................................................ 123 
7.5 
Use of Computerized Systems ............................................ 124 
7.6 
Retention of Records ........................................................... 124 


Etrolizumab—F. Hoffmann-La Roche Ltd 
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8. 
ETHICAL CONSIDERATIONS .................................................................. 124 
8.1 
Compliance with Laws and Regulations .............................. 124 
8.2 
Informed Consent ................................................................ 125 
8.3 
Institutional Review Board or Ethics Committee .................. 126 
8.4 
Confidentiality ...................................................................... 126 
8.5 
Financial Disclosure ............................................................ 127 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 127 
9.1 
Study Documentation .......................................................... 127 
9.2 
Protocol Deviations .............................................................. 127 
9.3 
Site Inspections ................................................................... 127 
9.4 
Administrative Structure....................................................... 128 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 128 
9.6 
Protocol Amendments ......................................................... 129 
10. REFERENCES ......................................................................................... 130 
 
LIST OF TABLES 
Table 1 
Efficacy Outcomes Definitions .................................................... 33 
Table 2 
Population Pharmacokinetic Modeling Predicted Percentage 
of Patients Achieving 1.7-µg/mL Steady-State Trough 
Concentration under Different Dosing Scenarios ........................ 44 
Table 3 
IFX Washout and Timing of Enrollment into Part 1 (OLE) of 
Study GA28951 ........................................................................... 59 
Table 4 
Study/Concomitant Background Treatments............................... 61 
Table 5 
Eligibility for Enrollment into Part 1 (OLE) of Study 
GA28951or Transfer to 12-Week Safety Follow-Up ................... 92 
Table 6 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 106 
Table 7 
Causal Attribution Guidance ..................................................... 107 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 41 
Figure 2 
Effects of High and Low Baseline Expression of the αE 
Biomarker in Colon on the Remission Status of TNF-Naive 
Ulcerative Colitis Patients Treated with Etrolizumab ................... 46 
Figure 3 
Schedule of Study Drug Administration ...................................... 57 
Figure  4  
Overview of Screening Activities  .................................................  88  


Etrolizumab—F. Hoffmann-La Roche Ltd 
10/Protocol GA29103, Version 7 
 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments ......................................................... 132 
Appendix 2 
12-Week Safety Follow-Up ....................................................... 140 
Appendix 3 
Childbearing Potential, Pregnancy Testing, and 
Contraception ............................................................................ 141 
Appendix 4 
Mayo Clinic Score Measurement .............................................. 143 
Appendix 5 
PML Subjective and Objective Checklists ................................. 151 
Appendix 6 
Algorithm for the Evaluation of Progressive Multifocal 
Leukoencephalopathy ............................................................... 158 
Appendix 7 
Patient Daily Diary .................................................................... 159 
Appendix 8 
Clinical Criteria for Diagnosing Anaphylaxis.............................. 160 
Appendix 9 
Quality of Life in Inflammatory Bowel Disease Questionnaire 
(IBDQ) ....................................................................................... 161 
Appendix 10 EuroQoL Five-Dimension (EQ-5D) Questionnaire .................... 164 


Etrolizumab—F. Hoffmann-La Roche Ltd 
11/Protocol GA29103, Version 7 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
PHASE III, RANDOMIZED, MULTICENTER, 
DOUBLE-BLIND, DOUBLE-DUMMY 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 
PROTOCOL NUMBER: GA29103 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
2013-004282-14 
IND NUMBER: 
100366 
TEST PRODUCT: 
Etrolizumab (PRO145223, RO5490261) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return the signed original of this form to a Sponsor representative.  Please retain 
a copy for your study files. 
 


 
Etrolizumab—F. Hoffmann-La Roche Ltd 
12/Protocol GA29103, Version 7 
PROTOCOL SYNOPSIS 
TITLE: 
PHASE III, RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
DOUBLE-DUMMY 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 
PROTOCOL NUMBER: 
GA29103 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
2013-004282-14 
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 infliximab in achieving both clinical response at Week 10 and clinical 
remission at Week 54 in patients with ulcerative colitis (UC) as determined by the Mayo 
Clinic Score (MCS). 
 
Secondary efficacy objectives for this study are as follows: 
• 
To evaluate clinical remission at Week 10 
• 
To evaluate clinical remission at Week 54 
• 
To evaluate clinical remission achieved at both Week 10 and Week 54 
• 
To evaluate clinical remission at Week 54 among patients with a clinical response at 
Week 10 
• 
To evaluate improvement in endoscopic appearance of the mucosa at Week 10 
• 
To evaluate improvement in endoscopic appearance of the mucosa at Week 54 
• 
To evaluate improvement in endoscopic appearance of the mucosa achieved at both 
Week 10 and Week 54 
• 
To evaluate endoscopic remission at Week 54 
• 
To evaluate clinical response at Week 10 
• 
To evaluate clinical response achieved at both Week 10 and Week 54 
• 
To evaluate corticosteroid-free clinical remission at Week 54 (off corticosteroids for at least 
24 weeks prior to Week 54) in patients who were receiving corticosteroids at baseline 


 
Etrolizumab—F. Hoffmann-La Roche Ltd 
13/Protocol GA29103, Version 7 
• 
To evaluate change from baseline in patient-reported health-related quality of life (QOL) at 
Weeks 10, 30, and 54, as assessed by the Inflammatory Bowel Disease Questionnaire 
(IBDQ) 
 
The exploratory efficacy objectives for this study are as follows: 
• 
To evaluate remission at Week 10  
• 
To evaluate remission at Week 54  
• 
To evaluate remission at both Week 10 and Week 54 
• 
To evaluate change in health utilities, as assessed by the EuroQoL Five-Dimension 
Questionnaire (EQ-5D), from baseline to Weeks 10, 30, and 54 
• 
To evaluate the frequency and duration of hospitalizations from baseline to Week 54 
 
Safety Objectives 
The safety objectives for this study are as follows: 
• 
To evaluate the overall safety and tolerability of etrolizumab over a period of 54 weeks 
• 
To evaluate the incidence and severity of infection-related adverse events 
• 
To evaluate the incidence of malignancies 
• 
To evaluate the incidence and severity of hypersensitivity reactions 
• 
To evaluate the incidence and the clinical significance of anti-therapeutic antibodies (ATAs) 
to etrolizumab, or if necessary, infliximab 
 
Pharmacokinetic Objectives 
The pharmacokinetic (PK) objectives for this study are as follows: 
• 
To evaluate the etrolizumab serum concentration at the time of primary endpoint evaluation 
and at a predose timepoint (Week 12) 
• 
To evaluate the interindividual variability of and potential covariate effects on etrolizumab 
(or potentially infliximab) serum exposure 
 
Exploratory Pharmacodynamic, Predictive, and Prognostic Objectives 
The exploratory pharmacodynamics (PD), predictive, and prognostic objectives for this study 
are as follows: 
• 
To evaluate the relationship between baseline colonic mucosal and/or peripheral blood 
biomarkers, including, but not limited to, αE integrin, and response to study treatment 
• 
To evaluate the expression levels of biomarkers in colonic tissue and/or peripheral blood, 
including, but not limited to, αE integrin, at baseline and during the treatment period  
• 
To evaluate the PD effects on biomarkers in stool samples through assessments that may 
include, but are not limited to, analyses of the microbiota and bacterial cultures at baseline 
and during the treatment period 
 
Study Design 
Description of Study 
This is a multicenter, Phase III, randomized, double-blind, double-dummy, parallel-group study 
to evaluate the safety, efficacy, and tolerability of etrolizumab (105 mg SC Q4W) compared with 
infliximab (5 mg/kg intravenous [IV] Weeks 0, 2, and 6, then every 8 weeks [Q8W]) in the 
treatment of moderate to severe UC. 
Patients enrolled in this study may be eligible to participate in an open-label extension and 
safety monitoring (OLE-SM) study (GA28951), which consists of two parts:  Part 1 (designated 
OLE [open-label extension]) and Part 2 (designated SM [safety monitoring]). 


 
Etrolizumab—F. Hoffmann-La Roche Ltd 
14/Protocol GA29103, Version 7 
Disease activity will be measured using the MCS, which is the current outcome measure 
accepted by regulatory authorities for drug development in UC.  The target population consists 
of 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 protocol, a rectal 
bleeding subscore ≥ 1, and a stool frequency subscore ≥ 1) and involvement that extends a 
minimum of 20 cm from the anal verge. 
All patients are to be naive to tumor necrosis factor (TNF) inhibitors. 
Patients must have had an inadequate response, loss of response, or intolerance to prior 
immunosuppressant and/or corticosteroid treatment. 
Patients who are on background immunosuppressant therapy (6-MP, AZA, MTX) may be 
enrolled if they have received a stable dose for at least 8 weeks prior to randomization (Day 1).  
Such patients should continue on their stable baseline doses of their background 
immunosuppressant therapy throughout the study unless dose reduction or discontinuation is 
required due to toxicity.  Generally accepted criteria for discontinuation of immunosuppressants 
due to toxicity include, but are not limited to, acute pancreatitis, severe leukopenia, severe 
thrombocytopenia, or clinically significant elevations of the liver-associated enzymes from 
baseline, especially in the presence of an elevated total bilirubin.  The ultimate decision to 
reduce dose or discontinue immunosuppressants due to toxicity remains at the discretion of the 
investigator. 
Patients 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 just been initiated, the dose has to be stable for at 
least 4 weeks immediately prior to randomization (Day 1) 
• 
If corticosteroids are being tapered, the dose has to be stable for 2 weeks immediately prior 
to randomization (Day 1)  
 
Such patients should continue stable doses of their background corticosteroid until Week 10, at 
which point a corticosteroid taper will be initiated for all patients entering the Maintenance 
Phase. 
Initiation of corticosteroid or an increase in corticosteroid dose above the patients’ entry dose 
(up to a maximum of 30 mg/day of 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 (Day 1).  Oral 5-aminosalicylate (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 
(Day 1).  Certain concomitant treatments are prohibited (see protocol for list of all prohibited 
concomitant treatments). 
Patients must have discontinued topical treatments for UC at least 2 weeks prior to 
randomization (Day 1).  
The study will be divided into:  
• 
Screening period of up to 35 days (for details see protocol) 
• 
Double-blind treatment period of 54 weeks, composed of an Induction Phase (up to 
Week 10) and a Maintenance Phase (Week 10 to Week 54) 
• 
Safety follow-up period of 12 weeks.  
 
A total of approximately 390 patients will be recruited from approximately 200 sites.  Patients 
will be stratified by concomitant treatment with corticosteroids (including budesonide) at 
baseline (yes/no), concomitant treatment with immunosuppressants at baseline (yes/no), and 
baseline disease activity as measured during screening (MCS ≤ 9 vs. MCS ≥ 10).  
Patients completing the Maintenance Phase at Week 54, patients identified as having disease 
worsening between Weeks 10 and 54, or patients who receive defined rescue medication(s) 
may enroll in Part 1 (OLE) of Study GA28951, if eligible, where they will receive open-label 
etrolizumab after a brief washout phase.  If they do not enroll in Part 1 (OLE) of Study 
GA28951, they will enter the 12-week safety follow-up period of this study  and will then be 
requested to enroll in Part 2 (SM) of Study GA28951 for 92 weeks of extended PML monitoring. 


 
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Study Drug Administration 
Following screening, patients will be randomized in a 1:1 ratio to receive 105 mg etrolizumab or 
5 mg/kg infliximab.  The study design is double-blind, double-dummy, so all patients will receive 
two study treatments, either active etrolizumab + infliximab dummy or active 
infliximab + etrolizumab dummy.  The dummy for etrolizumab will be a matched SC placebo, 
whereas the dummy for infliximab will be an IV saline infusion.  Patients will receive either 
105 mg etrolizumab or etrolizumab dummy by SC administration Q4W until Week 52.  Infliximab 
will be administered by IV infusion at Weeks 0, 2, and 6, then Q8W until Week 46.  
Consequently, administration of SC study medication and IV study medication occurs at 
different timepoints throughout the study. 
The first 2 doses of etrolizumab/etrolizumab dummy will be administered via a prefilled syringe 
(PFS) by a health care professional (HCP) in the clinic.  The subsequent two doses will be 
self-administered by the patient or administered by his or her caregiver in the clinic and 
monitored by the HCP.   
If deemed appropriate by HCP, the remaining doses of etrolizumab/etrolizumab dummy study 
drug, starting at Week 16, will be self-administered by the patient or administered by his or her 
caregiver at home Q4W (action to be taken as a result of a hypersensitivity reaction provided in 
the protocol).  On occasions when the patient has to attend the clinic the same day as an 
etrolizumab/etrolizumab dummy administration, the administration of study medication by the 
patient or his or her caregiver will occur at home after his or her study assessments in the clinic 
setting.  If necessary, patients or their HCPs may choose to continue administration of study 
medication in the clinic.  The details of study medication administration are provided in the 
protocol. 
In addition, patients will receive either infliximab (5 mg/kg IV at Weeks 0, 2, and 6, then Q8W) or 
infliximab dummy (saline) IV at the same timepoints, administered in the clinic setting until 
Week 46. 
Number of Patients 
A total of approximately 390 patients will be enrolled in this study from approximately 200 sites. 
Target Population 
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, a rectal bleeding subscore 
≥ 1, and a stool frequency subscore ≥ 1 during the screening period (prior to randomization 
[Day 1]).  See also the protocol for additional information regarding this 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 (Day 1).  See also the protocol for additional information 
regarding this time window. 
• 
Naive to treatment with any TNF inhibitor therapy (including TNF inhibitor biosimilars) 


 
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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-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(or equivalent) 
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 (Day 1) 
May be receiving oral corticosteroid therapy (prednisone at a stable dose of ≤ 30 mg a 
day, or equivalent steroid)  
If corticosteroid therapy is ongoing or has recently been initiated, the dose has to 
be stable for at least 4 weeks immediately prior to randomization (Day 1).  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 
for ≥ 4 weeks prior to randomization (Day 1) 
May be receiving probiotics (e.g., Culturelle, Saccharomyces boulardii), provided that 
the dose has been stable for ≥ 2 weeks immediately prior to randomization (Day 1) 
May be receiving AZA, 6-MP, or MTX, provided that the dose has been stable 
for ≥ 8 weeks immediately prior to randomization (Day 1) 
• 
For women who are not postmenopausal (at least 12 months of non−therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  agreement to remain 
abstinent or use a highly effective method of contraception during the treatment period and 
for at least 24 weeks after the last dose of study drug 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception. 


 
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• 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below: 
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 
24 weeks after the last dose of study drug to avoid exposing the embryo to study drug.  
Men must refrain from donating sperm during this same period.   
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception. 
• Must have received a colonoscopy within the past year or be willing to undergo a 
colonoscopy in lieu of a flexible sigmoidoscopy at screening.  This colonoscopy must: 
Confirm disease extent (defined as 1) left-sided colitis [up to the splenic flexure], 
2) extensive colitis [beyond the splenic flexure but not involving the entire colon], and 
3) pancolitis) 
Include removal of any adenomatous polyps  
Document evidence of surveillance for dysplasia for all patients with left-sided colitis 
of > 12 years’ duration and total/extensive colitis of > 8 years’ duration 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Exclusion Criteria Related to Inflammatory Bowel Disease 
• 
Prior extensive colonic resection, subtotal or total colectomy, or planned surgery for UC 
• 
Past or present ileostomy or colostomy 
• 
Diagnosis of indeterminate colitis 
• 
Suspicion of ischemic colitis, radiation colitis, or microscopic colitis 
• 
Diagnosis of toxic megacolon within 12 months of initial screening visit 
• 
Any diagnosis of Crohn’s disease 
• 
Past or present fistula or abdominal abscess 
• 
A history or current evidence of colonic mucosal dysplasia 
• 
Patients with any stricture (stenosis) of the colon 
• 
Patients with history or evidence of adenomatous colonic polyps that have not been 
removed 
 
Exclusion Criteria Related to Prior or Concomitant Therapy 
• 
Any prior treatment with etrolizumab or other anti-integrin agents (including natalizumab, 
vedolizumab, and efalizumab) 
• 
Any prior treatment with anti-adhesion molecules (e.g., anti-MAdCAM-1) 
• 
Any prior treatment with rituximab 
• 
Any treatment with tofacitinib during screening 
• 
Use of IV steroids within 30 days prior to screening with the exception of a single 
administration of IV steroid 
• 
Use of agents that deplete B or T cells (e.g., alemtuzumab or visilizumab) within 12 months 
prior to randomization (Day 1), with the exception of AZA and 6-MP 
• 
Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF) within 4 weeks 
prior to randomization (Day 1) 
• 
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.)  


 
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• 
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 (Day 1) 
• 
Apheresis (i.e., Adacolumn apheresis) within 2 weeks prior to randomization (Day 1) 
• 
Received any investigational treatment including investigational vaccines within  5 half-lives 
of the investigational product or 28 days after the last dose (whichever is greater) prior to 
randomization (Day 1) of the study 
• 
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 (Day 1) 
 
Exclusion Criteria Related to General Safety 
• 
Pregnant or lactating 
• 
Lack of peripheral venous access 
• 
Hospitalized (other than for elective reasons) during the screening period 
• 
Inability to comply with study protocol, in the opinion of the investigator 
• 
Significant uncontrolled comorbidity, such as cardiac (e.g., moderate to severe heart failure 
New York Heart Association [NYHA] Class III/IV), pulmonary, renal, hepatic, endocrine, or 
gastrointestinal disorders (excluding UC) 
• 
Neurologic conditions or diseases that may interfere with monitoring for PML 
• 
History of demyelinating disease  
• 
Clinically significant abnormalities on screening neurologic examination (PML Objective 
Checklist) 
• 
Clinically significant abnormalities on the screening PML Subjective Checklist 
• 
History of alcohol, drug, or chemical abuse ≤ 6 months prior to screening 
• 
Conditions other than UC that could require treatment with > 10 mg/day of prednisone (or 
equivalent) during the course of the study 
• 
History of cancer, including hematologic malignancy, solid tumors, and carcinoma in situ, 
within 5 years before screening with the following exceptions: 
Local basal or squamous cell carcinoma of the skin that has been excised and is 
considered cured is not exclusionary. 
A history of chronic myelogenous leukemia, hairy cell leukemia, melanoma, renal cell 
carcinoma, or Kaposi sarcoma is exclusionary irrespective of the duration of time before 
screening. 
History of a cervical smear indicating the presence of adenocarcinoma in situ (AIS), 
high-grade squamous intraepithelial lesions (HSIL), or cervical intraepithelial neoplasia 
(CIN) of Grade > 1, is exclusionary irrespective of the duration of time before screening. 
 
Exclusion Criteria Related to Infection Risk 
• 
Congenital or acquired immune deficiency 
• 
Patients must undergo screening for HIV and test positive for preliminary and confirmatory 
tests  


 
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• 
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 result 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 (Day 1) or other intestinal pathogens (as assessed by 
stool culture and ova and parasite evaluation) within 30 days prior to randomization (Day 1) 
• 
Evidence of or treatment for clinically significant cytomegalovirus (CMV) colitis (based on 
the investigator’s judgment) within 60 days prior to randomization (Day 1).  Laboratory 
confirmation of CMV from a colon biopsy sample is required during screening evaluation 
only if clinical suspicion is high and to determine the need for CMV treatment 
• 
History of active or latent treated tuberculosis (TB) regardless of treatment history 
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 
enrollment 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 
• 
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 (Day 1) 
Fungal infections of the nail beds 
Oral or vaginal candidiasis that has resolved with or without treatment prior to 
randomization (Day 1) 


 
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• 
Any major episode of infection requiring treatment with IV antibiotics within 8 weeks prior to 
screening or oral antibiotics 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 (Day 1) 
• 
History of organ transplant 
 
Exclusion Criteria Related to Laboratory Values (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/µL 
• 
Hemoglobin < 8 g/dL 
• 
Absolute neutrophil count < 1500/µL 
• 
Absolute lymphocyte count < 500/µL 
 
Length of Study 
The total length of the treatment period will be 54 weeks.  Patients who have disease worsening 
between Weeks 10 and 54, patients who receive defined rescue treatment(s), and patients who 
complete 54 weeks of the study may be given the option of enrolling in the Part 1 (OLE) of 
Study GA28951, where they will receive open-label etrolizumab treatment.  
Those who do not enroll in Part 1 (OLE) of Study GA28951 will continue to 12 weeks of safety 
follow-up in this protocol (without the washout phase) and then be requested to enroll in 
Part 2 (SM) of Study GA28951 for 92 weeks of PML monitoring. 
The total length of the study is expected to last from the first patient screened to either the last 
patient in last safety follow-up visit in this protocol or the 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 in Study GA28951, whichever is later. 
Outcome Measures 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
Primary Efficacy Outcome Measure 
• 
Both clinical response at Week 10 and clinical remission at Week 54 in patients with UC as 
determined by the MCS 
 
Secondary Efficacy Outcome Measures 
• 
Clinical remission at Week 10 
• 
Clinical remission at Week 54 
• 
Clinical remission achieved at both Week 10 and Week 54 
• 
Clinical remission at Week 54 among patients with a clinical response at Week 10 
• 
Improvement in endoscopic appearance of the mucosa at Week 10 
• 
Improvement in endoscopic appearance of the mucosa at Week 54 
• 
Improvement in endoscopic appearance of the mucosa achieved at both Week 10 and 
Week 54 
• 
Endoscopic remission Week 54 
• 
Clinical response at Week 10 


 
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• 
Clinical response achieved at both Week 10 and Week 54 
• 
Corticosteroid-free  clinical remission at Week 54 (off corticosteroids for at least 24 weeks 
prior to Week 54) in patients who were receiving corticosteroids at baseline 
• 
Change from baseline in patient-reported health-related QOL at Weeks 10, 30, and 54 as 
assessed by the IBDQ 
 
Exploratory Efficacy Outcome Measures 
• 
Remission at Week 10 
• 
Remission at Week 54 
• 
Remission at both Week 10 and Week 54 
• 
Change in health utilities, as assessed by the EQ-5D, from baseline to Weeks 10, 30, 
and 54 
• 
Frequency and duration of hospitalizations from baseline to Week 54 
 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence and severity of adverse events 
• 
Incidence of serious adverse events 
• 
Incidence and severity of infection-related adverse events 
• 
Incidence of serious infection-related adverse events 
• 
Incidence and severity of injection-site reactions  
• 
Incidence of adverse events leading to study drug discontinuation 
• 
Incidence of laboratory abnormalities 
• 
Incidence of malignancies 
• 
Incidence of ATAs to etrolizumab, or if necessary, infliximab 
• 
Incidence and severity of hypersensitivity reaction events 
 
Pharmacokinetic Outcome Measures 
The etrolizumab PK assessment will be performed in a subset of etrolizumab-treated patients.  
The PK outcome measures for this study are as follows: 
• 
Serum concentration 2 weeks after the first dose and at steady state during the dosing 
period from Week 12 to Week 54  
• 
Serum concentration at timepoints (Weeks 10, 30, and 54) 
 
Exploratory Biomarker Outcome Measures 
The exploratory biomarker outcome measures for this study are as follows: 
• 
Relationship between remission and baseline levels of colonic tissue biomarkers and/or 
peripheral blood including, but not limited to, αE integrin.  These may be outcomes 
predictive or prognostic of response.  
• 
Changes in stool biomarkers, which may include, but are not limited to, those in the 
microbiota and bacterial cultures, during the Induction and Maintenance Phases as 
compared to baseline 
 
Investigational Medicinal Products 
Test Product 
Etrolizumab PFS:  containing SC formulation, 105 mg given as 0.7 mL of a 150-mg/mL solution 
will be administered by SC injection Q4W. 


 
Etrolizumab—F. Hoffmann-La Roche Ltd 
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Comparator 
Infliximab, 5 mg/kg IV Weeks 0, 2, and 6, then Q8W.  Each infliximab vial contains 100 mg of 
lyophilized infliximab antibody in a 20-mL vial for IV use.  An unblinded pharmacist will 
reconstitute and then dilute the infliximab to a dose of 5 mg/kg and a total volume of 250 mL 
with sterile 0.9% sodium chloride for infusion.  
Non-Investigational Medicinal Products 
Patients are to continue on their baseline dose of corticosteroid (including budesonide) to the 
end of the Induction Phase (Week 10).  Tapering of corticosteroid (including budesonide) is to 
be attempted during the Maintenance Phase (Week 10 to Week 54). 
Immunosuppressants (AZA, 6-MP, MTX) are to continue on the patient’s baseline dose of 
immunosuppressant to the end of induction (Week 10) and then to continue on stable doses of 
immunosuppressants throughout the Maintenance Phase. 
Probiotics and oral 5-ASA may be continued at a stable dose throughout the study. 
Occasional use of NSAIDs and acetaminophen (e.g., headache, arthritis, myalgias, and 
menstrual cramps) and aspirin up to 325 mg daily are permitted throughout the study. 
Anti-diarrheals (e.g., loperamide, diphenoxylate with atropine) for control of chronic diarrhea are 
permitted throughout the study. 
Statistical Methods 
Efficacy Analyses 
The primary and secondary efficacy analyses will include all randomized patients who received 
at least one dose of study drug with patients grouped according to the treatment assigned at 
randomization (Day 1) (intent-to-treat [ITT] population).  A per-protocol population will be 
defined in the Statistical Analysis Plan (SAP) for the purpose of testing for non-inferiority in 
induction of clinical remission at Week 10.  
To manage the overall type I error, the testing of hypotheses will be performed sequentially.  
The primary endpoint will be tested first at an overall two-sided significance level of α = 0.05.  
The testing hierarchy for the secondary endpoints will be described in the SAP.  
Unless otherwise noted, analyses of efficacy outcome measures will be stratified by the 
stratification factors used at randomization (Day 1):  baseline corticosteroids use (yes/no), 
baseline immunosuppressants use (yes/no), and baseline disease severity as measured during 
screening (MCS ≤ 9/MCS ≥ 10). 
Patients who are non-evaluable for efficacy at a specific timepoint (e.g., due to missing data or 
early transfer to the Part 1 [OLE] of Study GA28951) will be considered non-responders for all 
response/remission type endpoints.  In addition, initiation of an agent not allowed in combination 
with etrolizumab or infliximab, an immunosuppressant, oral or topical 5-ASA (up to Week 10), or 
corticosteroid, or increase in dose over baseline levels for treatment of worsening disease 
symptoms as defined in the protocol will lead to non-responder classification thereafter.   
For continuous outcomes, 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 the protocol, the following analyses will be performed for 
the primary efficacy endpoint and key secondary efficacy endpoints.  Details of these analyses 
will be described in the SAP: 
• 
Sensitivity analyses to evaluate the robustness of results to the primary analysis methods 
(e.g., handling of dropouts) 
• 
Subgroup analyses to evaluate the consistency of results across prespecified subgroups 
(e.g., based on age, sex, race/ethnicity, baseline UC medications, baseline CS dose) 
 


 
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Determination of Sample Size   
Approximately 390 patients will be randomized in a 1:1 ratio to etrolizumab + infliximab dummy 
or infliximab + etrolizumab dummy.  The sample size of 195 patients per group provides 
approximately 80% power to detect a clinically meaningful difference of 12% (18% vs 30%) 
between the two groups for the primary endpoint, using a two-sided χ2 test at a significance 
level of 0.05. 
 


 
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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 
ELISA 
enzyme-linked immunosorbent assay 
ePRO  
electronic patient-reported outcome 
EQ-5D 
EuroQoL Five-Dimension Questionnaire 
FDA 
U.S. Food and Drug Administration 
HBsAg 
HBV surface antigen 
HBV 
hepatitis B virus 
HCP 
health care professional 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HSIL 
high-grade squamous intraepithelial lesions  
IBD 
inflammatory bowel disease 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICH 
International Council for Harmonisation 
IDCC 
independent data coordinating center  
iDMC 
independent Data Monitoring Committee 
IHC 
Immunohistochemistry 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 


 
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Abbreviation 
Definition 
IV  
Intravenous 
IxRS 
interactive voice/Web-based response system  
JCV 
John Cunningham virus 
JAK 
Janus kinase  
LD 
loading dose 
LFT 
liver function test 
MAb 
monoclonal antibody 
MAdCAM-Fc 
mucosal addressin cell adhesion molecule 
fragment-crystallizable region 
MCS 
Mayo Clinic Score 
MMF 
mycophenolate mofetil 
MP 
mercaptopurine 
MRI 
magnetic resonance imaging 
MTX 
methotrexate 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NSAID 
nonsteroidal anti-inflammatory drug  
NYHA 
New York Heart Association  
OLE 
open-label extension 
OLE−SM 
open-label extension−safety-monitoring 
PA 
Posteroanterior 
PD 
pharmacodynamics 
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 
Q8W 
every 8 weeks 
QOL 
quality of life 
qPCR 
quantitative polymerase chain reaction 
RCR 
Roche Clinical Repository 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 


 
Etrolizumab—F. Hoffmann-La Roche Ltd 
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Abbreviation 
Definition 
SDV 
source data verification 
SM 
safety monitoring 
SmPC 
Summary of Product Characteristics 
SOC 
standard of care 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis 
TNF 
tumor necrosis factor 
TNF-α 
tumor necrosis factor−alpha 
TNF-IR 
inadequate response to anti-tumor necrosis factor 
UC 
ulcerative colitis 
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 quality of life (QOL), and avoid disability.  For mildly 
to moderately active UC, oral and rectal preparations of 5-aminosalicylate (5-ASA) 
medications are used either alone or together and result in remission in approximately 
50% of patients.  Patients whose UC fails to respond to 5-ASA drugs or who have 
moderately to severely active UC often receive conventional therapy, including 
corticosteroids and immunomodulator therapy (e.g., azathioprine [AZA], 
6-mercaptopurine [6-MP], and methotrexate [MTX]).  Corticosteroids achieve remission 
in about 70% of patients, but approximately 20% become steroid dependent and only 
half maintain steroid-free remission (Faubion et al. 2001).  Corticosteroids are also 
associated with significant side effects, such as infections, osteopenia, glucose 
intolerance, and adrenal suppression.  Immunomodulators, such as 6-MP, AZA, and 
MTX, have also been used to achieve steroid-free remission, but efficacy in maintaining 
steroid-free remission is modest (Lobel et al. 2004; Chebli et al. 2010; 
Mañosa et al. 2011; Khan et al. 2013).  In addition, these medications are associated 
with significant side effects, including hepatotoxicity, pancreatitis, and bone marrow 
suppression. 


 
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Monoclonal antibodies (MAbs) targeting tumor necrosis factor−alpha (TNF-α), 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 
achieve 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-α4) for Crohn’s disease (CD) (Sandborn et al. 2005) and vedolizumab (anti-α4β7) 
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 β7 subunit, 
found in both α4β7 (Holzmann et al. 1989; Hu et al. 1992) and αEβ7 (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 α4β1 (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, 
κ 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 α4β7-expressing cells to 
mucosal addressin cell adhesion molecule−fragment crystallizable region (MAdCAM-Fc). 
Safety assessments for etrolizumab have been completed in the adult Phase I, Phase II, 
and Phase II open-label extension (OLE) studies without significant safety concerns. 
The following is a summary of the etrolizumab safety experience to date: 
• 
There were no observed significant adverse effects in multiple nonclinical toxicity 
studies of up to 6 months’ duration in adult animals or in embryo-fetal 
developmental toxicity studies.  No adverse effects were seen in any organ system 
(including the CNS, hematologic, and cardiovascular systems), no effects were seen 
in embryo-fetal development, and there was no evidence of increased rates of 
infection. 
• 
No significant adverse safety signal, including any evidence of increased rates of 
serious or opportunistic infections, was associated with etrolizumab treatment in the 
Phase I or Phase II trials in adult patients with moderately to severely active UC who 
received either single or multiple doses of intravenous (IV) or subcutaneous (SC) 
etrolizumab. 
• 
No events of PML have been reported in etrolizumab-treated patients. 
 
See the most recent Etrolizumab Investigator's Brochure for details on nonclinical and 
clinical studies. 


 
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1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Although 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 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); commonly associated with neutropenia, anemia, 
depression, allergic respiratory symptoms, arthralgias, myalgias, tachycardia, and 
vascular disorders; and very commonly associated with infusion-related reactions, 
abdominal pain, and nausea (REMICADE Summary of Product Characteristics [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 αEβ7 in addition to α4β7 and so 
regulates retention as well as trafficking leukocyte/lymphocyte in the intestinal mucosa.  
No clinically significant safety signals have been detected on administration of 
etrolizumab to patients with moderate to severe UC across a dose range of 
0.3−10.0 mg/kg IV/SC in the single ascending dose stage and of 0.5−3.0 mg/kg SC and 
4 mg/kg IV monthly for three doses in the multidose stage of the Phase I study. 
A global Phase II multicenter study (Study ABS4986g; EUCALYPTUS) designed to 
determine the exposure-response relationship and to further characterize the safety and 
tolerability of etrolizumab in treatment of adult patients with moderately to severely active 
UC patients has been completed.  Patients who had failed standard therapy and/or TNF 
inhibitors 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 receiving 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 clinical remission with etrolizumab against 
infliximab in a previously TNF-naive population.  
The present double-blinded and active-controlled study employs a robust design, 
utilizing independent and centrally read endoscopy to confirm patient eligibility and 
endpoint determination. 
All patients will receive an active therapy throughout the duration of the study with ability 
to receive rescue therapy or enroll in an OLE study, if eligible, to receive open-label 
etrolizumab therapy in case of non-response or disease worsening.  Patients who 
respond to blinded therapy may also be given the option to enroll in the OLE study at 
54 weeks. 
There is no known safety risk identified for etrolizumab at this time, but as an 
investigational medicinal product with limited Phase II data, the full safety profile for 
etrolizumab will be further characterized as Phase III clinical development progresses.  A 
safety plan is provided in Section 5.1, describing potential risks for etrolizumab and the 
risk-mitigation strategies to minimize risks for the patients in this study.   
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 
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 infliximab in achieving both clinical response at Week 10 and clinical 
remission at Week 54 in patients with UC, as determined by the MCS 
 
Secondary efficacy objectives for this study are as follows: 
• 
To evaluate clinical remission at Week 10  
• 
To evaluate clinical remission at Week 54 
• 
To evaluate clinical remission achieved at both Week 10 and Week 54  
• 
To evaluate clinical remission at Week 54 among patients with a clinical response 
at Week 10 
• 
To evaluate improvement in endoscopic appearance of the mucosa at Week 10 
• 
To evaluate improvement in endoscopic appearance of the mucosa at Week 54 
• 
To evaluate improvement in endoscopic appearance of the mucosa achieved at 
both Week 10 and Week 54 
• 
To evaluate endoscopic remission at Week 54 
• 
To evaluate clinical response at Week 10 
• 
To evaluate clinical response achieved at both Week 10 and Week 54  
• 
To evaluate corticosteroid-free clinical remission at Week 54 (off corticosteroids for 
at least 24 weeks prior to Week 54) in patients who were receiving corticosteroids at 
baseline 
• 
To evaluate change from baseline in patient-reported health-related QOL at 
Weeks 10, 30, and 54, as assessed by the Inflammatory Bowel Disease 
Questionnaire (IBDQ) 
 
The exploratory efficacy objectives for this study are as follows: 
• 
To evaluate remission at Week 10  
• 
To evaluate remission at Week 54  
• 
To evaluate remission at both Week 10 and Week 54  
• 
To evaluate change in health utilities, as assessed by the EuroQoL Five-Dimension 
Questionnaire (EQ-5D), from baseline to Weeks 10, 30, and 54 
• 
To evaluate the frequency and duration of hospitalizations from baseline to Week 54 
 
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 
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 
Composite of clinical response and 
clinical remission (primary outcome)  
Achievement of both clinical response at Week 10 and clinical remission at Week 54 
Corticosteroid-free clinical remission 
Clinical remission with no corticosteroid use for 12 weeks or 24 weeks prior to Week 54 
Improvement in endoscopic appearance 
of the mucosa 
Endoscopic subscore ≤ 1 
Endoscopic remission 
Endoscopic subscore = 0 
MCS = Mayo Clinic Score; pMCS = partial Mayo Clinic Score. 
 


 
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2.2 
SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
• 
To evaluate the overall safety and tolerability of etrolizumab over a period of 
54 weeks 
• 
To evaluate the incidence and severity of infection-related adverse events 
• 
To evaluate the incidence of malignancies 
• 
To evaluate the incidence and severity of hypersensitivity reactions 
• 
To evaluate the incidence and the clinical significance of anti-therapeutic antibodies 
(ATAs) to etrolizumab, or if necessary, infliximab 
 
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 endpoint 
evaluation and at a predose timepoint (Week 12) 
• 
To evaluate the interindividual variability of and potential covariate effects on 
etrolizumab (or potentially infliximab) 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 relationship between baseline colonic mucosal and/or peripheral 
blood biomarkers, including, but not limited to, αE integrin, and response to study 
treatment 
• 
To evaluate the expression levels of biomarkers in colonic tissue and/or peripheral 
blood, including, but not limited to, αE integrin, at baseline and during the treatment 
period  
• 
To evaluate the PD effects on biomarkers in stool samples through assessments 
that may include, but are not limited to, analyses of the microbiota and bacterial 
cultures at baseline and during the treatment period 
 
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, parallel-group 
study to evaluate the safety, efficacy, and tolerability of etrolizumab (105 mg SC Q4W) 
compared with infliximab (5 mg/kg IV Weeks 0, 2, and 6, then Q8W) in the treatment of 
moderate to severe UC (see Figure 1). 


 
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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 activity 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 
target population consists of 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 4.7.1.4, a rectal bleeding subscore ≥ 1, and a stool 
frequency subscore ≥ 1) and involvement that extends a minimum of 20 cm from the anal 
verge.  
All patients are to be naive to tumor necrosis factor (TNF) inhibitors. 
Patients must have had an inadequate response, loss of response, or intolerance to 
prior immunosuppressant and/or corticosteroid treatment. 
Patients who are on background immunosuppressant therapy (6-MP, AZA, MTX) may 
be enrolled if they have received a stable dose for at least 8 weeks prior to 
randomization (Day 1).  Such patients should continue on their stable baseline doses of 
their background immunosuppressant therapy throughout the study unless dose 
reduction or discontinuation is required due to toxicity.  Generally accepted criteria for 
discontinuation of immunosuppressants due to toxicity include, but are not limited to, 
acute pancreatitis, severe leukopenia, severe thrombocytopenia, or clinically significant 
elevations of the liver-associated enzymes from baseline, especially in the presence of 
an elevated total bilirubin.  The ultimate decision to reduce dose or discontinue 
immunosuppressants due to toxicity remains at the discretion of the investigator. 
Patients 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 just been initiated, the dose has to be 
stable for at least 4 weeks immediately prior to randomization (Day 1) 
• 
If corticosteroids are being tapered, the dose has to be stable for 2 weeks 
immediately prior to randomization (Day 1)  
 
Such patients should continue stable doses of their background corticosteroid until 
Week 10, at which point a corticosteroid taper will be initiated for all patients entering the 
Maintenance Phase. 
Initiation of corticosteroid or an increase in corticosteroid dose above the patients’ entry 
dose (up to a maximum of 30 mg/day of 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 (Day 1).  Oral 5-ASA 


 
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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 (Day 1).  Certain concomitant treatments are prohibited (see 
Section 4.5.2 for list of all prohibited concomitant treatments). 
Patients must have discontinued topical treatments for UC at least 2 weeks prior to 
randomization (Day 1).  
The study will be divided into:  
• 
Screening period of up to 35 days (for details see Section 4.7.2.1) 
• 
Double-blind treatment period of 54 weeks, composed of an Induction Phase (up to 
Week 10) and a Maintenance Phase (Week 10 to Week 54) 
• 
Safety follow-up period of 12 weeks  
 
A total of approximately 390 patients will be recruited (see Figure 1) from approximately 
200 sites.  Patients will be stratified by concomitant treatment with corticosteroids 
(including budesonide) at baseline (yes/no), concomitant treatment with 
immunosuppressants at baseline (yes/no), and baseline disease activity as measured 
during screening (MCS ≤ 9 vs. MCS ≥ 10).  
Patients completing the Maintenance Phase at Week 54, patients identified as having 
disease worsening between Weeks 10 and 54 (Section 3.1.1.1), or patients who receive 
defined rescue medication(s) (Section 3.1.1.2) may enroll in Part 1 (OLE) of 
Study GA28951, if eligible, where they will receive open-label etrolizumab after a brief 
washout phase.  If they do not enroll in Part 1 (OLE) of Study GA28951, they will enter 
the 12-week safety follow-up period of this study and will then be requested to enroll in 
Part 2 (SM) of Study GA28951 for 92 weeks of extended PML monitoring. 
Study Drug Administration 
Following screening, patients will be randomized in a 1:1 ratio to receive 
105 mg etrolizumab or 5 mg/kg infliximab.  The study design is double-blind, 
double-dummy, so all patients will receive two study treatments, either active 
etrolizumab + infliximab dummy, or active infliximab + etrolizumab dummy.  The dummy 
for etrolizumab will be a matched SC placebo, whereas the dummy for infliximab will be 
an IV saline infusion.  Patients will receive either 105 mg etrolizumab or etrolizumab 
dummy by SC administration Q4W until Week 52.  Infliximab will be administered by 
IV infusion at Weeks 0, 2, and 6 and then every 8 weeks (Q8W) until Week 46.  
Consequently, administration of SC study medication and IV study medication occurs at 
different timepoints throughout the study.  


 
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The first 2 doses of etrolizumab/etrolizumab dummy will be administered via a prefilled 
syringe (PFS) by a health care professional (HCP) in the clinic.  The subsequent two 
doses will be self-administered by the patient or administered by his or her caregiver in 
the clinic and monitored by the HCP.   
If deemed appropriate by HCP, the remaining doses of etrolizumab/etrolizumab dummy 
study drug, starting at Week 16, will be self-administered by the patient or administered 
by his or her caregiver at home Q4W (action to be taken as a result of a hypersensitivity 
reaction provided in Section 5.1.1.2).  On occasions when the patient has to attend the 
clinic the same day as an etrolizumab/etrolizumab dummy administration, the 
administration of study medication by the patient or his or her caregiver will occur at 
home after his or her study assessments in the clinic setting.  If necessary, patients or 
their HCPs may choose to continue administration of study medication in the clinic.  The 
details of study medication administration are provided in Section 4.4.2. 
In addition, patients will receive either infliximab (5 mg/kg IV at Weeks 0, 2, and 6, then 
Q8W) or infliximab dummy (saline) IV at the same timepoints, administered in the clinic 
setting until Week 46. 
Oral Corticosteroids during the Study 
During the Induction Phase, patients are to maintain their stable, baseline corticosteroid 
dose.  Corticosteroids are to be tapered starting from Week 10 for all patients entering 
the Maintenance Phase.  Patients receiving prednisone at a dose of > 10 mg/day (or 
equivalent) are to have their dose reduced at a rate of 5 mg per week until a 10 mg/day 
dose is achieved.  Patients receiving prednisone at doses ≤ 10 mg/day (or equivalent), or 
once a 10 mg/day dose (or equivalent) is achieved by tapering, are to have their dose 
reduced at a rate of 2.5 mg/week until discontinuation.  Beginning at Week 10, patients 
receiving budesonide should taper their dose of 9 mg every day to 9 mg every other day 
for 2 weeks and then discontinue budesonide treatment.  For patients who cannot 
tolerate the corticosteroid taper without recurrence of clinical symptoms of either UC or 
steroid withdrawal, corticosteroid dose may be increased (up to the dose at study entry if 
required), but tapering must begin again within 2 weeks. 
Investigators are to inform their patients to contact them if they are experiencing disease 
symptoms or steroid withdrawal symptoms during the taper. 
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 
discontinuation of immunosuppressants due to toxicity include, but are not limited to, 
acute pancreatitis, severe leukopenia, severe thrombocytopenia, or clinically significant 
elevations of the liver associated enzymes from baseline, especially in the presence of 


 
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an elevated total bilirubin.  The ultimate decision to reduce dose or discontinue 
immunosuppressants due to toxicity remains at the discretion of the investigator. 
3.1.1.1 
Disease Worsening  
Disease worsening is defined as: 
An increase in the partial Mayo Clinic Score (pMCS) ≥ 3 points from Week 10  
AND an absolute pMCS ≥ 5 
AND an endoscopy subscore of ≥ 2  
OR  
An absolute pMCS score ≥ 7  
AND an endoscopy subscore of ≥ 2 
 
If a patient meets criteria for disease worsening during the Maintenance Phase of the 
study (Week 10 to Week 54), he or she may withdraw from this study and enroll, if 
eligible, in Part 1 (OLE) of Study GA28951 to receive open-label etrolizumab after 
completing a brief washout phase. 
3.1.1.2 
Rescue Therapy 
Rescue Therapy That Can Be Given with Study Medication for the 
Treatment of Ulcerative Colitis 
During the Induction Phase (Prior to Week 10) 
Patients should maintain stable doses of their concomitant medications (e.g., oral 5-ASA, 
corticosteroids, immunosuppressants) for UC. 
During the Induction Phase, any patient who requires initiation of an immunosuppressant 
(AZA, 6 MP, or MTX), corticosteroid, or oral or topical 5-ASA, or who requires an 
increase in dose over baseline levels for treatment of worsening disease symptoms, 
should stay in the study.  These patients will be considered non-responders for the 
Induction timepoint. 
During the Maintenance Phase (Week 10 to Week 54) 
Initiation or escalation of oral 5-ASA should be avoided but is permitted if deemed 
clinically necessary by the investigator.  Patients who initiate or escalate oral 5-ASA 
therapy may continue blinded treatment. 
Corticosteroids: Use of topical or IV corticosteroids, or topical 5-ASA is not desired as 
concomitant medication.  If these are used to treat clinical symptoms of UC, the patient 
may remain in the blinded study or may enter, if eligible, Part 1 (OLE) of Study GA28951 
after a brief washout phase and based on the investigator’s discretion. 
Patients on corticosteroids at baseline must begin the specified corticosteroid taper at 
Week 10.  For patients who cannot tolerate the corticosteroid taper without recurrence of 
clinical symptoms of either UC or steroid withdrawal, corticosteroids may be increased 


 
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(up to the baseline dose, only if required).  In such cases, the tapering regimen must be 
reinitiated within 2 weeks.  An increase in corticosteroid dose back to baseline is not 
considered rescue medication if it occurs during the corticosteroid taper.  These patients 
should remain in the study. 
Patients who were not receiving corticosteroids at baseline and patients who have 
completed the steroid taper who subsequently require oral corticosteroids at a dose 
greater than 10 mg for 5 days or longer for the treatment of worsening UC symptoms or 
steroid withdrawal may remain in the study or may enroll, if eligible, in Part 1 (OLE) of 
Study GA28951 after a brief washout phase and based on the investigator’s discretion. 
Immunosuppressants (AZA, 6-MP, or MTX):  Patients are to remain on their stable 
baseline dose of immunosuppressant therapy throughout the study unless dose 
reduction or discontinuation is required due to toxicity.  Generally accepted criteria for 
discontinuation of immunosuppressants due to toxicity include, but are not limited to, 
acute pancreatitis, severe leukopenia, severe thrombocytopenia, or clinically significant 
elevations of the liver associated enzymes from baseline, especially in the presence of 
an elevated total bilirubin.  The ultimate decision to reduce dose or discontinue 
immunosuppressants due to toxicity remains at the discretion of the investigator.  
Patients who do initiate or escalate immunosuppressant therapy may remain in the study 
or may be given the option to enter Part 1 (OLE) of Study GA28951, if eligible, after a 
brief washout phase and based on the investigator’s discretion. 
Endoscopy to document disease activity for patients exiting the treatment period early 
for any reason may be performed at the discretion of the investigator. 
Prohibited Rescue Therapy  
At ANY time during the conduct of the study, use of other immunosuppressive agents 
including, but not limited to, anti-integrins, T- or B-cell depleters (except agents such as 
AZA and 6-MP), TNF inhibitors (including TNF inhibitor biosimilars), anti-adhesion 
molecules, Janus kinase (JAK) inhibitors, cyclosporine, tacrolimus, or investigational 
agents are prohibited.  Use of anakinra, abatacept, tocilizumab, and other biological 
therapeutics are also prohibited. 
Patients who receive such therapies are not to receive further study treatment or 
open-label treatment, and will be required to enter the 12-week safety follow-up period of 
this study (see Appendix 2).  These patients will also be requested to enroll in Part 2 
(SM) of Study GA28951 for 92 weeks of extended PML monitoring. 


 
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3.1.1.3 
Infliximab Washout Period 
Infliximab Washout Period for Patients Who Will Receive Open-Label 
Etrolizumab Treatment in Study GA28951 
Prior to switching to Part 1 (OLE) of Study 28951, eligible patients (see Section 4.7.2.3.1 
for eligibility criteria for switch to open-label treatment) are to undergo a blinded washout 
period of 6 or 8 weeks (see Table 3) measured since the last infusion of 
infliximab/infliximab dummy.  This is required to ensure adequate washout of infliximab 
in those patients randomized to active infliximab.  
During this washout, all patients will remain on blinded SC study medication 
(etrolizumab/etrolizumab dummy) and blinded IV study medication (infliximab/infliximab 
dummy) will cease.  Consequently, patients randomized to active etrolizumab will 
continue to receive etrolizumab and patients randomized to active infliximab will continue 
to receive etrolizumab dummy during the blinded washout period.  This mandated 
washout phase will lead to delayed entry into Part 1 (OLE) of Study GA28951 by 0 to 
5 weeks (see Table 3 for schedule). 
The evaluation of eligibility for Part 1 (OLE) of Study GA28951 can be made at study 
visits, telephone contacts, and/or unscheduled visits.  If eligible, the decision to switch to 
(but not necessarily enter) Part 1 (OLE) of Study GA28951 can occur at the visits listed 
in Table 3, with the earliest timepoint being the Week 10 visit, and occurring every week 
up to Week 52.  The assessments listed for “Unscheduled Visit/Decision to Switch to 
OLE” should be followed (see Appendix 1).  The earliest timepoint for entry into Part 1 
(OLE) of Study GA28951 is at the Week 12 visit and the latest is at the Week 54 visit.  
Due to the washout period, entry into Part 1 (OLE) of Study GA28951 may be delayed 
by up to 5 weeks from the visit date at which the decision to switch is made and detailed 
scenarios are outlined in Table 3. 
During the blinded washout period, rescue therapy with corticosteroids (IV, oral, or 
topical) and/or immunosuppressants (AZA, 6-MP, or MTX) for worsening UC is permitted 
at the discretion of the investigator.  Addition of or increases in doses of 5-ASA (oral or 
topical) will also be permitted per the investigator’s discretion.  
At the end of the washout period, patients are to have early withdrawal/end of washout 
assessments AND NOT their scheduled clinic visit/telephone contact assessments prior 
to enrollment into (Part 1) (see Appendix 1). 
A complete list of study visits and assessments can be found in the Schedule of 
Assessments (see Appendix 1).  A complete list of eligibility for enrollment of patients 
into Part 1 (OLE) of Study GA28951 can be found in Table 5.  
 


 
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Figure 1 Study Schema 
 
6-MP = 6-mercaptoprine; AZA = azathioprine; CS = corticosteroid; EP = endpoint; IV = intravenous; MTX = methotrexate; OLE = open-label extension; 
SM =  safety-monitoring; Q4W = every 4 weeks; Q8W = every 8 weeks; qd = once a day; QOD = every other day; SC = subcutaneous; SM = safety 
monitoring; TNF-naive = naive to tumor necrosis factor inhibitor; Wk = week.


 
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3.1.1.4 
Number of Patients 
A total of approximately 390 patients will be enrolled in this study from approximately 
200 sites.  Patients will be randomized into one of two study groups in a 1:1 ratio as 
follows: 
• 
Group A:  105 mg etrolizumab SC Q4W until Week 52 plus infliximab dummy IV at 
Weeks 0, 2, and 6 and Q8W thereafter until Week 46. 
• 
Group B:  5 mg/kg infliximab IV at Weeks 0, 2, and 6 and Q8W thereafter until 
Week 46 plus etrolizumab dummy SC Q4W until Week 52. 
 
3.1.2 
Data Monitoring Committee  
An independent data monitoring committee (iDMC) will monitor safety and study conduct 
on an ongoing basis.  Members of the iDMC will be external to the Sponsor and will 
follow a charter that outlines the iDMC roles and responsibilities.  The iDMC will meet 
approximately every 6 months (frequency adjustable as required) to review unblinded 
safety and study conduct data prepared by an independent data coordinating center 
(IDCC).  If the iDMC deems a benefit−risk assessment necessary, the iDMC may also 
review unblinded efficacy data.  The iDMC may recommend stopping the study early for 
safety reasons.  However, the iDMC may not recommend stopping the study early for 
positive efficacy or solely for futility. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
Length of Study 
The total length of the treatment period will be 54 weeks.  Patients who have disease 
worsening between Weeks 10 and 54, patients who receive defined rescue treatment(s) 
(see Section 4.4.2.3), and patients who complete 54 weeks of the study may be given 
the option of enrolling in Part 1 (OLE) of Study GA28951, where they will receive 
open-label etrolizumab treatment.  
Those who do not enroll in Part 1 (OLE) of Study GA28951 will continue to 12 weeks of 
safety follow-up in this protocol (without the washout phase) and then be requested to 
enroll in Part 2 (SM) of Study GA28951 for 92 weeks of PML monitoring. 
The total length of the study is expected to last from the first patient screened to either 
the last patient in last safety follow-up visit in this protocol or the 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 in Study GA28951, 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 nominal 100-mg Q4W regimen is sufficient to maintain β7 receptor 
occupancy both in blood and in colonic tissue, is well tolerated, and results in meaningful 
clinical efficacy, and therefore, will be evaluated further in this Phase III study.  The 
rationale for proposing a 105-mg Q4W SC regimen is discussed below. 
• 
In the Phase II, the nominal 100-mg Q4W SC dose (0.7 mL of 150 mg/mL solution 
via vial and syringe, with an actual dose of 105 mg) showed clinically meaningful 
efficacy without clinically meaningful safety imbalances (see Section 1.2).  The 
Phase III formulation is a PFS containing 0.7 mL of 150 mg/mL etrolizumab solution, 
corresponding to delivering a dose of 105 mg etrolizumab per injection. 
In the Phase II EUCALYPTUS study, the 100-mg SC Q4W dose resulted in an 
increased clinical remission rate in TNF-naive patients (43.8%; p = 0.007), as 
well as in the combined TNF-naive and 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 β7 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 β7 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 β7 receptor 
occupancy is dose dependent.  A single dose of 0.3 mg/kg IV maintained 
β7 receptor occupancy for only approximately 2 weeks, which is likely 
insufficient to ensure maximal β7 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 β7 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 µg/mL (the minimum serum concentration 
observed that maintained colonic tissue β7 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 β7 receptor occupancy at all times during 
the Q4W dosing interval, since only 56% of patients were predicted to reach a 
1.7 µg/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-µg/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 > 1.7µg/mL 
98 
84 
56 
Ctrough,ss = steady-state trough concentrations; Q4W = every 4 weeks; 
SC = subcutaneous. 
Note:  1.7 µg/mL is the minimum serum concentration observed in the 
Phase II study that maintained β7 occupancy in the colonic tissue. 
 
In conclusion, on the basis of available etrolizumab efficacy, PK, PD, and safety data 
(see Section 1.2), a PFS delivering a dose of 105 mg Q4W is considered the most 
appropriate dosing regimen for this Phase III study. 
3.3.2 
Rationale for Patient Population  
There is a high unmet medical need in moderately to severely active UC due to current 
treatments being associated with significant adverse events, resulting in low rates of 
sustained remission, or being highly invasive (i.e., colectomy) (see Section 1.1 for 
details).   
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 arms, 
compared with 0% in the placebo arm.  In the TNF-naive subgroup, clinical remission at 


 
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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, the decrease in clinical remission seen 
over time with TNF inhibitors, 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 compared with the current 
standard-of-care (SOC) medication infliximab. 
3.3.3 
Rationale for Active Comparator  
Although at present, TNF inhibitors appear to be the most effective biologic therapy in 
moderately to severely active UC, no currently available therapy achieves sustained 
remission in more than 10%−30% of patients with IBD who have chronic disease 
(Hanauer et al. 2002; Sandborn et al. 2005).  Furthermore, adverse events associated 
with TNF inhibitors include elevated rates of serious bacterial infection, including TB, and 
(more rarely) lymphoma and demyelination (Chang and Lichtenstein 2006).   
This study is designed to compare the efficacy and safety of etrolizumab with that of an 
active comparator, infliximab (TNF inhibitor), which is an SOC biologic for the treatment 
of moderately to severely active UC. 
3.3.4 
Rationale for Biomarker Assessments 
A biomarker that may predict an increased chance of response to therapy would be 
valuable to patients and treating physicians to aid in guiding treatment decisions.  
Etrolizumab binds to the β7 integrin and blocks α4β7:MAdCAM and αEβ7:E-cadherin 
binding.  In exploratory analyses from the Phase II EUCALYPTUS study, patients with 
higher baseline biopsy αE gene expression by quantitative polymerase chain reaction 
(qPCR) and αE+ cell counts by immunohistochemistry (IHC) had a higher rate of 
remission at Week 10 (see Figure 2).  The baseline levels of αE and other biomarkers 
will be evaluated in the Phase III study to further evaluate whether they may function as 
predictive response biomarkers in the TNF-naive patient population. 


 
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Figure 2 Effects of High and Low Baseline Expression of the αE 
Biomarker in Colon on the Remission Status of TNF-Naive 
Ulcerative Colitis Patients Treated with Etrolizumab 
 
LD = loading dose; SC = subcutaneous. 
 
All patients enrolled in the current study will have mandatory colonic mucosal sampling 
at the baseline visit to analyze the relationship of αE levels (and possibly other 
biomarkers) with response to treatment.  In addition, biomarker samples from blood and 
tissue will be collected at Weeks 10 and 54 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. 
In addition, stool samples will be collected at Week 10 and Week 54 for assessment of 
stool biomarkers including, but not limited to, microbiome or products of bacterial 
cultures. 
3.4 
OUTCOME MEASURES  
3.4.1 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
Primary Efficacy Outcome Measure 
• 
Both clinical response at Week 10 and clinical remission at Week 54 in patients with 
UC as determined by the MCS 
 
Secondary Efficacy Outcome Measures 
• 
Clinical remission at Week 10  
• 
Clinical remission at Week 54 


 
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• 
Clinical remission achieved at both Week 10 and Week 54  
• 
Clinical remission at Week 54 among patients with a clinical response at Week 10 
• 
Improvement in endoscopic appearance of the mucosa at Week 10 
• 
Improvement in endoscopic appearance of the mucosa at Week 54 
• 
Improvement in endoscopic appearance of the mucosa achieved at both Week 10 
and Week 54 
• 
Endoscopic remission at Week 54 
• 
Clinical response at Week 10 
• 
Clinical response achieved at both Week 10 and Week 54  
• 
Corticosteroid-free clinical remission at Week 54 (off corticosteroids for at least 
24 weeks prior to Week 54) in patients who were receiving corticosteroids at 
baseline 
• 
Change from baseline in patient-reported health-related QOL at Weeks 10, 30, and 
54, as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ) 
 
Exploratory Efficacy Outcome Measures 
• 
Remission at Week 10  
• 
Remission at Week 54  
• 
Remission at both Week 10 and Week 54  
• 
Change in health utilities, as assessed by the EuroQoL Five-Dimension 
Questionnaire (EQ-5D), from baseline to Weeks 10, 30, and 54 
• 
Frequency and duration of hospitalizations from baseline to Week 54 
 
3.4.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence and severity of adverse events 
• 
Incidence of serious adverse events 
• 
Incidence and severity of infection-related adverse events 
• 
Incidence of serious infection-related adverse events 
• 
Incidence and severity of injection-site reactions  
• 
Incidence of adverse events leading to study drug discontinuation 
• 
Incidence of laboratory abnormalities 
• 
Incidence of malignancies 
• 
Incidence of ATAs to etrolizumab, or if necessary, infliximab 
• 
Incidence and severity of hypersensitivity reaction events 
 


 
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3.4.3 
Pharmacokinetic Outcome Measures 
The etrolizumab PK assessment will be performed in a subset of etrolizumab-treated 
patients.  The PK outcome measures for this study are as follows: 
• 
Serum concentration 2 weeks after the first dose and at steady state during the 
dosing period from Week 12 to Week 54  
• 
Serum concentration at timepoints Weeks 10, 30, and 54 
 
3.4.4 
Exploratory Biomarker Outcome Measures  
The exploratory biomarker outcome measures for this study are as follows: 
• 
Relationship between remission and baseline levels of colonic tissue biomarkers 
and/or peripheral blood including, but not limited to, αE integrin.  These may be 
outcomes predictive or prognostic of response.  
• 
Changes in stool biomarkers, which may include, but are not limited to, those in the 
microbiota and bacterial cultures, during the Induction and Maintenance Phases as 
compared to baseline 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
The target population is 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 4.7.1.4, a rectal bleeding subscore ≥ 1, a stool 
frequency subscore ≥ 1, and colonic involvement extending a minimum of 20 cm from 
the anal verge). 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Able and willing to provide written informed consent 
• 
18−80 years of age, inclusive 
• 
Diagnosis of UC established at least 3 months prior to 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 4.7.1.4, a rectal bleeding subscore ≥ 1, and a stool frequency subscore 
≥ 1 during the screening period (prior to randomization [Day 1]).  See also 
Section 4.7.2.1 for additional information regarding this time window.   


 
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• 
Evidence of UC extending a minimum of 20 cm from the anal verge as determined 
by baseline endoscopy (flexible sigmoidoscopy or colonoscopy) performed during 
screening, 4−16 days prior to randomization (Day 1).  See also Section 4.7.2.1 for 
additional information regarding this time window.   
• 
Naive to treatment with any TNF inhibitor therapy (including TNF inhibitor biosimilars) 
• 
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-
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 (Day 1) 
May be receiving oral corticosteroid therapy (prednisone at a stable dose of 
≤ 30 mg a day, or equivalent steroid)   
If corticosteroid therapy is ongoing or has recently been initiated, the dose 
has to be stable for at least 4 weeks immediately prior to randomization 
(Day 1).  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 for 
≥ 4 weeks prior to randomization (Day 1) 


 
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May be receiving probiotics (e.g., Culturelle, Saccharomyces boulardii), 
provided that the dose has been stable for ≥ 2 weeks immediately prior to 
randomization (Day 1) 
May be receiving AZA, 6-MP, or MTX, provided that the dose has been stable 
for ≥ 8 weeks immediately prior to randomization (Day 1) 
• 
For women who are not postmenopausal (at least 12 months of 
non−therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or 
uterus):  agreement to remain abstinent or use a highly effective method of 
contraception during the treatment period and for at least 24 weeks after the last 
dose of study drug (see Appendix 3). 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
• 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:  
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at 
least 24 weeks after the last dose of study drug to avoid exposing the embryo 
to study drug.  Men must refrain from donating sperm during this same period.   
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• 
Must have received a colonoscopy within the past year or be willing to undergo a 
colonoscopy in lieu of a flexible sigmoidoscopy at screening.  This colonoscopy 
must: 
Confirm disease extent (defined as 1) left-sided colitis [up to the splenic 
flexure], 2) extensive colitis [beyond the splenic flexure but not involving the 
entire colon], and 3) pancolitis; see Section 4.7.1.4) 
Include removal of any adenomatous polyps  
Document evidence of surveillance for dysplasia for all patients with left-sided 
colitis of > 12 years’ duration and total/extensive colitis of > 8 years’ duration  
 


 
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4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Exclusion Criteria Related to Inflammatory Bowel Disease 
• 
Prior extensive colonic resection, subtotal or total colectomy, or planned surgery for 
UC 
• 
Past or present ileostomy or colostomy 
• 
Diagnosis of indeterminate colitis 
• 
Suspicion of ischemic colitis, radiation colitis, or microscopic colitis 
• 
Diagnosis of toxic megacolon within 12 months of initial screening visit 
• 
Any diagnosis of Crohn’s disease 
• 
Past or present fistula or abdominal abscess 
• 
A history or current evidence of colonic mucosal dysplasia 
• 
Patients with any stricture (stenosis) of the colon 
• 
Patients with history or evidence of adenomatous colonic polyps that have not been 
removed 
 
Exclusion Criteria Related to Prior or Concomitant Therapy 
• 
Any prior treatment with etrolizumab or other anti-integrin agents (including 
natalizumab, vedolizumab, and efalizumab) 
• 
Any prior treatment with anti-adhesion molecules (e.g., anti-MAdCAM-1) 
• 
Any prior treatment with rituximab 
• 
Any treatment with tofacitinib during screening 
• 
Use of IV steroids within 30 days prior to screening with the exception of a single 
administration of IV steroid 
• 
Use of agents that deplete B or T cells (e.g., alemtuzumab or visilizumab) within 
12 months prior to randomization (Day 1), with the exception of AZA and 6-MP 
• 
Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF) within 
4 weeks prior to randomization (Day 1) 
• 
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 
(Day 1) 
• 
Apheresis (i.e., Adacolumn apheresis) within 2 weeks prior to randomization (Day 1) 


 
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• 
Received any investigational treatment including investigational vaccines within 
5 half-lives of the investigational product or 28 days after the last dose (whichever is 
greater) prior to randomization (Day 1) of the study  
• 
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 (Day 1) 
 
Exclusion Criteria Related to General Safety 
• 
Pregnant or lactating 
• 
Lack of peripheral venous access 
• 
Hospitalized (other than for elective reasons) during the screening period 
• 
Inability to comply with study protocol, in the opinion of the investigator 
• 
Significant uncontrolled comorbidity, such as cardiac (e.g., moderate to severe heart 
failure New York Heart Association [NYHA] Class III/IV), pulmonary, renal, hepatic, 
endocrine, or gastrointestinal disorders (excluding UC) 
• 
Neurologic conditions or diseases that may interfere with monitoring for PML 
• 
History of demyelinating disease  
• 
Clinically significant abnormalities on screening neurologic examination (PML 
Objective Checklist) 
• 
Clinically significant abnormalities on the screening PML Subjective Checklist 
• 
History of alcohol, drug, or chemical abuse ≤ 6 months prior to screening 
• 
Conditions other than UC that could require treatment with > 10 mg/day of 
prednisone (or equivalent) during the course of the study 
• 
History of cancer, including hematologic malignancy, solid tumors, and carcinoma 
in situ, within 5 years before screening with the following exceptions: 
Local basal or squamous cell carcinoma of the skin that has been excised and 
is considered cured is not exclusionary. 
A history of chronic myelogenous leukemia, hairy cell leukemia, melanoma, 
renal cell carcinoma, or Kaposi sarcoma is exclusionary irrespective of the 
duration of time before screening. 
History of a cervical smear indicating the presence of adenocarcinoma in situ 
(AIS), high-grade squamous intraepithelial lesions (HSIL), or cervical 
intraepithelial neoplasia (CIN) of Grade > 1, is exclusionary, irrespective of the 
duration of time before screening. 
 


 
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Exclusion Criteria Related to Infection Risk 
• 
Congenital or acquired immune deficiency 
• 
Patients must undergo screening for HIV and test positive for preliminary and 
confirmatory tests  
• 
Positive hepatitis C virus (HCV) antibody test result, unless the patient (1) has 
undetectable HCV RNA levels for > 6 months after completing a successful course 
of HCV anti-viral treatment and an undetectable HCV RNA at screening or (2) has a 
known history of HCV antibody positivity with a history of undetectable HCV RNA for 
> 6 months and undetectable HCV RNA at screening in the absence of history of 
HCV anti-viral treatment. 
• 
Patients must undergo screening for hepatitis B virus (HBV).  This includes testing 
for HBsAg (HBV surface antigen), anti-HBc total (HBV core antibody total), and 
HBV DNA (patients who test negative for these tests are eligible for this study): 
Patients who test positive for surface antigen (HBsAg +) are not eligible for this 
study, regardless of the results of other hepatitis B tests. 
Patients who test positive only for core antibody (anti-HBc +) must undergo 
further testing for hepatitis B DNA (HBV DNA test).   
If the HBV DNA test result is positive, the patient is not eligible for this 
study.   
In the event 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 (Day 1) or other intestinal pathogens 
(as assessed by stool culture and ova and parasite evaluation) within 30 days prior 
to randomization (Day 1) 
• 
Evidence of or treatment for clinically significant cytomegalovirus (CMV) colitis 
(based on the investigator’s judgment) within 60 days prior to randomization (Day 1).  
Laboratory confirmation of CMV from a 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 4.7.1.5) 
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 4.7.1.5) are not eligible for this study. 
Patients with a chest X-ray (posteroanterior [PA] and lateral) within 3 months of 
enrollment 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. 


 
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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 
• 
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 (Day 1) 
Fungal infections of the nail beds 
Oral or vaginal candidiasis that has resolved with or without treatment prior to 
randomization (Day 1) 
• 
Any major episode of infection requiring treatment with IV antibiotics within 8 weeks 
prior to screening or oral antibiotics within 4 weeks prior to screening 
Treatment with antibiotics as adjunctive therapy for UC in the absence of 
documented infection is not exclusionary. 
• 
Received a live attenuated vaccine within 4 weeks prior to randomization (Day 1) 
• 
History of organ transplant 
 
Exclusion Criteria Related to Laboratory Values (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/µL 
• 
Hemoglobin < 8 g/dL 
• 
Absolute neutrophil count < 1500/µL 
• 
Absolute lymphocyte count < 500/µL 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
Patients will be randomized to the two treatment arms through an interactive 
voice/Web-based response system (IxRS).  After written informed consent has been 
obtained, all patients will receive a screening number that will be assigned by the IxRS.  
Following completion of up to a 35-day screening period and after all patient eligibility 
requirements are confirmed, patients will be assigned a subject number (a different 


 
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number from the screening number) on Day 1 and will be randomized in a 1:1 ratio to 
one of two treatment arms (105 mg etrolizumab SC or 5 mg/kg infliximab IV) for the 
54-week double-blind period (see Figure 3 for details of study drug administration 
schedule).  
Patients will be randomized on the same day that treatment is to be initiated (Day 1).  
Randomization will be stratified by concomitant treatment with corticosteroids including 
budesonide at baseline (yes/no), concomitant treatment with immunosuppressants at 
baseline (yes/no), and baseline disease activity as measured during screening 
(MCS ≤ 9/MCS ≥ 10).  A permuted blocks randomization method will be used to obtain 
approximately a 1:1 ratio between the two treatment arms and within each stratum.  
During the 54-week double-blind treatment period and the infliximab washout period, the 
IxRS will make etrolizumab/etrolizumab dummy kit assignments.  Each kit will consist of 
one prefilled 1-mL syringe (0.7 mL nominal volume).  Study drug kits will be assigned for 
administration to each patient; the number of kits assigned will allow for administration 
up until the next clinic visit.  The placebo and active kits are filled and packaged to look 
identical.  
The IxRS will also make infliximab/infliximab dummy treatment assignments at Weeks 0, 
2, and 6 and then at 8-week intervals until Week 46.  An unblinded pharmacist will 
reconstitute and then dilute the infliximab to a dose of 5 mg/kg and a total volume of 
250 mL with sterile 0.9% sodium chloride for infusion to patients on active infliximab.  
Patients randomized to infliximab dummy will be administered 250 mL sterile 0.9% 
sodium chloride infusion. 
Patients, all study site personnel (except the unblinded pharmacist or designee 
responsible for infliximab accountability), the Sponsor, and its agents (with the exception 
of the IxRS service provider and laboratory personnel responsible for the PK sample 
analysis) will be blinded to treatment assignment throughout the 54-week double-blind 
treatment period.  As described in Section 6, treatment assignment will be unblinded to 
the Sponsor personnel performing the analysis when all data through Week 54 are in the 
database and the data have been cleaned and verified and the database is locked.  
Personnel responsible for performing PK assays will be unblinded to patients’ 
randomized treatment assignments in order to identify appropriate dilutions of PK 
samples to be analyzed.  Patients and all study site personnel (except unblinded 
pharmacist or designee) will remain blinded to individual treatment assignment until after 
the study is completed (after all patients have either completed the active-treatment and 
safety follow-up period or discontinued early from the study) and the database is locked.  
If unblinding is necessary for patient management (in the case of a serious adverse 
event), the investigator will be able to break the treatment code by contacting the IxRS.  
Treatment codes should not be broken except in emergency situations.  If the 
investigator wishes to know the identity of the study drug for any other reason, he or she 


 
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should contact the Medical Monitor.  The investigator should document and provide an 
explanation for any premature unblinding (e.g., accidental unblinding, unblinding due to 
a serious adverse event as per health authority reporting requirements).  The 
Sponsor Safety Reporting Department (independent from the study team) will break the 
treatment code for all unexpected serious adverse events (see Section 5.2.2) that are 
considered by the investigator to be related to study drug for the purpose of regulatory 
reporting.  The study team will remain blinded to study treatment. 
 


 
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Figure 3 Schedule of Study Drug Administration 
 
CS = corticosteroid; EP = endpoint; Etro = etrolizumab; HCP = health care professional; IFX = infliximab; 
OLE−SM = open-label extension−safety-monitoring study; Q4W = every 4 weeks; Q8W = every 8 weeks; qd = once a day; QOD = every other day; 
TC = telephone call; Wk = week. 


 
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4.3 
STUDY MEDICATION BLINDED WASHOUT OF INFLIXIMAB 
Prior to switching to Study GA28951, eligible patients (see Section 4.7.2.3.1 for eligibility 
criteria for switch to open-label treatment) are to undergo a blinded washout period of 
6 or 8 weeks (see Table 3) measured since the last infusion of infliximab/infliximab 
dummy.  This is required to ensure adequate washout of infliximab in those patients 
randomized to active infliximab.  During this washout, all patients will remain on blinded 
SC study medication (etrolizumab or etrolizumab dummy) and blinded IV study 
medication (infliximab/infliximab dummy) will cease.  Consequently, patients randomized 
to active etrolizumab will continue to receive etrolizumab and patients randomized to 
active infliximab will continue to receive etrolizumab dummy during the blinded washout 
period. 
The evaluation of eligibility for Part 1 (OLE) of Study GA28951 can be made at study 
visits, telephone contacts, and/or unscheduled visits.  If eligible, the decision to switch to 
(but not necessarily enter) Part 1 (OLE) of Study GA28951 can occur at any timepoint 
listed in Column 2 of Table 3, with the earliest timepoint being the Week 10 visit, and 
occurring every week up to Week 52.  The assessments listed for “Unscheduled 
Visit/Decision to Switch to OLE” should be followed (see Appendix 1).  The earliest 
timepoint for entry into Part 1 (OLE) of Study GA28951is at the Week 12 visit and the 
latest is at the Week 54 visit.  Due to the washout period, entry into Study GA28951 may 
be delayed by up to 5 weeks from the visit date at which the decision to switch is made, 
and detailed scenarios are outlined in Table 3. 
During the blinded washout period, rescue therapy with corticosteroids (IV, oral, or 
topical) and/or immunosuppressants (AZA, 6-MP, or MTX) for worsening UC is permitted 
at the discretion of the investigator.  Addition of or increases in doses of 5-ASA (oral or 
topical) will also be permitted per the investigator’s discretion.  
At the end of the washout period, patients are to have early withdrawal/end of washout 
assessments AND NOT their scheduled clinic visit/telephone contact assessments prior 
to enrollment into Part 1 (OLE) of Study GA28951 (see Appendix 1).  The first open-label 
dose of etrolizumab in Part 1 (OLE) ofStudy GA28951 can be administered on the same 
day, or at Week 54, as long as they remain eligible for Part 1 (OLE) ofStudy GA28951.  
Patients will be required to attend the clinic at the timepoint of Day 1 of Study GA28951 
(and thereafter in accordance with the Study GA28951 protocol) and unused medication 
that has been given to them as part of this study is to be returned to the study site. 
A complete list of study visits and assessments can be found in the Schedule of 
Assessments (see Appendix 1).  A complete list of eligibility for enrollment of patients 
into Part 1 (OLE) of Study GA28951 is in Table 5.   


 
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Table 3 
IFX Washout and Timing of Enrollment into Part 1 (OLE) of 
Study GA28951 
IFX/IFX 
Dummy Dose 
Last 
Administered 
On 
Decision to 
Switch to OLE 
Visit 
Next Expected Dose of 
Etrolizumab/Etrolizumab 
Dummy  
End of Washout 
Visit/Enrollment into 
Part 1(OLE) with 1st 
Administration of 
Open-Label Etrolizumab 
Week 6 
Week 10 
NA 
Week 12 
Week 6 
Week 11 
NA 
Week 12 
Week 6 
Week 12 
NA 
Week 12 
Week 6 
Week 13 
NA 
Week 14 
Week 6 
Week 14 
NA 
Week 14 
Week 14 
Week 15 
Week 16 
Week 20 
Week 14 
Week 16 
Week 16 
Week 20 
Week 14 
Week 17 
Week 16 
Week 20 
Week 14 
Week 18 
NA 
Week 20 
Week 14 
Week 19 
NA 
Week 20 
Week 14 
Week 20 
NA 
Week 20 
Week 14 
Week 21 
NA 
Week 22 
Week 14 
Week 22 
NA 
Week 22 
Week 22 
Week 23 
Week 24 
Week 28 
Week 22 
Week 24 
Week 24 
Week 28 
Week 22 
Week 25 
Week 24 
Week 28 
Week 22 
Week 26 
NA 
Week 28 
Week 22 
Week 27 
NA 
Week 28 
Week 22 
Week 28 
NA 
Week 28 
Week 22 
Week 29 
NA 
Week 30 
Week 22 
Week 30 
NA 
Week 30 
Week 30 
Week 31 
Week 32 
Week 36 
Week 30 
Week 32 
Week 32 
Week 36 
Week 30 
Week 33 
Week 32 
Week 36 
Week 30 
Week 34 
NA 
Week 36 
Week 30 
Week 35 
NA 
Week 36 
Week 30 
Week 36 
NA 
Week 36 
Week 30 
Week 37 
NA 
Week 38 
Week 30 
Week 38 
NA 
Week 38 
Week 38 
Week 39 
Week 40 
Week 44 
Week 38 
Week 40 
Week 40 
Week 44 
Week 38 
Week 41 
Week 40 
Week 44 


 
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Table 3 
IFX Washout and Timing of Enrollment into Part 1 (OLE) of 
Study GA28951 (cont.)  
Week 38 
Week 42 
NA 
Week 44 
Week 38 
Week 43 
NA 
Week 44 
Week 38 
Week 44 
NA 
Week 44 
Week 38 
Week 45 
NA 
Week 46 
Week 38 
Week 46 
NA 
Week 46 
Week 46 
Week 47 
Week 48 
Week 52 
Week 46 
Week 48 
Week 48 
Week 52 
Week 46 
Week 49 
Week 48 
Week 52 
Week 46 
Week 50 
NA 
Week 52 
Week 46 
Week 51 
NA 
Week 52 
Week 46 
Week 52 
NA 
Week 52 
IFX = infliximab; NA = not applicable; OLE = open-label extension. 
 
During the blinded washout period, rescue therapy with corticosteroids (IV, oral, or 
topical) and/or immunosuppressants (AZA, 6-MP, or MTX) for worsening UC is permitted 
at the discretion of the investigator.  Addition of or increases in doses of 5-ASA (oral or 
topical) will also be permitted if clinically indicated by the investigator. 
 


 
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4.4 
STUDY TREATMENT  
Table 4 
Study/Concomitant Background Treatments 
Treatment 
Investigational medicinal products 
Test product 
Etrolizumab, 105 mg SC Q4W 
Comparators and 
placebo 
Infliximab, 5 mg/kg IV Weeks 0, 2, and 6, then Q8W 
Etrolizumab dummy, SC Q4W 
Infliximab dummy, IV Weeks 0, 2, and 6, then Q8W 
Non-investigational medicinal products 
Concomitant 
background  
treatment 
To Week 10 continuation of stable doses of the following: 
 
5-ASA (oral); AZA; 6-MP; MTX  
 
Corticosteroid up to 30 mg/day of prednisone (or equivalent) 
 
Budesonide up to 9 mg/day 
At Week 10, for patients on corticosteroids at doses > 10 mg/day (prednisone equivalents), the dose should be reduced at a rate of 
5 mg/week until a 10-mg/day dose is reached.  For patients receiving prednisone at doses ≤ 10 mg/day (or equivalent) or once a 
10-mg/day dose (or equivalent) is achieved by tapering, the dose should be reduced at a rate of 2.5 mg/week until discontinuation.  
Patients receiving budesonide at study entry who achieve clinical response at Week 10 are to taper their dose starting from Week 10 
from 9 mg every day to 9 mg every other day for 2 weeks and then to discontinue budesonide treatment.  Should patients have 
increased disease activity during the taper period, corticosteroid dose may be increased up to the dose at study entry if required, but 
tapering must begin again within 2 weeks. 
5-ASA = 5-aminosalicylate; 6-MP = 6-mercaptopurine; AZA = azathioprine; IV = intravenous; MTX = methotrexate; NSAID = nonsteroidal anti-inflammatory drug; 
OLE-SM = open-label extension−safety monitoring; Q4W = every 4 weeks; Q8W = every 8 weeks; SC = subcutaneous; UC = ulcerative colitis. 
 
 


 
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Table 4 
Study/Concomitant Background Treatments (cont.) 
 
Treatment 
Throughout study 
Throughout the study, immunosuppressants (AZA, 6-MP, or MTX) are to be maintained at the stable baseline dose unless dose 
reduction or discontinuation is required due to toxicity.  Generally accepted criteria for discontinuation of immunosuppressants due to 
toxicity include, but are not limited to, acute pancreatitis, severe leukopenia, severe thrombocytopenia, or clinically significant elevations 
of the liver-associated enzymes from baseline, especially in the presence of an elevated total bilirubin.  The ultimate decision to reduce 
dose or discontinue immunosuppressants due to toxicity remains at the discretion of the investigator. 
Probiotics and oral 5-ASA may be continued at a stable dose throughout. 
Occasional use of NSAIDs and acetaminophen for headache, arthritis, myalgias, menstrual cramps, and daily use of low-dose (up to 
325 mg daily) aspirin for cardiovascular prophylaxis are permitted. 
Antidiarrheals (e.g., loperamide, diphenoxylate with atropine) for control of chronic diarrhea. 
During washout period 
prior to entering 
OLE−SM 
During the blinded washout period, rescue therapy with corticosteroids (IV, oral, or topical) and/or immunosuppressants (AZA, 6-MP, or 
MTX) for worsening UC is permitted at the discretion of the investigator.  Addition of or increases in doses of 5-ASA (oral or topical) will 
also be permitted if clinically indicated by the investigator.   
5-ASA = 5-aminosalicylate; 6-MP = 6-mercaptopurine; AZA = azathioprine; IV = intravenous; MTX = methotrexate; NSAID = nonsteroidal anti-inflammatory drug; 
OLE-SM = open-label extension−safety monitoring; SC = subcutaneous; UC = ulcerative colitis. 


 
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4.4.1 
Formulation, Packaging, and Handling 
4.4.1.1 
Etrolizumab and Etrolizumab Dummy 
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 105 mg of etrolizumab 
(0.7 mL nominal volume of 150 mg/mL solution).  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. 
Drug product composition for the etrolizumab dummy is identical to 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.  
  In the home setting, patients should be instructed to contact the study site 
staff for a replacement. 
Used PFS 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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4.4.1.2 
Infliximab and Infliximab Dummy 
Each infliximab vial contains 100 mg of lyophilized infliximab antibody in a 20-mL vial for 
IV use.  An unblinded pharmacist will reconstitute and then dilute the infliximab to a dose 
of 5 mg/kg and a total volume of 250 mL with sterile 0.9% sodium chloride for infusion.  
Infliximab dummy will consist of 250 mL sterile 0.9% sodium chloride for infusion and will 
not be provided by the Sponsor. 
Study drug packaging will be overseen by the Sponsor’s clinical study supplies 
department and have 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 Sponsor’s 
standards and local regulations. 
Upon arrival of investigational products at the site, the unblinded pharmacist or designee 
should check the infliximab vials for damage and verify proper identity, quantity, integrity 
of seals, and temperature conditions and report any deviations or product complaints to 
the monitor upon discover.  Infliximab is to be maintained out of view of blinded study 
staff. 
The study drug must be stored according to the details on the product label.  The drug 
label indicates the storage temperature.  Vials of study medication should be refrigerated 
at 2°C–8°C and protected from excessive light and heat.  Vials should not be frozen, 
shaken, or stored at room temperature. 
For further details, see the Infliximab SmPCs. 
4.4.1.3 
Concomitant Background Treatment for Ulcerative Colitis 
For concomitant background treatment for UC see Table 4. 
For further details, refer to respective SmPCs or product labels, local prescribing dosage, 
administration, and compliance information for the formulation, packaging, and handling 
details of agents prescribed as concomitant background treatment for UC. 
4.4.2 
Dosage, Administration, and Compliance 
During the double-blind period of 54 weeks, all patients will receive two study 
treatments, either active etrolizumab + infliximab dummy or active infliximab + etrolizumab 
dummy.  The dummy for etrolizumab will be a matched SC placebo, and the dummy for 
infliximab will be an IV saline infusion.  


 
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4.4.2.1 
Etrolizumab and Etrolizumab Dummy 
All patients will receive one 0.7-mL injection with use of a PFS device once Q4W.  The 
device is a 1-mL long glass syringe with a staked-in stainless steel needle.  
 
 
 
A part of the needle cap of the PFS may contain natural rubber latex that may cause 
allergic reactions in latex-sensitive individuals. 
Study site HCPs will be trained on the use of the PFS device and SC administration of 
study medication into the thigh, abdomen, or upper arm.  Patients will in turn be trained 
in the use of the device by an HCP and an “Information for Use” leaflet.  In the event that 
a caregiver will ultimately administer study drug to the patient in the home setting, the 
caregiver is to be trained.  The upper arm site may be used for caregiver but not patient 
administration of study treatment. 
For the initial four dose administrations of SC etrolizumab/etrolizumab dummy, study 
medication is to be administered under close supervision of the HCP in a setting where 
medications and resuscitation facilities are available.  The first two treatments (each 
0.7 mL delivered via PFS; Week 0 [Day 1] and Week 4) will be administered by the HCP 
and observed by the patient (and/or caregiver).  The following two treatments (Week 8 
and Week 12) will be administered by the patient (or caregiver) and observed by the 
HCP in the clinic setting.  Following the first four study treatment administrations, 
patients will be monitored for acute hypersensitivity reactions for at least 1 hour after the 
end of the injection.  Epinephrine must be readily available at site for immediate use if 
required to treat anaphylaxis.  Adjunctive medications such as parenteral 
diphenhydramine and inhaled bronchodilators may be used IN ADDITION TO 
epinephrine if necessary.  Resuscitation equipment should also be available.  Site 
personnel must be able to detect and treat such reactions.   
Patients with severe hypersensitivity reactions (e.g., stridor, angioedema, life-threatening 
change in vital signs) must be withdrawn from study treatment.  These patients will not 
be eligible to receive open-label etrolizumab in Part 1 (OLE) of Study GA28951 and are 
to enter the 12-week safety follow-up in this study followed by enrollment in Part 2 (SM) 
of Study GA28951 for 92 weeks of extended PML monitoring. 
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 Section 5.1.1.2) (see the Study Manual for 
contact information). 


 
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Following the first four drug administrations (Weeks 0−12) and, therefore, completion of 
the first 3-month training period in a clinical setting, study drug administration (Week 16 
and then Q4W onwards) will be continued in the home setting, by the patient or a 
caregiver, if considered appropriate by the investigator.  Study medication will be 
administered in the patients’ home after return from the clinic visit.  Patients and/or the 
caregiver will be provided with contact information for questions related to 
self-administration between visits.  Competence of the patient or caregiver to administer 
at home will be documented in the site’s source documentation.  Compliance in the 
home setting is to be monitored by use of an e-diary to record drug administration and 
return of used and unused medication syringes (see Appendix 7).  Patients and/or the 
caregiver will be provided with alert cards for themselves and a partner/caregiver, which 
they will be requested to carry at all times.  These will include guidance on recognizing 
allergic/anaphylactic/anaphylactoid reactions and how to obtain emergency care in the 
event such a reaction occurs.  Patients will also be given information regarding the 
recognition of signs and symptoms of PML. 
If the HCP/patient cannot administer study medication on the scheduled dosing day, 
study medication is to be administered within a window of + 3 days from the scheduled 
dosing date.  If the patient experiences a minor illness (e.g., minor infection), at the 
discretion of the investigator, study medication may be delayed for a maximum period of 
2 weeks.  Following the delay, study medication dosing is to be resumed in accordance 
with the original dosing schedule.  Any potential deviation from this window is to be 
discussed with the Medical Monitor for the study. 
If necessary, patients or their HCP may choose to continue administration of study 
medication in the clinic. 
The recommended injection sites are the front of the middle thighs and the lower part of 
the abdomen below the navel except for the 2-inch area directly around the navel.  
Patients should place themselves in a comfortable position before self-administering 
study drug.  As previously recommended, caregivers responsible for administering the 
injection should utilize the outer area of the upper arm, abdomen, or thigh.  Injections 
should never be given into areas where the skin is not intact or is tender, bruised, red, or 
hard.  The injection sites will be inspected by the site personnel at each clinic visit.  Any 
injection-site reactions (including those following an injection in the home setting) (see 
Section 5.1.1.3) should be documented appropriately on the adverse event electronic 
Case Report Form (eCRF) page. Patients administering the SC injection at home should 
be taught to report any injection-site reactions as adverse events (e.g., redness and/or 
swelling). 
Guidelines for treatment interruption or discontinuation are provided in Section 4.8. 


 
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4.4.2.2 
Infliximab and Infliximab Dummy 
In addition to etrolizumab/etrolizumab dummy, patients will receive either infliximab 
(5 mg/kg IV at Weeks 0, 2, and 6, then Q8W) or infliximab dummy IV administered in the 
clinic setting until Week 46.  
For infliximab, an unblinded pharmacist will reconstitute and then dilute the infliximab to 
a dose of 5 mg/kg and a total volume of 250 mL with sterile 0.9% sodium chloride for 
infusion.  The patient will be dosed on the basis of the patient’s weight at baseline.  
Under aseptic conditions, reconstitute each infliximab vial with 10 mL of water for 
injections using a syringe equipped with a 21-gauge (0.8 mm) or smaller needle.  
Remove flip-top from the vial and wipe the top with a 70% alcohol swab.  Insert the 
syringe needle into the vial through the center of the rubber stopper and direct the 
stream of water for injections to the glass wall of the vial.  Gently swirl the solution by 
rotating the vial to dissolve the lyophilized powder.  Avoid prolonged or vigorous 
agitation.  DO NOT SHAKE.  Foaming of the solution on reconstitution is not unusual.  
Allow the reconstituted solution to stand for 5 minutes.  Check that the solution is 
colorless to light yellow and opalescent.  The solution may develop a few fine translucent 
particles, as infliximab is a protein.  Do not use if opaque particles, discoloration, or other 
foreign particles are present. 
Dilute the total volume of the reconstituted infliximab solution dose to 250 mL with 
sodium chloride 9 mg/mL (0.9%) solution for infusion.  This can be accomplished by 
withdrawing a volume of the sodium chloride 9 mg/mL (0.9%) solution for infusion from 
the 250-mL glass bottle or infusion bag equal to the volume of reconstituted infliximab.  
Slowly add the total volume of reconstituted infliximab solution to the 250-mL infusion 
bottle or bag.  Gently mix. 
The infusion is to be administered over a period of not less than 2 hours.  Use only an 
infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 
1.2 µm or less).  Since no preservative is present, it is recommended that the 
administration of the solution for infusion is to be started as soon as possible and within 
3 hours of reconstitution and dilution.  When reconstitution and dilution are performed 
under aseptic conditions, infliximab infusion solution can be used within 24 hours if 
stored at 2oC−8oC.  Do not store any unused portion of the infusion solution for reuse. 
No physical biochemical compatibility studies have been conducted to evaluate the 
co-administration of infliximab with other agents.  Do not infuse infliximab concomitantly 
in the same IV line with other agents. 
Visually inspect infliximab for particulate matter or discoloration prior to administration.  
Do not use if visibly opaque particles, discoloration, or foreign particles are observed. 


 
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Any unused product or waste material should be disposed of in accordance with local 
requirements. 
The infliximab dummy infusion will consist of 250 mL sterile 0.9% sodium chloride 
injection and will also be administered over a period of not less than 2 hours.   
Patients will be monitored during infusion and for 1 to 2 hours after the infusion.  Patients 
and investigators will remain blind to the infliximab study treatment. 
The patient is to be provided with the alert card for infliximab. 
For guidelines for dosage modification and treatment interruption or discontinuation, 
refer to the Infliximab Investigator's Brochure and infliximab SmPC. 
4.4.2.3 
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 
 


 
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Management of Concomitant Medications during the Study 
During Induction Phase (Prior to Week 10): 
Patients are required to maintain stable doses of their concomitant medications (oral 
5-ASA, corticosteroids, immunosuppressants) for UC. 
During Maintenance Phase (After Week 10) 
Corticosteroids 
Patients on corticosteroids from baseline must begin the specified corticosteroid taper at 
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 until discontinuation.  Patients receiving budesonide at study entry should 
taper their dose of 9 mg every day to 9 mg every other day for 2 weeks and then 
discontinue budesonide treatment.  For patients who cannot tolerate the corticosteroid 
taper without recurrence of clinical symptoms of either UC or steroid withdrawal, 
corticosteroid dose may be increased (up to the dose at study entry, if required), but 
tapering must begin again within 2 weeks.  An increase in corticosteroid dose back to 
baseline is not considered rescue medication if it occurs during the corticosteroid taper.  
These patients should remain in the study. 
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 
because of a toxicity related to the medication (see Section 3.1.1 for symptoms of 
toxicity to AZA, 6 MP, or MTX). 
Rescue Therapy That Can Be Given with Study Medication for the 
Treatment of Ulcerative Colitis 
During the Induction Phase (Prior to Week 10):  
Patients are required to maintain stable doses of their concomitant medications (5-ASA, 
corticosteroids, immunosuppressants) for UC. 
In the Induction Phase, any patient who requires initiation of an immunosuppressant 
(AZA, 6-MP, or MTX), corticosteroid, or oral or topical 5-ASA, or increase in dose over 
baseline levels for treatment of worsening disease symptoms, should stay in the blinded 
study.  These patients will be considered non-responders for the Induction timepoint.  
During the Maintenance Phase 
Initiation or escalation of oral 5-ASA should be avoided but is permitted if deemed 
clinically necessary by the investigator.  Patients who initiate or escalate oral 5-ASA 
therapy should continue blinded treatment. 
Use of topical or IV corticosteroids or topical 5-ASA should also be avoided as 
concomitant medication.  However, if these are clinically required to treat symptoms of 


 
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UC, then the patient may either remain in the blinded phase of the study or be given the 
option to enroll in Part 1 (OLE) of Study GA28951, if eligible, based on the investigator’s 
discretion and after completion of the washout phase (see Table 3), including the 
decision to switch to OLE visit and early withdrawal/end of washout visit (see 
Appendix 1). 
Patients who were not receiving corticosteroids at baseline and patients who have 
completed the steroid taper who subsequently receive oral corticosteroids at a dose 
greater than 10 mg for 5 days or longer for the treatment of worsening UC symptoms or 
steroid withdrawal may remain in the blinded study or may be given the option to enroll 
in Part 1 (OLE) of Study GA28951, if eligible, based on the investigator’s discretion and 
after completion of the washout phase (see Table 3), including the decision to switch to 
OLE visit and the early withdrawal/end of washout visit (see Appendix 1). 
Immunosuppressants (AZA, 6-MP, or MTX):  Patients are to remain on their stable 
baseline dose of immunosuppressant therapy throughout the study unless dose 
reduction or discontinuation is required due to toxicity.  Generally accepted criteria for 
discontinuation of immunosuppressants due to toxicity include, but are not limited to, 
acute pancreatitis, severe leukopenia, severe thrombocytopenia, or clinically significant 
elevations of the liver-associated enzymes from baseline, especially in the presence of 
an elevated total bilirubin.  The ultimate decision to reduce dose or discontinue 
immunosuppressants due to toxicity remains at the discretion of the investigator.  
Patients who do initiate or escalate immunosuppressant therapy may remain in the 
blinded study or may be given the option to enter Part 1 (OLE) of Study GA28951, if 
eligible, based on the investigator’s discretion and after completion of the washout phase 
(see Table 3), including the decision to switch to OLE visit and the early withdrawal/end 
of washout visit (see Appendix 1). 
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, 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.  Use 
of anakinra, abatacept, tocilizumab, and other biological therapeutics are also prohibited. 
Patients who receive such therapies are not to receive further study treatment or 
open-label treatment, and will be required to enter 12 weeks of safety follow-up in this 
study (see Appendix 2).  After completion of safety follow-up, these patients will be 
requested to enroll in Part 2 (SM) of Study GA28951 for 92 weeks of extended PML 
monitoring.  


 
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4.4.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(etrolizumab, etrolizumab dummy, and infliximab, will be provided by the Sponsor.  
Infliximab dummy is saline (sodium chloride 9 mg/mL [0.9%]) solution for infusion and 
will not be provided.  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 
infliximab accountability and storage will be conducted by an unblinded study staff 
member.  Infliximab 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 by the patient 
 
All records and drug supplies must be available for inspection by the study monitor. 
4.4.4 
Assessment of Compliance 
Etrolizumab 
Patient compliance will be assessed by maintaining adequate drug dispensing logs, the 
patient e-diary, and return records. 
Etrolizumab/etrolizumab dummy home injection:  An e-diary will be provided to patients 
to record home injections. 
Patients will be asked to return all unused PFSs in the provided boxes at each visit as a 
measure of drug accountability and patient compliance.  Site personnel will monitor the 
medication records from the e-diary via an online portal.  However, patients should also 
bring their e-diary to the clinic during visit. 
Sharps containers for any used PFS will be provided to patients for home usage.  After 
home injections, the used syringes must be placed into the sharps containers 
immediately.  The sharps containers should be returned to sites.  Sharps containers will 
be discarded by the site staff at the frequency per local schedule. 


 
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A Drug Dispensing Log must be kept as described in Section 4.4.3.  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 (see Section 4.4.3).  The investigator's copy of the Drug Return 
Record(s) must accurately document the return of all study drug supplies to Sponsor. 
Infliximab 
A Drug Dispensing Log must be kept as described in Section 4.4.3.  The blinded study 
staff are responsible for ensuring that dosing is administered in compliance with the 
protocol.  When the study is completed, the study staff 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 (see Section 4.4.3).  The investigator's copy of the Drug Return 
Record(s) must accurately document the return of all study drug supplies to Sponsor. 
4.4.5 
Destruction of the Investigational Medicinal Product 
Any used etrolizumab/etrolizumab dummy PFS will be placed into sharps containers 
immediately after SC injections either at site or at home.  Any used needles for infliximab 
infusion will be placed into sharps containers immediately after completion of infusion 
period at the site.  The sharps containers should be discarded at the study site by the 
site staff per local schedule.  Written documentation of destruction of unused study drug 
must contain the following: 
• 
Identity (batch numbers or subject numbers) of IMP(s) destroyed 
• 
Quantity of IMP(s) destroyed 
• 
Date of destruction 
• 
Method of destruction 
• 
Name and signature of responsible person who destroyed investigational product(s). 
 
In case of device failure or if there are any issues with the drug, the 
etrolizumab/etrolizumab dummy PFS should not be destroyed, and instead should be 
returned to the investigator site in the packaging provided for this purpose.  The device 
is to be sent from the investigator site to the appropriate Sponsor’s clinical trial supplies 
department for further assessment (see Section 4.4.3). 


 
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4.4.6 
Reporting of Prefilled Syringe Complaints/Events 
The investigator should report all medical device complaints to the Sponsor.  The 
investigator must document as much information as possible on the PD103 IMP 
deviation form, including product batch number and expiration date, and forward the 
complaint form to the Sponsor within 24 hours of the investigator becoming aware of the 
event.  PD103 IMP deviation form, together with pictures of the defective PFS, should be 
sent to kaiseraugst.global_impcomplaint_management@roche.com. 
Where possible, the investigator will retrieve the PFS unit(s) involved in the complaint 
and attempt to return it to the Sponsor for further assessment, if necessary. 
If the medical device complaint results in an adverse event, an Adverse Event eCRF 
must be completed and submitted through the electronic data capture (EDC) system 
immediately (i.e., no more than 24 hours after learning of the event).  If the event is 
serious, the Adverse Event eCRF must be completed and submitted through the EDC 
immediately (i.e., no more than 24 hours after learning of the event), as outlined in 
Section 5.4.2.  If the medical device complaint results in an adverse event to an 
individual other than the study patient (e.g., nurse at the site or relative/caregiver during 
a home administration), the device complaint must be reported on the PD103 IMP 
Deviation form.  The adverse event must be reported as a spontaneous adverse event 
to the Sponsor (see Section 5.3.5). 
4.5 
CONCOMITANT THERAPY 
4.5.1 
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 (Day 1) to the study 
completion/early termination visit.  All concomitant medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF. 
Patients who use oral contraceptives or maintenance therapy for comorbidities should 
continue their use. 
For concomitant therapy for UC and rescue treatment see Section 4.4.2.3. 
4.5.2 
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 
agents such as AZA and 6-MP 
• 
Use of cyclosporine, tacrolimus, sirolimus, or MMF 
• 
Use of natalizumab, vedolizumab, or rituximab  


 
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• 
Use of TNF-inhibitors (including TNF inhibitor biosimilars) other than infliximab 
(study drug) 
• 
Use of anakinra, abatacept, tocilizumab, and 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 
entered into safety follow-up within this study. 
4.6 
DISEASE WORSENING  
4.6.1 
Definition of Disease Worsening  
Disease worsening is defined as: 
• 
An increase in the pMCS ≥ 3 points from Week 10 AND an absolute pMCS ≥ 5 AND 
an endoscopy subscore of ≥ 2 
• 
OR absolute pMCS ≥ 7 AND an endoscopy subscore of ≥ 2 
 
If a patient meets criteria for disease worsening during the Maintenance Phase of the 
study (Week 10 to Week 54), he or she may withdraw from this study and enroll in Part 1 
(OLE) of Study GA28951, if eligible, after a brief washout phase to receive open-label 
etrolizumab. 
4.7 
STUDY ASSESSMENTS  
4.7.1 
Description of Study Assessments 
4.7.1.1 
Medical History and Demographic Data 
Medical history includes clinically significant diseases and procedures.  All medication 
taken in the 8 weeks prior to randomization (Day 1) (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 5 years prior to 
screening. 
Demographic data including age, sex, whether the patient is a fraternal or identical twin, 
and self-reported race/ethnicity will be collected during the screening period. 
4.7.1.2 
Physical Examinations 
A complete physical examination should include the evaluation of head, eye, ear, nose, 
and throat, and cardiovascular, dermatological, musculoskeletal, respiratory, GI, and 
neurologic systems, including administration of the PML Subjective Checklist and the 
PML Objective Checklist by the investigator (see Appendix 5 for PML assessment 
details and Appendix 6 for PML algorithm).  New or worsened abnormalities from 
screening should be recorded as adverse events if appropriate.  In addition, a 
symptom-driven examination should be conducted as indicated in the Schedule of 
Assessments (see Appendix 1 and Appendix 2). 


 
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4.7.1.3 
Vital Signs 
Vital signs will include measurement of heart rate and systolic and diastolic blood 
pressure, after the patient has been in a seated position for 5 minutes, and are to be 
recorded before study drug administration at clinic visits only at the indicated timepoints 
in Schedule of Assessments (see Appendix 1). 
4.7.1.4 
Ulcerative Colitis Disease Activity Assessments 
Extent and duration of patient’s disease is to be recorded on the eCRF from the patient 
medical records and should include therapies from the last 5 years.  Extent of disease 
should be defined as follows:  1) left-sided colitis (up to the splenic flexure), 2) extensive 
colitis (beyond the splenic flexure but not involving the entire colon), and 3) pancolitis. 
All measurable disease must be documented at screening and re-assessed at each 
subsequent evaluation.  Responses will be assessed by the investigator or designee 
with use of the MCS and pMCS.  The MCS has a range of 0−12, whereas pMCS has 
range 0−9, with higher scores indicating more severe disease.  MCS is a composite of 
four assessments, each rated from 0−3:  stool frequency, rectal bleeding, endoscopy, 
and 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 use and complete 
questions on the e-diary.  The patients’ normal number of stools is to be recorded.  This 
is defined as the number of stools passed when a patient is in remission, not in flare.  
This is to be taken from the most recent available data in the patient’s medical notes or 
taken during patient interview at screening.  
One of the components of the MCS is the endoscopic subscore.  The time window for 
performing endoscopy during the screening is 4−16 days prior to 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 Day 1.  Note that the total screening 
period is up to 35 days (see Section 4.7.2.1 and Appendix 4).  
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/end of 
washout 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. 


 
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Colonoscopy/Flexible Sigmoidoscopy with Colonic Biopsies 
Patients are to prepare their bowel prior to the colonoscopy/flexible sigmoidoscopy 
procedures.  Medications used for bowel preparation should be recorded on concomitant 
medications pages of eCRF. 
Stool samples for analysis of fecal calprotectin and other exploratory biomarkers (such 
as analyses of the microbiota and bacterial cultures) are to be collected prior to bowel 
preparation (polyethylene glycol [PEG]-based preparation or enema). 
Full colonoscopy within a year of screening is required to ensure against enrollment of 
patients with colonic carcinoma and dysplasia.  If full colonoscopy has not been 
performed within the year before screening, it should be conducted in place of the 
flexible sigmoidoscopy at screening.  For patients not requiring a colonoscopy, a flexible 
sigmoidoscopy will be performed on all patients for inclusion in the study.  Endoscopy 
will be performed 4-16 days prior to randomization (Day 1). 
Endoscopy will be also performed at Weeks 10 and 54 and/or at unscheduled visits 
(including the decision to switch to OLE visit) if clinically indicated and/or at withdrawal 
from the study (early withdrawal visit, Appendix 1).  An endoscopy is not required at the 
end of washout visit if an endoscopy was already performed at the decision to switch to 
OLE visit.  
Central reading of endoscopies will be performed throughout this study and a detailed 
charter will address the standardization of endoscopic procedures, video recordings, and 
equipment, as well as the criteria for endoscopic assessment.  For each patient, video 
recording of the entire endoscopic procedure will be performed as specified in the Video 
Submission Guidelines.  All video recordings will be edited by central read vendor to 
produce video clips that are representative of each segment of the colon visualized up to 
the splenic flexure only (rectum, sigmoid, and descending colon).  The video clips will be 
read centrally for mucosal lesions and endoscopic severity by an independent 
gastroenterologist experienced in IBD who is blind to the patient’s clinical activity and 
treatment allocation. The MCS endoscopic subscore is to be determined both locally (at 
the investigator site) and centrally as described above.  Each segment of the colon up to 
the splenic flexure (rectum, sigmoid, and descending colon) will be assigned an 
endoscopic subscore.  The score from the worst affected segment up to the splenic 
flexure is to be used for the MCS calculation, for study conduct, except at post-baseline 
time points, when the sigmoid colon MCS endoscopic subscore will be used if the 
baseline sigmoid colon MCS endoscopic subscore is 2−3.   
In the event that there is a discrepancy between the endoscopic subscore obtained by 
the local versus the central reader, a third read (performed by a second central reader) 
is to be conducted.  From these three endoscopic MCS subscores, the score with which 
two readers agree will be reported as the final overall MCS endoscopic subscore.  If no 
two readers agree on an MCS endoscopic subscore, the median score of the three 


 
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completed reads (i.e., local read, central read #1, and central read #2) will be chosen as 
the final reported overall MCS endoscopic subscore. 
In all cases the video recordings are to be taken prior to biopsy. 
Each patient entered into the study will have colonic biopsies obtained during flexible 
sigmoidoscopy/full colonoscopy as follows.  
At Screening 
A total of five to six paired biopsy samples (10 to 12 samples) will be taken at screening. 
• 
Five paired biopsy samples (10 samples) from the most inflamed area of the colon 
within 20−40 cm from the anal verge (sigmoid colon).   
– 
Three pairs (6 samples) will go into formalin. 
– 
Two pairs (4 samples) will be placed in stabilization buffer (such as RNAlater or 
a similar buffer) and be shipped to a central laboratory for storage at −80°C. 
– 
In U.K. sites ONLY, one of the latter pair of biopsies (two samples) will be placed 
in storage solution and shipped at 4°C to the U.K. laboratory.  
• 
ONLY if there is suspicion for clinically significant CMV colitis, one biopsy sample 
should be taken from the base of an ulcer to evaluate for histological presence of 
CMV but otherwise is not necessary for inclusion in the study.  Analysis should be 
performed locally if possible, or can be sent to a central laboratory if necessary. 
• 
Only if histopathologic confirmation of UC is needed to meet study eligibility, an 
additional biopsy sample can be used for histopathologic confirmation of UC if 
necessary (analysis should be performed locally if possible or can be sent to a 
central laboratory if necessary). 
• 
If neither CMV testing nor histopathologic confirmation of UC is needed, these 
additional 2 biopsy samples should not be obtained. 
 
At Weeks 10 and 54 and/or at early withdrawal visit and/or unscheduled 
visits/decision to switch to OLE visit, if indicated (see Appendix 1) 
Four paired biopsy samples (8 samples) will be obtained at subsequent visits, as 
specified in Appendix 1.  Four paired biopsy samples (8 samples) are to be taken 
from the most inflamed area of the colon within 20−40 cm from the anal verge 
(sigmoid colon, approximately at the same endoscopic depth of the original 
screening endoscopy).  If there is no clearly inflamed area, a blind biopsy should be 
taken.  
– 
Two pairs will go into formalin. 
– 
Two pairs will be placed in stabilization buffer (such as RNAlater or a similar 
buffer) and shipped to a central laboratory for storage at −80 C. 
In U.K. sites ONLY, one of the latter pair of biopsies (two samples) will be 
placed in storage solution and shipped at 4°C to the U.K. laboratory. 
 


 
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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 (see Appendix 5) by a qualified HCP and will be 
performed at screening and as indicated on the Schedule of Assessments. 
During the in-clinic visits, patients will undergo PML monitoring assessments. 
If a patient has a positive finding on the PML Subjective Checklist that is accompanied 
by a positive finding on the PML Objective Checklist or if there is strong clinical suspicion 
for PML, the event should be expeditiously reported as an adverse event of special 
interest within 24 hours (see Section 5.2 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 be resumed only in patients where PML has been 
ruled out.  See Appendix 6 for the Algorithm for Evaluation of Progressive Multifocal 
Leukoencephalopathy. 
After completing the treatment phase of the study, patients not enrolling in Part 1 (OLE) 
of Study GA28951 to receive treatment with open-label etrolizumab will enter the 
12-week safety follow-up in this study (see Appendix 2).  The PML neurologic 
examination is to be performed at Week 12 of this safety follow-up. 


 
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Following 12-week safety follow-up, all patients will be requested to continue to be 
monitored for PML for an additional 92 weeks by enrolling in Part 2 (SM) of Study 
GA28951, thus providing a total of 2 years PML follow-up after the last dose of study 
medication.  During Part 2 (SM) of Study GA28951, patients will not be administered 
study drug.  
The PML extended follow-up period in Study GA28951 will consist of the PML 
assessment interview conducted by telephone at 6-month intervals. 
4.7.1.5 
Laboratory Assessments 
Laboratory assessments will be performed as indicated on the Schedule of 
Assessments; see the Study Flowchart in Appendix 1.  All laboratory investigations will 
be sent to one or more central laboratories for analysis with the exception of CMV.  If 
there is suspicion for clinically significant CMV colitis, a colonic biopsy sample should be 
sent for CMV evaluation, which may be conducted locally depending on local 
requirements for the timing of the test result.  Urine pregnancy testing will also be 
conducted locally or in the home setting.  If a full colonoscopy is required at screening, 
laboratory samples should be drawn prior to the initiation of bowel preparation.   
On days of study drug administration, laboratory samples should be drawn before the 
administration of study drug.  Laboratory assessments will include the following: 
• 
Hematology (hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
absolute count [neutrophils, eosinophils, lymphocytes, monocytes, basophils, other 
cells], mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, and RBC distribution width) 
• 
Serum chemistries, including liver function test (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. 


 
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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 plasma 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) 
• 
C. difficile toxin assay in stool, stool culture and sensitivity testing, and 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 either in 
the clinic or in the home setting.  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 


 
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• 
Anti-therapeutic antibody (ATA) assays 
Serum samples will be collected in subset of patients for the detection and 
characterization of antibodies against etrolizumab, or if necessary, infliximab.  
Samples will be analyzed using a validated assay if possible.  For ATA samples 
without matched PK determinations, etrolizumab or infliximab 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 from 400 patients at selected sites for potential 
determination of etrolizumab concentrations.  Separate informed consents will 
be required for these 400 patients for this PK sample.  Samples will be 
analyzed using a validated assay. 
• 
CMV testing of colonic biopsy if there is suspicion for clinically significant CMV 
colitis 
Baseline colon biopsy (to be obtained at the base of the ulcer) will be analyzed 
for histologic presence of CMV 
• 
Fecal calprotectin 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. 
• 
Exploratory PD biomarker assays 
Peripheral blood, stool, and serum samples will be collected from a subset of 
patients at designated sites (see Appendix 1 for samples to which this applies).  
Colon biopsy sample will be collected from all patients.   
Peripheral blood, serum, stool, and colon biopsy samples will be collected for 
exploratory PD biomarker analysis.  For samples that are to be assessed, 
qualified methods, including, but not limited to, ELISA, IHC, bacterial culture, 
RNA sequencing, and/or qPCR will be utilized.  Biopsy tissue may also be used 
for exploratory determination of drug concentration.  Stool samples may be 
used for assessments that include, but are not limited to, analyses of the 
microbiota and bacterial cultures. 
 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.7.1.10), 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 PK and immunogenicity assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed. 


 
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• 
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. 
 
4.7.1.6 
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. 
4.7.1.7 
Electrocardiograms 
Electrocardiograms (ECGs) for each patient should be obtained from the same machine 
whenever possible.  To minimize variability, it is important that patients be in a resting 
position for ≥ 10 minutes prior to each ECG evaluation.  Body position should be 
consistently maintained for each ECG evaluation to prevent changes in heart rate.  
Environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording.  ECGs should be 
performed prior to meals and any scheduled vital sign measurements and blood draws. 
For safety monitoring purposes, the investigator or designee must review, sign, and date 
all ECG tracings.  Paper copies will be kept as part of the patient's permanent study file 
at the site.  ECG outputs will be stored at site. 
4.7.1.8 
Patient-Reported Outcomes 
Patient-reported outcomes (PROs) (IBDQ, EQ-5D, and the stool frequency and rectal 
bleeding components of the MCS and pMCS), 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 stool frequency and rectal bleeding 
components of the MCS daily from the first screening visit for the patient throughout the 
study. 
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 


 
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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. 
Inflammatory Bowel Disease Questionnaire  
The IBDQ will be used to assess patients’ health-related QOL (Guyatt et al. 1989; 
Irvine 1999).  The 32-item questionnaire contains four domains:  bowel symptoms 
(10 items), systemic symptoms (5 items), emotional function (12 items), and social 
function (5 items).  The items are scored on a 7-point Likert scale with a higher score 
indicating better health-related QOL.  The IBDQ has a recall specification of 2 weeks.  
A copy of the IBDQ is provided in Appendix 9. 
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 as determined by the 
central reading procedure described in Section 4.7.1.4.  The pMCS is a composite of 
three assessments, each rated from 0−3:  stool frequency, rectal bleeding, and PGA.  
The MCS has a range of 0−12 and the pMCS has a range of 0−9.  Higher scores 
indicate more severe disease.  Copies of the MCS and pMCS scoring system are 
provided in Appendix 4. 
EuroQol Five-Dimension Questionnaire 
The EQ-5D is a generic preference-based health-related QOL questionnaire that 
provides a single index value for health status (Rabin and deCharro 2001).  This tool 
includes questions about mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression that are used to build a composite of the patient’s health status.  The 
EQ-5D questionnaire will be utilized in this study for economic modeling.  A copy of the 
assessment is provided in Appendix 10. 
4.7.1.9 
Medication Use and Compliance 
Following each home administration of study medication, the patient is to record the 
location of each injection and whether the injection was successfully administered.  The 
e-diary will automatically collect date and time information for when the patient 
completes the study medication administration report.  Note that details of the study 
medication administration are to be entered directly into the eCRF following clinic 
administrations. 


 
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4.7.1.10 
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 
characteristics of these assays 
 
Approval by the Institutional Review Board or Ethics Committee 
Sampling for the RCR is contingent upon the review and approval of the exploratory 
research and the RCR portion of the Informed Consent Form by each site's Institutional 
Review Board or Ethics Committee (IRB/EC) and, if applicable, an appropriate 
regulatory body.  If a site has not been granted approval for RCR sampling, this section 
of the protocol will not be applicable at that site. 
Sample Collection 
Whole blood (DNA) will be collected for genetic analysis from consenting patients (RCR 
ICF). 
Samples that are obtained for exploratory analysis of biomarkers (listed below) but were 
not utilized or were not entirely consumed will be transferred to the RCR. 


 
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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). 
All biomarker specimens will be subject to the confidentiality standards described in 
Section 8.4.  The genetic biomarker specimens will undergo additional processes to 
ensure confidentiality, as described below. 
Confidentiality 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is “double-coded” by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A “linking key” between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 


 
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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. 
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 GA29103 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 GA29103. 


 
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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. 
4.7.2 
Timing of Study Assessments 
4.7.2.1 
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 randomized patients and for patients who are not subsequently randomized 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 (Day 1) (see Figure 4).  The screening 
period will not exceed 35 calendar days.  
Laboratory samples should be collected from the patient early in the screening period to 
allow time for the laboratory results to be available for review by the site for eligibility 
(see  Section 4.7.1.4).  However, the ECG and chest X-ray can be obtained any time 
before randomization (Day 1) to study medication (see Section 4.7.1.6 and 
Section 4.7.1.7 for additional details on the chest X-ray and ECG).  Colon biopsy 
specimen collection is detailed in Section 4.7.1.4. 
A blood sample to test for antibodies to JCV will be taken and stored for possible later 
assessment of how widespread the JCV infection is in the study population.  Sample 
testing for the presence of JCV antibodies is not helpful in predicting risk for PML or for 
evaluating neurologic symptoms.  The sample may be tested if there is a strong belief 
that this information will be helpful in managing a patient's condition. 
The screening endoscopy for MCS should be performed 4−16 days prior to 
randomization (Day 1) (i.e., Day − 16 to Day − 4).  The endoscopy score from the worst 
affected segment up to the splenic flexure (rectum, sigmoid, and descending colon) is to 
be used for the MCS calculation (see Section 4.7.1.4). 
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 
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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 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 4 Overview of Screening Activities 
 
Note: Endoscopy should be performed 4−16 days prior to randomization (Day 1) 
 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization (Day 1).  The investigator will maintain a 
screening log to record details of all patients screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
4.7.2.1.1 
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. 


 
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4.7.2.1.2 
Re-Screening 
Re-screening is required if a patient has not met all the eligibility criteria within 35 days 
of the original screening visit.  Patients who are found to be ineligible for entry into the 
study may be re-screened once onlyfor example, if the patient develops additional 
manifestations of UC, a worsening of existing manifestations at a later time, if 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 4.7.1.5, 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 
 
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 
sample is required during re-screening evaluation to rule out CMV infection.   
See Appendix 1 for the schedule of screening and pretreatment assessments. 


 
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4.7.2.2 
Assessments during Treatment 
All assessments will be performed on the day of the specified visit, except where a time 
window is specified.  Assessments scheduled on the day of study drug administration 
should be performed prior to dosing, unless otherwise noted.  When study drug 
administration in the home is required on the same day as a clinic visit, drug is to be 
administered at home AFTER the clinic visit. 
For visits that are associated with a MCS requiring endoscopy, every effort should be 
made to schedule the endoscopy on the same day as the clinic visit.  If this is not 
possible, endoscopy should be performed as close to the clinic visit as possible, with a 
maximal window of 3 days prior to and 5 days after the visit.  The endoscopy score 
should be considered when determining the PGA (as applicable), a component of the 
MCS (see Appendix 4). 
On a number of occasions during the Maintenance Phase (see Appendix 1 and Figure 3), 
patients will be contacted by telephone for the purpose of study assessment, rather than 
making a clinic visit.  During these telephone visits, data will be collected as for a clinic 
visit at this time with the exception of blood sample and in-clinic PRO assessments (see 
Appendix 1, Schedule of Assessments).  All adverse events and concomitant 
medications will be recorded and the patient questioned regarding a potential disease 
worsening.  An unscheduled visit is to be conducted as required (see Section 4.7.2.5). 
All patients will receive hands-on training in the 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. 
4.7.2.3 
Assessments at Study Completion/Early Withdrawal/End of 
Washout Visit 
The completion of the study treatment period is defined as the Week 54 visit.  Patients 
who complete the study will be asked to visit the clinic for the Week 54 assessments 
(see Appendix 1).  If a patient leaves the study prior to Week 54, an early withdrawal/end 
of washout visit is to be conducted following infliximab washout, as defined in 
Sections 3.1.1.3 and Section 4.3.  Assessments are specified in the Schedule of 
Assessments (Appendix 1). 
Patients who are eligible and consent to receive open-label etrolizumab in Part 1 (OLE) 
of Study GA28951 are to enroll into Part 1 (OLE) of Study GA28951 directly after the 
Week 54 visit or the early withdrawal/end of washout visit is completed; they do not enter 
the 12-week safety follow-up phase of this study.   
For patients who are not eligible or who choose not to enroll in Part 1 (OLE) of Study 
GA28951, the end of study visit, Week 54, or the early withdrawal/end of washout visit is 


 
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followed by a 12-week safety follow-up phase consisting of one telephone call 6 weeks 
after Week 54, and one clinic visit 12 weeks from Week 54, respectively (see 
Appendix 2).  Patients are to then enroll in Part 2 (SM) of Study GA28951 for extended 
PML follow-up after completion of the 12-week safety follow-up in this study. 
4.7.2.3.1 
Eligibility for Entry to Open-Label Extension-and 
Safety-Monitoring Study 
Study GA28951 will be conducted under a separate protocol and eligible patients as 
described below (also see Table 5) will need to be willing and able to provide separate 
informed consent to enter the study. 
Note:  Patients who are not eligible or who do not wish to receive open-label etrolizumab 
in Part 1 (OLE) of Study GA28951 will be requested to enroll in the 92-week extended 
PML monitoring (Part 2 [SM] of Study GA28951) after completing the 12-week safety 
follow-up in this study. 
The following patients may be eligible to enroll in Part 1 (OLE) of Study GA28951 
after the washout period: 
• 
Patients who meet the criteria for disease worsening (see Section 4.6.1 for definition) 
at any time between Week 10 and Week 54  
• 
All remaining patients at end of Week 54 
• 
Patients who were not receiving corticosteroids at baseline and patients who have 
completed the steroid taper may be eligible for Part 1 (OLE) of Study GA28951 if 
they receive oral corticosteroids at a dose greater than 10 mg for 5 days or longer 
for the treatment of clinical symptoms of either UC or steroid withdrawal during the 
Maintenance Phase. 
• 
Patients who use IV or topical corticosteroids or topical 5-ASA or who initiate or 
escalate dose of oral 5 ASA to treat worsening symptoms of UC in the Maintenance 
Phase 
• 
Patients who require initiation of or an increase in the dose of immunosuppressants 
during the Maintenance Phase 
 
The following patients are NOT eligible to enroll in Part 1 (OLE) of Study GA28951: 
• 
Patients who discontinue study medication prior to Week 10 
• 
Patients who require rescue medications that are prohibited in conjunction with 
etrolizumab (see Section 4.4.2.3) 
• 
Patients with severe hypersensitivity reactions (see Section 4.4.2.1), malignancies, 
specific de novo or reactivated serious viral infections, PML, or other life-threatening 
infections during the study (see Sections 4.8.1.1, 5.1.1.2, 5.1.1.5, and 5.1.1.1)  
 
A complete list of exclusion criteria for the OLE−SM study can be found in protocol 
GA28951. 


 
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Table 5 
Eligibility for Enrollment into Part 1 (OLE) of Study GA28951or Transfer to 12-Week Safety Follow-Up 
Time Period 
Rationale 
May Enroll in Part 1 (OLE) 
of Study GA28951 after 
Washout Period 
Must Transfer to 
12-Week Safety 
Follow-Up 
Day 1 to Week 10 
Discontinuation of study treatment 
No 
Yes  
(transfer after dosing 
termination visit) 
Week 10 to Week 54 Met criteria for disease worsening (see Section 4.6.1) at any 
time between Week 10 and Week 54 
Yes 
Yes (must transfer to SFU if 
patient does not choose 
OLE) 
 
Week 10 to Week 54 Initiation or an increase in dose of immunosuppressants 
Yes 
Day 1 to Week 54 
Use of oral corticosteroids at a dose greater than 10 mg for 
5 days or longer for patients who were not receiving 
corticosteroids at baseline and patients who have completed 
the steroid taper 
Yes 
Day 1 to Week 54 
Use of IV or topical corticosteroids or initiated or escalated 
oral 5 ASA or topical 5-ASA 
Yes 
Day 1 to Week 54 
Patients requiring rescue medications that are prohibited 
(see Section 4.4.2.3) 
No 
Yes  
(transfer after dosing 
termination visit) 
 
Day 1 to Week 54 
Occurrence of severe hypersensitivity reactions (see 
Section 4.4.2.1) malignancies, specific de novo or reactivated 
serious viral infections, PML, or other life-threatening 
infections during the study (see Sections 4.8.1.1, 5.1.1.2, 
5.1.1.4, and 5.1.1.1) 
No 
Week 54 
End of treatment period (all patients remaining in the study 
can transfer) 
Yes (no additional washout 
required) 
Yes (must transfer to 
SFU if patient does not 
choose OLE) 
5-ASA = 5-aminosalicylic acid; IV = intravenous; OLE = open-label extension; SFU = safety follow-up; PML = progressive multifocal 
leukoencephalopathy. 
 


 
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4.7.2.4 
Safety Follow-Up Assessments 
Safety follow-up will be conducted in this study for a period of 12 weeks for patients not 
enrolling in Part 1 (OLE) of Study GA28951 (see Table 5 for patients who should enter 
the 12-week safety follow-up phase within this protocol, Appendix 2).  Patients will be 
assessed at 6-week intervals during this period, one assessment by telephone and one 
in-person clinic visit.  The visits should be scheduled based on the date of the last dose 
of study drug (e.g., the Week 6 telephone visit should take place 6 weeks after the last 
dose of study drug).  Patients enrolling in Part 1 (OLE) of Study GA28951 will not enter 
the 12-week safety follow-up period in this study.  Adverse events should be followed as 
outlined in Section 5.4. 
Following the 12-week safety monitoring period, patients should enroll in Part 2 (SM) of 
Study GA28951, where they will be monitored for PML for an additional 92 weeks.  
Patients enrolling in Part 2 (SM) of Study GA28951 for extended PML monitoring will 
NOT receive treatment with open-label etrolizumab.  During the extended PML follow-up 
period in Study GA28951, patients will have telephone assessments every 6 months to 
assess emergence of symptoms and signs of PML.  In total, follow-up for the 
development of any signs or symptoms of PML will be conducted for a period of 2 years 
after last dose of study drug. 
Patients who do not wish to enter safety follow-up or who discontinue from the study 
during 12-week safety follow-up will be asked to return to the clinic within 30 days 
(± 7 days) after the last scheduled visit for a safety follow-up early termination visit (see 
Appendix 2). 
See Appendix 1 for the schedule of assessments performed at the Week 54 or early 
withdrawal/end of washout visit. 
After the Week 54 or early withdrawal/end of washout visit, adverse events should be 
followed as outlined in Section 5.5 and Section 5.6. 
See Appendix 2 for the schedule of 12-week safety follow-up assessments. 
4.7.2.5 
Assessments at Unscheduled Visits 
An unscheduled visit may occur at any time during the study (i.e., because of 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 disease 
worsening will undergo the following: 
• 
Symptom-directed physical examination 
• 
Vital sign assessment 
• 
Review of e-diary data 
• 
Recording of concomitant medications and procedures 
• 
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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 samples, if indicated 
 
See Appendix 1 for assessments that are to be performed in case of an unscheduled 
visit. 
4.8 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.8.1 
Patient Discontinuation 
The investigator has the right to discontinue a patient from study drug or withdraw a 
patient from the study at any time.  In addition, patients have the right to voluntarily 
discontinue study drug or withdraw from the study at any time for any reason.  Reasons 
for discontinuation of study drug or withdrawal from the study may include, but are not 
limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Patient non-compliance, specifically defined as missing scheduled visits or 
non-adherence with background medications 
 
4.8.1.1 
Discontinuation from Study Drug 
Patients must discontinue study medication (both etrolizumab/etrolizumab dummy and 
infliximab/infliximab dummy) 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 CMV colitis 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 4.5.2) 


 
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Patients who discontinue study drug prematurely for the reasons listed above will be 
asked to return to the clinic for an early withdrawal visit (see Section 4.7.2.3) followed by 
the 12-week safety follow-up.  Patients should then enroll in Part 2 (SM) of Study 
GA28951 to undergo safety follow-up assessments for up to 2 years after the last dose 
of study drug (see Section 4.7.2.4).  The primary reason for premature study drug 
discontinuation must be documented on the appropriate eCRF.  Patients who 
discontinue study drug prematurely will not be replaced. 
4.8.1.2 
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. 
4.8.2 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the study is placed on hold or if the Sponsor 
decides to discontinue the study or development program. 
The Sponsor has the right to replace a site at any time.  Reasons for replacing a site 
may include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
The safety plan for this study is designed to ensure patient safety and mitigate potential 
risks.  The principles of the safety plan include education of investigators and patients 
regarding all identified and potential safety risks, specific eligibility criteria to screen out 
at-risk patients, monitoring to ensure timely identification and management of a safety 
event, and management strategy such as guidelines for treating an event and for 
withholding or discontinuing study treatment, as appropriate.  These principles are to be 
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5.1.1 
Potential Risks for Etrolizumab 
Etrolizumab is an investigational drug that demonstrated a safety profile similar to 
placebo in the Phase II study, EUCALYPTUS.  Given the relatively limited size of 
Phase II studies, the full safety profile is not known at this time and will be further 
characterized during the Etrolizumab Phase III program.   
The potential and/or hypothetical risks for etrolizumab are based on its mechanism of 
action, available nonclinical and clinical data, data from other anti-integrin drugs, and 
general risks associated with biologic agents.   
Investigators should always refer to the Etrolizumab Investigator's Brochure (Section 6) 
for a complete summary of safety information. 
5.1.1.1 
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-α4 integrin natalizumab and immunosuppressives.   
Integrin α4β1, which is inhibited by natalizumab, is a pleiotropic integrin that is believed 
to facilitate T cell migration into the CNS.  Inhibition of integrin α4β1 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 α4β7 integrin and not the α4β1 
integrin, despite extensive treatment exposure (Dotan 2017). 
Etrolizumab targets cells expressing the β7 integrin (α4β7 and αEβ7 cells) and not 
α4β1 cells.  Despite the lack of theoretical or experimental evidence for a specific role of 
β7 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 studies.   
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. 


 
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A plasma 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. 
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 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) should be administered (see 
Appendix 5; PML Subjective and Objective Checklists) 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 to the Sponsor as an 
adverse event of special interest, within 24 hours (see Section 5.2.3 and Appendix 6 for 
the Algorithm for Evaluation of Progressive Multifocal Leukoencephalopathy).   
If PML is suspected, dosing with study treatment for that patient will be suspended and 
the patient should be promptly referred to a neurologist.  Following formal evaluation by 
a neurologist, if PML cannot be ruled out, the case will be referred to an expert PML 
adjudication committee for further work-up, which may include brain MRI with and 
without contrast.  If there remains any suspicion for PML, the PML adjudication 
committee may recommend performing a lumbar puncture with CSF analysis for JCV 
DNA by PCR.  If JCV DNA is detected, the patient should be treated as a PML case and 
the patient should permanently discontinue study drug and enter safety follow-up.  
Dosing with study treatments can be resumed only in patients where PML has been 
ruled out.  See Appendix 6 for the Algorithm for Evaluation of Progressive Multifocal 
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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 patients receiving placebo 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, Clostridium difficile, 
and other intestinal pathogens are excluded from the study (see Exclusion Criteria 
Related to Infection Risk in Section 4.1.2).  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 Exclusion Criteria 
Related to General Safety and Exclusion Criteria Related to Laboratory Values [at 
Screening] in Section 4.1.2). 
Education, Monitoring, and Management 
Patients should be monitored closely for other serious infections during the study.  
Patients and study staff should be informed of the possibility of increased susceptibility 
to infectious pathogens.  Investigators will be encouraged to promptly evaluate and 
aggressively treat any signs and symptoms consistent with an infection.   
Patients who experience a serious infection event should not receive further study drug 
until the event has completely resolved and treatment with anti-infective medications has 
been completed.  All efforts should be made to identify the infectious agent.  For those 
patients who recover from a serious infection, study drug may be restarted following 
consultation with the Medical Monitor.   
Patients who develop life-threatening infections, including specific de novo or reactivated 
serious viral infection such as HBV, HCV, HIV, during the study should discontinue study 
drug.  Any patient who develops CMV colitis should not receive further study drug until 
the event has resolved and treatment with appropriate anti-viral medication has been 
completed.  Re-initiation of therapy requires consultation with the Medical Monitor. 
5.1.1.2 
Hypersensitivity Reactions 
Background 
In completed Phase I/II clinical studies 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 
The first four injections should be administered in the clinic.  After each of these four 
injections, the patient must be monitored for 60 minutes.  Epinephrine must be readily 
available at site or 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 a HCP or seek immediate care 
in case of any such symptoms.  Patients are to be provided with alert cards to remind 
them and a caregiver or partner of the above. 
If the patient develops any systemic hypersensitivity or anaphylactic or anaphylactoid 
reaction, the event should be expeditiously reported to the Sponsor as an adverse event 
of special interest or serious adverse event, as appropriate, within 24 hours. 
If a patient has symptoms of anaphylaxis or severe hypersensitivity, the administration of 
etrolizumab must be discontinued permanently.  
See 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 studies 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 when administering drug at home or after the patient leaves the 
clinic. 
5.1.1.4 
Hepatic Effects 
Background 
Liver toxicity has been reported with other drugs that target α4 integrins (natalizumab) 
and α4β7 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 studies and nonclinical studies to date.  Nonetheless, 
given the elevated risk of malignancy in this patient population a priori, the study 
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 Exclusion Criteria Related to General History in 
Section 4.1.2).  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 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 
(Day 1) 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 Infliximab 
Investigators should be aware of the risks associated with infliximab and their 
management (see Infliximab Summary of Product Characteristics). 
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.  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.  See Section 4.7.2.5 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.   
Rescue therapy not permitted in conjunction with study drug include treatment with TNF 
inhibitors, cyclosporine, tacrolimus, sirolimus, MMF, natalizumab, vedolizumab, 
rituximab, other lymphocyte-depleting agents (except AZA and 6-MP), anakinra, 
abatacept, or other biological or investigational therapeutics 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 into the safety monitoring portion (Part 2 [SM]) of Study 
GA28951.  If a patient meets criteria for disease worsening (see Section 4.6.1) or 
requires the use of permitted rescue therapy, they may be eligible to enroll in Part 1 
(OLE) of Study GA28951) after a period of infliximab washout (see Table 3).  Patients 
who do not enter the Part 1 (OLE) of Study GA28951 will be requested to continue in 
safety follow-up followed by enrollment into the safety monitoring portion (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 International Council for Harmonisation (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) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Fatal (i.e., the adverse event actually causes or leads to death) 
• 
Life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that had it occurred in a more severe 
form, or was allowed to continue, might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 


 
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• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] criteria; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
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). 
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. 


 
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• 
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) 
Neurologic signs, symptoms, and adverse events that may suggest possible 
PML on the basis of a positive finding on the PML Subjective Checklist that is 
accompanied by a positive finding on the PML Objective Checklist, or if there is 
strong clinical suspicion for PML (see Appendix 6 and Section 5.1.1.1.1) 
 
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 ). 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsy sample collections, discontinuation of medications) should be 
reported (see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events, regardless of relationship to study drug, 
will be reported until the patient completes his or her last study visit.  After this period, for 
patients who enter Study GA28951, adverse event reporting should follow requirements 
of Study GA28951. 
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). 


 
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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?” 
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4. 0) will be used for 
assessing adverse event severity.  Table 6 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 6 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 


 
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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 (also 
see Table 7): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non−treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 7 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria as specified 
below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.  
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 


 
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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 at injection site) and symptoms (e.g., pain at injection site) rather than a 
diagnosis of allergic reaction or injection-site reaction. 
Other Adverse Events  
For adverse events other than injection-site reactions, a diagnosis (if known) should be 
recorded on the Adverse Event eCRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the Adverse Event eCRF.  If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  Medically significant adverse events occurring 
secondary to an initiating event that are separated in time should be recorded as 
independent events on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should be recorded only once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 


 
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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. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholecystitis), only the 
diagnosis (i.e., cholecystitis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).   


 
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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. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF, (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × ULN, in combination with total bilirubin 
> 2 × ULN  
• 
Treatment-emergent ALT or AST > 3 × ULN, in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.7 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of UC. 


 
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Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
If the death is attributed to progression of UC, "ulcerative colitis progression” should be 
recorded on the Adverse Event eCRF. 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
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 


 
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• 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration) 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease. 
The patient has not suffered an adverse event. 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse 
event instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.11 
Adverse Events Associated with an Overdose or Error in Study 
Drug Administration 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  An overdose or error in administration of study drug is not 
an adverse event unless it results in untoward medical effects. 
Any study drug overdose or error in administration of study drug (e.g., dosing outside of 
the allowed window or injection without completion of full volume administration) should 
be noted on the Study Drug Administration eCRF. 
All adverse events associated with an overdose or error in administration of study drug 
(e.g., dosing outside of the allowed window or injection without completion of full volume 
administration) should be recorded on the Adverse Event eCRF.  If the associated 
adverse event fulfills serious criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.3.5.12 
Electronic Patient-Reported Outcome Data 
Adverse event reports will not be derived from electronic Patient-Reported Outcome 
(ePRO) data by the Sponsor, and safety analyses will not be performed using ePRO 
data.  Sites are not expected to review the ePRO data for adverse events. 


 
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5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events (see Section 5.4.2 for further details) 
• 
Adverse events of special interest (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
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. 


 
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5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators. 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until the patient completes his or her last study visit.  
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the EDC system.  A report will be generated and sent to Roche Safety Risk 
Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form with use of 
the fax numbers or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system. 
Instructions for reporting serious adverse events that occur after the final dose of study 
treatment are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 24 weeks after the final 
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators. Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  


 
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In addition, the investigator will submit a paper Clinical Trial Pregnancy Reporting Form 
when updated information on the course and outcome of the pregnancy 
becomes available. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
24 weeks after the final dose of study drug.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.   
When permitted by the site, the pregnant partner would need to sign an Authorization for 
Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy.  If the authorization has been signed, the investigator should submit a paper 
Clinical Trial 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 4.4.6 for reporting requirements for medical devices. 


 
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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 study-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome.   
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
For patients who enter Study GA28951, adverse event reporting should follow the 
requirements for Study GA28951.  
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 numbers or 
email address provided to investigators. 


 
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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 (Identified Risks and Adverse Drug Reactions [Reference Safety 
Information]).  
 
To determine reporting requirements for single adverse event cases for infliximab, the 
Sponsor will assess the expectedness of these events using the reference safety 
information in the E.U. SmPC for infliximab. 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
All serious related (as assessed by the investigator and/or Sponsor) adverse events 
occurring in a patient administered etrolizumab at any time during the study and 
assessed as unexpected per the reference safety information will be considered 
Suspected Unexpected Serious Adverse Reactions (SUSARs) for the purpose of 
regulatory reporting to all health authorities, with the exception of the FDA.  For the FDA, 
SUSARs will be submitted as IND Safety Reports in line with the FDA guidance “Safety 
Reporting Requirements for INDs and BA/BE Studies” dated December 2012.   
The Sponsor will report all SUSARs into the EudraVigilance database in accordance 
with the ”Detailed guidance on the collection, verification and presentation of adverse 
event/reaction reports arising from clinical trials on medicinal products for human use 
(‘CT-3’).” 
To satisfy local regulatory reporting criteria while maintaining the blind, investigators will 
be informed of all unexpected serious adverse events regardless of study drug 
assignment (i.e., they may also receive reports of patients on placebo). 


 
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6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The analysis of data from the 54-week treatment period will be performed when all data 
from this period are in the database and data have been cleaned and verified.   
Sponsor personnel will be unblinded to treatment assignment to perform the primary 
Week 54 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.  
Detailed specifications of the statistical methods will be described in the Statistical 
Analysis Plan (SAP). 
6.1 
DETERMINATION OF SAMPLE SIZE 
Approximately 390 patients will be randomized in a 1:1 ratio to etrolizumab + infliximab 
dummy or infliximab + etrolizumab dummy.  The sample size of 195 patients per group 
provides approximately 80% power to detect a clinically meaningful difference of 12% 
(18% vs 30%) between the two groups for the primary endpoint, using a two-sided χ2 
test at a significance level of 0.05.   
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 each 
study period) will be tabulated by treatment arm.  Reasons for premature study drug 
discontinuation or withdrawal from study, any eligibility criteria deviations and other 
major protocol deviations will be summarized by treatment arm. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics such as age, sex, race, region, use of 
corticosteroids and immunosuppressants at baseline, duration of disease and baseline 
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) and comparator (infliximab/infliximab dummy) will 
be summarized by treatment arm. 
Baseline is defined as the last assessment prior to the initiation of study treatment. 
6.4 
EFFICACY ANALYSES 
The primary and secondary efficacy analyses will include all randomized patients who 
received at least one dose of study drug with patients grouped according to the 
treatment assigned at randomization (Day 1) (intent-to-treat [ITT] population).  A 
per-protocol population will be defined in the SAP for the purpose of testing for 
non-inferiority in induction of clinical remission at Week 10.  


 
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To manage the overall type I error, the testing of hypotheses will be performed 
sequentially.  The primary endpoint will be tested first at an overall two-sided 
significance level of α = 0.05.  The testing hierarchy for the secondary endpoints will be 
described in the SAP.  
Unless otherwise noted, analyses of efficacy outcome measures will be stratified by the 
stratification factors used at randomization (Day 1):  baseline corticosteroids use 
(yes/no), baseline immunosuppressants use (yes/no), and baseline disease severity as 
measured during screening (MCS ≤ 9 vs. MCS ≥ 10). 
Patients who are non-evaluable for efficacy at a specific timepoint (e.g., due to missing 
data or early transfer to the Part 1 (OLE) of Study GA28951) will be considered 
non-responders for all response/remission type endpoints.  In addition, initiation of an 
agent not allowed in combination with etrolizumab or infliximab, an immunosuppressant, 
oral or topical 5-ASA (up to Week 10), or corticosteroid, or increase in dose over 
baseline levels for treatment of worsening disease symptoms as defined in 
Section 3.1.1.1 will lead to non-responder classification thereafter.   
For continuous outcomes, 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 6.4.1 and Section 6.4.2, the following 
analyses will be performed for the primary efficacy endpoint and key secondary efficacy 
endpoints.  Details of these analyses will be described in the SAP: 
• 
Sensitivity analyses to evaluate the robustness of results to the primary analysis 
methods (e.g., handling of dropouts) 
• 
Subgroup analyses to evaluate the consistency of results across prespecified 
subgroups (e.g., based on age, sex, race/ethnicity, baseline UC medications, 
baseline CS dose) 
 
6.4.1 
Primary Efficacy Endpoints 
The primary efficacy endpoint is the proportion of patients achieving both clinical 
response at Week 10 and clinical remission at Week 54.  
The primary endpoint will be compared between the etrolizumab and infliximab arms by 
using the Cochran-Mantel-Haenszel test statistic, stratified by the factors used at 
randomization (Day 1).  The absolute difference in remission rates and 95% CI for the 
point estimate will be provided. 
Further details will be included in the SAP.  


 
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6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints for this study are as follows: 
• 
Proportion of patients achieving clinical remission at Week 10 
• 
Proportion of patients achieving clinical remission at Week 54 
• 
Proportion of patients achieving clinical remission at both Week 10 and Week 54 
• 
Proportion of patients achieving clinical remission at Week 54 among patients with 
a clinical response at Week 10 
• 
Proportion of patients achieving improvement in endoscopic appearance of the 
mucosa at Week 10 
• 
Proportion of patients achieving improvement in endoscopic appearance of the 
mucosa at Week 54 
• 
Proportion of patients achieving improvement in endoscopic appearance of the 
mucosa at both Week 10 and Week 54 
• 
Proportion of patients in endoscopic remission at Week 54 
• 
Proportion of patients achieving clinical response at Week 10 
• 
Proportion of patients achieving clinical response at both Week 10 and Week 54 
• 
Proportion of patients in corticosteroid-free (off corticosteroid for at least 24 weeks 
prior to Week 54) clinical remission at Week 54 in patients who were receiving 
corticosteroids at baseline 
• 
Change from baseline in patients’ health-related QOL at Weeks 10, 30, and 54 as 
assessed by the overall score of the IBDQ 
 
Induction of remission will be evaluated at Week 10.  Remission is defined as an 
MCS ≤ 2, with no individual score > 1 and a rectal bleeding subscore of 0.  
For secondary responder type endpoints, superiority will be assessed in the same 
fashion as for the primary endpoint.  
A 95% two-sided CI will be constructed for the difference in clinical remission rates at 
Week 10 between the two groups (etrolizumab minus infliximab).  If the lower limit of the 
CI is ≥ 12.5%, it will be inferred that etrolizumab is non-inferior to infliximab for induction 
of clinical remission at Week 10.  If the lower limit of the CI is > 0%, it will be inferred that 
etrolizumab is superior to infliximab for induction of clinical remission at Week 10.  
Continuous endpoints will be analyzed using an analysis of covariance (ANCOVA) 
model, adjusting for baseline score, and the stratification factors used at randomization 
(Day 1).  
Further details will be provided in the SAP.  


 
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6.4.3 
Exploratory Efficacy Endpoints  
• 
Proportion of patients achieving remission at Week 10 
• 
Proportion of patients achieving remission at Week 54 
• 
Proportion of patients achieving remission at both Week 10 and Week 54 
• 
Change in health utilities, as assessed by EQ-5D, from baseline to weeks 10, 30, 
and 54 
• 
Frequency and duration of hospitalizations from baseline to Week 54 
 
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. 
6.5.1 
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, 
or, if required, infliximab at baseline and during the study will be tabulated by treatment 
arm. 
6.5.2 
Adverse Events 
Verbatim descriptions of treatment-emergent adverse events will be coded, and their 
incidence will be summarized by treatment arm, as appropriate.  A treatment-emergent 
adverse event is defined as any new adverse event reported or any worsening of an 
existing condition on or after the first dose of study drug.  In addition, separate 
summaries will be generated for serious adverse events, deaths, and adverse events 
leading to discontinuation of study drug.  Adverse events will be summarized by mapped 
term, appropriate thesaurus level, and toxicity grade. 
Analyses will be performed for: 
• 
Systemic hypersensitivity events 
Specific analyses will be performed for anaphylactic reactions using the 
anaphylactic reaction Sampson’s criteria (see Appendix 8). 
• 
Serious infections 
The frequency of serious infections, in particular GI infections, will be 
summarized for each treatment arm. 
• 
Opportunistic infections 
The occurrence of opportunistic infections will be summarized for each 
treatment arm. 


 
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• 
Malignancies 
Events that occur in the Neoplasms, Benign, Malignant, and Unspecified 
(Including Cysts and Polyps) System Organ Class will also be summarized for 
each treatment arm.  
• 
Injection-site reactions 
The frequency of injection-site reactions will be summarized for each treatment 
arm. 
 
6.6 
PHARMACOKINETIC, PHARMACODYNAMIC, AND 
BIOMARKER ANALYSES 
For PK assessment (PK substudy on approximately 200 etrolizumab-treated patients), 
group average serum−etrolizumab concentration versus time data will be tabulated and 
plotted.  The serum PKs of etrolizumab will be summarized at Week 12 and at Weeks 10, 
30, and 54.  Estimates for these parameters will be tabulated and summarized (mean, 
standard deviation, coefficient of variation, median, minimum, and maximum). 
Additional PK analyses may be conducted as appropriate. 
Biomarker analyses will include examination of the relationship between baseline 
biomarkers and response to treatment at Week 10 and Week 54, and of changes relative 
to baseline in exploratory biomarkers during and at end of treatment.  Results will be 
summarized descriptively. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
Sponsor, contract research organization (CRO), and Data Management vendor will be 
responsible for the data management of this study, including quality checking of the data.  
Sites will be responsible for data entry into an eCRF via the EDC system.  In the event of 
discrepant data, data queries will be issued to the sites and resolved by the sites via the 
EDC system.  The Sponsor will produce an EDC Study Specification document that 
describes the quality checking to be performed on the data.  In addition, eCRF Help Text 
will be provided to the sites through the EDC system.  eCRFs and correction 
documentation will be maintained in the EDC system’s audit trail. 
Central laboratory data will be transferred directly to the Sponsor, with use of the 
Sponsor’s standard procedures to handle and process the electronic transfer of these 
data. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and have access to the Help Text in Medidata RAVE for appropriate eCRF 
completion.  eCRFs will be submitted electronically to the Sponsor and should be 
handled in accordance with instructions from the Sponsor. 


 
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All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
Patient-reported data will be collected electronically through use of electronic devices 
provided by an ePRO vendor.  The electronic 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 SDV 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, 
ECGs, MRIs, patient files, and records kept at pharmacies, laboratories, and 
medico-technical departments involved in a clinical trial. 


 
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Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate SDV, 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 (including PRO) data, 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 


 
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ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the EU/EEA will comply 
with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the “Consent Forms”) before IRB/EC 
submission.  The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a patient's agreement to allow 
any remaining specimens to be used for exploratory research.  Patients who decline to 
participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
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. 


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


 
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Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient last visit). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, which include an audit trail containing a complete record of all changes 
to data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 


 
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9.4 
ADMINISTRATIVE STRUCTURE 
This study is sponsored by F. Hoffmann−La Roche Ltd.  Approximately 200 international 
study centers will participate in this study to enroll approximately 390 patients. 
A CRO will be contracted to manage the study and perform monitoring activities. 
Centralized facilities (vendors) will be used to collect endoscopy reading and 
interpretation; however, the investigator or a designee will also read the endoscopy as 
part of the MCS evaluation. 
A central laboratory (i.e., Roche or a vendor) will be used for most laboratory 
assessments.  A selected group of assessments will be performed on site or by a local 
laboratory and urine pregnancy tests will be conducted by the patient at home if 
appropriate. 
The eCRF data will be recorded via a Sponsor-designated EDC system.  An IxRS will be 
used for study drug inventory management and to randomize patients to study drug. 
An iDMC will be established to perform regular review of the safety data to ensure the 
ongoing safety of participating patients.  Its composition and a description of its 
responsibilities will be provided in an iDMC charter. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Website:   
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.   


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


 
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10. 
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Appendix 1  
Schedule of Assessments 
Assessment 
Clinic Visit Schedule 
(Etrolizumab/Etrolizumab 
Dummy Administration in Clinic) 
Weeks (± 3 days) 
Clinic Visit/Telephone Contact Schedule  
(Etrolizumab/Etrolizumab Dummy Administration at Home) 
UV/ 
D-OLE b 
EW/ 
WO 
 
SD −35 to −1 
0 c 
2 
4 
6 
8 
10 
12 
14 
16 18 d 20 
22 
24 26 d 28 
30 
32 34 d 36 
38 
40 42 d 46 
48 50 d 52 
54 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review eligibility criteria 
x e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test f 
x 
x 
 
x 
 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Vital signs  
(BP and pulse) 
x 
x 
 
x 
 
x 
 
 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
x 
x 
 
x 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Chest X-ray g 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination h 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
x b 
x 
PML neurologic 
examination i 
x 
 
 
x 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x b 
x 
Hematology 
x 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x b 
x j 


Appendix 1  
Schedule of Assessments (cont.) 
 
Etrolizumab—F. Hoffmann-La Roche Ltd 
133/Protocol GA29103, Version 7 
Assessment 
Clinic Visit Schedule 
(Etrolizumab/Etrolizumab 
Dummy Administration in Clinic) 
Weeks (± 3 days) 
Clinic Visit/Telephone Contact Schedule  
(Etrolizumab/Etrolizumab Dummy Administration at Home) 
UV/ 
D-OLE b 
EW/ 
WO 
 
SD −35 to −1 
0 c 
2 
4 
6 
8 
10 
12 
14 
16 18 d 20 
22 
24 26 d 28 
30 
32 34 d 36 
38 
40 42 d 46 
48 50 d 52 
54 
Chemistry 
x 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x b 
x j 
Urinalysis 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x b 
 
TB screen k 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV test 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C 
serology l 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B DNA m 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
Hepatitis C RNA 
(Amplicor) n 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sampling (serum) o, p 
 
x 
x 
 
 
 
x 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
x b 
x j 
Anti-therapeutic ant body 
sample 
(serum) o, p, q 
 
x 
 
x 
 
 
x 
x o 
 
 
 
 
 
 
 
 
x o 
 
 
 
 
 
 
 
 
 
 
x r 
x b 
x j r 
Plasma sample (storage 
for JCV antibody testing) 
s  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 1  
Schedule of Assessments (cont.) 
 
Etrolizumab—F. Hoffmann-La Roche Ltd 
134/Protocol GA29103, Version 7 
Assessment 
Clinic Visit Schedule 
(Etrolizumab/Etrolizumab 
Dummy Administration in Clinic) 
Weeks (± 3 days) 
Clinic Visit/Telephone Contact Schedule  
(Etrolizumab/Etrolizumab Dummy Administration at Home) 
UV/ 
D-OLE b 
EW/ 
WO 
 
SD −35 to −1 
0 c 
2 
4 
6 
8 
10 
12 
14 
16 18 d 20 
22 
24 26 d 28 
30 
32 34 d 36 
38 
40 42 d 46 
48 50 d 52 
54 
MCS (includes  
endoscopy) t, u 
x v 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x b 
x j, gg 
pMCS (excludes  
endoscopy)  u, w 
 
x v 
 
x 
 
x 
 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
x b 
x j 
Stool sample collection 
x x 
x y 
 
 
 
 
x y 
 
 
 
 
 
 
 
 
 
x y 
 
 
 
 
 
 
 
 
 
 
x y 
x b 
x y 
Colonic biopsy (CMV if 
required) 
x z 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x b 
 
Colonic biopsy 
(histopathological 
confirmation of UC if 
required) 
x aa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Colonic biopsies 
(formalin)  
x bb 
 
 
 
 
 
x cc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x cc 
x b, cc 
x j, cc, gg 
Colonic biopsies (for 
qPCR) 
x bb 
 
 
 
 
 
x cc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x cc 
x b, cc 
x j, cc, gg 
Serum sample (CRP) p 
 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x b 
x j 
Serum sample (future 
exploratory PD) o, p 
 
x 
x 
 
 
 
x 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
x 


Appendix 1  
Schedule of Assessments (cont.) 
 
Etrolizumab—F. Hoffmann-La Roche Ltd 
135/Protocol GA29103, Version 7 
Assessment 
Clinic Visit Schedule 
(Etrolizumab/Etrolizumab 
Dummy Administration in Clinic) 
Weeks (± 3 days) 
Clinic Visit/Telephone Contact Schedule  
(Etrolizumab/Etrolizumab Dummy Administration at Home) 
UV/ 
D-OLE b 
EW/ 
WO 
 
SD −35 to −1 
0 c 
2 
4 
6 
8 
10 
12 
14 
16 18 d 20 
22 
24 26 d 28 
30 
32 34 d 36 
38 
40 42 d 46 
48 50 d 52 
54 
Blood sample (RNA 
Paxgene) o, p, dd 
 
x 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Whole blood (EDTA) 
optional p 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IBDQ ee 
 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
EQ-5D ee 
 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Infliximab/ 
infliximab dummy 
administration 
 
x 
x 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
Etrolizumab/ 
etrolizumab dummy 
administration 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
x 
 
x 
 
 
 
 


Appendix 1  
Schedule of Assessments (cont.) 
 
Etrolizumab—F. Hoffmann-La Roche Ltd 
136/Protocol GA29103, Version 7 
Ab = antibody; ATA = anti-therapeutic antibody; BP = blood pressure; CMV = cytomegalovirus; CRP = C-reactive protein; D-OLE = decision to switch to 
OLE; ECG = electrocardiogram; EQ-5D = EuroQoL Five-Dimension Questionnaire; eCRF = electronic case report form; EW = early withdrawal; 
HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IBDQ = Inflammatory Bowel Disease Questionnaire; 
JCV = John Cunningham virus; MCS = Mayo Clinic Score; PD = pharmacodynamics; PK = pharmacokinetic; pMCS = partial Mayo Clinic Score; 
PML = progressive multifocal leukoencephalopathy; qPCR = quantitative polymerase chain reaction; SD = screening day; TB = tuberculosis; 
UC = ulcerative colitis; UV = unscheduled visit; WO = washout. 
Notes: 
– 
Study assessments and blood draws are to be conducted prior to study drug administration 
– 
All colonic biopsy samples will be taken during flexible sigmoidoscopy/colonoscopy procedure. 
– 
Etrolizumab administration at home for eligible patients on Weeks: 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (negative urine pregnancy test, 
preferably performed in home setting, required prior to administration) 
a All assessments must be performed after obtaining informed consent.  Endoscopy is to be performed 4−16 days prior to randomization (Day 1).  The 
total screening period is 35 days. Under no circumstances will either window be extended. 
b Unscheduled visit (including decision to switch to OLE) represents a visit that is not as per schedule of assessment and is required for an adverse 
event or for potential disease worsening 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 disease worsening is performed by the Mayo Clinic Score 
assessment).  Assessments corresponding to items noted in this column should be recorded on the eCRF.  Refer to Table 3 for details regarding 
washout and timing of enrollment in Part 1 (OLE) of Study GA28951. 
c Day 1 of Week 0. 
d Telephone contact for patients performing home administration:  patients requiring in-clinic drug administration throughout the study will have their 
study assessments conducted in clinic or via telephone call after their clinic visit at the sites’ discretion. 
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 have had a hysterectomy.  Urine test at 
other visits; if urine test is positive, perform a confirmatory serum test.  Pregnancy test will be carried out at home once patient starts etrolizumab 
administration at home.  Patient is to report the pregnancy test via e-diary. Patients must be instructed at screening and reminded throughout the 
study that in case of positive pregnancy test they must stop self-administration of study drug and call the site immediately.  Do not administer 
etrolizumab unless the serum pregnancy test result is negative.  After Week 12, pregnancy tests to be performed prior to administration and 
preferably in home setting at Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52. 
g Not required if normal chest X–ray result within 3 months prior to screening.  


Appendix 1  
Schedule of Assessments (cont.) 
 
Etrolizumab—F. Hoffmann-La Roche Ltd 
137/Protocol GA29103, Version 7 
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 or decision to switch to OLE (Part 1) and assessment was 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 aka 
Mantoux test), INF-γ based test (e.g., QuantiFERON-TB Gold). 
l Patients must undergo screening for HBV and HCV.  This includes testing for HBsAG (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 only when the patient has a known history of HCV antibody positivity with 
past documentation of undetectable HCV RNA, either with or without history of anti-viral treatment.  Patients with newly diagnosed HCV antibody 
positivity are not eligible for this study, and therefore do not require measurement of HCV RNA. 
o Samples to be collected from a subset of patients (approximately 400 at designated sites) for PK (all scheduled timepoints), ATA (indicated times) 
and exploratory PD assessment (all scheduled timepoints).  ATA samples at baseline Week 0, Week 10, and Week 54 are to be collected from all 
patients and all ATA samples may be used for exploratory PD and/or PK assessment. 
p Samples are to be collected prior to dose administration (blood, serum, colonic biopsies). 
q 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. 
r 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). 
s 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. 
t Endoscopy + rectal bleeding assessment + stool frequency assessment + Physician’s Global Assessment.  Patients who have not undergone full 
colonoscopy with documented results within one year prior to screening should undergo colonoscopy in lieu or sigmoidoscopy at the screening 
visit to allow for screening for cancer/dysplasia (yes/no).  Rectal bleeding and stool frequency to be collected daily on e-diary. 
u During screening, patients must be trained on the use of the e-diary.  Patients are to complete the e-diary on a daily basis for the stool frequency 
and rectal bleeding score (for MCS/pMCS) from first screening visit.  


Appendix 1  
Schedule of Assessments (cont.) 
 
Etrolizumab—F. Hoffmann-La Roche Ltd 
138/Protocol GA29103, Version 7 
v Partial MCS during screening is defined as the MCS score excluding the endoscopy score.  Screening endoscopy (for the MCS) is to be 
performed between 4−16 days prior to randomization (Day 1) (i.e., Day −16 to Day −4.  For baseline measurements, the Physician's Global 
Assessment will be obtained only once, on Day 1 (prior to randomization [Day 1)]), and the Physician’s Global Assessment score will be used to 
calculate both the baseline (screening) MCS and the baseline (Day 1) pMCS. 
w Rectal bleeding assessment + stool frequency assessment + Physician’s Global Assessment.  Rectal bleeding and stool frequency to be collected 
daily on e-diary.  
x For culture and sensitivity testing; ova, parasites, and Clostridium difficile toxin testing. 
y Sample analyses may include, but are not limited to, analyses of fecal calprotectin, and other exploratory PD biomarkers (such as analyses of the 
microbiota and bacterial cultures). 
z 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.   
aa 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. 
bb In addition to the optional biopsy noted in footnote “z” and “aa” above, five pairs (10 biopsy samples) will be obtained at screening (all taken from 
the most inflamed area of colon within 20−40 cm of anal verge [sigmoid]).  These five biopsy pairs will be sent to the central laboratory for further 
storage or distribution.  Two pairs will be placed in stabilization buffer (such as RNAlater or a similar buffer) and stored at −80°C (one pair for 
diagnostic qPCR and one pair for PD biomarkers qPCR).  In the United Kingdom (U.K.) sites only, one of the latter pair of biopsies (two samples) 
will be placed in storage solution and shipped at 4°C to the U.K. laboratory.  The other three pairs will be placed in formalin and then paraffin 
embedded; these biopsy samples will be used for exploratory PD biomarkers and/or diagnostic biomarkers.  Original biopsy location and 
endoscopic depth should be clearly indicated. 
cc A total of four pairs (8 biopsy samples) will be obtained from all patients (all taken from the most inflamed area of colon within 20−40 cm of anal 
verge [sigmoid]).  All will be sent to the central laboratory for further storage or distribution.  Two pairs will be placed in a stabilization buffer (such 
as RNAlater or a similar buffer) and stored at −80°C for exploratory PD biomarker and/or diagnostic biomarker qPCR. 
In the U.K. sites only, one of the latter pair of biopsies (two samples) will be placed in storage solution and shipped at 4°C to the U.K. laboratory. 
The other two pairs will be placed in formalin and then paraffin; these biopsy samples will be used for exploratory PD biomarkers and/or diagnostic 
biomarkers.  Original biopsy location and endoscopic depth should be clearly indicated. 
dd Paxgene blood RNA samples must be collected after all other blood and serum samples. 
ee With the exception of Week 0, the IBDQ and EQ-5D will be completed in-clinic by the patient before any other non-PRO assessments and before 
the patient receives any disease-status information or study drug during that visit. 


Appendix 1  
Schedule of Assessments (cont.) 
 
Etrolizumab—F. Hoffmann-La Roche Ltd 
139/Protocol GA29103, Version 7 
ff Where indicated, patients must be instructed to administer study drug at home within 3 days (maximum) after clinic visit. 
gg 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 
140/Protocol GA29103, Version 7 
Appendix 2  
12-Week Safety Follow-Up 
Assessment 
Week (± 3 days) 
Unscheduled Visit c 
6 a 
12/Early Termination b 
ECG 
 
x 
 
PML neurologic examination d 
 
x 
 
PD sampling (serum) e 
 
x 
 
PK sampling (serum) e 
 
x 
 
Anti-therapeutic antibody sample 
(serum) f 
 
x 
 
Medication changes 
x 
x 
x 
Adverse events 
x 
x 
x 
ATA = anti-therapeutic antibody; ECG = electrocardiogram; PK = pharmacokinetic; 
PD = pharmacodynamic; PML = progressive multifocal leukoencephalopathy. 
a Week 6 study assessments are to be made by telephone call and not by clinic visit. 
b Denotes early termination visit from safety follow-up period. 
c Unscheduled visit for safety monitoring. 
d PML neurologic examination consists of the PML Subjective Checklist and the PML Objective 
Checklist. Administer before other assessments as per Appendix 5. 
e Samples taken from the 400-patient subset at designated sites. 
f Samples taken from all patients and whenever serum sickness is suspected.  Samples may be 
used for PK and/or exploratory PD assessments. 
 
 


 
Etrolizumab—F. Hoffmann-La Roche Ltd 
141/Protocol GA29103, Version 7 
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 
• 
Sole sexual partner consisting of surgically sterilized male partner with appropriate 
postsurgical verification of the absence of spermatozoa in the ejaculate 


 
Etrolizumab—F. Hoffmann-La Roche Ltd 
142/Protocol GA29103, Version 7 
Appendix 3  
Childbearing Potential, Pregnancy Testing, and Contraception 
(cont.) 
• 
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 
143/Protocol GA29103, Version 7 
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 
144/Protocol GA29103, Version 7 
DATA COLLECTION REQUIREMENTS  
Data will be collected on e-diary and other electronic media; during conversion to 
these media the format of the questions may change  
• 
A CRITICAL DATA POINT TAKEN AT BASELINE IS THE PATIENT’S NORMAL 
NUMBER OF STOOLS.  This is defined as the number of stool passed when a 
patient is in remission/not in flare.  This is to be taken from the most recent available 
data in the patient’s medical notes or taken during patient interview at screening.  
This value will remain stable throughout the study. 
• 
Normal number of stools is to be rounded up (e.g., normal number of stools = 1−2 
would be rounded to 2)  
• 
The NORMAL number of stools is to be recorded on the e-diary and made visible to 
the patient to assist with their scoring relative to this number  
NOTE:  Data recorded during bowel preparation procedures and day of endoscopy 
is to be ignored (bowel preparation and endoscopy procedure days are to be loaded 
into the e-diary by the patient and excluded from the MCS calculation). 
 
1. 
Stool frequency  
• 
Stool frequency is to be recorded daily from start of screening to the end of the 
study in the e-diary  
• 
The stool frequency is to be compared with the normal 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 
145/Protocol GA29103, Version 7 
• 
For patients undergoing re-screening who meet the criteria to waive the endoscopy 
(see Section 4.7.2.1.2 ), 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) of the three most recent stool 
frequency scores that were entered in the e-diary within the 7 days prior to the clinic 
visit (and prior to the days devoted to bowel preparation and endoscopy.  
 
2. 
Rectal bleeding  
• 
Rectal bleeding is to be recorded daily from screening to the end of the study in the 
e-diary.  
• 
The rectal bleeding score is to be categorized from 0−3 according to the definition 
given in 2 above.  
• 
Patients are to be instructed to ignore any blood that is caused by menstruation or 
hemorrhoids.  
• 
The baseline value for the rectal bleeding score will be taken from patient e-diary 
recordings that are entered between Day −22 (inclusive) and bowel preparation for 
the screening endoscopy and will be determined by the worst recording from the 
three most recent scores that were entered just prior to the day of bowel preparation.  
However, up to three post-endoscopy scores, starting with the score recorded 2 
days after the endoscopy, may be used to calculate baseline rectal bleeding, but 
ONLY when fewer than three scores are available between Day −22 and bowel 
preparation (see Figure 1 below).  The days selected for this calculation are 
intended to prevent the use of rectal bleeding recordings during the screening 
period that are impacted by bowel preparation and endoscopy, including the day 
immediately following the endoscopy. 
• 
For patients undergoing re-screening who meet the criteria to waive the endoscopy 
(see Section 4.7.2.1.2),, 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 
146/Protocol GA29103, Version 7 
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 
147/Protocol GA29103, Version 7 
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 Disease Worsening 
Disease worsening is defined as an increase in pMCS ≥ 3 points compared to 
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 
148/Protocol GA29103, Version 7 
Figure 1 Derivation of Stool Frequency and Rectal Bleeding Subscores at Screening 
 


Appendix 4  
Mayo Clinic Score Measurement (cont.) 
 
Etrolizumab—F. Hoffmann-La Roche Ltd 
149/Protocol GA29103, Version 7 
MCS = Mayo Clinic Score; RND = randomization; RB = rectal bleeding; SF = stool frequency. 
 
Notes: 
• 
If 3 days of e-diary data are available between Day −22 (inclusive) and bowel preparation, use e-diary data from the 3 most recent days prior 
to the bowel preparation day. 
• 
Up to 3 days of post-endoscopy e-diary data, starting 2 days after the endoscopy, may be used, but ONLY when < 3 days of e-diary data are 
available between Day −22 and bowel preparation. 
• 
If 2 days of e-diary data are available between Day −22 and bowel preparation, use those data and supplement with data from the first 
available e-diary entry after the endoscopy, starting 2 days after the endoscopy. 
• 
If 1 day of e-diary data is available between Day −22 and bowel preparation, use those data and supplement with data from the first two 
available e-diary entries after the endoscopy, starting 2 days after the endoscopy. 
• 
If 0 days of e-diary data are available between Day −22 and bowel preparation, use data from the first three available e-diary entries after the 
endoscopy, starting 2 days after the endoscopy. 
 
Derivation of stool frequency and rectal bleeding subscores at re-screening in circumstances where a second endoscopy is 
not required: 
In cases of screen failure, patients whose endoscopy was performed during screening will not undergo a second endoscopic 
procedure at re-screening, provided this was performed within 28 days from the new enrollment day and all endoscopy-related 
inclusion criteria have been met (see Section 4.7.2.1.2).  For these patients, the RB and SF e-diary data will be taken from the 3 most 
recent 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 
150/Protocol GA29103, Version 7 
PARTIAL MAYO CLINIC SCORE 
The partial Mayo Clinic Score is identical to the Mayo Clinic Score BUT EXCLUDES THE 
ENDOSCOPY SUBSCORE 
• 
Timepoints for partial Mayo Clinic Score can be found in the protocol schedule of 
assessments 
Partial MCS is also required at time of suspected clinical relapse.  If partial MCS 
≥ 3 points compared to Week 10 AND absolute partial MCS ≥ 5 an endoscopy would 
be conducted and endoscopy subscore and full MCS calculated 
 
E-DIARY MALFUNCTION OR LOSS 
The help desk for the e-diary vendor (CRF Health) should be contacted in the event of 
e-diary malfunction or loss.  Until a working e-diary can be provided to the patient, site 
staff should, after the e-diary malfunction or loss, retrospectively collect the previous 
day's stool frequency and rectal bleeding subscores from the patient via telephone 
interview within the next working day following the e-diary failure or loss.  These data 
will then be transcribed into a data clarification form within CRF Health’s TrialManager 
system for approval. 
 
REFERENCE 
Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for 
mildly to moderately active ulcerative colitis: a randomized study. N Engl J Med 
1987;317:1625−9). 
 
 


 
Etrolizumab—F. Hoffmann-La Roche Ltd 
151/Protocol GA29103, Version 7 
Appendix 5  
PML Subjective and Objective Checklists 
PML SUBJECTIVE AND OBJECTIVE CHECKLISTS OF NEUROLOGIC 
ASSESSMENTS TO MONITOR FOR PROGRESSIVE MULTIFOCAL 
LEUKOENCEPHALOPATHY (PML) IN THE ETROLIZUMAB PHASE III STUDIES 
PML usually manifests with subacute, progressive neurologic deficits including: 
Neurologic Domain 
Signs/Symptoms 
Relevant PML 
Subjective/Objective 
Checklist Question 
Altered mental status 
Can encompass a variety of presenting signs 
and symptoms including cognitive changes 
(confusion, difficulty concentrating, memory loss) 
and altered behavior (including personality 
changes) 
Q2, Q5, Q6 
Higher cortical dysfunction Impaired comprehension and/or formulation of 
language (aphasia), loss of ability to recognize 
objects, persons, sounds, shapes, or smells 
(agnosia) 
Q2, Q5, Q6 
Visual changes 
Loss of visual fields (homonymous 
hemianopsia), double vision (diplopia) 
Q1 
Motor deficits 
Weakness (hemiparesis or monoparesis), 
seizures (generalized or partial), difficulties with 
speech (dysarthria) or swallowing (dysphagia) 
Q2, Q3 
Sensory deficits 
Sensory loss (i.e. paresthesia) 
Q7 
Coordination 
Difficulty walking and maintaining balance 
(ataxia), lack of voluntary coordination of limb 
movement (limb ataxia) 
Q4 
 
In order to monitor patients for PML, a neurologic exam (including evaluation of cranial 
nerves, motor and sensory function, coordination, and mental status) will be performed 
as per the 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  
PML Subjective and Objective Checklists (cont.)  
Etrolizumab—F. Hoffmann-La Roche Ltd 
152/Protocol GA29103, Version 7 
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  
PML Subjective and Objective Checklists (cont.)  
Etrolizumab—F. Hoffmann-La Roche Ltd 
153/Protocol GA29103, Version 7 
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  
PML Subjective and Objective Checklists (cont.)  
Etrolizumab—F. Hoffmann-La Roche Ltd 
154/Protocol GA29103, Version 7 
Please refer to the PML Algorithm in the Protocol Appendix for details. 
• 
If there is an abnormal finding on the PML Subjective Checklist, this should be 
appropriately documented on the worksheet and in the eCRF. 
• 
If there is an abnormal finding on the PML Objective Checklist, this should be 
appropriately documented on the worksheet and in the eCRF. 
• 
If there are any abnormalities found on the PML Subjective Checklist that are 
accompanied by the corresponding abnormality on the PML Objective Checklist, or if 
there is high clinical suspicion for PML (in the opinion of the investigator): 
 This must be reported as an adverse event of special interest (AESI) within 
24 hours 
 An urgent referral to a neurologist should be made. 
 Dosing with study drug will be suspended until PML can be ruled out. 
 Further evaluation will proceed according to the PML Algorithm in the 
Protocol Appendix. 
 Any confirmed diagnosis of PML should be reported as a serious adverse 
event (SAE). 
 
Please complete the PML eCRF. 
Was the PML Subjective Checklist administered? (Yes/No) 
If yes, date of administration of PML Subjective Checklist (Date) 
If yes, were there any abnormalities on the PML Subjective Checklist? (Yes/No)  
Was the PML Objective Checklist administered? (Yes/No) 
If yes, were there any abnormalities on the PML Objective Checklist? (Yes/No)  
Is PML suspected? (Yes/No) 
 


Appendix 5  
PML Subjective and Objective Checklists (cont.)  
Etrolizumab—F. Hoffmann-La Roche Ltd 
155/Protocol GA29103, Version 7 
More detailed instructions for the PML Objective Checklist Neurologic Evaluations 
(please refer to the PML Neurologic Exam Video for more information): 
1.  Visual fields and ocular motility 
Visual Field Testing: 
• 
Position yourself approximately 3 feet away from the patient, with eyes at the same 
level. 
• 
Keeping both eyes open, ask the patient to cover one eye and ask if all parts of your 
face and head are clear to them. Ask them to repeat, covering the other eye. 
• 
Have the patient cover one eye and stare at your nose, and then ask them how 
many fingers you are holding up, testing each of the 4 visual quadrants. Repeat with 
the other eye covered. 
 
Ocular Motility Testing: 
• 
Evaluate the patient for conjugate eye movement. 
• 
Starting about 3 feet from center, move in a big “H”, pausing at the center and at 
lateral gaze, and finishing with convergence (finger to their nose). Watch for 
nystagmus in lateral gaze, smooth pursuits, and pupillary constriction with 
convergence. Note: a couple of beats of nystagmus upon extreme lateral gaze is 
considered normal. 
 
2.  Speech 
• 
Observe the patient’s speech output for dysarthria or aphasia. 
• 
Dysarthria is a motor speech disorder.  Findings can include “slurred” speech, 
decreased volume, slow rate of speech, limited tongue, lip, and jaw movement, 
abnormal rhythm when speaking, changes in vocal quality, and drooling or poor 
control of saliva. 
• 
Aphasia is a disorder that results from damage to parts of the brain that control 
language, and can lead to problems with any or all of the following: speaking, 
listening, reading or writing. 
 
3.  Strength 
Pronator drift test (Barre maneuver): 
• 
Ask the patient to stand with their feet together and extend their arms out in front of 
them at 90 degrees (parallel to floor) with palms facing upwards toward the ceiling. 
• 
Ask the patient to close their eyes and keep their arms extended for 15 seconds. 
• 
If either arm drifts downward, upward, or starts to pronate (i.e. thumb turns up), this 
is considered an abnormal exam. 
 


Appendix 5  
PML Subjective and Objective Checklists (cont.)  
Etrolizumab—F. Hoffmann-La Roche Ltd 
156/Protocol GA29103, Version 7 
Gait testing: 
• 
Ask the patient to walk across the room (~10 feet).  The patient should have a 
normal gait, with their left arm swinging forward when the right foot leads, and vice 
versa.  Be certain to note whether there is symmetric arm swinging, because a 
slight decrease in arm swinging may be an indicator of upper extremity weakness. 
• 
Ask the patient to walk on their heels across the room (~10 feet). Carefully observe 
whether they have any difficulty maintaining their toes off the ground or loss of 
balance. 
• 
Ask the patient to walk on their toes across the room (~10 feet). Carefully observe if 
they have any difficulty maintaining their heels off the ground or loss of balance. 
 
Additional strength testing (ONLY if the patient has any subjective complaints of 
weakness): 
• 
Test muscle strength of the relevant muscle groups based on the patient’s 
subjective complaints. 
• 
General guidelines for a basic muscle strength exam: 
• 
Upper extremity: 
o 
Finger grip strength 
o 
Flexion at elbow 
o 
Extension at elbow 
o 
Deltoid strength: Maintain bent arms up (perpendicular to floor) and 
resist while investigator pushes down 
o 
Shoulder shrug against resistance 
• 
Lower extremity: (examine while patient is sitting down) 
o Raise thigh (while bent) 
o Straighten leg 
o Flex leg 
o Flex foot 
o Extend foot 
 
4.  Coordination 
Tandem gait: 
• 
As the patient is looking at his feet, ask them to walk 8 steps with one foot touching 
in front of the other (demonstrate for them). 
 


Appendix 5  
PML Subjective and Objective Checklists (cont.)  
Etrolizumab—F. Hoffmann-La Roche Ltd 
157/Protocol GA29103, Version 7 
Finger to nose: 
• 
Hold your finger out so they need to reach out and lean. Start near the center, and 
move your finger slowly so that they reach across their body. Make sure they 
alternate touching your finger and their nose at a good speed. Inability to perform 
this accurately is considered an abnormal test. 
 
5.  Comprehension 
• 
Test ability to follow serial commands 
• 
“Take a piece of paper in your hand, fold it in half, and put it on the floor.” 
 
6.  Memory and Thinking 
• 
(ONLY if the patient has subjective complaints about their memory or thinking) test 
the ability of the patient to recall 3 objects over 1 minute with distraction. 
 
7.  Sensation 
• 
(ONLY if the patient has subjective sensory complaints) evaluate relevant areas 
based on the patient’s subjective complaints by comparing left vs. right side 
sensation to cold (e.g. alcohol swab or cold stethoscope) or pinprick (e.g. broken 
Q-tip). Confirm that the patient is able to feel the sensation symmetrically. 
 
 
 




 
Etrolizumab—F. Hoffmann-La Roche Ltd 
159/Protocol GA29103, Version 7 
Appendix 7  
Patient Daily Diary  
 
 


 
Etrolizumab—F. Hoffmann-La Roche Ltd 
160/Protocol GA29103, Version 7 
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. 


 
Etrolizumab—F. Hoffmann-La Roche Ltd 
161/Protocol GA29103, Version 7 
Appendix 9  
Quality of Life in Inflammatory Bowel Disease Questionnaire 
(IBDQ) 
 






 
Etrolizumab—F. Hoffmann-La Roche Ltd 
164/Protocol GA29103, Version 7 
Appendix 10  
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
165/Protocol GA29103, Version 7
Etrolizumab—F. Hoffmann-La Roche Ltd


By placing a checkmark in one box in each group below, please indicate which 
statements best describe your own health state today.
Mobility
I have no problems in walking about

I have some problems in walking about

I am confined to bed

Self-Care
I have no problems with self-care

I have some problems washing or dressing myself

I am unable to wash or dress myself

Usual Activities (e.g. work, study, housework, family or
leisure activities)
I have no problems with performing my usual activities

I have some problems with performing my usual activities

I am unable to perform my usual activities

Pain/Discomfort
I have no pain or discomfort

I have moderate pain or discomfort

I have extreme pain or discomfort

Anxiety/Depression
I am not anxious or depressed

I am moderately anxious or depressed

I am extremely anxious or depressed

© 1998 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group
166/Protocol GA29103, Version 7
Etrolizumab—F. Hoffmann-La Roche Ltd



SAP_001.pdf: 
 
Official Title: 
Phase III, Randomized, Multicenter Double-Blind, Double Dummy 
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 
NCT Number: 
NCT02136069 
Document Dates: 
SAP Amendment 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 GA29103
STATISTICAL ANALYSIS PLAN
TITLE:
PHASE III, RANDOMIZED, MULTICENTER, 
DOUBLE-BLIND, DOUBLE-DUMMY 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
PROTOCOL NUMBER:
GA29103 (Gardenia)
STUDY DRUG:
Etrolizumab
VERSION NUMBER:
3
IND NUMBER:
100366
EUDRACT NUMBER:
2013-004282-14
SPONSOR:
F. Hoffmann-La Roche Ltd.
PLAN PREPARED BY:
 M.Sc.
, 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 14:26:34
Company Signatory


Etrolizumab—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan GA29103
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE FOR VERSION 3

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 4.4.4 (Sensitivity Analyses) to add additional sensitivity 
analyses for key secondary endpoints as applicable.

Changes to Appendix 4 (Per Protocol Population [Exclusion Criteria]) were made to 
update the list of protocol deviations specified for exclusion from the per protocol 
population.
Additional minor changes have been made to improve clarity and consistency.


Etrolizumab—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan GA29103
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
2.3.1
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
Per Protocol Population......................................................... 10
4.1.3
Safety Population .................................................................. 10
4.1.4
Pharmacokinetic (PK)-Evaluable Population ......................... 10
4.2
Analysis of Study Conduct..................................................... 10
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
Clinical Responders and Clinical Remission 
Definition................................................................................ 13
4.4.2
Secondary Efficacy Endpoints............................................... 13
4.4.2.1
Control of Type I Error ........................................................... 13
4.4.2.2
Clinical Remission ................................................................. 14


Etrolizumab—F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan GA29103
4.4.2.3
Improvement in Endoscopic Appearance of the 
Mucosa.................................................................................. 15
4.4.2.4
Endoscopic Remission .......................................................... 15
4.4.2.5
Corticosteroid-Free Clinical Remission at 
Week 54 (Off Corticosteroid for At Least 
24 Weeks Prior to Week 54) in Patients Who 
Were Receiving Corticosteroids at Baseline.......................... 16
4.4.2.6
Clinical Remission at Week 54 Among patients 
with Clinical Response at Week 10 ....................................... 16
4.4.2.7
Clinical Response.................................................................. 16
4.4.2.8
Inflammatory Bowel Disease Questionnaire 
(IBDQ) ................................................................................... 16
4.4.3
Exploratory Efficacy Endpoints.............................................. 17
4.4.4
Sensitivity Analyses............................................................... 17
4.4.5
Supplementary Analyses....................................................... 18
4.4.6
Subgroup Analyses ............................................................... 18
4.5
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 18
4.6
Safety Analyses..................................................................... 18
4.6.1
Exposure of Study Medication............................................... 18
4.6.2
Adverse Events ..................................................................... 18
4.6.3
Laboratory Data..................................................................... 18
4.6.4
Vital Signs.............................................................................. 18
4.6.5
Concomitant Medications, ..................................................... 18
4.6.6
Medical History...................................................................... 18
4.7
Missing Data.......................................................................... 19
4.8
Interim Analyses .................................................................... 19
5.
REFERENCES ........................................................................................... 19
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 8
Figure 2
Multiple Testing Procedure for Endpoints ................................... 14


Etrolizumab—F. Hoffmann-La Roche Ltd
5/Statistical Analysis Plan GA29103
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 20
Appendix 2
Schedule of Assessments........................................................... 32
Appendix 3
Rescue Therapy.......................................................................... 39
Appendix 4
Per Protocol Population (Exclusion Criteria) ............................... 40


Etrolizumab—F. Hoffmann-La Roche Ltd
6/Statistical Analysis Plan GA29103
GLOSSARY OF ABBREVIATIONS
AE adverse event
CCOD clinical cutoff date
CI confidence interval
CMH Cochran Mantel Haenszel
CS corticosteroids
ES Endoscopic Subscore
Etro etrolizumab
IBDQ Inflammatory Bowel Disease Questionnaire
ICE intercurrent event
INFX infliximab
IxRS interactive voice/web based response system
MCS Mayo Clinic Score
mITT modified intent-to-treat
mMCS modified Mayo Clinic Score
OLE open-label extension
PBO placebo
PK pharmacokinetic
pMCS partial Mayo Clinic Score
PP per protocol
SAP Statistical Analysis Plan
SM safety monitoring
TNF tumor necrosis factor
UC ulcerative colitis


Etrolizumab—F. Hoffmann-La Roche Ltd
7/Statistical Analysis Plan GA29103
1.
BACKGROUND
This Statistical Analysis Plan (SAP) describes the analyses to be performed for 
Study GA29103.  Study GA29103 is part of a large Phase III development program for 
etrolizumab.  Details which are common among Studies GA28950, GA29102, GA28948, 
GA28949, and GA29103 are described in the project SAP.
Study GA29103 is a treat-through induction and maintenance study; however, given the 
treat-through design, the study will not be reported in two distinct Induction and 
Maintenance Phases (in contrast to the GA28950 and GA29102 etrolizumab studies 
which incorporate the randomized withdrawal Maintenance Phase).  Therefore patients 
are not required to reach clinical response criteria to be entered into the Maintenance 
Phase.
The study will be reported once data from the Week 54 treatment period has been 
collected in the database and data have been cleaned and verified.  This will be referred 
to as the primary analysis.
2.
STUDY DESIGN
Study GA29103 is a multicenter, Phase III, double-blind, head-to-head study evaluating 
the safety, efficacy, and tolerability of etrolizumab compared to infliximab. The 
population is made up of moderate to severe ulcerative colitis (UC) patients who are 
naive to tumor necrosis factor (TNF) inhibitors (see Figure 1).




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2.3
DETERMINATION OF SAMPLE SIZE
2.3.1
Sample Size
Approximately 390 patients will be randomized in a 1:1 ratio to 
etrolizumab infliximab dummy or infliximab etrolizumab dummy.  The sample size of 
N≈195 patients per group provides approximately 80% power to detect a clinically 
meaningful difference of 12% (18% vs. 30%) between the two groups for the primary 
endpoint of proportion of patients with clinical response at Week 10 and clinical 
remission at Week 54, using a two-sided test at a significance level of 0.05.
2.4
ANALYSIS TIMING
The primary analysis will be conducted once the last patients visit to completed their 
Week 54 treatment period or discontinue from the study treatment has been conducted.  
The date associated with this visit will be termed the clinical cutoff date (CCOD) for the 
primary analysis, and data in the study database to the CCOD will be cleaned and 
verified.  Sponsor personnel will be unblinded to treatment assignment to perform the 
primary analysis.  Patients and study site personnel will remain blinded to individual 
treatment assignment until after the study is completed (after all patients have either 
completed the safety follow-up periods or discontinued early from the study) and the 
database is locked.
Additional analyses will be conducted once all patients have completed 12-week safety 
follow-up and the database has been locked.  These analyses will report all adverse 
events (AEs) including the data collected in the 12-week safety followup period.
3.
STUDY CONDUCT
3.1
RANDOMIZATION
Details of the randomization process are included in the project SAP, Section 3.1.  The 
statistical analyses will be conducted using the stratification factors entered into the 
interactive voice/web based response system (IxRS) system at randomization.  
Sensitivity analysis of the primary endpoints using data collected in the clinical database 
will be conducted as required, if the database does not match IxRS due to incorrect 
stratification data being collected in IxRS at randomization.  Due to low or zero counts in 
any one stratum, the stratification factors may need to be combined or removed in the 
primary analysis to ensure the Cochran-Mantel-Haenszel (CMH) test is not invalidated.
Patients were randomized at baseline to etrolizumabinfliximab dummy or 
infliximabetrolizumab dummy using a 1:1 ratio and a permuted blocks stratified 
randomization (dynamically generated).  Patients were stratified using the following 
stratification factors:

Concomitant treatment with corticosteroids (CS) at baseline (yes/no)

Concomitant treatment with immunosuppressants at baseline (yes/no)

Disease activity at screening (Mayo Clinic Score [MCS] 9/MCS 10)


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3.2
INDEPENDENT REVIEW FACILITY
Details are included in the project SAP, Section 3.2.
3.3
DATA MONITORING
Details are included in the project SAP, Section 3.3.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
4.1.1
Modified Intent-to-Treat (mITT) Population
Efficacy analyses will be performed using a modified intent-to-treat (mITT) analysis 
population including all patients randomized into the study who received at least one 
dose of study drug with patients grouped according to the treatment assigned at 
randomization.
To allow consistency across the program, the mITT population is being used.  This 
differs to terminology in the Protocol Version 7, Section 6.4, which uses intent-to-treat 
population.  The definition of the population has not changed from what is in the protocol.
4.1.2
Per Protocol Population
The per-protocol (PP) population is defined as the subset of the mITT population 
excluding major protocol deviations which may impact the efficacy outcome at Week 10.  
The list of protocol deviations leading to exclusion from the PP population can be found 
in Appendix 4.
4.1.3
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.
4.1.4
Pharmacokinetic (PK)-Evaluable Population
The PK evaluable population includes patients who have received at least one dose of 
study drug and have at least one quantifiable concentration measured post baseline.
4.2
ANALYSIS OF STUDY CONDUCT
All data available in the database up to the point the last patient has completed their 
Week 54 visit will be included to evaluate study conduct.  This will include all available 
data from at the time of cutoff for the primary analysis.  The following analyses will be 
performed to evaluate the study conduct:

Summary of protocol deviations

Summaries of mITT, PK-evaluable, and PP and safety populations, including 
numbers of patients in each population


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
Summary of patient disposition, including the number of doses received, the number 
of patients experiencing disease worsening, reasons for patients withdrawing from 
the study and from study treatment, and number of patients taking study treatment 
and number of patients taking rescue therapy treatment
Disease worsening can be determined between and including Week 10 and Week 54 if 
there is 

An increase in the partial Mayo Clinic Score (pMCS)3 points from Week 10 and an 
absolute pMCS5 AND an endoscopic subscore of 2,
OR

absolute pMCS7 AND an endoscopic subscore of 2
Details of the pMCS assessment are available in the project SAP in Section 4.4.2.1.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Details are included in the project SAP, Section 4.3.
4.4
EFFICACY ANALYSIS
All statistical hypotheses for the primary and key secondary endpoints will be evaluated 
under a multiple testing procedure to ensure an overall type I error no greater than 5%.  
Details on this testing procedure are provided in Section 4.4.3.
All comparisons between the etrolizumab and infliximab arms for binary 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 effect 
(estimands) is described for the primary treatment effect in Section 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 54) 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]), these patients’ data will be set to missing. Handling of 
missing data is described in the project SAP, Section 4.8.

Use of rescue therapy: Increased or new background medications compared to 
baseline for the treatment of UC is considered rescue therapy.  Rescue therapy use 
is described in the protocol and also summarized in Appendix 3.  All patients 
receiving permitted rescue therapy during the study will be asked to continue the 
study through endpoint assessment and safety follow-up.  All patients receiving 


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prohibited rescue therapy during the Week 54 treatment period will be asked to 
enter safety follow-up, with no assessment of any future Week 10 or Week 54 
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) 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: Clinical response at Week 10 and clinical remission at Week 54.
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 infliximab treatment groups.
4.4.1.2
Primary Efficacy Endpoint
The primary efficacy endpoint is the difference in the proportion of patients in clinical 
response at Week 10 and clinical remission at Week 54 between the etrolizumab and 
infliximab treatment patients.
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The calculation will be done within treatment groups using the mITT population
Null hypothesis H0:  EtroINFX0; the proportion of patients achieving clinical 
response at Week 10 and clinical remission at Week 54 in the infliximab arm is the same 
as the proportion of patients achieving clinical response and clinical remission in the 
respective etrolizumab arm.


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Alternative hypothesis H1:  EtroINFX ≠0; the proportion of patients achieving 
clinical response at Week 10 and clinical remission at Week 54 in the infliximab arm is 
not the same as the proportion of patients achieving clinical response and clinical 
remission in the respective etrolizumab arm.
4.4.1.3
Clinical Responders and Clinical Remission Definition
Details of clinical responder and clinical remission and definition are provided in the 
project SAP, Section 4.4.2.1.4.
4.4.2
Secondary Efficacy Endpoints
4.4.2.1
Control of Type I Error
The primary and key secondary endpoints (Figure 2) will be evaluated in a hierarchical 
manner with multiplicity control via multistage gatekeeping under the truncated Holm 
multiple testing procedure (Dmitrienko et al. 2008).  In Families 1 and 2 of key secondary 
endpoints, the same truncation parameter value of 0.5 will be applied; no truncation is 
applied in Family 3, since it is prioritized lowest in the hierarchy and imposes no 
gatekeeping restrictions on subsequent families.  The truncation parameter and the 
relative effect sizes of the endpoints influence how power is balanced over the 
secondary endpoint families.  Truncation parameter values close to 1 should generally 
be chosen when the effect sizes in high-priority endpoints are relatively large in order to 
maximize overall power.  In other settings where the effect sizes might be smaller or 
mixed, a truncation parameter value closer to 0 could improve overall power.  A 
parameter value strictly less than 1 in testing families that impose parallel gatekeeping 
(i.e., at least one endpoint is considered statistically significant after multiplicity 
adjustment in order to test the next family) is needed to achieve strong overall type I 
error control (Dmitrienko et al. 2009).
Under this multistage gatekeeping approach, multiplicity-adjusted p-values will reflect the 
gatekeeping restrictions depicted in Figure 2 In particular, the adjusted p-values for all 
key secondary endpoints in Families 1, 2, and 3 will be no smaller than the p-value for
the primary endpoint.  Similarly, the smallest adjusted p-value in Family 2 (3) will be no 
smaller than the smallest adjusted p-value in Family 1 (2).  Endpoints for which the 
multiplicity-adjusted p-value is greater than 5%1 will not be considered statistically 
significant.  These endpoints and all endpoints not under multiplicity control will be 
considered to provide supportive information.  By repeated application of Proposition 4.1
of Dmitrienko et al. (2008), this testing strategy ensures that the overall type I error is no 
greater than 5%.
                                           
1 The non-inferiority endpoint in Family 2 will be compared against 2.5%.  Further details on this one-sided 
test and handling of both one
-
sided and tw
o-
sided p
-
values are deferred to Section 4.4.2.2
.


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Figure 2
Multiple Testing Procedure for Endpoints
Hierarchy
Endpoints
Primary

Clinical response at Week 10 and clinical remission at Week 54
Success on primary endpoint
Key secondary
(Family 1)

Endoscopic improvement of the Mucosa at Week 54

Endoscopic remission at Week 54

Clinical remission at Week 54
Success on at least one endpoint
(Family 2)

Corticosteroid-free (off corticosteroid for at least 24 weeks prior to 
Week 54) clinical remission at Week 54 in patients who were 
receiving corticosteroids at baseline

Clinical remission at Week 10 (non-Inferiority)
Success on at least one endpoint
(Family 3)

Clinical remission at Week 54 among patients with a clinical 
response at Week 10

Clinical remission at Week 10 and Week 54
Ordering of endpoints within a family will be based on the p-value results from the hypotheses 
tests of the endpoints in Figure 2.
4.4.2.2
Clinical Remission
Definition of clinical remission is provided in the project SAP, Section 4.4.2.1.4.  The 
proportion of patients in clinical remission at Week 54, and both Week 10 and Week 54 
will be analyzed using the same methods as the primary endpoint.
The difference in the proportion of patients in clinical remission between the two 
treatment groups (etrolizumab minus infliximab) at Week 10 will be assessed for 
non-inferiority.
Null hypothesis H0:  Etro-Infx≤12.5%, etrolizumab is considered inferior to 
infliximab for clinical remission at Week 10 by more than 12.5%.
Alternative hypothesis H1:  Etro-Infx12.5%, etrolizumab is considered at least 
non-inferior to infliximab for clinical remission at Week 10.
95% confidence limits for the difference in clinical remission rates will be constructed 
using the stratified Newcombe confidence interval (Yan and Su 2010) with CMH weights.  
This is the same interval that will be evaluated in all stratified analysis of binary efficacy 
outcomes, including the primary endpoint.  The non-inferiority margin of magnitude 12.5% 
is based on the ACT 1 and 2 placebo-controlled Phase III trials of infliximab in 
aTNF-naive moderate-to-severe UC patients (Rutgeerts et al. 2005). Pooling the 
infliximab 5 mg results presented in Table 3 of Rutgeerts et al. (2005), the treatment 


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effect of infliximab versus placebo on clinical remission at Week 8 is 26% (95% CI: 19%, 
33%).  Therefore the magnitude of the margin is below the 95% lower confidence limit 
for this treatment effect (19%) and represents approximately 50% of the effect point 
estimate (26%).
In order to adjust the non-inferiority assessment for multiplicity and to determine 
statistical significance, the above null and alternative hypotheses will be examined via 
the Farrington-Manning non-inferiority test (Farrington and Manning 1990).  This test will 
be stratified following the approach described in Mehrotra (2001) and Wang et al. (2006), 
using CMH weights and null variance estimator.  The nominal p-value for this stratified 
Farrington-Manning test will be multiplicity-adjusted as part of Family 2 in the multiple 
testing strategy described in Section 4.4.2.1.  Note that this non-inferiority test is 
one-sided, whereas all other tests under multiplicity control are two-sided.  In order to 
account for this, all nominal two-sided p-values will be converted to one-sided (by 
examining the direction of the effect of etrolizumab) and multiplicity adjustment will be 
applied to the resulting nominal one-sided p-values (ensuring strong control at 2.5%).  
Multiplicity-adjusted p-values will then be converted to back to two-sided p-values for all 
two-sided tests.
An additional analysis will be conducted where the analysis population used to assess
non-inferiority is the PP population.  This supplementary analysis will examine the lower 
limit of the stratified Newcombe confidence interval against the margin of 12.5%.
In the Study GA29103 Protocol Version 7, Section 6.4.2, 12.5% is quoted which is 
incorrect; the correct value is 12.5% as used above.
4.4.2.3
Improvement in Endoscopic Appearance of the Mucosa
The proportion of patients with improvement in endoscopic appearance of the mucosa at 
Week 10, Week 54, and both Week 10 and Week 54 will be analyzed using the same 
methods as the primary endpoint.  As detailed in Figure 2 (Section 4.4.2.1), the 
endpoints for Week 10 and both Week 10 and Week 54 are not included in the multiple 
testing procedure for endpoints.  Definition of improvement in the appearance of the 
endoscopic mucosa is provided in the project SAP, Section 4.4.2.
4.4.2.4
Endoscopic Remission
The proportion of patients with endoscopic remission at Week 54 will be analyzed using 
the same methods as the primary endpoint.  Definition of endoscopic remission is 
provided in the project SAP, Section 4.4.2.1.4.


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4.4.2.5
Corticosteroid-Free Clinical Remission at Week 54 (Off 
Corticosteroid for At Least 24 Weeks Prior to Week 54) in 
Patients Who Were Receiving Corticosteroids at Baseline
These analyses will only be conducted on a subgroup of patients who were receiving 
corticosteroids at baseline as per the data collected in electronic Case Report Form 
(e-CRF) database.  Clinical Remission is defined in the project SAP, Section 4.4.2.1.4.  
Patients are defined as being off CS if they have no record of taking corticosteroids 
since the date which is twenty four weeks prior to Week 54.  This date is defined as the 
Week 54 visit date 168 days.
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4.4.2.6
Clinical Remission at Week 54 Among patients with Clinical 
Response at Week 10
The proportion of patients in clinical remission at Week 54 among patients with clinical 
response at Week 10 will be analyzed using the same methods as the primary endpoint. 
The definition of clinical remission and clinical response is provided in the project SAP, 
Section 4.4.2.1.4.
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4.4.2.7
Clinical Response
Definition of clinical response is provided in the project SAP, Section 4.4.2.1.4.  The 
proportion of patients in clinical response at Week 10 and both Week 10 and Week 54 
will be analyzed using the same methods as the primary endpoint. As detailed in 
Figure 2 (Section 4.4.2.1), these endpoints are not included in the multiple testing 
procedure for endpoints.
4.4.2.8
Inflammatory Bowel Disease Questionnaire (IBDQ)
Details of the IBDQ endpoint and the analyses are provided in the project SAP, 
Section 4.4.2.4.  The change from baseline at Week 10, Week 30, and Week 54 in IBDQ 
between etrolizumab and infliximab treatment groups will be analyzed. As detailed in 
Figure 2 (Section 4.4.2.1), these endpoints are not included in the multiple testing 
procedure for endpoints.


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4.4.3
Exploratory Efficacy Endpoints
Exploratory endpoints detailed in the protocol will also be analyzed.  Binary endpoints 
will use the same statistical methods used for the primary endpoint.  Continuous 
endpoints will use the same statistical methods used for the change from baseline 
secondary endpoints.
4.4.4
Sensitivity Analyses
To support the primary analyses the following sensitivity analyses will be conducted: 
definitions of pMCS and modified Mayo Clinic Score (mMCS) are included in the project 
SAP, Section 4.4.2.1.4.

Proportion of patients in clinical response at Week 10 and clinical remission at 
Week 54 (clinical response and clinical remission derived using mMCS including 
mild friability in ES1)

Proportion of patients in clinical response at Week 10 and clinical remission at 
Week 54 (clinical response and clinical remission derived using pMCS)

Proportion of patients in clinical response at Week 10 and clinical remission at 
Week 54 (clinical response and clinical remission derived using mMCS excluding 
friability from ES1)

Proportion of patients in clinical response at Week 10 and clinical remission at 
Week 54 (tipping point analysis)
All key secondary endpoints included in Figure 2 which are calculated using MCS or the 
endoscopic subscore will be re analyzed as a sensitivity analyses using the mMCS 
excluding friability from ES1 or the endoscopic subscore excluding friability from ES1
if applicable. These analyses will be conducted on the mITT population and are listed 
below:

Proportion of patients with improvement in endoscopic appearance of the mucosa at 
Week 54 (excluding friability from ES1)

Proportion of patients in clinical remission at Week 54 (clinical remission derived 
using mMCS excluding friability from ES1)

Proportion of patients in corticosteroid-free clinical remission at Week 54 (off 
corticosteroid for at least 24 weeks prior to Week 54) in patients who were receiving 
corticosteroids at baseline (clinical remission derived using mMCS excluding 
friability from ES1)

Proportion of patients in clinical remission at Week 10 (clinical remission derived 
using mMCS excluding friability from ES1) (non-inferiority)

Proportion of patients in clinical remission at Week 54 among patients with clinical 
response at Week 10 (clinical response and clinical remission derived using mMCS 
excluding friability from ES1)

Proportion of patients in clinical remission at Week 10 and Week 54 (clinical 
remission derived using mMCS excluding friability from ES1)


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4.4.5
Supplementary Analyses
To support the primary analyses the following supplementary analyses will be conducted:

Proportion of patients in clinical response at Week 10 and clinical remission at 
Week 54 (including data collected whilst patients received rescue therapy)

Proportion of patients in clinical response at Week 10 and clinical remission at 
Week 54 (using logistic regression model).  

Proportion of patients in clinical response at Week 10 and remission at Week 54
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 from baseline up 
until the patient completes/withdraws from the study.  If a patient is ongoing in the study 
due to being in safety follow-up at the time of the primary data analyses, all available 
data at time of the CCOD will be reported.  Baseline is defined as the last available 
assessment prior to first receipt of study drug.
Further details of the safety analyses are provided in the project SAP, Section 4.7.
4.6.1
Exposure of Study Medication
The number of etrolizumab injections or infliximab vials will be summarized using 
descriptive statistics.
4.6.2
Adverse Events
Details are included in the project SAP, Section 4.7.1.
4.6.3
Laboratory Data
Details are included in the project SAP, Section 4.7.2.
4.6.4
Vital Signs
Details are included in the project SAP, Section 4.7.3.
4.6.5
Concomitant Medications, 
Details are included in the project SAP, Section 4.7.5.
4.6.6
Medical History
Details are provided in the project SAP, Section 4.7.4.


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4.7
MISSING DATA
Details are included in the project SAP, Section 4.8.
4.8
INTERIM ANALYSES
No efficacy interim analyses are planned, or have been undertaken.
5.
REFERENCES
Dmitrienko A, Tamhane AC, Wiens BL. General multistage gatekeeping procedures. 
Biom J. 2008;50(5):66777.
Dmitrienko A, Tamhane AC, Bretz F, editors. Multiple testing problems in pharmaceutical 
statistics. CRC Press 2009;16591.
Farrington C, Manning G. Test statistics and sample size formulae for comparative 
binomial trials with null hypothesis of nonzero risk difference or nonunity relative 
risk. Statistics in medicine. 1990;9(12):1447-54.
Mehrotra DV. Stratification Issues with Binary Endpoints. Drug Information Journal : DIJ / 
Drug Information Association 2001;35(4):1343–50.
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.
Wang WWB.,Mehrotra DV, Chan ISF, Heyse JF. 2006. Statistical Considerations for 
NonInferiority/Equivalence Trials in Vaccine Development. Journal of 
Biopharmaceutical Statistics 2006;16(4):429–41.
Yan X, Su XG. Stratified Wilson and Newcombe Confidence Intervals for Multiple 
Binomial Proportions. Statistics in Biopharmaceutical Research 2010;2(3):329–35.


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Appendix 1 Protocol Synopsis
TITLE:
PHASE III, RANDOMIZED, MULTICENTER, DOUBLE-BLIND,
DOUBLE-DUMMY 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
PROTOCOL NUMBER:
GA29103
VERSION NUMBER:
7
EUDRACT NUMBER:
2013-004282-14
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 infliximab in achieving both clinical response at Week 10 and clinical 
remission at Week 54 in patients with ulcerative colitis (UC) as determined by the Mayo 
Clinic Score (MCS).
Secondary efficacy objectives for this study are as follows:

To evaluate clinical remission at Week 10

To evaluate clinical remission at Week 54

To evaluate clinical remission achieved at both Week 10 and Week 54

To evaluate clinical remission at Week 54 among patients with a clinical response at 
Week 10

To evaluate improvement in endoscopic appearance of the mucosa at Week 10

To evaluate improvement in endoscopic appearance of the mucosa at Week 54

To evaluate improvement in endoscopic appearance of the mucosa achieved at both
Week 10 and Week 54

To evaluate endoscopic remission at Week 54

To evaluate clinical response at Week 10

To evaluate clinical response achieved at both Week 10 and Week 54

To evaluate corticosteroid-free clinical remission at Week 54 (off corticosteroids for at least 
24 weeks prior to Week 54) in patients who were receiving corticosteroids at baseline

To evaluate change from baseline in patient-reported health-related quality of life (QOL) at 
Weeks 10, 30, and 54, as assessed by the Inflammatory Bowel Disease Questionnaire 
(IBDQ)


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The exploratory efficacy objectives for this study are as follows:

To evaluate remission at Week 10 

To evaluate remission at Week 54 

To evaluate remission at both Week 10 and Week 54

To evaluate change in health utilities, as assessed by the EuroQoL Five-Dimension 
Questionnaire (EQ-5D), from baseline to Weeks 10, 30, and 54

To evaluate the frequency and duration of hospitalizations from baseline to Week 54
Safety Objectives
The safety objectives for this study are as follows:

To evaluate the overall safety and tolerability of etrolizumab over a period of 54 weeks

To evaluate the incidence and severity of infection-related adverse events

To evaluate the incidence of malignancies

To evaluate the incidence and severity of hypersensitivity reactions

To evaluate the incidence and the clinical significance of anti-therapeutic antibodies (ATAs) 
to etrolizumab, or if necessary, infliximab
Pharmacokinetic Objectives
The pharmacokinetic (PK) objectives for this study are as follows:

To evaluate the etrolizumab serum concentration at the time of primary endpoint evaluation 
and at a predose timepoint (Week 12)

To evaluate the interindividual variability of and potential covariate effects on etrolizumab 
(or potentially infliximab) serum exposure
Exploratory Pharmacodynamic, Predictive, and Prognostic Objectives
The exploratory pharmacodynamics (PD), predictive, and prognostic objectives for this study 
are as follows:

To evaluate the relationship between baseline colonic mucosal and/or peripheral blood 
biomarkers, including, but not limited to, E integrin, and response to study treatment

To evaluate the expression levels of biomarkers in colonic tissue and/or peripheral blood, 
including, but not limited to, E integrin, at baseline and during the treatment period 

To evaluate the PD effects on biomarkers in stool samples through assessments that may 
include, but are not limited to, analyses of the microbiota and bacterial cultures at baseline 
and during the treatment period
Study Design
Description of Study
This is a multicenter, Phase III, randomized, double-blind, double-dummy, parallel-group study 
to evaluate the safety, efficacy, and tolerability of etrolizumab (105 mg SC Q4W) compared with 
infliximab (5 mg/kg intravenous [IV] Weeks 0, 2, and 6, then every 8 weeks [Q8W]) in the 
treatment of moderate to severe UC.
Patients enrolled in this study may be eligible to participate in an open-label extension and 
safety monitoring (OLE-SM) study (GA28951), which consists of two parts:  Part 1 (designated 
OLE [open-label extension]) and Part 2 (designated SM [safety monitoring]).


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Disease activity will be measured using the MCS, which is the current outcome measure 
accepted by regulatory authorities for drug development in UC.  The target population consists 
of 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 protocol, a rectal 
bleeding subscore 1, and a stool frequency subscore 1) and involvement that extends a 
minimum of 20 cm from the anal verge.
All patients are to be naive to tumor necrosis factor (TNF) inhibitors.
Patients must have had an inadequate response, loss of response, or intolerance to prior 
immunosuppressant and/or corticosteroid treatment.
Patients who are on background immunosuppressant therapy (6-MP, AZA, MTX) may be 
enrolled if they have received a stable dose for at least 8 weeks prior to randomization (Day 1).  
Such patients should continue on their stable baseline doses of their background 
immunosuppressant therapy throughout the study unless dose reduction or discontinuation is 
required due to toxicity.  Generally accepted criteria for discontinuation of immunosuppressants 
due to toxicity include, but are not limited to, acute pancreatitis, severe leukopenia, severe 
thrombocytopenia, or clinically significant elevations of the liver-associated enzymes from 
baseline, especially in the presence of an elevated total bilirubin.  The ultimate decision to 
reduce dose or discontinue immunosuppressants due to toxicity remains at the discretion of the
investigator.
Patients 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 just been initiated, the dose has to be stable for at 
least 4 weeks immediately prior to randomization (Day 1)

If corticosteroids are being tapered, the dose has to be stable for 2 weeks immediately prior 
to randomization (Day 1) 
Such patients should continue stable doses of their background corticosteroid until Week 10, at 
which point a corticosteroid taper will be initiated for all patients entering the Maintenance 
Phase.
Initiation of corticosteroid or an increase in corticosteroid dose above the patients’ entry dose 
(up to a maximum of 30 mg/day of 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 (Day 1).  Oral 5-aminosalicylate (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 
(Day 1).  Certain concomitant treatments are prohibited (see protocol for list of all prohibited 
concomitant treatments).
Patients must have discontinued topical treatments for UC at least 2 weeks prior to 
randomization (Day 1). 
The study will be divided into: 

Screening period of up to 35 days (for details see protocol)

Double-blind treatment period of 54 weeks, composed of an Induction Phase (up to 
Week 10) and a Maintenance Phase (Week 10 to Week 54)

Safety follow-up period of 12 weeks. 
A total of approximately 390 patients will be recruited from approximately 200 sites.  Patients 
will be stratified by concomitant treatment with corticosteroids (including budesonide) at 
baseline (yes/no), concomitant treatment with immunosuppressants at baseline (yes/no), and 
baseline disease activity as measured during screening (MCS 9 vs. MCS 10). 
Patients completing the Maintenance Phase at Week 54, patients identified as having disease 
worsening between Weeks 10 and 54, or patients who receive defined rescue medication(s) 
may enroll in Part 1 (OLE) of Study GA28951, if eligible, where they will receive open-label 
etrolizumab after a brief washout phase.  If they do not enroll in Part 1 (OLE) of Study 
GA28951, they will enter the 12-week safety follow-up period of this study  and will then be 
requested to enroll in Part 2 (SM) of Study GA28951 for 92 weeks of extended PML monitoring.


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Study Drug Administration
Following screening, patients will be randomized in a 1:1 ratio to receive 105 mg etrolizumab or 
5 mg/kg infliximab.  The study design is double-blind, double-dummy, so all patients will receive 
two study treatments, either active etrolizumab infliximab dummy or active 
infliximab etrolizumab dummy.  The dummy for etrolizumab will be a matched SC placebo, 
whereas the dummy for infliximab will be an IV saline infusion.  Patients will receive either 
105 mg etrolizumab or etrolizumab dummy by SC administration Q4W until Week 52.  Infliximab 
will be administered by IV infusion at Weeks 0, 2, and 6, then Q8W until Week 46.  
Consequently, administration of SC study medication and IV study medication occurs at 
different timepoints throughout the study.
The first 2 doses of etrolizumab/etrolizumab dummy will be administered via a prefilled syringe 
(PFS) by a health care professional (HCP) in the clinic. The subsequent two doses will be 
self-administered by the patient or administered by his or her caregiver in the clinic and 
monitored by the HCP.  
If deemed appropriate by HCP, the remaining doses of etrolizumab/etrolizumab dummy study 
drug, starting at Week 16, will be self-administered by the patient or administered by his or her 
caregiver at home Q4W (action to be taken as a result of a hypersensitivity reaction provided in 
the protocol).  On occasions when the patient has to attend the clinic the same day as an 
etrolizumab/etrolizumab dummy administration, the administration of study medication by the 
patient or his or her caregiver will occur at home after his or her study assessments in the clinic 
setting.  If necessary, patients or their HCPs may choose to continue administration of study 
medication in the clinic.  The details of study medication administration are provided in the 
protocol.
In addition, patients will receive either infliximab (5 mg/kg IV at Weeks 0, 2, and 6, then Q8W) or 
infliximab dummy (saline) IV at the same timepoints, administered in the clinic setting until 
Week 46.
Number of Patients
A total of approximately 390 patients will be enrolled in this study from approximately 200 sites.
Target Population
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, a rectal bleeding subscore 
1, and a stool frequency subscore 1 during the screening period (prior to randomization 
[Day 1]).  See also the protocol for additional information regarding this 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 (Day 1).  See also the protocol for additional information 
regarding this time window.

Naive to treatment with any TNF inhibitor therapy (including TNF inhibitor biosimilars)


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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-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(or equivalent)
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 (Day 1)
May be receiving oral corticosteroid therapy (prednisone at a stable dose of 30 mg a 
day, or equivalent steroid) 
If corticosteroid therapy is ongoing or has recently been initiated, the dose has to 
be stable for at least 4 weeks immediately prior to randomization (Day 1).  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 
for 4 weeks prior to randomization (Day 1)
May be receiving probiotics (e.g., Culturelle, Saccharomyces boulardii), provided that 
the dose has been stable for 2 weeks immediately prior to randomization (Day 1)
May be receiving AZA, 6-MP, or MTX, provided that the dose has been stable 
for 8 weeks immediately prior to randomization (Day 1)

For women who are not postmenopausal (at least 12 months of nontherapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain 
abstinent or use a highly effective method of contraception during the treatment period and 
for at least 24 weeks after the last dose of study drug
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.


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
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 
24 weeks after the last dose of study drug to avoid exposing the embryo to study drug.  
Men must refrain from donating sperm during this same period.  
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.

Must have received a colonoscopy within the past year or be willing to undergo a 
colonoscopy in lieu of a flexible sigmoidoscopy at screening.  This colonoscopy must:
Confirm disease extent (defined as 1) left-sided colitis [up to the splenic flexure], 
2) extensive colitis [beyond the splenic flexure but not involving the entire colon], and 
3) pancolitis)
Include removal of any adenomatous polyps 
Document evidence of surveillance for dysplasia for all patients with left-sided colitis 
of 12 years’ duration and total/extensive colitis of 8 years’ duration
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Exclusion Criteria Related to Inflammatory Bowel Disease

Prior extensive colonic resection, subtotal or total colectomy, or planned surgery for UC

Past or present ileostomy or colostomy

Diagnosis of indeterminate colitis

Suspicion of ischemic colitis, radiation colitis, or microscopic colitis

Diagnosis of toxic megacolon within 12 months of initial screening visit

Any diagnosis of Crohn’s disease

Past or present fistula or abdominal abscess

A history or current evidence of colonic mucosal dysplasia

Patients with any stricture (stenosis) of the colon

Patients with history or evidence of adenomatous colonic polyps that have not been 
removed
Exclusion Criteria Related to Prior or Concomitant Therapy

Any prior treatment with etrolizumab or other anti-integrin agents (including natalizumab, 
vedolizumab, and efalizumab)

Any prior treatment with anti-adhesion molecules (e.g., anti-MAdCAM-1)

Any prior treatment with rituximab

Any treatment with tofacitinib during screening

Use of IV steroids within 30 days prior to screening with the exception of a single 
administration of IV steroid

Use of agents that deplete B or T cells (e.g., alemtuzumab or visilizumab) within 12 months 
prior to randomization (Day 1), with the exception of AZA and 6-MP

Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF) within 4 weeks 
prior to randomization (Day 1)

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.) 


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
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 (Day 1)

Apheresis (i.e., Adacolumn apheresis) within 2 weeks prior to randomization (Day 1)

Received any investigational treatment including investigational vaccines within  5 half-lives 
of the investigational product or 28 days after the last dose (whichever is greater) prior to 
randomization (Day 1) of the study

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 (Day 1)
Exclusion Criteria Related to General Safety

Pregnant or lactating

Lack of peripheral venous access

Hospitalized (other than for elective reasons) during the screening period

Inability to comply with study protocol, in the opinion of the investigator

Significant uncontrolled comorbidity, such as cardiac (e.g., moderate to severe heart failure 
New York Heart Association [NYHA] Class III/IV), pulmonary, renal, hepatic, endocrine, or 
gastrointestinal disorders (excluding UC)

Neurologic conditions or diseases that may interfere with monitoring for PML

History of demyelinating disease 

Clinically significant abnormalities on screening neurologic examination (PML Objective 
Checklist)

Clinically significant abnormalities on the screening PML Subjective Checklist

History of alcohol, drug, or chemical abuse 6 months prior to screening

Conditions other than UC that could require treatment with 10 mg/day of prednisone (or 
equivalent) during the course of the study

History of cancer, including hematologic malignancy, solid tumors, and carcinoma in situ, 
within 5 years before screening with the following exceptions:
Local basal or squamous cell carcinoma of the skin that has been excised and is 
considered cured is not exclusionary.
A history of chronic myelogenous leukemia, hairy cell leukemia, melanoma, renal cell 
carcinoma, or Kaposi sarcoma is exclusionary irrespective of the duration of time before 
screening.
History of a cervical smear indicating the presence of adenocarcinoma in situ (AIS), 
high-grade squamous intraepithelial lesions (HSIL), or cervical intraepithelial neoplasia 
(CIN) of Grade 1, is exclusionary irrespective of the duration of time before screening.
Exclusion Criteria Related to Infection Risk

Congenital or acquired immune deficiency

Patients must undergo screening for HIV and test positive for preliminary and 
confirmatory tests 


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
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 result 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 (Day 1) or other intestinal pathogens (as assessed by 
stool culture and ova and parasite evaluation) within 30 days prior to randomization (Day 1)

Evidence of or treatment for clinically significant cytomegalovirus (CMV) colitis (based on 
the investigator’s judgment) within 60 days prior to randomization (Day 1).  Laboratory 
confirmation of CMV from a colon biopsy sample is required during screening evaluation 
only if clinical suspicion is high and to determine the need for CMV treatment

History of active or latent treated tuberculosis (TB) regardless of treatment history
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 
enrollment 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

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 (Day 1)
Fungal infections of the nail beds
Oral or vaginal candidiasis that has resolved with or without treatment prior to 
randomization (Day 1)


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
Any major episode of infection requiring treatment with IV antibiotics within 8 weeks prior to 
screening or oral antibiotics 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 (Day 1)

History of organ transplant
Exclusion Criteria Related to Laboratory Values (at Screening)

Serum creatinine 2 upper limit of normal (ULN)

ALT or AST 3 ULN or alkaline phosphatase 3 ULN or total bilirubin 2.5 ULN 
(unconjugated hyperbilirubinemia that is associated with known Gilbert’s syndrome is not an 
exclusion criterion)

Platelet count 100,000/L

Hemoglobin 8 g/dL

Absolute neutrophil count 1500/L

Absolute lymphocyte count 500/L
Length of Study
The total length of the treatment period will be 54 weeks.  Patients who have disease worsening 
between Weeks 10 and 54, patients who receive defined rescue treatment(s), and patients who 
complete 54 weeks of the study may be given the option of enrolling in the Part 1 (OLE) of 
Study GA28951, where they will receive open-label etrolizumab treatment. 
Those who do not enroll in Part 1 (OLE) of Study GA28951 will continue to 12 weeks of safety 
follow-up in this protocol (without the washout phase) and then be requested to enroll in 
Part 2 (SM) of Study GA28951 for 92 weeks of PML monitoring.
The total length of the study is expected to last from the first patient screened to either the last 
patient in last safety follow-up visit in this protocol or the 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 in Study GA28951, whichever is later.
Outcome Measures
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:
Primary Efficacy Outcome Measure

Both clinical response at Week 10 and clinical remission at Week 54 in patients with UC as 
determined by the MCS
Secondary Efficacy Outcome Measures

Clinical remission at Week 10

Clinical remission at Week 54

Clinical remission achieved at both Week 10 and Week 54

Clinical remission at Week 54 among patients with a clinical response at Week 10

Improvement in endoscopic appearance of the mucosa at Week 10

Improvement in endoscopic appearance of the mucosa at Week 54

Improvement in endoscopic appearance of the mucosa achieved at both Week 10 and 
Week 54

Endoscopic remission Week 54

Clinical response at Week 10


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
Clinical response achieved at both Week 10 and Week 54

Corticosteroid-free  clinical remission at Week 54 (off corticosteroids for at least 24 weeks 
prior to Week 54) in patients who were receiving corticosteroids at baseline

Change from baseline in patient-reported health-related QOL at Weeks 10, 30, and 54 as 
assessed by the IBDQ
Exploratory Efficacy Outcome Measures

Remission at Week 10

Remission at Week 54

Remission at both Week 10 and Week 54

Change in health utilities, as assessed by the EQ-5D, from baseline to Weeks 10, 30, 
and 54

Frequency and duration of hospitalizations from baseline to Week 54
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence and severity of adverse events

Incidence of serious adverse events

Incidence and severity of infection-related adverse events

Incidence of serious infection-related adverse events

Incidence and severity of injection-site reactions 

Incidence of adverse events leading to study drug discontinuation

Incidence of laboratory abnormalities

Incidence of malignancies

Incidence of ATAs to etrolizumab, or if necessary, infliximab

Incidence and severity of hypersensitivity reaction events
Pharmacokinetic Outcome Measures
The etrolizumab PK assessment will be performed in a subset of etrolizumab-treated patients.  
The PK outcome measures for this study are as follows:

Serum concentration 2 weeks after the first dose and at steady state during the dosing 
period from Week 12 to Week 54 

Serum concentration at timepoints (Weeks 10, 30, and 54)
Exploratory Biomarker Outcome Measures
The exploratory biomarker outcome measures for this study are as follows:

Relationship between remission and baseline levels of colonic tissue biomarkers and/or 
peripheral blood including, but not limited to, E integrin. These may be outcomes 
predictive or prognostic of response.

Changes in stool biomarkers, which may include, but are not limited to, those in the 
microbiota and bacterial cultures, during the Induction and Maintenance Phases as 
compared to baseline
Investigational Medicinal Products
Test Product
Etrolizumab PFS: containing SC formulation, 105 mg given as 0.7 mL of a 150-mg/mL solution 
will be administered by SC injection Q4W.


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Comparator
Infliximab, 5 mg/kg IV Weeks 0, 2, and 6, then Q8W. Each infliximab vial contains 100 mg of 
lyophilized infliximab antibody in a 20-mL vial for IV use. An unblinded pharmacist will 
reconstitute and then dilute the infliximab to a dose of 5 mg/kg and a total volume of 250 mL 
with sterile 0.9% sodium chloride for infusion.
Non-Investigational Medicinal Products
Patients are to continue on their baseline dose of corticosteroid (including budesonide) to the 
end of the Induction Phase (Week 10). Tapering of corticosteroid (including budesonide) is to 
be attempted during the Maintenance Phase (Week 10 to Week 54).
Immunosuppressants (AZA, 6-MP, MTX) are to continue on the patient’s baseline dose of 
immunosuppressant to the end of induction (Week 10) and then to continue on stable doses of 
immunosuppressants throughout the Maintenance Phase.
Probiotics and oral 5-ASA may be continued at a stable dose throughout the study.
Occasional use of NSAIDs and acetaminophen (e.g., headache, arthritis, myalgias, and 
menstrual cramps) and aspirin up to 325 mg daily are permitted throughout the study.
Anti-diarrheals (e.g., loperamide, diphenoxylate with atropine) for control of chronic diarrhea are 
permitted throughout the study.
Statistical Methods
Efficacy Analyses
The primary and secondary efficacy analyses will include all randomized patients who received 
at least one dose of study drug with patients grouped according to the treatment assigned at 
randomization (Day 1) (intent-to-treat [ITT] population).  A per-protocol population will be 
defined in the Statistical Analysis Plan (SAP) for the purpose of testing for non-inferiority in 
induction of clinical remission at Week 10. 
To manage the overall type I error, the testing of hypotheses will be performed sequentially.  
The primary endpoint will be tested first at an overall two-sided significance level of 0.05.  
The testing hierarchy for the secondary endpoints will be described in the SAP. 
Unless otherwise noted, analyses of efficacy outcome measures will be stratified by the 
stratification factors used at randomization (Day 1):  baseline corticosteroids use (yes/no), 
baseline immunosuppressants use (yes/no), and baseline disease severity as measured during 
screening (MCS 9/MCS 10).
Patients who are non-evaluable for efficacy at a specific timepoint (e.g., due to missing data or 
early transfer to the Part 1 [OLE] of Study GA28951) will be considered non-responders for all 
response/remission type endpoints.  In addition, initiation of an agent not allowed in combination 
with etrolizumab or infliximab, an immunosuppressant, oral or topical 5-ASA (up to Week 10), or 
corticosteroid, or increase in dose over baseline levels for treatment of worsening disease 
symptoms as defined in the protocol will lead to non-responder classification thereafter.  
For continuous outcomes, 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 the protocol, the following analyses will be performed for 
the primary efficacy endpoint and key secondary efficacy endpoints.  Details of these analyses 
will be described in the SAP:

Sensitivity analyses to evaluate the robustness of results to the primary analysis methods 
(e.g., handling of dropouts)

Subgroup analyses to evaluate the consistency of results across prespecified subgroups 
(e.g., based on age, sex, race/ethnicity, baseline UC medications, baseline CS dose)


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31/Statistical Analysis Plan GA29103
Determination of Sample Size  
Approximately 390 patients will be randomized in a 1:1 ratio to etrolizumabinfliximab dummy 
or infliximabetrolizumab dummy.  The sample size of 195 patients per group provides 
approximately 80% power to detect a clinically meaningful difference of 12% (18% vs 30%) 
between the two groups for the primary endpoint, using a two-sided 2 test at a significance 
level of 0.05.


Etrolizumab—F. Hoffmann-La Roche Ltd
32/Statistical Analysis Plan GA29103
Appendix 2 Schedule of Assessments
Assessment
Clinic Visit Schedule 
(Etrolizumab/Etrolizumab 
Dummy Administration in Clinic)
Weeks (3 days)
Clinic Visit/Telephone Contact Schedule 
(Etrolizumab/Etrolizumab Dummy Administration at Home)
UV/
D-
OLE
b
EW
/
W
O
SD 35 to 1
0 c
2
4
6
8
10
12
14
16
18 d
20
22
24
26 d
28
30
32
34 d
36
38
40
42 d
46
48
50 d
52
54
Informed consent
x
Review elig bility criteria
x e
x
Demographic data
x
Pregnancy test f
x
x
x
x
x
x
Vital signs
(BP and pulse)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG
x
x
x
Chest X-ray g
x
Height 
x
Weight
x
Medical history
x
Physical examination h
x
x
x
x
x
x
x
x b
x
PML neurologic 
examination i
x
x
x
x
x
x
x b
x


Etrolizumab—F. Hoffmann-La Roche Ltd
33/Statistical Analysis Plan GA29103
Appendix 2 Schedule of Assessments (cont.)
Assessment
Clinic Visit Schedule 
(Etrolizumab/Etrolizumab 
Dummy Administration in Clinic)
Weeks (3 days)
Clinic Visit/Telephone Contact Schedule 
(Etrolizumab/Etrolizumab Dummy Administration at Home)
UV/
D-
OLE
b
EW/
WO
SD 35 to 1
0 c
2
4
6
8
10
12
14
16
18 d
20
22
24
26 d
28
30
32
34 d
36
38
40
42 d
46
48
50 d
52
54
Hematology
x
x
x
x
x
x
x b
x j
Chemistry
x
x
x
x
x
x
x b
x j
Urinalysis
x
x
x b
TB screen k
x
HIV test
x
Hepatitis B and C 
serology l
x
Hepatitis B DNA m
x
x
x
x
x
Hepatitis C RNA 
(Amplicor) n
x
PK sampling (serum) o, p
x
x
x
x
x
x
x b
x j
Anti-therapeutic antibody 
sample
(serum) o, p, q
x
x
x
x o
x o
x r
x b
x j r
Plasma sample (storage 
for JCV antibody testing)
s
x


Etrolizumab—F. Hoffmann-La Roche Ltd
34/Statistical Analysis Plan GA29103
Appendix 2 Schedule of Assessments (cont.)
Assessment
Clinic Visit Schedule 
(Etrolizumab/Etrolizumab
Dummy Administration in Clinic)
Weeks (3 days)
Clinic Visit/Telephone Contact Schedule 
(Etrolizumab/Etrolizumab Dummy Administration at Home)
UV/
D-
OLE
b
EW/
WO
SD 35 to 1
0 c
2
4
6
8
10
12
14
16
18 d
20
22
24
26 d
28
30
32
34 d
36
38
40
42 d
46
48
50 d
52
54
MCS (includes 
endoscopy) t, u
x v
x
x
x b
x j, 
gg
pMCS (excludes 
endoscopy) u, w
x v
x
x
x
x
x
x
x
x b
x j
Stool sample collection
x x
x y
x y
x y
x y
x b
x y
Colonic biopsy (CMV if 
required)
x z
x b
Colonic biopsy 
(histopathological 
confirmation of UC if 
required)
x aa
Colonic biopsies 
(formalin)
x bb
x cc
x cc
x b, cc
x j, 
cc, gg
Colonic biopsies (for 
qPCR)
x bb
x cc
x cc
x b, cc
x j, 
cc, gg
Serum sample (CRP) p
x
x
x
x b
x j
Serum sample (future 
exploratory PD) o, p
x
x
x
x
x
x
x


Etrolizumab—F. Hoffmann-La Roche Ltd
35/Statistical Analysis Plan GA29103
Appendix 2 Schedule of Assessments (cont.)
Assessment
Clinic Visit Schedule 
(Etrolizumab/Etrolizumab 
Dummy Administration in Clinic)
Weeks (3 days)
Clinic Visit/Telephone Contact Schedule 
(Etrolizumab/Etrolizumab Dummy Administration at Home)
UV/
D-
OLE
b
EW
/
W
O
SD 35 to 1
0 c
2
4
6
8
10
12
14
16
18 d
20
22
24
26 d
28
30
32
34 d
36
38
40
42 d
46
48
50 d
52
54
Blood sample (RNA 
Paxgene) o, p, dd
x
x
x
x
x
x
Whole blood (EDTA) 
optional p
x
IBDQ ee
x
x
x
x
EQ-5D ee
x
x
x
x
Concomitant 
medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Infliximab/
infliximab dummy 
administration
x
x
x
x
x
x
x
x
Etrolizumab/
etrolizumab dummy 
administration
x
x
x
x
x
x
x
x
x
x
x
x
x


Etrolizumab—F. Hoffmann-La Roche Ltd
36/Statistical Analysis Plan GA29103
Appendix 2 Schedule of Assessments (cont.)
Abantibody; ATAanti-therapeutic antibody; BPblood pressure; CMVcytomegalovirus; CRPC-reactive protein; D-OLEdecision to switch to 
OLE; ECGelectrocardiogram; EQ-5DEuroQoL Five-Dimension Questionnaire; eCRFelectronic case report form; EW early withdrawal; 
HBVhepatitis B virus; HCVhepatitis C virus; HIVhuman immunodeficiency virus; IBDQInflammatory Bowel Disease Questionnaire;
JCVJohn Cunningham virus; MCSMayo Clinic Score; PDpharmacodynamics; PKpharmacokinetic; pMCSpartial Mayo Clinic Score; 
PMLprogressive multifocal leukoencephalopathy; qPCRquantitative polymerase chain reaction; SDscreening day; TBtuberculosis; 
UCulcerative colitis; UVunscheduled visit; WOwashout.
Notes:
–
Study assessments and blood draws are to be conducted prior to study drug administration
–
All colonic biopsy samples will be taken during flexible sigmoidoscopy/colonoscopy procedure.
–
Etrolizumab administration at home for eligible patients on Weeks: 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (negative urine pregnancy test, 
preferably performed in home setting, required prior to administration)
a All assessments must be performed after obtaining informed consent.  Endoscopy is to be performed 416 days prior to randomization (Day 1).  The 
total screening period is 35 days. Under no circumstances will either window be extended.
b Unscheduled visit (including decision to switch to OLE) represents a visit that is not as per schedule of assessment and is required for an 
adverse event or for potential disease worsening 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 disease worsening is performed by the 
Mayo Clinic Score assessment).  Assessments corresponding to items noted in this column should be recorded on the eCRF.  Refer to Table 3 
for details regarding washout and timing of enrollment in Part 1 (OLE) of Study GA28951.
c Day 1 of Week 0.
d Telephone contact for patients performing home administration:  patients requiring in-clinic drug administration throughout the study will have 
their study assessments conducted in clinic or via telephone call after their clinic visit at the sites’ discretion.
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 have had a hysterectomy.  Urine test 
at other visits; if urine test is positive, perform a confirmatory serum test.  Pregnancy test will be carried out at home once patient starts 
etrolizumab administration at home.  Patient is to report the pregnancy test via e-diary. Patients must be instructed at screening and reminded 
throughout the study that in case of positive pregnancy test they must stop self-administration of study drug and call the site immediately.  Do not 
administer etrolizumab unless the serum pregnancy test result is negative.  After Week 12, pregnancy tests to be performed prior to 
administration and preferably in home setting at Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52.
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.


Etrolizumab—F. Hoffmann-La Roche Ltd
37/Statistical Analysis Plan GA29103
Appendix 2 Schedule of Assessments (cont.)
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 or decision to switch to OLE (Part 1) and assessment was 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 aka 
Mantoux test), INF-based test (e.g., QuantiFERON-TB Gold).
l
Patients must undergo screening for HBV and HCV.  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 only when the patient has a known history of HCV antibody positivity with 
past documentation of undetectable HCV RNA, either with or without history of anti-viral treatment.  Patients with newly diagnosed HCV antibody 
positivity are not eligible for this study, and therefore do not require measurement of HCV RNA.
o Samples to be collected from a subset of patients (approximately 400 at designated sites) for PK (all scheduled timepoints), ATA (indicated times) 
and exploratory PD assessment (all scheduled timepoints).  ATA samples at baseline Week 0, Week 10, and Week 54 are to be collected from 
all patients and all ATA samples may be used for exploratory PD and/or PK assessment.
p Samples are to be collected prior to dose administration (blood, serum, colonic biopsies).
q 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.
r
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).
s 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.
t
Endoscopyrectal bleeding assessmentstool frequency assessmentPhysician’s Global Assessment.  Patients who have not undergone full 
colonoscopy with documented results within one year prior to screening should undergo colonoscopy in lieu or sigmoidoscopy at the screening 
visit to allow for screening for cancer/dysplasia (yes/no).  Rectal bleeding and stool frequency to be collected daily on e-diary.
u During screening, patients must be trained on the use of the e-diary.  Patients are to complete the e-diary on a daily basis for the stool frequency 
and rectal bleeding score (for MCS/pMCS) from first screening visit. 
v Partial MCS during screening is defined as the MCS score excluding the endoscopy score. Screening endoscopy (for the MCS) is to be 
performed between 416 days prior to randomization (Day 1) (i.e., Day 16 to Day 4.  For baseline measurements, the Physician's Global 


Etrolizumab—F. Hoffmann-La Roche Ltd
38/Statistical Analysis Plan GA29103
Appendix 2 Schedule of Assessments (cont.)
Assessment will be obtained only once, on Day 1 (prior to randomization [Day 1)]), and the Physician’s Global Assessment score will be used to 
calculate both the baseline (screening) MCS and the baseline (Day 1) pMCS.
w Rectal bleeding assessment stool frequency assessment Physician’s Global Assessment.  Rectal bleeding and stool frequency to be 
collected daily on e-diary. 
x For culture and sensitivity testing; ova, parasites, and Clostridium difficile toxin testing.
y Sample analyses may include, but are not limited to, analyses of fecal calprotectin, and other exploratory PD biomarkers (such as analyses of 
the microbiota and bacterial cultures).
z 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.  
aa 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.
bb In addition to the optional biopsy noted in footnote “z” and “aa” above, five pairs (10 biopsy samples) will be obtained at screening (all taken from 
the most inflamed area of colon within 2040 cm of anal verge [sigmoid]).  These five biopsy pairs will be sent to the central laboratory for further 
storage or distribution.  Two pairs will be placed in stabilization buffer (such as RNAlater or a similar buffer) and stored at 80C (one pair for 
diagnostic qPCR and one pair for PD biomarkers qPCR).  In the United Kingdom (U.K.) sites only, one of the latter pair of biopsies (two samples) 
will be placed in storage solution and shipped at 4°C to the U.K. laboratory.  The other three pairs will be placed in formalin and then paraffin 
embedded; these biopsy samples will be used for exploratory PD biomarkers and/or diagnostic biomarkers.  Original biopsy location and 
endoscopic depth should be clearly indicated.
cc A total of four pairs (8 biopsy samples) will be obtained from all patients (all taken from the most inflamed area of colon within 2040 cm of anal 
verge [sigmoid]).  All will be sent to the central laboratory for further storage or distribution.  Two pairs will be placed in a stabilization buffer (such 
as RNAlater or a similar buffer) and stored at 80C for exploratory PD biomarker and/or diagnostic biomarker qPCR.
In the U.K. sites only, one of the latter pair of biopsies (two samples) will be placed in storage solution and shipped at 4°C to the U.K. laboratory.
The other two pairs will be placed in formalin and then paraffin; these biopsy samples will be used for exploratory PD biomarkers and/or 
diagnostic biomarkers.  Original biopsy location and endoscopic depth should be clearly indicated.
dd Paxgene blood RNA samples must be collected after all other blood and serum samples.
ee With the exception of Week 0, the IBDQ and EQ-5D will be completed in-clinic by the patient before any other non-PRO assessments and before 
the patient receives any disease-status information or study drug during that visit.
ff Where indicated, patients must be instructed to administer study drug at home within 3 days (maximum) after clinic visit.
gg
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
39/Statistical Analysis Plan GA29103
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)

Oral corticosteroid taper starts at Week 10 for patients on CS at baseline
Prohibited
Any use of other immunosuppressants, including:

TNF inhibitors and biosimilars thereof

Cyclosporine, tacrolimus, sirolimus, or MMF

Anti-adhesion molecules, including natalizumab and vedolizumab

Other biologics, such as efalizumab, alemtuzumab, visilizumab and rituximab, 
anakinra, abatacept, tocilizumab.

Other investigational agents, including vaccines (e.g., MAP or ChAdOx2 HAV, 
Janus kinase (JAK) inhibitors)
Patients receiving prohibited rescue therapy during the study should withdraw from 
the study and not receive further treatment including OLE
5-ASA5-aminosalicylic acid; 6-MP6-mercaptopurine ; AZAazathioprine; CScorticosteriods; 
ChAdOx2 HAVchimpanzee adenovirus Oxford 2 Hepatitis A vaccine; JAKJanus kinase; 
MAPMycobacterium avium subspecies paratuberculosis; MMFmycophenolate mofetil; 
MTXmethotrexate; OLEopen label extension; TNFtumor necrosis factor; UCulcerative colitis


Etrolizumab—F. Hoffmann-La Roche Ltd
40/Statistical Analysis Plan GA29103
Appendix 4 Per Protocol Population (Exclusion Criteria)
Patients will be excluded from the PP population if they are captured in the Protocol 
Deviation Management System (PDMS) under the following subcategories.  The 
subcategories listed below are based on the latest Study GA29103 Protocol 
(Version 7.0).  This is to ensure patients are excluded using the same criteria to allow for 
consistency in handling of patients within the PP population.  For some subcategories 
whether a patient is excluded from the PP population is time dependent (prior to 
Week 10) as the analysis being conducted on the PP population is at Week 10.
Category
Subcategory 
Time Dependent
Exclusion criteria
Agents that deplete B or T cells within 12 months
Exclusion criteria
Any diagnosis of Crohn's disease
Exclusion criteria
Any investigational treatment/vaccines within 12 w (till 
PA v5)
Exclusion criteria
Any prior treatment with anti-adhesion molecules
Exclusion criteria
Any prior treatment with other anti-integrin
Exclusion criteria
Any prior treatment with rituximab
Exclusion criteria
Any stricture (stenosis) of the colon
Exclusion criteria
Apheresis within 2 weeks prior to Day 1
Exclusion criteria
Corticosteroid enem/suppo & or topical 5 ASA 2Wks
Exclusion criteria
CS enem/suppo and or topical 5 ASA <= 2 wks
Exclusion criteria
Diagnosis of indeterminate colitis
Exclusion criteria
Diagnosis of toxic megacolon within 12 months
Exclusion criteria
IV steroids use within 30 days prior to screening
Exclusion criteria
Microscopic colitis
Exclusion criteria
Past or present ileostomy or colostomy
Exclusion criteria
Patients who are currently using anticoagulants
Exclusion criteria
Planned surgery for UC
Exclusion criteria
Prior extensive colonic resection
Exclusion criteria
Radiation colitis
Exclusion criteria
Subtotal or total colectomy


Etrolizumab—F. Hoffmann-La Roche Ltd
41/Statistical Analysis Plan GA29103
Appendix 4 Per Protocol Population (Exclusion Criteria) (cont.)
Category
Subcategory
Time Dependent
Exclusion criteria
Suspicion of ischemic colitis
Exclusion criteria
Tube feeding not discontinued 3 weeks
Exclusion criteria
Use of Chronic nonsteroidal anti-inflammatory drug
Exclusion criteria
Use of cyclosporine within 4 weeks prior to Day 1
Exclusion criteria
Use of mycophenolate mofetil (MMF) within 4 weeks
Exclusion criteria
Use of sirolimus within 4 weeks prior to Day 1
Exclusion criteria
Use of tacrolimus within 4 weeks prior to Day 1
Exclusion criteria
Evidence/treatment for Clostridium within 60 days
Exclusion criteria
Evidence/treatment for CMV colitis within 60d (V3)
Exclusion criteria
Treatment for intestinal pathogens within 30d
Exclusion criteria
Treatment with > 10 mg/day of prednisone or equal
Inclusion criteria
Able and willing to provide written IC
Inclusion criteria
Active UC with a rectal bleeding subscore 1
Inclusion criteria
Active UC with a stool frequency of 1
Inclusion criteria
Active UC with an endoscopic subscore 2
Inclusion criteria
Moderately to severely active UC  with MCS 6-12
Inclusion criteria
Diagnosis of UC at least 3 months prior to day1 (V7)
Inclusion criteria
Diagnosis of UC not confirmed prior to day 1
Inclusion criteria
Initiated CS, Stable/oral CS 30 mg qd for 4 w
Inclusion criteria
Initiated, Stable/oral CS <=30 mg qd for 4 w
Inclusion criteria
Naive to treatment with anti TNF/inhibitors therapy
Inclusion criteria
Naive to treatment with TNFInhibitor therapy
Inclusion criteria
Pts must had inad.Resp./LOR, or intol. to prior IS and/or 
corticosterois treatment
Inclusion criteria
Stable Immunosuppressant for 8 wks prior to D1
Inclusion criteria
Stable budesonide/MMX at 9 mg/day for 4 wks
Inclusion criteria
Stable doses  of probiotics for 2 W prior to D1
Inclusion criteria
Stable doses of oral 5 ASA compounds for 4 wks
Inclusion criteria
Tapered CS, Stable/oral CS<=30 mg qd for 2 w
Medication
Error in Study Drug Administration
Y
Medication
Overdose of study medication
Y
Medication
Patient/site staff with blinding being compromised
Y
Medication
Received incorrect study medication/incorrect Kit
Y
Medication
Three consecutive missed doses of study drug
Y
Medication
Treatment with any other investigational agent 
Y
Medication
Treatment with any prohibited therapies
Y


Etrolizumab—F. Hoffmann-La Roche Ltd
42/Statistical Analysis Plan GA29103
Appendix 4 Per Protocol Population (Exclusion Criteria) (cont.)
Category
Subcategory 
Time Dependent
Medication
Use of anakinra and abatacept during the study
Y
Procedural
Colonic mucosal dysplasia but treatment not discon
Y
Procedural
De novo viral infection but treatment NOT discont.
Y
Procedural
Major UC related surgery but study treat. Not disc
Y
Procedural
Missing MCS at defined timepoints
Y
Procedural
Non-compliance with daily/home e-diary within 7 d
Y
Procedural
Patient Non-compliance with study protocol
Y
Procedural
Patients who miss one endoscopy at EP assessment
Y
Procedural
Reactivated serious VI BUT treatment NOT discont. 
(Viral Infection)
Y
Procedural
Rescreening procedures not completed
Procedural
Rescreening tests/procedures not completed- updates 
in ( PA v 4)
Procedural
Sigmoidoscopy not done at week 10
Y
Procedural
Stable doses of immunosuppressants throughout the 
study (V3)
Y
Procedural
Video unreadable
Y


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


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


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


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


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


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GLOSSARY OF ABBREVIATIONS
WOCF Worse Observation Carried Forward


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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Appendix 6 Ulcerative Colitis Patient Reported Outcomes Signs 
and Symptoms
UC-PRO/SS 
Domain
Question
Response to 
Question
Functional
Symptoms
In the past 24 hours, did you pass gas?
0No
1Rarely 
2Sometimes 
3Often 
4Very often
In the past 24 hours, did you feel pain in your belly?
0No
1Mild 
2Moderate 
3Severe 
4Very Severe
In the past 24 hours, did you feel bloating in your belly?
0No
1Mild 
2Moderate 
3Severe 
4Very Severe


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


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