Clinical trial NCT02403323
Conditions: Crohn Disease
Sponsor: Hoffmann-La Roche
Start date: 2015-06-08; Completion date: 2023-10-09
Enrollment: 790 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This open-label extension and safety monitoring study is composed of two parts: Part 1 will evaluate the long-term safety and efficacy of continued etrolizumab treatment in participants with moderately to severely active Crohn's disease who were previously enrolled in the etrolizumab Phase III Study GA29144 (NCT02394028) and who meet eligibility criteria for enrollment into Part 1. In Part 2, participants who have stopped etrolizumab treatment (either by exiting Part 1 of this study or by entering directly from Study GA29144 \[NCT02394028\]) will be monitored for 92 weeks for progressive multifocal leukoencephalopathy (PML) and other safety events.

Detailed description:

Arms: arm 1: Participants will receive open-label treatment with etrolizumab once every 4 weeks until commercial availability in their country or sponsor's decision to terminate the study, whichever is earlier (up to approximately 10 years after the first patient is enrolled). arm 2: Participants who have stopped etrolizumab treatment (either by exiting Part 1 of this study or by entering directly from Study GA29144 \[NCT02394028\]) will be monitored for 92 weeks for progressive multifocal leukoencephalopathy (PML) and other safety events.
Interventions: intervention 1: Etrolizumab
Intervention descriptions: intervention 1: 105 mg etrolizumab subcutaneous administration once every 4 weeks

Protocol documents:
Prot_000.pdf: 
Official Title: 
An Open-Label Extension and Safety Monitoring Study of Patients 
With Moderately to Severely Active Crohn's Disease Previously 
Enrolled in the Etrolizumab Phase III Protocol GA29144 
NCT Number: 
NCT02403323 
Document Date: 
Protocol Version 6: 29-April-2019 


FINAL PROTOCOL APPROVAL 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Etrolizumab—F. Hoffmann-La Roche Ltd 
Protocol GA29145, Version 6 
PROTOCOL 
TITLE: 
AN OPEN-LABEL EXTENSION AND SAFETY 
MONITORING STUDY OF PATIENTS WITH 
MODERATELY TO SEVERELY ACTIVE 
CROHN’S DISEASE PREVIOUSLY ENROLLED 
IN THE ETROLIZUMAB PHASE III 
PROTOCOL GA29144 
PROTOCOL NUMBER: GA29145 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2014-003855-76 
IND NUMBER: 
119725 
TEST PRODUCT: 
Etrolizumab (PRO145223; RO5490261) 
MEDICAL MONITOR: 
, M.D., M.S. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  22 October 2014  
DATE AMENDED: 
Version 2:  9 December 2014 
Version 3:  4 November 2015 
Version 4: 16 December 2016 
Version 5:  14 May 2018 
Version 6:  See electronic date stamp below 
 
 
29-Apr-2019 19:52:54
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Etrolizumab—F. Hoffmann-La Roche Ltd
2/Protocol GA29145, Version 6
PROTOCOL AMENDMENT, VERSION 6:
RATIONALE
Protocol GA29145 has been amended primarily to address a change in the parent study 
GA29144.  Changes to the protocol, along with a rationale for each change, are 
summarized below: 

The duration of Part 1 of Study GA29145 has been changed from 6.5 years to 
approximately 10 years to better ensure continued availability (prior to commercial 
availability) of open-label etrolizumab for the treatment of Crohn’s disease
(Sections 3.1.2 and 3.2).

Eligibility criteria have been changed to account for the closure of enrollment into
the Maintenance Phase in parent study GA29144 after the projected sample size for 
the Maintenance Phase has been achieved.  Patients in Study GA29144 who 
complete the Induction Phase through Week 14 after closure of enrollment into the 
Maintenance Phase of Study GA29144 may enroll directly into this study, if eligible, 
as re-randomization into the Maintenance Phase will no longer be possible 
(Section 4.1.1).

Antagonists of IL-12 IL-23 (e.g., ustekinumab) have been added to the list of 
concommitant therapies prohibited for enrollment and during the study (Sections 
4.1.2 and 4.3.2).

Reference to patients with significant liver function test abnormalities has been 
removed from Section 5.1.1.3 as it is not applicable to this study.

Language related to safety monitoring for special situations, which had been 
modified in the last amendment (Version 5), has been reverted back to original 
protocol text for alignment with a GCP council decision to not implement those 
modifications for ongoing studies.  Sections have been renumbered accordingly
(Sections 5.4.6.12, 5.5, and 5.5.4). 
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.


TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................ 9
PROTOCOL SYNOPSIS .................................................................................... 10
1.
BACKGROUND .......................................................................................... 17
1.1
Background Crohn’s Disease ................................................ 17
1.2
Background on Etrolizumab................................................... 19
1.3
Study Rationale and Benefit-Risk Assessment...................... 20
1.3.1
Study Rationale for Part 1 (Open-Label 
Extension or “OLE”)............................................................... 20
1.3.2
Study Rationale for Part 2 (Safety Monitoring or 
“SM”)...................................................................................... 20
1.3.3
Benefit-Risk Assessment....................................................... 20
1.3.4
Rationale for Test Product Dosage........................................ 23
2.
OBJECTIVES.............................................................................................. 24
2.1
Objectives of the Study.......................................................... 24
2.2
Other Safety Objectives......................................................... 24
2.3
Exploratory Objective of the Study ........................................ 24
3.
STUDY DESIGN......................................................................................... 24
3.1
Description of Study .............................................................. 24
3.1.1
Overview of Study Design ..................................................... 24
3.1.2
Overview of Part 1 (OLE)....................................................... 25
3.1.3
Overview of Part 2 (SM) ........................................................ 26
3.1.4
Number of Patients................................................................ 29
3.2
Study Duration....................................................................... 29
3.2.1
End of Study.......................................................................... 29
3.3
Outcome Measures ............................................................... 29
3.3.1
Efficacy Outcome Measures (Part 1; OLE)............................ 29
3.3.2
Safety Outcome Measures (Part 1; OLE) .............................. 30
3.3.3
Safety Outcome Measure (Part 2; SM).................................. 30
3.3.4
Exploratory Outcome Measures (Part 1; OLE) ...................... 31


Etrolizumab—F. Hoffmann-La Roche Ltd
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4.
MATERIALS AND METHODS .................................................................... 31
4.1
Patients.................................................................................. 31
4.1.1
Inclusion Criteria.................................................................... 31
4.1.2
Exclusion Criteria................................................................... 32
4.2
Study Treatment.................................................................... 33
4.2.1
Formulation, Packaging, and Handling.................................. 33
4.2.2
Dosage, Administration, and Compliance.............................. 34
4.2.3
Investigational Medicinal Product Accountability ................... 36
4.2.4
Assessment of Compliance ................................................... 37
4.2.5
Destruction of the Investigational Medicinal 
Product .................................................................................. 37
4.2.6
Reporting of Prefilled Syringe Complaints/Events ................. 38
4.3
Concomitant Therapy ............................................................ 38
4.3.1
Permitted Therapy................................................................. 38
4.3.2
Prohibited Therapy ................................................................ 39
4.4
Study Assessments ............................................................... 39
4.4.1
Assessments during the Study .............................................. 39
4.4.2
Assessments at Unscheduled Visits in OLE 
(Part 1) and in 12-Week Safety Follow-Up ............................ 40
4.4.3
Assessments at Early Withdrawal ......................................... 41
4.4.4
Description of Study Assessments in Part 1 (OLE)
.............................................................................................. 41
4.4.4.1
Physical Examinations........................................................... 41
4.4.4.2
Vital Signs.............................................................................. 42
4.4.4.3
Crohn’s Disease Activity Assessments.................................. 42
4.4.4.4
Ileocolonoscopy with Biopsies............................................... 43
4.4.4.5
Progressive Multifocal Leukoencephalopathy 
Assessment........................................................................... 44
4.4.4.6
Pregnancy Testing................................................................. 45
4.4.4.7
Laboratory Assessments ....................................................... 45
4.4.4.8
Electrocardiograms................................................................ 46
4.4.4.9
Concomitant Medications ...................................................... 46
4.4.4.10
Adverse Events ..................................................................... 46
4.4.5
Description of Study Assessments in Part 2 (SM) ................. 46


Etrolizumab—F. Hoffmann-La Roche Ltd
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4.5
Patient, Study, and Site Discontinuation................................ 47
4.5.1
Patient Discontinuation.......................................................... 47
4.5.1.1
Withdrawal from Study........................................................... 47
4.5.2
Discontinuation from Study Drug........................................... 47
4.5.3
Study and Site Discontinuation.............................................. 48
5.
ASSESSMENT OF SAFETY....................................................................... 48
5.1
Safety Plan (Part 1, OLE) ...................................................... 48
5.1.1
Potential Risks for Etrolizumab.............................................. 48
5.1.1.1
Serious Infections.................................................................. 49
5.1.1.2
Hypersensitivity Reactions..................................................... 52
5.1.1.3
Hepatic Effects ...................................................................... 53
5.1.1.4
Local Injection-Site Reactions ............................................... 53
5.1.1.5
Malignancies.......................................................................... 53
5.1.1.6
Immunogenicity ..................................................................... 54
5.1.1.7
Decreased Effectiveness of Immunizations........................... 54
5.1.2
Risks Associated with Worsening of Crohn’s 
Disease.................................................................................. 55
5.1.3
Data Monitoring Committee................................................... 55
5.2
Safety Plan (Part 2, SM)........................................................ 55
5.3
Safety Parameters and Definitions ........................................ 56
5.3.1
Adverse Events ..................................................................... 56
5.3.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 57
5.3.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 58
5.4
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 58
5.4.1
Adverse Event Reporting Period for Part 1 (OLE) ................. 58
5.4.2
Adverse Event Reporting Period for Part 2 (SM)................... 59
5.4.3
Eliciting Adverse Event Information in Part 1 
(OLE)..................................................................................... 60
5.4.4
Assessment of Severity of Adverse Events ........................... 60
5.4.5
Assessment of Causality of Adverse Events ......................... 61
5.4.6
Procedures for Recording Adverse Events............................ 61


Etrolizumab—F. Hoffmann-La Roche Ltd
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5.4.6.1
Injection-Site Reactions......................................................... 62
5.4.6.2
Diagnosis versus Signs and Symptoms................................. 62
5.4.6.3
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 63
5.4.6.4
Persistent or Recurrent Adverse Events................................ 63
5.4.6.5
Abnormal Laboratory Values ................................................. 64
5.4.6.6
Abnormal Vital Sign Values ................................................... 64
5.4.6.7
Abnormal Liver Function Tests.............................................. 65
5.4.6.8
Deaths ................................................................................... 65
5.4.6.9
Preexisting Medical Conditions.............................................. 66
5.4.6.10
Lack of Efficacy or Worsening of Crohn’s 
Disease.................................................................................. 66
5.4.6.11
Hospitalization or Prolonged Hospitalization.......................... 66
5.4.6.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 67
5.4.6.13
Patient-Reported Outcome Data ........................................... 67
5.5
Immediate Reporting Requirements from 
Investigator to Sponsor during Part 1 (OLE) and 
Part 2 (SM) ............................................................................ 68
5.5.1
Emergency Medical Contacts................................................ 68
5.5.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 69
5.5.3
Reporting Requirements for Pregnancies.............................. 69
5.5.3.1
Pregnancies in Female Patients............................................ 69
5.5.3.2
Pregnancies in Female Partners of Male Patients................. 70
5.5.3.3
Abortions ............................................................................... 70
5.5.3.4
Congenital Anomalies/Birth Defects ...................................... 70
5.5.4
Reporting Requirements for Prefilled Syringe 
Complaints/Events................................................................. 71
5.6
Follow-Up of Patients after Adverse Events .......................... 71
5.6.1
Investigator Follow-Up........................................................... 71
5.6.2
Sponsor Follow-Up ................................................................ 71
5.7
Post-Study Adverse Events................................................... 72
5.7.1
Post-Study Adverse Events Part 1 (OLE).............................. 72
5.7.2
Post-Study Adverse Events Part 2 (SM)................................ 72


Etrolizumab—F. Hoffmann-La Roche Ltd
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5.8
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 72
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 73
6.1
Number of Patients................................................................ 74
6.2
Summaries of Conduct of Study............................................ 74
6.3
Safety Analyses for Part 1 (OLE)........................................... 74
6.3.1
Adverse Events ..................................................................... 74
6.3.2
Laboratory Tests.................................................................... 75
6.4
Safety Analyses for Part 2 (SM) ............................................ 75
7.
DATA COLLECTION AND MANAGEMENT ............................................... 75
7.1
Data Quality Assurance......................................................... 75
7.2
Electronic Case Report Forms............................................... 75
7.3
Electronic Patient-Reported Outcome Data........................... 76
7.4
Source Data Documentation.................................................. 76
7.5
Use of Computerized Systems .............................................. 77
7.6
Retention of Records............................................................. 77
8.
ETHICAL CONSIDERATIONS.................................................................... 77
8.1
Compliance with Laws and Regulations ................................ 77
8.2
Informed Consent.................................................................. 78
8.3
Institutional Review Board or Ethics Committee.................... 79
8.4
Confidentiality........................................................................ 79
8.5
Financial Disclosure .............................................................. 80
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 80
9.1
Study Documentation ............................................................ 80
9.2
Protocol Deviations................................................................ 80
9.3
Site Inspections ..................................................................... 80
9.4
Administrative Structure......................................................... 80
9.5
Publication of Data and Protection of Trade 
Secrets .................................................................................. 81
9.6
Protocol Amendments ........................................................... 81
10. REFERENCES ........................................................................................... 82


Etrolizumab—F. Hoffmann-La Roche Ltd
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LIST OF TABLES
Table 1
Efficacy Outcome Definitions ...................................................... 30
Table 2
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 60
Table 3
Causal Attribution Guidance ....................................................... 61
LIST OF FIGURES
Figure 1
Study Schema for Part 1 (Open-Label Extension; OLE) of 
the OLE-SM Study...................................................................... 27
Figure 2
Study Schema for Part 2 (Safety Monitoring; SM) of the 
OLE-SM Study............................................................................ 28
LIST OF APPENDICES
Appendix 1
Open-Label Extension (OLE, Part 1) Schedule of 
Assessments............................................................................... 85
Appendix 2
12-Week Safety Follow-Up (OLE, Part 1) Schedule of 
Assessments............................................................................... 89
Appendix 3
Extended Progressive Multifocal Leukoencephalopathy 
Safety Monitoring (SM, Part 2) Schedule of Assessments.......... 90
Appendix 4
Childbearing Potential, Pregnancy Testing, and 
Contraception.............................................................................. 91
Appendix 5
Crohn’s Disease Activity Index.................................................... 93
Appendix 6
Abdominal Pain Questionnaire (APQ)......................................... 94
Appendix 7
Bristol Stool Form Scale ............................................................. 95
Appendix 8
Worksheet for the PML Neurologic Examination......................... 96
Appendix 9
Algorithm for the Evaluation of Progressive Multifocal 
Leukoencephalopathy............................................................... 103
Appendix 10
Clinical Criteria for Diagnosing Anaphylaxis.............................. 104
Appendix 11
Simple Endoscopic Score for Crohn’s Disease (SES-CD)........ 105


Etrolizumab—F. Hoffmann-La Roche Ltd
9/Protocol GA29145, Version 6 
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
AN OPEN-LABEL EXTENSION AND SAFETY 
MONITORING STUDY OF PATIENTS WITH 
MODERATELY TO SEVERELY ACTIVE 
CROHN’S DISEASE PREVIOUSLY ENROLLED 
IN THE ETROLIZUMAB PHASE III 
PROTOCOL GA29144
PROTOCOL NUMBER:
GA29145
VERSION NUMBER:
6
EUDRACT NUMBER:
2014-003855-76
IND NUMBER:
119725
TEST PRODUCT:
Etrolizumab (PRO145223; RO5490261)
MEDICAL MONITOR:
Young (Danny) Oh, M.D., M.S.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy to 
the Sponsor Representative. 


Etrolizumab—F. Hoffmann-La Roche Ltd
10/Protocol GA29145, Version 6
PROTOCOL SYNOPSIS
TITLE:
AN OPEN-LABEL EXTENSION AND SAFETY MONITORING 
STUDY OF PATIENTS WITH MODERATELY TO SEVERELY 
ACTIVE CROHN’S DISEASE PREVIOUSLY ENROLLED IN THE 
ETROLIZUMAB PHASE III PROTOCOL GA29144
PROTOCOL NUMBER:
GA29145
VERSION NUMBER:
6
EUDRACT NUMBER:
2014-003855-76
IND NUMBER:
119725
TEST PRODUCT:
Etrolizumab (PRO145223; RO5490261)
PHASE:
III
INDICATION:
Crohn’s Disease
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
The objectives of this open-label extension-safety monitoring (OLE-SM) study are as follows:
Part 1 (Open-Label Extension; OLE)

To assess the long-term safety and efficacy of etrolizumab in patients eligible for
Part 1 (OLE)
Part 2 (Safety Monitoring; SM)

Progressive multifocal leukoencephalopathy (PML) safety monitoring in patients who have
stopped study treatment
Other Safety Objectives
The other safety objectives for this study are as follows:
Part 1 (OLE)

To evaluate the incidence, rate per subject-year, and severity of infection-related adverse
events

To evaluate the incidence and rate per subject-year of malignancies

To evaluate the incidence and severity of hypersensitivity reactions

To evaluate the incidence and the clinical significance of anti-therapeutic antibodies (ATAs)
Exploratory Objective of the Study
The exploratory objective for this study is as follows:
Part 1 (OLE)

To assess endoscopic appearance at Week 108


Etrolizumab—F. Hoffmann-La Roche Ltd
11/Protocol GA29145, Version 6
Study Design
Description of Study
This OLE-SM study is composed of two parts:

Part 1 is the OLE for eligible patients, during which etrolizumab, 105 mg subcutaneous (SC),
will be administered every 4 weeks (Q4W) followed by a 12-week safety follow-up
post-treatment.

Part 2 is the 92-week PML SM for all patients, during which no etrolizumab will be
administered.
Patients who are enrolled in Part 1 (OLE) should participate in Part 2 (SM).
There may be patients from Study GA29144 who are ineligible for or choose not to participate in 
Part 1 (OLE) who will be asked to directly enroll in Part 2 (SM).
Number of Patients
The OLE-SM study will be conducted in investigational sites that have participated in 
Study GA29144.  The maximum number of patients potentially enrolling in this study will be all 
patients from Study GA29144, approximately 1150 patients.  
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:
Part 1 (OLE)

Patients who were previously enrolled in Study GA29144 and experienced any of the
following:
CDAI score the baseline (Week 0) score 
CDAI score 100 points higher than the Week 14 score
Completed the Maintenance Phase including the Week 66 or Week 74 clinic visit in 
Study GA29144

Ability and willingness to provide written informed consent and comply with the
requirements of the OLE-SM protocol.

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 to use a highly effective method of contraception (e.g., combined oral
contraceptive pill or transdermal patch, spermicide and barrier [condoms], intrauterine
device, implants for contraception, injections for contraception [with prolonged release],
hormonal vaginal device, sterilization, or surgical tubal ligation) during the treatment period
and for at least 24 weeks after the last dose of study drug.
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.
Disease worsening in the Induction Phase of Study GA29144, defined as both Crohn’s 
Disease Activity Index (CDAI) and Patient-Reported Outcomes-2 (PRO2) scores at 
Week 10 or later in the Induction Phase being greater than the patient’s baseline 
(Week 0) score  
Not eligible for the Maintenance Phase in Study GA29144 
Completed the Week 14 visit in Study GA29144 and could not subsequently enter 
the Maintenance Phase, because the sample size for the Maintenance Phase has been 
achieved 
A clinical relapse during the Maintenance Phase of Study GA29144, defined as 
meeting at least one of the following criteria on two consecutive visits (may include 
unscheduled visits), with at least one of the two consecutive CDAI scores ≥ 220:  


Etrolizumab—F. Hoffmann-La Roche Ltd
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
For men: agreement to remain abstinent or to use a condom, as well as not donate sperm,
during the treatment period and for at least 24 weeks after the last dose of study drug
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.
PART 2 (SM)

Patients who participated in Study GA29144 and are not eligible or chose not to enroll in
Part 1 (OLE)

Patients who participated in Part 1 (OLE) of this protocol

Ability and willingness to provide written informed consent and comply with the
requirements of Part 2 (SM) of the OLE-SM protocol
All patients must have completed the 12-week safety follow-up in either GA29144 or GA29145, 
Part 1 (OLE), as applicable, prior to entering Part 2 (SM).
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Part 1 (OLE)

Patients who leave Study GA29144 before Week 10

Patients who discontinue study drug in the Induction Phase of Study GA29144, except for
those escaping between and including Weeks 10 and 14 due to disease worsening

Inability to comply with the study protocol, in the opinion of the investigator

Pregnancy or lactation

Patients who developed an anaphylactic/anaphylactoid or severe allergic reaction to study
medication during Study GA29144

Patients who have an untreated or unresolved serious infection event

Patients who experienced a de novo or reactivated serious viral infection such as hepatitis
B virus (HBV), hepatitis C virus (HCV), or HIV during Study GA29144

Patients who developed cytomegalovirus (CMV) colitis leading to early treatment
discontinuation during Study GA29144

Patients who developed life-threatening infections during Study GA29144

Patients who developed a malignancy (with the exception of local and resected basal or
squamous cell carcinoma of the skin) or who develop adenocarcinoma in situ (AIS),
high-grade squamous intraepithelial lesions (HSIL), or cervical intraepithelial neoplasia (CIN)
of Grade 1 on cervical Pap smear or who develop colonic dysplasia during
Study GA29144

Receipt of the following prohibited medications since commencement of Study GA29144:
Any investigational treatment, including investigational vaccines
Use of T or B cell depleting agents (e.g., rituximab, alemtuzumab, or visilizumab), with
the exception of azathioprine (AZA) and 6-mercaptopurine (6-MP), or equivalent
Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF)
Use of natalizumab or vedolizumab
Use of TNF antagonists
Use of antagonists of IL-12 IL-23 (e.g., ustekinumab)
Immunization with a live/attenuated vaccine
Use of anti-adhesion molecules (e.g., anti-MAdCAM-1)


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
In the opinion of the investigator, any new (since enrolling in Study GA29144), significant,
uncontrolled comorbidity, such as neurological, cardiac (e.g., moderate to severe heart
failure New York Heart Association [NYHA] Class III/IV), pulmonary, renal, hepatic,
endocrine, or gastrointestinal (GI) disorders (excluding CD)

Any patient who developed PML in Study GA29144

Any patient with neurological symptoms where suspected PML has not been ruled out
Part 2 (SM)

No exclusion criteria
Length of Study
Patients will be enrolled into this study from Study GA29144.  Part 1 (OLE) of OLE-SM will 
continue for up to approximately 10 years after the first patient is enrolled into the study, until 
commercial availability, or until the Sponsor’s decision to terminate the study, whichever is 
earlier.  Following Part 1 (OLE), patients will enter Part 2 (SM) for a period of 92 weeks.  The 
study will end when the last patient has the final telephone visit in Part 2 (SM).
End of Study
The end of the study is defined as the date when the last patient completes the 92-week PML 
safety-monitoring period.
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:
Part 1 (OLE)

CDAI remission assessed at 12-week intervals during Part 1 (OLE)

Clinical remission assessed at 12-week intervals during Part 1 (OLE), as defined by a stool
frequency (SF) mean daily score ≤3 and an abdominal pain (AP) mean daily score ≤1 with
no worsening in either subscore compared to baseline, averaged over 7 days prior to visit

Simplified Endoscopic Score for Crohn’s disease (SES-CD) score assessed at Week 108 or
at early withdrawal, if prior to Week 108, during Part 1 (OLE)
Safety Outcome Measures
The safety outcome measures for this study are as follows:
Part 1 (OLE)

Incidence and severity of adverse events

Incidence of serious adverse events

Incidence, rate per subject-year, and severity of infection-related adverse events

Incidence of serious infection-related adverse events

Incidence and severity of injection-site reactions

Incidence of adverse events leading to etrolizumab discontinuation

Incidence of laboratory abnormalities

Incidence and rate per subject-year of malignancies

Incidence of ATAs to etrolizumab

Incidence and severity of hypersensitivity reactions
Part 2 (SM)

Incidence of suspected or confirmed PML events


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Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows:
Part 1 (OLE)

SES-CD ≤4 (≤2 for ileal patients), with no segment having a subcategory score (i.e., for
ulceration size and extent, affected surface, or narrowing) that is >1, at Week 108

Change in SES-CD score between Week 0 (Study GA29144) and Week 108 or early
withdrawal (Study GA29145, Part 1; OLE)
Investigational Medicinal Products
Test Product
Etrolizumab prefilled syringe (PFS):  containing 105 mg will be administered by SC injection 
every 4 weeks.
Non-Investigational Medicinal Products
None
Statistical Methods
Primary Analysis
Because of the non-comparative character of the study, no statistical tests are planned; all 
efficacy parameters will be summarized descriptively.  Efficacy in Part 1 (OLE) will be assessed 
across visits using absolute values and change from baseline for continuous outcomes, and 
dichotomous data (e.g., CDAI remission, clinical remission) will be evaluated using frequency 
counts and proportions.  Demographic and baseline characteristics such as age, sex, race, 
region, use of corticosteroids and immunosuppressants, duration of disease, and CDAI, SF and 
AP scores will be summarized by use of descriptive statistics.
Determination of Sample Size  
The maximum number of patients enrolled in the OLE-SM study is approximately 1150 
(i.e., all patients enrolled in Study GA29144).  No formal sample size calculations were 
performed.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
6-MP
6-mercaptopurine
AIS
adenocarcinoma in situ
APQ
abdominal pain questionnaire
AP
abdominal pain
ATA
anti-therapeutic antibody
AZA
azathioprine
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
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
e-diary
electronic diary
ePRO
electronic patient-reported outcome
FDA
U.S. Food and Drug Administration
GI
gastrointestinal
HBV
hepatitis B virus
HCP
health care professional
HCV
hepatitis C virus
HIPAA
U.S. Health Insurance Portability and Accountability Act
HSIL
high-grade squamous intraepithelial lesion
IBD
inflammatory bowel disease
ICH
International Conference on Harmonisation
iDMC
independent Data Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IRB
Institutional Review Board
IV
intravenous
IxRS
interactive voice/Web-based response system
JCV
John Cunningham virus


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mAb
monoclonal antibody
MAdCAM-1
Mucosal addressin cell adhesion molecule 1
MOA
mechanism of action
MMF
mycophenolate mofetil
MRI
magnetic resonance imaging
MTX
methotrexate
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
OLE
open-label extension
OLE-SM
open-label extensionsafety monitoring 
PCR
polymerase chain reaction
PFS
prefilled syringe
PML
progressive multifocal leukoencephalopathy
PRO
patient-reported outcome
Q4W
every 4 weeks
RCR
Roche Clinical Repository
SC
subcutaneous
SES-CD
Simple Endoscopic Score for Crohn’s disease
SF
stool frequency
SM
safety monitoring
SUSAR
suspected unexpected serious adverse reaction
TNF
tumor necrosis factor
TNF-IR
non-responsive or refractory to anti-TNF therapy
UC
ulcerative colitis
ULN
upper limit of normal


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1.
BACKGROUND
1.1
BACKGROUND CROHN’S DISEASE 
Crohn’s disease (CD) is a chronic, relapsing inflammatory bowel disease (IBD) that can 
affect any portion of the gastrointestinal tract, with 40%50% of cases affecting the small 
bowel.  CD is characterized by patchy, transmural inflammation, ulcers, and 
granulomatous lesions that are interspersed with healthy sections of bowel (skip lesions).  
The disease is progressive; uncontrolled inflammation develops into stricturing or 
penetrating complications such as prestenotic dilatation, obstruction (stricturing), and 
intra-abdominal or perianal fistula and abscesses (penetrating).  Clinical signs and 
symptoms include chronic diarrhea, abdominal pain, cachexia, abdominal mass, or 
tenderness as well as the overt signs of fistulae. The disease course is variable; 
patients can experience a severe initial flare followed by few symptoms over the next 
10 years (43%), symptoms that are chronic and persistent (19%), or relapsing-remitting 
(32%) (Baumgart and Sandborn 2012).
The annual incidences of CD reported in Europe, Asia and the Middle East, and North 
America were 12.7, 5.0, and 20.2 per 100,000 person-years, respectively 
(Molodecky et al. 2012).  Current prevalence rates in North America are reported to be
319 per 100,000 persons (Molodecky et al. 2012).  Disease-related mortality in CD 
accounts for approximately 30% of deaths in this population, resulting from clinical 
and/or surgical complications that occur early in the disease course or intestinal cancer 
occurring later.  The global incidence of CD is expected to continue increasing 
substantially, affecting individuals in the most formative and productive years of life, with 
long-term costs to patients, healthcare systems, and society (Duricova et al. 2010).
So far, there is no cure for CD.  The treatment goals for CD are to induce and maintain 
symptom improvement, induce mucosal healing, avoid surgery, and improve quality of 
life (Lichtenstein et al. 2009; Van Assche et al. 2010).
Systemic corticosteroids have been the mainstay treatment for inducing remission and 
are effective in approximately 80% of patients (Summers et al. 1979; 
Malchow et al. 1984).  However, they are less effective as a maintenance therapy, with 
only 28% of patients achieving a prolonged response after 1 year of treatment and 32% 
of patients becoming steroid dependent (Faubion et al. 2001; Peyrin-Biroulet et al. 2010).  
Even if patients’ symptoms improve, fewer than 30% are expected to achieve 
endoscopic improvement with steroid treatment (Modigliani et al. 1990).  The adverse 
effects of steroids are well documented, and 50% of patients will stop their treatment 
because of this; long-term safety outcomes include osteoporosis, cataracts, and 
diabetes.
Immunosuppressants (e.g., azathioprine [AZA], 6-mercaptopurine [6-MP], or 
methotrexate [MTX]) are typically administered to induce remission in patients who are 
intolerant of or refractory to steroids and to maintain remission in patients who achieve 


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quiescent CD.  Immunosuppressants are given with or without a steroid bridge, 
depending on a patient’s symptoms during the 24-month onset of immunosuppressant 
efficacy.  In patients with ileal or ascending colonic disease, budesonide presents a less 
toxic, more tolerable bridge because of its low systemic bioavailability resulting from a 
rapid first-pass metabolism.  An earlier initiation of immunosuppressant to alter the 
inflammatory disease course has been advocated over the past 20 years.  However, a 
decrease in the rate of intestinal resections and complications has not been observed 
during this time (Cosnes et al. 2005).  This may reflect poor adoption of this top-down 
treatment over concern for systemic toxicities, including leukopenia, thrombocytopenia, 
and increased risk for lymphoma with AZA and 6-MP (Prefontaine et al. 2009) and 
hepatotoxicity and hair loss with MTX (Hausmann et al. 2010).
The development of monoclonal antibodies (mAbs) against tumor necrosis factor 
(TNF)has provided an additional treatment option.  Although anti-TNFs are effective 
in a significant proportion of patients, efficacy is suboptimal; remission rates after 
4 weeks of induction therapy are fewer than 35%, and among patients who respond to 
induction therapy, fewer than 50% achieve remission when assessed in maintenance at 
2030 weeks (Peyrin-Biroulet et al. 2011).  Furthermore, 30% of patients are reported to 
be primary non-responders to anti-TNF therapy when assessed after 4 weeks of 
induction therapy (Targan et al. 1997; Sandborn et al. 2007), possibly because of an 
underlying pathobiology that is not TNF-driven and as such may benefit from a 
different mechanistic class of drug.  It is estimated that 30%40% of patients will be 
secondary non-responders (i.e., initially responsive), but lose response or become 
intolerant in their first year of treatment (Colombel et al. 2007).  Secondary non-response 
has been attributed to the development of neutralizing antibodies, resulting in low drug 
serum levels, to accelerated drug clearance, or to a biological escape mechanism that 
may benefit from a therapy with a different pharmacological target.  These agents are 
also associated with significant side effects, including serious infection, opportunistic 
infection, lupus-like reactions, and an increased risk of lymphoma (Siegal et al. 2009).  
Tolerability concerns include infusion reactions (occurring in 9%17% of patients treated 
with infliximab, de Vries et al. 2011) and injection site reactions (occurring in 10% of 
patients receiving adalimumab, van der Heijde et al. 2006).  Overall, the benefits versus 
risks are considered acceptable for this drug class, but there continues to be a need for 
treatments with better benefit-risk profiles that attenuate inflammation and the clinical 
sequelae and improve the long-term prognosis of patients with CD.
The anti-integrins are another class of biologics approved for the treatment of CD.  
Natalizumab is an anti-integrin approved in the United States for the treatment of 
moderately to severely active CD.  The use of natalizumab, which blocks both 41 and 
47, has been limited because of concerns that inhibition of 41/VCAM-1 binding
increases the risk of progressive multifocal leukoencephalopathy (PML), a rare but
serious infection of the CNS.  Vedolizumab is the most recently approved gut-selective
anti-integrin for CD, but this targets only the α47 integrin receptor, inhibiting


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T-lymphocyte binding to the cell adhesion molecule MAdCAM-1, and is administered as
an intravenous (IV) infusion.  In the pivotal trials for vedolizumab, 31% of patients had a
clinical response with 6 weeks of induction treatment; up to 39% of the vedolizumab
responders achieved remission with 46 weeks of maintenance treatment, compared with
22% of patients given placebo (Sandborn et al. 2013).  While vedolizumab shows
promise as a new treatment for CD, there remains a need for a more convenient therapy
that is gut selective and achieves better response and remission rates.
1.2
BACKGROUND ON ETROLIZUMAB
Etrolizumab, a subcutaneously administered mAb, is a novel anti-integrin that, like 
vedolizumab, targets the 47 receptors that regulates trafficking of T-cell subsets in the 
intestinal mucosa, but unlike vedolizumab, etrolizumab also targets the E7 receptors 
that regulate retention of T-cell subsets in the intestinal mucosa.  Thus, etrolizumab 
offers the potential of an additive therapeutic effect in CD via a dual mechanism of action 
(MOA) without generalized immunosuppression. 
Etrolizumab is a humanized mAb based on the IgG1 subgroup-III VH, subgroup-I VL 
consensus sequences and is directed specifically against the 7 subunit of the integrin 
heterodimer (Andrew et al. 1994).  Etrolizumab binds with high affinity to 47 
(Holzmann et al. 1989; Hu et al. 1992) and E7 (Cepek et al. 1993).  By this 
mechanism, it blocks the homing and retention of leukocyte subpopulations in the 
intestinal mucosa that occur via binding with the cell adhesion molecules (MAdCAM-1) 
and E-cadherin, respectively.  As such, it represents a novel gut mucosalselective
anti-trafficking agent whose selectivity may eliminate generalized immunosuppression by 
preferentially targeting trafficking to the gut rather than to other organs and tissues.  
Data from multiple, non-clinical, general toxicity studies of up to 6 months’ duration 
demonstrated that etrolizumab had no adverse effects in any organ system.  In addition, 
etrolizumab had no adverse effects in the embryo fetal developmental toxicity studies or 
general reproductive toxicity study (see Etrolizumab Investigator’s Brochure).
It is important to note that unlike natalizumab, etrolizumab does not bind to 41 or 
inhibit either the interaction of 41 and VCAM-1 or the distribution and homing of 
lymphocytes to the CNS and peripheral lymphoid tissue (see Etrolizumab Investigator’s 
Brochure).  As such, etrolizumab is not expected to increase the risk of PML.  Safety 
assessments for etrolizumab have been completed in adult Phase I and Phase II studies, 
in which patients with moderately to severely active ulcerative colitis (UC) received either 
single or multiple doses of IV or subcutaneous (SC) etrolizumab.  Safety evaluation is 
ongoing in a Phase II open-label extension (OLE) study.  A total of 158 patients have 
been exposed to etrolizumab with no significant adverse safety signals, including any 
evidence of increased rates of serious or opportunistic infections, being associated with 
etrolizumab treatment.  No events of PML have been reported in patients treated with 
etrolizumab.


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1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
This open-label extensionsafety monitoring (OLE-SM) study consists of two parts.
1.3.1
Study Rationale for Part 1 (Open-Label Extension or “OLE”)
Part 1 (OLE) of this study is designed to assess the long-term safety and tolerability of 
105 mg SC etrolizumab every four weeks with regard to adverse events and laboratory 
abnormalities and to obtain long-term data on the efficacy and immunogenicity. 
Patients receiving etrolizumab or placebo in Study GA29144 may be eligible to 
participate and will receive etrolizumab in Part 1 (OLE) of this study.  Eligibility criteria 
and the timepoints for enrollment into the Part 1 (OLE) of this study are described in 
Section 4.1.1.
1.3.2
Study Rationale for Part 2 (Safety Monitoring or “SM”)
Part 2 (SM) of this study is designed to monitor for PML in patients who have stopped 
taking etrolizumab.  Patients who exit Part 1 (OLE) of this study will then enter 
Part 2 (SM) of this study for monitoring for events of PML.  In addition, all patients from 
Study GA29144 who do not enroll in Part 1 (OLE) of this study for continued etrolizumab 
treatment will be asked to enroll directly into Part 2 (SM) of this study for extended PML 
safety monitoring (following completion of the 12-week safety follow-up in 
Study GA29144).
1.3.3
Benefit-Risk Assessment
The current therapeutic options available for CD include corticosteroids, 
immunosuppressants, and biological agents. These treatments reduce symptoms and 
improve quality of life; however, patients often stop responding to treatments and the 
goals of maintaining clinical remission and healing mucosal inflammation are not 
achieved.  Moreover, these therapies are associated with adverse effects including 
diabetes (reported with corticosteroid use; Peyrin-Boulet et al. 2010), systemic toxicities 
such as leucopenia and thrombocytopenia (reported with immunosuppressant use; 
Prefontaine et al. 2009), and an increased risk for lymphoma and serious and 
opportunistic infections (reported with immunosuppressant and anti-TNF use when given 
as monotherapy or in combination; Siegal and Melmed 2009). 
The anti-integrins are another class of biologics approved for the treatment of CD.  The 
reported efficacy of the recently licensed anti-integrin vedolizumab, an intravenously 
administered anti-47 mAb, in CD demonstrates a role for 47 in the pathobiology of 
this disease (Sandborn et al. 2013).  In addition to demonstrating efficacy compared with 
placebo, vedolizumab had an acceptable safety profile in two Phase III trials for CD 
(Sandborn et al. 2013; Sands et al. 2014).  Although long-term safety data for 
vedolizumab are still being collected, to date no cases of PML attributed to vedolizumab
have been reported.  


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Similar to vedolizumab, etrolizumab is a gut-selective anti-integrin, which blocks homing 
of leukocyte subpopulations to the intestinal mucosa by blocking 47 integrin 
(see Etrolizumab Investigator’s Brochure).  In addition, etrolizumab may interfere with 
pathologic lymphocyte retention along the mucosa by blocking the interaction between 
E7 and E-cadherin.  Etrolizumab showed significant rates of remission at 10 weeks in
treating moderately to severely active UC when compared with placebo in the Phase II
Study ABS4986g (EUCALYPTUS study; Vermeire et al. 2014) and was associated with
ongoing high rates of clinical response among 108 of 124 patients from EUCALYPTUS
who received open-label etrolizumab after roll-over into the Phase II OLE SPRUCE
study (Study GA27927).
The most recent SPRUCE data cut (June 2014) demonstrates the median exposure to 
etrolizumab was 7.29 months, with 51% of patients experiencing at least 711 months 
of exposure and 11% experiencing at least 24 months.  In most cases, this duration 
of exposure to etrolizumab is in addition to 10 weeks of treatment with etrolizumab in the 
EUCALYPTUS study.  At the time of the data cut in this ongoing study, 80% of patients 
in SPRUCE experienced adverse events and 15% experienced at least one serious 
adverse event.  The most common adverse events were nasopharyngitis (occurring 
in 25% of patients), UC flare (23.1%), headache (12%), arthralgia, gastroenteritis, and 
upper respiratory tract infection (11.1% each).  
A potential safety risk associated with the use of anti-integrins includes the risk for 
infections related to gut-selective treatment blockade of lymphocyte trafficking and the 
potential for suppression of host defense against infectious pathogens.  However, an 
analysis of the EUCALYPTUS study showed that infection rates were similar between 
etrolizumab and placebo in the subgroups of patients taking concomitant 
immunosuppressant therapy and the subgroups not taking this concomitant treatment 
(see Etrolizumab Investigator’s Brochure).  A slightly higher rate of infection was 
observed during long-term exposure to etrolizumab in SPRUCE compared with 
EUCALYPTUS, but only 3 patients have discontinued from SPRUCE to date because of 
infection-related adverse events (see Etrolizumab Investigator’s Brochure).
Although the efficacy of etrolizumab has not been studied in patients with CD, 
preliminary expression studies of the pharmacological target for etrolizumab, the integrin 
7 receptor on gut CD4and CD8T cells isolated from resections of patients with UC
and patients with CD, show that expression levels are similar between both diseases.
In addition, because E expression is reportedly elevated in patients with CD
(Elewaut et al. 1998; Oshitani et al. 2003), with an observed increase in expression
from distal to proximal bowel, etrolizumab may bring enhanced efficacy in CD.  Given
the preliminary evidence of efficacy in patients with UC and that elements of
pathogenesis are shared across UC and CD, etrolizumab has the potential to be a novel,
effective treatment for CD and will be assessed as a treatment for patients who are
TNF-naive and patients who are non-responsive or refractory to anti-TNF therapy


(TNF-IR) with moderately to severely active CD in the combined Phase III, randomized, 
placebo-controlled induction and maintenance studies, Study GA29144.   
Patients who experience disease worsening that is confirmed at Week 10 in the 
Induction Phase of Study GA29144 will have the option of enrolling in Part 1 (OLE) of 
Study GA29145 between and including Weeks 10 and 14 of the Induction Phase.  
Patients who are not eligible for the Maintenance Phase may also have the option to 
enroll in Part 1 (OLE) of Study GA29145, if eligible.  During the Maintenance Phase in 
Study GA29144, patients will be able to withdraw and enter Part 1 (OLE) if they 
experience a clinical relapse (as defined in Section 4.1.1).  
Study GA29144 patients who experience disease progression or lack of response while 
assigned to placebo during either the Induction or Maintenance Phase are expected to 
benefit most from participation in Part 1 (OLE) of Study GA29145.  Patients who 
experienced disease progression or lack of response while assigned to etrolizumab in 
Study GA21944 may also experience treatment benefit by participating in Part 1 (OLE) 
depending on severity of disease and available treatment options, which include 
anticipated treatment benefit from rescue medication.  Consequently, eligible patients 
from Study GA29144 are encouraged to enroll in Part 1 (OLE) to receive open-label 
etrolizumab with rescue medications at the discretion of the investigator, including the 
use of concomitant immunosuppressant therapy.   
Patients may enter Part 1 (OLE) between Weeks 10 and 14 in Study GA29144, having 
received an induction regimen of either 210 mg or 105 mg etrolizumab.  Data from the 
SPRUCE OLE study, in which patients received either 100 mg etrolizumab every 
4 weeks (Q4W) or 300 mg etrolizumab Q4W (followed by a protocol-amendment driven 
reduction to 100 mg etrolizumab Q4W) after administration of placebo, 100 mg 
etrolizumab, or 300 mg etrolizumab (both are nominal doses) in the EUCALYPTUS 
Phase II study, showed that response and remission rates in SPRUCE were similar 
when the results were analyzed by treatment received in EUCALYPTUS.  The clinical 
response rates in SPRUCE at Week 4, for patients previously treated with 100 mg 
etrolizumab, 300 mg etrolizumab, or placebo, were 48%, 49%, and 53%, respectively 
(n = 31−38; see Etrolizumab Investigator’s Brochure).  Among TNF-IR patients, clinical 
response rates in SPRUCE at Week 4, for patients previously treated with 100 mg 
etrolizumab, 300 mg etrolizumab, or placebo, were 42%, 50%, and 44%, respectively 
(n = 8 − 12).  Given that both induction doses (105 mg and 210 mg) in Study GA29144 
are expected to achieve full β7 receptor occupancy and assuming that receptor 
occupancy is required for efficacy, these data suggest that patients who enter Part 1 
(OLE) from the 210 mg arm of the Induction Phase of Study GA29144 may experience a 
treatment benefit with longer etrolizumab treatment.  As described earlier, permitted use 
of corticosteroid and immunosuppressant therapy with etrolizumab in the OLE may 
benefit all patients escaping from Study GA29144 because of disease worsening.  
Safety events will be carefully and regularly monitored while patients are taking 
etrolizumab in Part 1 (OLE) and for 2 years after their last dose of etrolizumab (12-week 
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safety follow-up plus 92-week PML safety monitoring).  The investigator will review 
patient safety in Part 1 (OLE) every month for the first 3 months and then every 
3 months thereafter until a patient completes the study or withdraws.  Safety 
assessments will include:  assessment of vital signs, safety laboratory results, 
neurological exams, and continuous review of adverse events.  Pregnancy, development 
of anaphylaxis, PML, malignancy, colonic mucosal dysplasia, or certain specific serious 
infections (see Section 5) will lead to permanent discontinuation from etrolizumab 
treatment.  In addition, after treatment of etrolizumab has stopped, patients will be 
followed for 12 weeks for all safety events and then 92 weeks for any signs and 
symptoms of PML.  Patients will be carefully monitored for symptoms of PML through 
regular neurological examinations and with the use of the PML subjective and objective 
checklists (Section 4.4.4.5) 
In summary, there is a strong rationale and a positive benefit-risk assessment for 
studying etrolizumab in Crohn’s Disease.  Safety and efficacy results from the UC OLE 
SPRUCE study suggest that etrolizumab has an acceptable clinical safety profile and 
could benefit patients who are eligible to receive long-term treatment after exiting 
Study GA29144.   
1.3.4 
Rationale for Test Product Dosage 
Patients enrolling in Part 1 (OLE) of this open-label extension−safety monitoring 
(OLE−SM) study from Study GA29144 will receive a dose of 105 mg of etrolizumab.  
A dosing regimen of 105 mg SC Q4W is specified in Part 1 (OLE) on the basis of the 
following considerations: 
•
The 105-mg SC Q4W dose planned for the Phase III study in CD is anticipated (by
population modeling) to maintain full β7−receptor occupancy at all times in > 85% of
patients.  The nominal dose of 100 mg SC Q4W administered in the UC Phase II
study demonstrated an acceptable safety profile.
•
The in-class anti-integrin vedolizumab was successful in maintaining remission with
an every 8-week regimen that provided an average steady-state trough serum
concentration sufficient to maintain maximal receptor occupancy
(Rosario et al. 2013; Sandborn et al. 2013).
Of note, no etrolizumab will be administered during Part 2 (SM) of this OLE−SM study. 


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2.
OBJECTIVES
2.1
OBJECTIVES OF THE STUDY
The objectives of this OLE-SM study are as follows:
Part 1 (OLE)

To assess the long-term safety and efficacy of etrolizumab in patients eligible for
Part 1 (OLE)
Part 2 (SM)

PML safety monitoring in patients who have stopped study treatment
2.2
OTHER SAFETY OBJECTIVES
The other safety objectives for this study are as follows:
Part 1 (OLE)

To evaluate the incidence, rate per subject-year, and severity of infection-related
adverse events

To evaluate the incidence and rate per subject-year of malignancies

To evaluate the incidence and severity of hypersensitivity reactions

To evaluate the incidence and the clinical significance of anti-therapeutic antibodies
(ATAs)
2.3
EXPLORATORY OBJECTIVE OF THE STUDY
The exploratory objective for this study is as follows:
Part 1 (OLE)

To assess endoscopic appearance at Week 108
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
3.1.1
Overview of Study Design
This OLE-SM study is composed of two parts:

Part 1 is the OLE for eligible patients, during which etrolizumab, 105 mg SC, will be
administered Q4W followed by a 12-week safety follow-up post-treatment.

Part 2 is the 92-week PML SM for all patients, during which no etrolizumab will be
administered.
Patients who are enrolled in Part 1 (OLE) should participate in Part 2 (SM).
There may be patients from Study GA29144 who are ineligible for or choose not to 
participate in Part 1 (OLE) who will be asked to directly enroll in Part 2 (SM).


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3.1.2
Overview of Part 1 (OLE)
Part 1 (OLE) of this study is an open-label, multicenter study to evaluate the long-term 
efficacy and safety of etrolizumab in patients with moderate to severe CD who were 
enrolled in Study GA29144 and who meet the eligibility criteria for enrollment into 
Part 1 (OLE; see Section 4.1.1). 
All patients in Part 1 (OLE) will receive 105 mg etrolizumab Q4W by the SC route.  All 
patients will be required to receive their first four doses (Weeks 0, 4, 8, and 12) of 
etrolizumab in the clinic setting as described in Section 4.2.2.  Following the first four 
doses, etrolizumab may be administered in the home setting, and patients may 
self-administer the dose or have a caregiver administer the dose after being trained at 
the study clinic (see Section 4.2.2).  If necessary, patients or their health care 
professional (HCP) may choose to continue administration of etrolizumab in the clinic.
Throughout Part 1 (OLE), patients will be monitored for safety by collection of safety 
parameters such as vital signs, laboratory tests, and adverse events (both serious and 
non-serious) and will be monitored for symptoms of PML with use of the PML subjective 
and objective checklists.  Efficacy data will be evaluated by CDAI score, patient reported 
stool frequency (SF), and abdominal pain (AP) scores every 12 weeks until safety 
follow-up.  In addition, patient’s scoring on the abdominal pain questionnaire on an 
11-point scale will be evaluated (see Appendix 6). Patients will have in-clinic visits at
Weeks 0, 4, 8, and 12 and every 12 weeks thereafter (see Figure 1 and Appendix 1) and
can continue to receive open-label etrolizumab in Part 1 (OLE) until commercial
availability in their country or up to approximately 10 years after the first patient is
enrolled (see Section 3.2), whichever is earlier, or until the Sponsor’s decision to
terminate the study.  Upon the completion of Part 1 (OLE) or early withdrawal from
Part 1 (OLE), all patients will enter a 12-week safety follow-up, which consists of a
telephone visit at Week 6 and an in-clinic visit at Week 12 (see Appendix 2).
During Part 1 (OLE), patients who have worsening CD may receive corticosteroid 
concomitantly (IV, oral, or topical) at the discretion of the investigator (see Section 4.3.1). 
Patients may continue immunosuppressant therapy (i.e., AZA, 6-MP, or MTX) with dose 
changes or initiate immunosuppressant therapy, at the discretion of the investigator 
(see Section 4.3.1).  Any patient taking a prohibited therapy (described in Section 4.3.2) 
must withdraw from Part 1 (OLE), discontinue etrolizumab, and complete the 12-week 
safety follow-up, and then enter Part 2 (SM). 
Upon completion of the 12-week safety follow-up, patients will enter Part 2 (SM) of the 
study, which will consist of 92 weeks of extended PML monitoring.  See Figure 1 and 
Figure 2 for schemas of the study and see Section 3.1.3.


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3.1.3
Overview of Part 2 (SM)
Patients may enroll into Part 2 (SM) of this study for 92 weeks of PML monitoring via 
two routes:

Patients exiting Part 1 (OLE) 

Patients from Study GA29144 who are not eligible or choose not to receive 
etrolizumab in this study (e.g., due to receipt of prohibited medication)
Regardless of route of entry, patients will enroll following completion of the 12-week 
safety follow-up period within Part 1 of this study (OLE; for those entering from OLE) or 
within Study GA29144 (for those enrolling directly from Study GA29144).
During Part 2 (SM), patients will be assessed for PML and safety events via telephone 
visits at Weeks 24, 48, 68, and 92 (see Figure 2 and Appendix 3).  If there are any signs 
or symptoms suggestive of PML during the telephone visit, the patient will be asked to 
come into the clinic for a neurologic examination (see Section 4.4.5).


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Figure 1
Study Schema for Part 1 (Open-Label Extension; OLE) of the OLE-SM Study
OLEopen-label extension; OLE-SMopen-label extensionsafety monitoring; Q4W every 4 weeks; Q12W every 12 weeks; 
SCsubcutaneous.




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3.1.4
Number of Patients
The OLE-SM study will be conducted in investigational sites that have participated in 
Study GA29144.  The maximum number of patients potentially enrolling in this study will 
be all patients from Study GA29144, approximately 1150 patients.
3.2
STUDY DURATION
Part 1 (OLE)
Part 1 (OLE) of this study will continue for up to approximately 10 years after the first 
patient is enrolled into the study, until commercial availability, or until the Sponsor’s 
decision to terminate the study, whichever is earlier.  Patients who withdraw from 
Part 1 (OLE) will complete the 12-week safety follow-up and then enter Part 2 (SM) for 
PML monitoring.
Part 2 (SM)
For patients who enter Part 2 (SM) of this study either from Part 1 (OLE) or enroll directly 
from Study GA29144, Part 2 (SM) of the study will last 92 weeks.
3.2.1
End of Study
The end of the study is defined as the date when the last patient completes the 92-week 
PML safetymonitoring period.
3.3
OUTCOME MEASURES 
The efficacy outcome definitions are given in Table 1.
3.3.1
Efficacy Outcome Measures (Part 1; OLE)
The efficacy outcome measures for this study are as follows:  

CDAI remission assessed at 12-week intervals during Part 1 (OLE)

Clinical remission assessed at 12-week intervals during Part 1 (OLE), as defined by
a SF mean daily score ≤3 and an AP mean daily score ≤1 with no worsening in
either subscore compared to baseline, averaged over 7 days prior to visit

Simple Endoscopic Score for Crohn’s disease (SES-CD) score assessed at
Week 108 or at early withdrawal, if prior to Week 108, during Part 1 (OLE)


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Table 1
Efficacy Outcome Definitions
Outcome Term
Definition
CDAI
CDAI is a composite of eight assessments:  number of liquid or soft 
stools, abdominal pain, general well-being, presence of complications, 
taking Lomotil(diphenoxylate/atropine) or other opiates for diarrhea, 
presence of an abdominal mass, hematocrit, and percentage deviation 
from standard weight
SES-CD
SES-CD is an endoscopic score derived from four variables (ulcers, 
ulcerated surface, inflamed surface, and presence of narrowing) that are 
scored in five ileocolonic segments. 
CDAI Remission
CDAI score 150 
Clinical Remission
An SF mean daily score ≤3 and an AP mean daily score ≤1 with no 
worsening in either subscore compared to baseline, where the average 
is taken over 7 days prior to visit
AP = abdominal pain; CDAI Crohn’s Disease Activity Index; SES-CD Simple Endoscopic 
Score for Crohn’s disease; SF = liquid/soft stool frequency.
3.3.2
Safety Outcome Measures (Part 1; OLE)
The safety outcome measures for Part 1 (OLE) of this study are as follows:

Incidence and severity of adverse events

Incidence of serious adverse events

Incidence, rate per subject-year, and severity of infection-related adverse events

Incidence of serious infection-related adverse events

Incidence and severity of injection-site reactions

Incidence of adverse events leading to etrolizumab discontinuation

Incidence of laboratory abnormalities

Incidence and rate per subject-year of malignancies

Incidence of ATAs to etrolizumab

Incidence and severity of hypersensitivity reactions
3.3.3
Safety Outcome Measure (Part 2; SM)
The safety outcome measure for Part 2 (SM) of this study is as follows:  

Incidence of suspected or confirmed PML events


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3.3.4
Exploratory Outcome Measures (Part 1; OLE)
The exploratory outcome measures for Part 1 (OLE) of this study are as follows:

SES-CD ≤4 (≤2 for ileal patients), with no segment having a subcategory score
(i.e., for ulceration size and extent, affected surface, or narrowing) that is >1, at
Week 108

Change in SES-CD score between Week 0 (Study GA29144) and Week 108 or
early withdrawal (Study GA29145, Part 1; OLE)
4.
MATERIALS AND METHODS
4.1
PATIENTS
Part 1 (OLE)
The study population will consist of patients from Study GA29144 who meet all of the 
eligibility criteria for Part 1 (OLE) listed in Section 4.1.1.  
Part 2 (SM)
The study population will consist of patients from Study GA29144 who either do not 
meet the eligibility criteria for Part 1 (OLE) or choose not to enroll in Part 1 (OLE) and 
patients from Study GA29145 who either completed or discontinued Part 1 (OLE), and 
who meet all the eligibility criteria for Part 2 (SM) listed in Section 4.1.1.
4.1.1
Inclusion Criteria
Part 1 (OLE)

Patients who were previously enrolled in Study GA29144 and experienced any of
the following:
CDAI score the baseline (Week 0) score 
CDAI score 100 points higher than the Week 14 score
Completed the Maintenance Phase including the Week 66 or Week 74 clinic 
visit in Study GA29144
Disease worsening in the Induction Phase of Study GA29144, defined as a 
CDAI score at Week 10 or later in the Induction Phase being greater than the 
patient’s baseline (Week 0) score  
Not eligible for the Maintenance Phase in Study GA29144 
Completed the Week 14 visit in Study GA29144 and could not subsequently 
enter the Maintenance Phase, because the sample size for the Maintenance 
Phase has been achieved 
A clinical relapse during the Maintenance Phase of Study GA29144, defined as 
meeting at least one of the following criteria on two consecutive visits (may 
include unscheduled visits), with at least one of the two consecutive CDAI 
scores ≥ 220:  


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
Ability and willingness to provide written informed consent and comply with the 
requirements of the OLE-SM protocol.

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 to use a highly effective method of 
contraception (e.g., combined oral contraceptive pill or transdermal patch, 
spermicide and barrier [condoms], intrauterine device, implants for contraception, 
injections for contraception [with prolonged release], hormonal vaginal device, 
sterilization, or surgical tubal ligation) during the treatment period and for at least 
24 weeks after the last dose of study drug (see Appendix 4). 
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.

For men: agreement to remain abstinent or to use a condom, as well as not donate 
sperm, during the treatment period and for at least 24 weeks after the last dose of 
study drug
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.
PART 2 (SM)

Patients who participated in Study GA29144 and are not eligible or chose not to 
enroll in Part 1 (OLE) 

Patients who participated in Part 1 (OLE) of this protocol

Ability and willingness to provide written informed consent and comply with the 
requirements of Part 2 (SM) of the OLE-SM protocol
All patients must have completed the 12-week safety follow-up in either GA29144 or 
GA29145, Part 1 (OLE), as applicable, prior to entering Part 2 (SM).
4.1.2
Exclusion Criteria
Part 1 (OLE)

Patients who leave Study GA29144 before Week 10

Patients who discontinue study drug in the Induction Phase of Study GA29144, 
except for those escaping between and including Weeks 10 and 14 due to disease 
worsening

Inability to comply with the study protocol, in the opinion of the investigator

Pregnancy or lactation

Patients who developed an anaphylactic/anaphylactoid or severe allergic reaction to 
study medication during Study GA29144


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
Patients who have an untreated or unresolved serious infection event 

Patients who experienced a de novo or reactivated serious viral infection such as 
hepatitis B virus (HBV), hepatitis C virus (HCV), or HIV during Study GA29144

Patients who developed cytomegalovirus (CMV) colitis leading to early treatment 
discontinuation during Study GA29144 

Patients who developed life-threatening infections during Study GA29144

Patients who developed a malignancy (with the exception of local and resected
basal or squamous cell carcinoma of the skin) or who develop adenocarcinoma in 
situ (AIS), high-grade squamous intraepithelial lesions (HSIL), or cervical 
intraepithelial neoplasia (CIN) of Grade 1 on cervical Pap smear or who develop 
colonic dysplasia during Study GA29144

Receipt of the following prohibited medications since commencement of 
Study GA29144:
Any investigational treatment, including investigational vaccines
Use of T or B cell depleting agents (e.g., rituximab, alemtuzumab, or 
visilizumab), with the exception of AZA and 6-MP (or equivalent)
Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF)
Use of natalizumab or vedolizumab
Use of TNF antagonists
Use of antagonists of IL-12 IL-23 (e.g., ustekinumab)
Immunization with a live/attenuated vaccine
Use of anti-adhesion molecules (e.g., anti-MAdCAM-1)

In the opinion of the investigator, any new (since enrolling in Study GA29144), 
significant, uncontrolled comorbidity, such as neurological, cardiac (e.g., moderate 
to severe heart failure New York Heart Association [NYHA] Class III/IV), pulmonary, 
renal, hepatic, endocrine, or gastrointestinal (GI) disorders (excluding CD)

Any patient who developed PML in Study GA29144

Any patient with neurological symptoms where suspected PML has not been ruled 
out
Part 2 (SM)

No exclusion criteria
4.2
STUDY TREATMENT
4.2.1
Formulation, Packaging, and Handling
Part 1 (OLE)
Etrolizumab
Etrolizumab will be supplied by the Sponsor as a liquid formulation in prefilled syringes 
(PFSs) with needle safety device (hereafter referred to as PFS) and is administered as a 
SC injection.  Each 1mL PFS contains 105 mg etrolizumab (0.7 mL nominal volume of 


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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 SC administration and contains no preservatives.
Packaging
Study drug packaging will be overseen by the Sponsor’s Clinical Trial Supplies 
Department and will be labelled with the identification required by local law, the protocol 
number, drug identification, and dosage.  The packaging and labelling 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, use by date, quantity, integrity 
of seals, and temperature conditions, and report any deviations or product complaints to 
the monitor upon discovery.
Handling
The study drug must be stored according to the details on the product label.  PFSs of 
study medication should be refrigerated at 2°C8°C and protected from light (i.e., remain 
in box).  PFSs should not be frozen, shaken, or stored at room temperature.
The PFS containing study drug is stable for no longer than 8 hours at room temperature 
(should not exceed 30C).  If a syringe is left at room temperature for longer than this 
time, it should not be used.  In the home-setting, patients should be instructed to contact 
the study site staff for a replacement.
Used PFS with study drug must be discarded 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 labelling of the study drug will be provided in the 
protocol-supporting documents.
For further details, see the current Etrolizumab Investigator's Brochure.
4.2.2
Dosage, Administration, and Compliance
Part 1 (OLE) 
All patients will receive one 0.7-mL etrolizumab 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 
prefilled with 0.7 mL (105 mg) of etrolizumab.  The needle is a 27G ½‘’ thin-wall design.  
The needle-safety device is a standard design, and the device is fitted with a 
custom-designed plunger rod and an extended finger flange.


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A part of the needle cap of the prefilled syringe may contain natural rubber latex that 
may cause allergic reactions in latex-sensitive individuals.
The recommended injection sites are the front of the middle thighs and the lower part of 
the abdomen below the navel except for the two inch area directly around the navel.  
Patients should place themselves in a comfortable position before self-administering 
study drug. Injections should never be given into areas where the skin is not intact or is 
tender, bruised, red, or hard.  The injection sites will be inspected by the site personnel 
at each clinic visit.  Any injection site reactions (see Section 5.1.1.4) should be 
documented on the appropriate Adverse Event electronic Case Report Form (eCRF) 
page.  Patients administering at home should be taught to report any injection site 
reactions as adverse events (e.g., redness and swelling).
Patients must receive their first dose of etrolizumab in Part 1 (OLE) no more than 
8 weeks after their last dose of study medication in Study GA29144.  Whenever possible, 
patients should receive their first dose in this study within 4 weeks after their last dose in 
Study GA29144. Upon enrolling in Part 1 (OLE), the first four drug administrations of 
etrolizumab will be conducted in the clinic setting by the trained patient, the trained 
caregiver, or the HCP, in order to monitor for any possible hypersensitivity reactions.  
For those patients who choose to self-administer drug for the first time in this study, they 
will be trained how to use the device by a 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.  
During the first four study treatment administrations, patients will be monitored for acute 
hypersensitivity reactions for at least 60 minutes after the end of the injection.  
Epinephrine and parenteral diphenhydramine must be readily available for immediate 
use if required to treat a hypersensitivity reaction; site personnel must be able to detect 
and treat such reactions.  Patients with severe hypersensitivity reactions (e.g., stridor, 
angioedema, life-threatening change in vital signs) must be withdrawn from study 
treatment.  These patients are to enter the 12-week safety follow-up in this study 
followed by PML monitoring in Part 2 (SM) of this study.
All adverse events of systemic hypersensitivity reactions or anaphylactoid or anaphylaxis 
reactions must be reported within 24 hours to the Sponsor and the Medical Monitor must 
be informed as soon as is practical (see the Study Manual for contact information).
Following the first four drug administrations (typically expected at 12 weeks), study drug 
administration will be continued in the home setting by the patient or a caregiver if 
considered appropriate by the investigator. If a caregiver is administering the injection, 
the outer area of the upper arm may be used in addition to the abdomen or thigh. If a 
patient is administering the injection to themselves, they are not allowed to administer 
the injection in their upper arm.  Study medication will be administered in the patient’s 
home after return from the clinic visit on days when drug administration is to take place 


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on the same day as a clinic visit day.  Patients and/or the caregiver will be provided with
contact information for questions related to self-administration between visits.  
Competence of the patient or caregiver to administer at home will be documented in 
source documents.  Compliance in the home setting is to be monitored by use of a 
patient diary to record drug administration and return of used and unused medication
syringes.  Patients and/or the caregiver will be provided with alert cards for themselves 
and a partner/caregiver, which they will be requested to carry at all times.  These will
include guidance on recognizing allergic/anaphylactic/anaphylactoid reactions and how to
obtain emergency care in the event such a reaction occurs and information regarding 
recognition of symptoms of PML.
If the patient cannot administer study medication on the scheduled dosing day, study 
medication is to be administered within a window of 5 days from the scheduled dosing 
date.  If the patient experiences a minor illness (e.g., minor infection), at the discretion of 
the investigator, study medication may be delayed for a maximum period of 2 weeks.  
Study medication dosing is to be resumed in accordance with the original dosing 
schedule.  
If necessary, patients or their HCP may choose to continue administration of study 
medication in the clinic.
Guidelines for treatment interruption or discontinuation are provided in Section 4.5.
Part 2 (SM)
No study drug will be administered during Part 2 (SM) of this protocol.
4.2.3
Investigational Medicinal Product Accountability
Part 1 (OLE) 
All investigational medicinal products (IMPs) required for completion of this study, 
namely, etrolizumab, will be provided by the Sponsor.  The investigator is responsible for 
the control of the drugs under investigation.  The investigational site will acknowledge 
receipt of IMP (e.g., drug receipt record) and disposition (e.g., drug dispensing log).  
Accountability will be assessed by maintaining adequate drug dispensing and return 
records.  Interactive voice/Web-based response system (IxRS) will be used to confirm 
the shipment condition and content.  Any damaged shipments will be replaced.
Accurate records must be kept for all study drug provided by the Sponsor.
These records must contain the following:

Documentation of drug shipments received from the Sponsor (date received and 
quantity)

Disposition of unused study drug not dispensed to patients 


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
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.
4.2.4
Assessment of Compliance
Part 1 (OLE) 
Patient compliance will be assessed by maintaining adequate drug dispensing logs, the 
patient diary, and return records.
Home-injection:  A patient 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 patient diary and patients should bring the patient diary to 
the clinic during each visit.
Sharps containers for any used PFSs will be provided to patients for home usage.  After 
home injections, the used syringes must be placed into the sharps containers 
immediately.  The sharps containers should be returned to sites.  Sharps containers will 
be discarded by the site staff at the frequency per local schedule.
A Drug Dispensing Log must be kept as described in Section 4.2.3.  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 4.2.5).  The investigator's copy of the Drug Return 
Record(s) must accurately document the return of all study drug supplies to Sponsor.
4.2.5
Destruction of the Investigational Medicinal Product
Part 1 (OLE)
Any used PFS will be placed into the sharps containers immediately after SC injections 
either at the site or at home.  The sharps containers should be discarded at the study 
site by the site staff per local schedule.  Written documentation of destruction of unused 
study drug must contain the following:

Identity (batch numbers or subject numbers) of IMP(s) destroyed

Quantity of IMP(s) destroyed




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Part 2 (SM)
During Part 2 (SM), investigators should follow standard practice and prescribe the local 
standard of care or treatments that in their opinion meet the needs of the patient.
ONLY concomitant medications used to treat event-related neurological abnormalities 
that are recorded and ongoing on the Adverse Event eCRF during Part 2 (SM) must be 
entered on the Concomitant Medication eCRF. 
4.3.2
Prohibited Therapy
Part 1 (OLE)
Use of the following therapies is prohibited during Part 1 (OLE) of this study.  Any patient 
taking the following therapies is to be withdrawn into Part 2 (SM) of this study following 
12-week safety follow-up.

Any investigational treatment, including investigational vaccines

Use of T or B cell depleting agents (e.g., rituximab, alemtuzumab, or visilizumab),
with the exception of AZA and 6-MP (or equivalent)

Use of cyclosporine, tacrolimus, sirolimus, or MMF

Use of anti-integrins (e.g., natalizumab or vedolizumab)

Use of TNF antagonists

Use of antagonists of IL-12 IL-23 (e.g., ustekinumab)

Use of anti-adhesion molecules (e.g., anti-MAdCAM-1)
Part 2 (SM)
There are no prohibited therapies in Part 2 (SM).
4.4
STUDY ASSESSMENTS
The Schedules of Assessments are provided in the Study Flowcharts in Appendix 1, 
Appendix 2, and Appendix 3.  Study assessments are detailed below and will be 
undertaken at study visits as indicated in the Schedule of Assessments.  Assessments 
will be performed only after informed consent has been obtained.
4.4.1
Assessments during the Study
Part 1 (OLE)
For patients enrolling into Part 1 (OLE) of this study, the informed consent for enrollment 
into Part 1(OLE) also includes informed consent for Part 2 (SM) of the study.  Note that 
patients enrolling only in Part 2 (SM) from Study GA29144 will be required to sign a 
separate informed consent. 
Eligibility criteria will be reviewed prior to the initial administration of etrolizumab in this 
study.  Patients must meet all inclusion and exclusion criteria for study entry 
(see Sections 4.1.1 and 4.1.2).  Informed Consent Forms for enrolled patients and for 
patients who are not subsequently enrolled will be maintained at the study site.


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All assessments will be performed during the specified visit week, except where a time 
window is specified. Assessments scheduled on the day of etrolizumab administration 
should be performed prior to dosing, unless otherwise noted.  When etrolizumab 
administration in the home is required on the same day as a clinic visit, drug is to be 
administered at home AFTER the clinic visit.
Patients enrolling in Part 1 (OLE) are to record their abdominal pain severity (using the 
abdominal pain questionnaire [APQ] and the 4-point ordinal pain scale provided in their 
study diary), loose stool frequency, and general well-being in the patient diary for 
10 days prior to their clinic visit for Crohn’s disease activity assessment 
(see Appendix 6).  The Bristol Stool Scale will be provided to patients as a reference for 
determining loose stools (see Appendix 7).  Patients will also be instructed to contact the 
site promptly if they have any questions about the use of the device at any time during 
the study.
See the Study Flowcharts provided in Appendix 1 and Appendix 2 for the schedule of 
assessments to be performed during the treatment period.
Part 2 (SM)
For patients enrolling directly into Part 2 (SM) of this study, written informed consent for 
participation in Part 2 (SM) of the study must be obtained prior to entry.  Note that for 
patients enrolling only into Part 2 (SM), a separate informed consent form detailing only 
Part 2 (SM) assessments will be available. 
See the Study Flowchart provided in Appendix 3 for the assessments to be performed 
during the safety monitoring period.
4.4.2
Assessments at Unscheduled Visits in OLE (Part 1) and in 
12-Week Safety Follow-Up
An unscheduled visit may occur at any time during the treatment period in Part 1 (OLE), 
including during the 12-week safety follow-up period (e.g., due to relapse of disease, 
disease worsening, or an adverse event). Patients who are seen by the investigator or 
site staff at a timepoint not required by the protocol due to assessment of potential 
relapse or disease worsening will undergo assessments consistent with the purpose of 
the unscheduled visit.  Such assessments may include:

Review of patient diary

Recording of concomitant medications and procedures

Collection of adverse events and serious adverse events

Clinical chemistry and hematology, and C-reactive protein, if indicated

Collection of ATA sample, if indicated
For unscheduled visits for reasons other than possible disease worsening or an adverse 
event, assessments will be done at the discretion of the investigator.


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4.4.3
Assessments at Early Withdrawal
Part 1 (OLE)
Discontinuation during the OLE 
Patients who discontinue treatment for any reason will be asked to complete the early 
withdrawal from treatment visit for Part 1 (OLE; see Appendix 1).  The early withdrawal 
from treatment visit will be followed by a 12-week safety follow-up consisting of one 
telephone visit at Week 6 and one clinic visit at Week 12 (see Appendix 2).  The patient 
should then enter the extended PML monitoring in Part 2 (SM; see Appendix 3).  
Discontinuation during the 12-Week Safety Follow-Up Period after OLE 
Patients who discontinue the study during the 12-week safety follow-up will be asked to 
complete the early withdrawal visit from the 12-week safety follow-up (see Appendix 2) 
and then enter the extended PML monitoring in Part 2 (SM).
Part 2 (SM)
Discontinuation during the Extended PML Monitoring Period of SM 
Patients who discontinue from Part 2 (SM) of this study prior to completion of the 
extended PML monitoring period will be asked to complete the early termination visit 
from the extended PML monitoring period (see Appendix 3).
After the study completion/early termination visit, adverse events should be followed as 
outlined in Section 5.7.
See Appendix 3 for specified follow-up assessments.
4.4.4
Description of Study Assessments in Part 1 (OLE)
Data from the final visit of Study GA29144 will be used for analysis and data sets for the 
first visit of the OLE-SM study.  If any procedure and assessment was missed at the time 
of the final visit, it should be performed for the first visit of the OLE-SM study.
4.4.4.1
Physical Examinations
A partial physical examination will be performed at Weeks 0, 4, and 12, every 12 weeks 
thereafter, and at Study Completion (or Early Withdrawal visit) and the partial physical 
examination is to be recorded as “normal” or “abnormal.”  New or worsened clinically 
significant abnormalities should be recorded as adverse events on the Adverse Event 
eCRF.  Past resolved adverse events will be recorded in the medical history according to 
their medical relevance.  Adverse events reported as ongoing at the end of 
Study GA29144 will be stated unresolved in that study and also reported in 
Study GA29145.  The adverse event will be reported with the start date and adverse 
event term identical to those in Study GA29144.  The initial intensity should be evaluated 
by the investigator at Part I (OLE) study start with the current intensity entered into the 
event in the eCRF.


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4.4.4.2
Vital Signs
Vital signs will include measurements of heart rate and systolic and diastolic blood 
pressure, after the patient has been in a seated position for 5 minutes, and are to be 
recorded before study drug administration at clinic visit only.
Vital signs will be collected at Weeks 0 and 12, every 12 weeks thereafter, and at Study 
Completion (or Early Withdrawal visit).
4.4.4.3
Crohn’s Disease Activity Assessments
Disease severity will be evaluated using the CDAI, SF, AP, and SES-CD, which are 
described below.  
Crohn’s Disease Activity Index 
The CDAI quantifies the signs and symptoms of patients with CD (see Appendix 5).  The 
CDAI consists of eight factors; each factor is summed after adjustment with a weighting 
factor (Best et al. 1979).  The components of the CDAI include number of liquid or soft 
stools, abdominal pain, general well-being, presence of complications, use of Lomotil
(diphenoxylate/atropine) or other opiates for diarrhea, presence of an abdominal mass, 
hematocrit, and percentage deviation from standard weight. Of the eight factors of the 
CDAI, three are patient reported (number of liquid or soft stools, abdominal pain, and 
general well-being), four are based on physician assessment (presence of complications, 
use of Lomotilor other opiates for diarrhea, presence of abdominal mass, and 
percentage of deviation from standard weight, which is based on the patient’s weight at 
the visit), and one factor is based on a blood test (hematocrit).  Patients are to report 
their abdominal pain severity, loose-stool frequency, and general well-being for 10 days 
prior to each study visit on a patient diary. The weighted sum of the average scores 
over 7 days is calculated for the PRO component of the CDAI score.  The Bristol Stool 
Scale is provided to patients as a reference for determining loose stools (see 
Appendix 7).  
Stool Frequency and Abdominal Pain 
Two patient reported factors will be evaluated: the frequency of liquid or soft stools and 
abdominal pain.  A mean daily score will be calculated for each factor, where the 
average will be taken over 7 days prior to the assessment visit.  Patients are to report 
their loose-stool frequency (the Bristol Stool Scale will be provided) and abdominal pain 
severity for 10 days prior to each study visit on a patient diary.
Simple Endoscopic Score for Crohn’s Disease (SES-CD)
The SES-CD is assessed by the investigator through endoscopy and is a composite of 
four factors (ulcer size, percentage of ulcerated surface, percentage of surface affected 
by other lesions, and extent of stenosis) in up to five ileocolonic segments 
(see Appendix 11 for further details) and will be entered into the RAVE eCRF. Unlike 
the parent study, GA29144, there will be no central adjudication performed; only the 
investigator’s evaluation of SES-CD will be used.


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Abdominal Pain Questionnaire
The 0-10 point Abdominal Pain Questionnaire (APQ) is an 11-point numeric rating scale 
to assess the worst abdominal pain on a daily basis.  A higher score indicates a greater 
severity of abdominal pain.  The APQ has a recall specification of 24 hours.  As with the 
CDAI, SF and AP, patients are to report their abdominal pain severity using the APQ for 
10 days prior to each study visit on a patient diary.  
The CDAI, SF and AP scores will be calculated, and the APQ will be completed every 
12 weeks and at Study Completion (or Early Withdrawal visit if the patient completed the 
patient diary); SES-CD assessment will take place at the Week 108 visit or early 
withdrawal visit.
4.4.4.4
Ileocolonoscopy with Biopsies
An ileocolonoscopy will be performed at the Week 108 visit or Early Withdrawal visit if 
prior to Week 108.  If the early withdrawal visit occurs after the Week 108 visit, then the 
ileocolonoscopy with biopsies should be conducted only at Week 108.  The 
ileocolonoscopy should take place on the day of the Week 108 or Early Withdrawal visit 
or no later than 10 days after the visit.  The ileocolonoscopy is being performed to 
assess the endoscopic change in response to prolonged continuous treatment with 
etrolizumab.
Patients are to prepare their bowel prior to the ileocolonoscopy procedures with a 
polyethylene glycol (PEG)-based preparation.  Medications used for bowel preparation 
should be reported on the concomitant medications pages of eCRF.
Each patient entered into the study will have the opportunity to donate a single paired 
biopsy sample from the ileocolonoscopy procedure.  The paired biopsy sample will be 
stored in the Roche Clinical Repository (RCR) and used in future research for Crohn’s 
disease.  Sample donation is optional and requires separate informed consent from the 
patient. 
In consenting patients, the paired biopsy sample should be taken from the terminal ileum
during the ileocolonoscopy.  Necrotic areas of ulcerated mucosa should be avoided 
during biopsy sample collection.  The paired biopsy sample should be placed in formalin 
and sent to the central laboratory where it will be paraffin embedded and distributed to 
the RCR.


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4.4.4.5
Progressive Multifocal Leukoencephalopathy Assessment
Study site personnel and patients will be educated regarding the signs and symptoms 
of PML.  New symptoms or signs suggestive of PML will be evaluated by a qualified 
HCP (e.g., investigator, physician assistant, nurse, nurse practitioner; a neurology 
consult is not required) with use of the PML Subjective Checklist (symptom assessment) 
and the PML Objective Checklist (neurologic evaluation; see Appendix 8) during Part 1 
(OLE), 12-week safety follow-up, and Part 2 (SM) (see Appendix 1, Appendix 2, and
Appendix 3, respectively).
During Part 1 (OLE), the PML monitoring assessments will take place at Weeks 0 and 
12 and every 12 weeks thereafter and at Study Completion (or Early Withdrawal visit).  
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 neurologic symptom or sign should be expeditiously reported to the 
Sponsor as adverse events of special interest or serious adverse events, as appropriate, 
within 24 hours (see Section 5.5.2 and Appendix 9 for the Algorithm for Evaluation of 
Progressive Multifocal Leukoencephalopathy).  If PML is suspected, dosing with 
etrolizumab for that patient will be suspended and the patient should be promptly 
referred to a neurologist.  
Following formal evaluation by a neurologist, if PML cannot be ruled out, the case will be 
referred to an expert PML adjudication committee for further work-up, which may include 
brain magnetic resonance imaging (MRI) with and without contrast.  If there remains any 
suspicion for PML, the PML adjudication committee may recommend performing a 
lumbar puncture with cerebrospinal fluid (CSF) analysis for JCV by polymerase chain 
reaction (PCR).  If JCV is detected, the patient should be treated as a PML case, and 
the patient should permanently discontinue study drug and enter safety follow-up.  
Dosing with study treatments can only be resumed in patients where PML has been 
ruled out.  Refer to Appendix 9 for the Algorithm for Evaluation of Progressive Multifocal 
Leukoencephalopathy.
After completing Part 1 (OLE), patients will enter the 12-week safety follow-up 
(see Appendix 2).  The PML monitoring assessment is to be performed at Week 12 of 
this safety follow-up.
Following the 12-week safety follow-up, all patients (i.e., patients entering from Part 1 
[OLE] and those enrolling directly from Study GA29144) will be requested to continue to 
be monitored for PML for an additional 92 weeks by enrolling in Part 2 (SM) of this study, 
for a total of 2 years PML follow-up after the last dose of study medication 
(see Section 4.4.5 for details of assessments in Part 2 [SM]).


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4.4.4.6
Pregnancy Testing
All women of childbearing potential (including those who have had a tubal ligation) will 
have a urine pregnancy test performed prior to each drug administration (Q4W).  
Pregnancy tests are to be conducted at home when drug administration is in the home 
setting and the outcome of the pregnancy test should be recorded on a patient diary. 
If a urine pregnancy test result is positive, it must be confirmed by a serum pregnancy 
test.
4.4.4.7
Laboratory Assessments
Laboratory assessments will be performed as indicated on the Schedule of Assessments 
(see Appendix 1 and Appendix 2).  
General guidelines:

Week 0 laboratory assessments that have been performed as part of the final visit 
for Study GA29144 do not need to be repeated, with the exception of ATAs, which 
must be recollected at Week 0 if the Week 0 visit occurs 7 days after the final visit 
for Study GA29144.

With the exception of urine pregnancy tests, all laboratory investigations will be 
performed by a central laboratory.  

On days of etrolizumab administration, indicated laboratory samples should be 
drawn prior to study drug administration.
Laboratory assessments will include the following:

Hematology (hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
absolute count [neutrophils, eosinophils, lymphocytes, monocytes, basophils, other 
cells], mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, and red cell distribution width)
Collected at Weeks 0 and 12 and every 12 weeks thereafter and at Study 
Completion (or Early Withdrawal visit) 

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)
Collected at Weeks 0 and 12, every 12 weeks thereafter, and at Study 
Completion (or Early Withdrawal visit) 

C-reactive protein (CRP)
Collected at Week 0, every 48 weeks thereafter, and at Study Completion (or 
Early Withdrawal visit)


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
Anti-therapeutic antibody (ATA) 
Collected at Week 0 (if Week 0 visit is 7 days from final visit in Study 
GA29144), Week 12, every 48 weeks thereafter, and at Study Completion (or 
Early Withdrawal visit)

Hepatitis B DNA (only for those patients who are Hepatitis B core antibody positive)
Collected at Weeks 0 and 12 and every 12 weeks thereafter
4.4.4.8
Electrocardiograms
A 12-lead electrocardiogram (ECG) with formal readings will be taken every 48 weeks as
well as at Study Completion (or Early Withdrawal visit) as indicated on the Schedule of 
Assessments.  ECGs for each patient should be obtained from the same machine 
whenever possible.  To minimize variability, it is important 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.  Perform ECGs prior to 
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 are kept as part of the patient's permanent study file at 
the site.  ECG outputs are stored at the site.
4.4.4.9
Concomitant Medications
Concomitant medications will be monitored and reviewed at each study visit, including 
any unscheduled visit(s).
4.4.4.10
Adverse Events
Adverse events will be monitored and reviewed at each study visit, including any 
unscheduled visit(s).  See Section 5 for more details about adverse events and safety 
reporting.
4.4.5
Description of Study Assessments in Part 2 (SM)
During the SM portion of the OLE-SM study, patients will not be administered study 
drug.
The PML safety monitoring portion of the OLE-SM study will consist of a telephone visit
approximately every 6 months (see Appendix 3), with administration of the PML 
Subjective Checklist.  If there are any signs or symptoms suggestive of PML identified 
on this subjective checklist during the telephone visit, the patient will be asked to come 
into the clinic for a neurologic examination, including administration of the PML Objective 
Checklist (see Appendix 8).  The PML Algorithm (see Appendix 9) will be followed for 
any suspected case of PML, and any confirmed case of PML will be reported as a 
serious adverse event (see Section 5.1.1.1).


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4.5
PATIENT, STUDY, AND SITE DISCONTINUATION
4.5.1
Patient Discontinuation
Part 1 (OLE) and Part 2 (SM)
The investigator has the right to discontinue a patient from study drug or withdraw a 
patient from the study at any time.  In addition, patients have the right to voluntarily 
discontinue study drug or withdraw from the study at any time for any reason.  Reasons 
for discontinuation of study drug or withdrawal from the study may include, but are not 
limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance, specifically defined as missing scheduled visits
4.5.1.1
Withdrawal from Study
Part 1 (OLE) and Part 2 (SM)
Every effort should be made to obtain information about patients who withdraw consent 
or are withdrawn from the study.  The primary reason for withdrawal from the study 
should be documented on the Study Completion/Early Discontinuation eCRF.  Patients 
will not be followed for any reason after consent has been withdrawn.  Patients who 
withdraw from the study will not be replaced.
4.5.2
Discontinuation from Study Drug
Part 1 (OLE)
Patients must permanently discontinue study drug if they experience any of the following:

Pregnancy

Anaphylaxis or other severe hypersensitivity reaction

Confirmed PML

Develop colonic mucosal dysplasia

Malignancy (with the exception of local and resected basal or squamous cell 
carcinoma of the skin), or who develop AIS, HSIL, or CIN of Grade 1 on cervical 
Pap smear.  

Any patient who experiences a de novo or reactivated serious viral infection, such 
as HBV, HCV, HIV

Develop life-threatening infections during the study 

Use of any prohibited medication as a concomitant therapy (see Section 4.3.2)
Every effort should be made to obtain information about patients who discontinue early 
from the study.  Patients who discontinue study drug prematurely for the reasons listed 
above will be asked to return to the clinic for an early withdrawal from treatment visit 
(see Section 4.4.3) and will undergo follow-up assessments for 12 weeks within Part 1 


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(OLE) of this study.  Patients should then enter Part 2 (SM) for 92 weeks of monitoring 
for PML (see Section 4.4.5).  The primary reason for premature study drug 
discontinuation should be documented on the Study Completion/Early Discontinuation 
eCRF.
4.5.3
Study and Site Discontinuation
Part 1 (OLE)
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.
The Sponsor will notify the investigator if the study is placed on hold or if the Sponsor 
decides to discontinue the study or development program.
The Sponsor has the right to replace a site at any time.  Reasons for replacing a site 
may include but are not limited to the following:

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice
Part 2 (SM)

In the event of discontinuation of Part 1 (OLE), Part 2 (SM) may continue depending 
on the reason for study or site discontinuation.
5.
ASSESSMENT OF SAFETY
The safety plan for Part 1 (OLE) and the 12-week safety follow-up is provided first, 
followed by the safety plan for Part 2 (SM), which focuses on PML safety monitoring in 
patients off etrolizumab.
5.1
SAFETY PLAN (PART 1, OLE)
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 of study treatment, as appropriate.  These principles are to 
be applied for all safety risks in the clinical program.  
5.1.1
Potential Risks for Etrolizumab
CD and UC share a common pathogenesis in which inflammation is caused by immune 
dysregulation in the gut leading to overproduction of inflammatory cytokines and 


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trafficking of effector leukocytes into the bowel.  Although no clinical trials of etrolizumab 
have been conducted to date in patients with CD, etrolizumab has shown a favorable 
safety profile in a Phase II clinical trial in patients with moderately to severely active UC.  
In addition, preliminary expression studies of the pharmacological target for etrolizumab, 
the integrin 7 receptor, on gut CD4and CD8T cells isolated from resections of both 
UC and CD patients suggest that expression levels are similar between both diseases.  
Given the clinical results in patients with UC and the common mechanism underlying 
both diseases, the safety profile for etrolizumab for CD is likely to be similar to UC.
The potential and/or hypothetical risks for etrolizumab are based on its mechanism of 
action, available nonclinical and clinical data, data from other anti-integrin drugs, and 
general risks associated with biologic agents.  
Investigators should always refer to the Etrolizumab Investigator's Brochure (Section 6) 
for a complete summary of safety information.
Important potential risks for etrolizumab include:

Infections, in particular, serious or life-threatening infections, such as:
PML 
Other serious infections (e.g., gastrointestinal, opportunistic)

Hypersensitivity reactions, in particular:
Anaphylactic, anaphylactoid reactions 
Other systemic hypersensitivity reactions

Hepatic effects

Local injection-site reactions

Malignancies

Immunogenicity

Decreased effectiveness of immunization
5.1.1.1
Serious Infections 
5.1.1.1.1
Progressive Multifocal Leukoencephalopathy 
Background
PML is a potentially fatal neurological condition linked to reactivation of a polyomavirus 
(JCV) and active viral replication in the brain.  Cases of PML have been reported in 
patients with CD and multiple sclerosis who received concomitant treatment with the 
anti-4 integrin natalizumab and immunosuppressives.  Integrin 41, which is inhibited 
by natalizumab, is a pleiotropic integrin that is believed to facilitate T cell migration into 
the CNS.  Inhibition of integrin 41 is thought to reduce (CNS) immune surveillance 
and facilitate development of PML.


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On the other hand, extensive treatment exposure with vedolizumab, which selectively
impedes lymphocyte trafficking into gut tissue by specifically blocking only the
47integrin and not the 41 integrin, has not been associated with PML (Dotan 2017).
Etrolizumab targets cells expressing the 7 integrin (47 and E7 cells) and not 
41 cells.  Despite the lack of theoretical or experimental evidence for a specific role of 
7 integrins in leukocyte homing to the CNS and given the observation of PML risk with 
natalizumab, the Sponsor will continue to conduct extensive risk-monitoring procedures 
during this study.  To date, there have been no cases of PML in patients treated with 
etrolizumab.
Screening, Patient Selection, and PML Education
No known interventions can reliably prevent or 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, rituximab, B or T cell depleting agents 
(e.g., alemtuzumab or visilizumab [with the exception of AZA and 6-MP, or equivalent),
cyclosporine, tacrolimus, sirolimus, or MMF.  Patients with a history of PML or 
neurological symptoms where suspected PML has not been ruled out should also be 
excluded.  
Study site personnel and patient participants should be educated regarding the signs 
and symptoms of PML.  Patients and partners/caregivers should be issued with alert 
cards to remind them of these and to advise them to contact the investigator right away if 
they notice any new or worsening neurological abnormalities.  
See Appendix 1 for details of assessments regarding PML.  
PML Monitoring
During the etrolizumab treatment, patients should be closely monitored for any signs and 
symptoms of PML via regular (approximately once every 12 weeks) subjective and 
objective tests employing the use of checklists to assess the patient’s mental and 
neurological status.  These will comprise regular neurologic examinations (including 
evaluation of cranial nerves, motor and sensory function, coordination, and mental 
status) as per the Schedule of Assessments (see Appendix 1).  The PML Subjective 
Checklist (symptom assessment) and the PML Objective Checklist (neurologic 
evaluation) will be administered (Appendix 8; Worksheet for the PML Neurologic 
Examination) by a qualified HCP and will be performed 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 neurologic symptom or sign should be expeditiously reported to the 


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Sponsor as adverse events of special interest or serious adverse events, as appropriate, 
within 24 hours (see Section 5.5.2 and Appendix 9 for the Algorithm for Evaluation of 
Progressive Multifocal Leukoencephalopathy).  
If PML is suspected, dosing with study treatment for that patient will be suspended and 
the patient should be promptly referred to a neurologist. Following formal evaluation by 
a neurologist, if PML cannot be ruled out, the case will be referred to an expert PML 
adjudication committee for further work-up, which may include brain MRI with and 
without contrast.  If there remains any suspicion for PML, the PML adjudication
committee may recommend performing a lumbar puncture with CSF analysis for JCV
DNA by PCR.  If JCV DNA is detected, the patient should be treated as a PML case and 
the patient should permanently discontinue study drug and enter safety follow-up.  
Dosing with study treatments can only be resumed in patients where PML has been 
ruled out.  Refer to Appendix 9 for the Algorithm for Evaluation of Progressive Multifocal 
Leukoencephalopathy.
PML Treatment
There is no known effective treatment for PML.  Plasmapheresis has been employed in 
some patients where the event has been thought to be due to administration of a drug 
(Tan et al. 2011).  If an event of PML occurs, subsequent management of PML will be at 
the direction of the consulting neurologist. 
Additional information for the management of this potential risk is provided in Appendix 8
(Worksheet for the PML Neurologic Examination) and Appendix 9 (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 who received 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 who experienced a life-threatening infection or a de novo or reactivated serious 
viral infection, such as HBV, HCV, or HIV, during Study GA29144 should not be enrolled 
in Part 1 (OLE) of this study.  Similarly, patients who developed CMV colitis leading to 
early treatment discontinuation in Study GA29144 should be excluded  
Patients who have an ongoing serious infection event should not receive study drug until 
the event has completely resolved and treatment with anti-infective medications has 
been completed.  Patients with hepatitis B infection who test positive only for core 


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antibody (anti-HBc) and test negative for HBV DNA test are eligible for the study; 
however, these patients must undergo periodic monitoring for HBV DNA during the study.  
Education, Monitoring, and Management
Patients should be monitored closely for serious infections during the study.  Patients 
and study staff should be informed of the possibility of increased susceptibility to 
infectious pathogens.  Investigators will be encouraged to promptly evaluate and 
aggressively treat any signs and symptoms consistent with an infection.  
Patients who experience a serious infection event should not receive further study drug 
until the event has completely resolved and treatment with anti-infective medications has 
been completed.  All efforts should be made to identify the infectious agent.  For those 
patients who recover from a serious infection, study medication may be restarted 
following consultation with the Medical Monitor.  
Patients who develop life-threatening infections, including de novo or reactivated serious 
viral infection, such as HBV, HCV, HIV, during the study should discontinue study drug.  
Any patient who develops CMV colitis should not receive further study drug until the 
event has resolved and treatment with appropriate anti-viral medication has been 
completed.  Re-initiation of study treatment requires consultation with the Medical 
Monitor.
5.1.1.2
Hypersensitivity Reactions
Background
In completed Phase I/II clinical trials of etrolizumab in UC, one serious adverse event of 
hypersensitivity (Grade 2) has been reported.  No anaphylactic, anaphylactoid, or severe 
hypersensitivity reactions were observed; however, anaphylaxis, anaphylactoid, and 
hypersensitivity reactions will be closely monitored during the study.  
Patient Selection
Patients who developed an anaphylactic/anaphylactoid or severe allergic reaction to 
study medication during Study GA29144 will be excluded from participation in Part 1 
(OLE) of this study.
Education, Monitoring, and Management
The first four injections should be administered in the clinic in order to monitor for any 
possible hypersensitivity reactions, given that patients who received blinded placebo in 
Study GA29144 may receive their first etrolizumab dose upon enrolling in the OLE-SM 
study.  After each of these four injections, the patient must be monitored for 60 minutes.  
Medicinal products for the treatment of hypersensitivity reactions (e.g., epinephrine, 
antihistamines, and glucocorticoids) must be available for immediate use in the clinic for 
the event of an allergic reaction during administration of the study drug.  Resuscitation 
equipment should also be available.  


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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, anaphylactic, or anaphylactoid 
reaction, the event should be expeditiously reported to the Sponsor as an adverse event 
of special interest or serious adverse event, as appropriate, within 24 hours.
If a patient has symptoms of anaphylaxis or severe hypersensitivity, the administration of 
etrolizumab must be discontinued permanently. 
Refer to Appendix 10 (Clinical Criteria for Diagnosing Anaphylaxis).
5.1.1.3
Hepatic Effects
Background
Liver toxicity has been reported with other class drugs that target 4 integrins 
(natalizumab) and 47 integrins (vedolizumab).  Therefore, this potential risk is being 
monitored in all etrolizumab studies.  In nonclinical chronic toxicology studies, no 
abnormalities indicating liver toxicity with etrolizumab were observed.  The risk in 
humans is currently unknown.
Education, Monitoring, and Management
Patients should receive guidance on reporting liver problems if they occur.  Liver function 
tests should continue to be monitored according to the schedule of assessments and as 
clinically indicated.  Significant hepatic events should be evaluated promptly and 
managed accordingly.
5.1.1.4
Local Injection-Site Reactions
Background
A local injection-site reaction is any local reaction occurring at the site of injection 
following study drug administration.  In completed Phase I/II trials, injection-site reactions 
were reported at a rate of 10%, all of which were of mild intensity.
Monitoring
In the clinic setting, patients should be monitored for signs of injection-site reactions in 
the period immediately following injections.  Patients should be given guidance on 
reporting injection-site reactions when administering drug at home or after the patient 
leaves the clinic.
5.1.1.5
Malignancies
Background
There has been no evidence for increased incidence of malignancy in completed 
Phase I/II trials and nonclinical studies to date.  Nonetheless, given the elevated risk of 


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malignancy in this patient population a priori, the study includes selection criteria and 
additional information to minimize any hypothetical risk. 
Patient Selection
Patients who developed a malignancy (with the exception of local and resected basal or 
squamous cell carcinoma of the skin) during Study GA29144, including AIS, HSIL, or 
CIN of Grade 1 or colonic dysplasia, are to be excluded from this study. 
Monitoring and Management
Investigators should remain vigilant for signs or symptoms of malignancy 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, with potential for allergic reactions.  On the basis of 
the clinical experience to date, approximately 5% of patients develop ATAs to 
etrolizumab; however, this has not been correlated with any efficacy or safety sequelae.
Monitoring
To assess for the potential development of immunogenicity, antibody samples will be 
obtained at baseline, at regular intervals during treatment, and during the Safety 
Follow-Up Period (see Appendix 1 and Appendix 2), and stored appropriately for further 
evaluation as needed.
5.1.1.7
Decreased Effectiveness of Immunizations
Background
The effect of etrolizumab upon the efficacy of vaccinations is unknown. 
Patient Selection and Risk Mitigation
Patients who received a live attenuated vaccine during Study GA29144 or within 
4 weeks prior to enrollment in the OLE are excluded from the study.  Patients should not 
receive live attenuated vaccines during the study and for at least 5 half-lives 
(approximately 12 weeks) after final study drug administration.


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5.1.2
Risks Associated with Worsening of Crohn’s Disease
The worsening of CD may result in the use of rescue medications.  In severe cases, 
worsening of CD may lead to hospitalization or require surgery.  
At any time during the study, patients who have worsening of their CD will be permitted 
to receive additional therapy with corticosteroids (IV, oral, or topical).  Addition of or 
increases in doses of immunosuppressants (i.e., AZA, 6-MP, or MTX) will also be 
allowed if clinically indicated by the Principal Investigator. 
Rescue therapy with anti-TNF agents (including TNF inhibitor biosimilars), cyclosporine, 
tacrolimus, sirolimus, MMF, natalizumab, vedolizumab, anti-adhesion agents, rituximab, 
other lymphocyte depleting agents (except AZA and 6-MP, or equivalent), or other 
biological or investigational therapeutics will not be allowed in conjunction with 
etrolizumab because of the level of immunosuppression anticipated with the use of these 
agents.  Patients who receive any of these prohibited rescue medications are not to 
receive further treatment with etrolizumab, are to complete the 12-week safety follow-up, 
and should then enter into Part 2 (SM) of the study.  
See Section 4.4.2 and Appendix 1 for the schedule of assessments to be performed in 
the event of worsening of CD, which may lead to an unscheduled visit.
5.1.3
Data Monitoring Committee
An independent Data Monitoring Committee (iDMC) will monitor safety and study 
conduct for Study GA29144 on an ongoing basis until the study is unblinded to the 
Sponsor.  Safety data from Study GA29145 will also be available for review by the iDMC 
on an ongoing basis to inform their assessment of the overall safety of etrolizumab in CD. 
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 data prepared by an independent 
data coordinating center.  The iDMC may recommend stopping the study early for safety 
reasons.
Because of the open-label design of the OLE-SM study, the Sponsor will retain the 
primary responsibility for monitoring its safety and study conduct.
5.2
SAFETY PLAN (PART 2, SM)
PML Monitoring Part 2 (SM)
Following the 12-week safety follow-up period in Study GA29144 or in Part 1 (OLE) of 
the OLE-SM study, all patients are to continue to be monitored for PML for an additional 
92 weeks (extended PML monitoring) in Part 2 (SM) of this study, providing a total of 
2 years PML follow-up after the last dose of study drug.  No etrolizumab will be 
administered during this time. 


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PML monitoring during this period will consist of the PML assessment interview 
conducted by telephone at intervals of approximately 6 months (see Appendix 3).  Any 
signs or symptoms suggestive of PML or cases of suspected PML (see Appendix 8) 
should be documented and handled and expeditiously reported to the Sponsor as 
adverse events of special interest or serious adverse events, as appropriate, within 
24 hours, as described in Section 5.1.1.1.1 and Appendix 9 (Algorithm for the Evaluation 
of Progressive Multifocal Leukoencephalopathy).  Study site personnel and patient 
participants will be educated regarding the signs and symptoms of PML and suspected 
cases of PML will be managed as in Section 5.1.1.1.1.  Patients are to be instructed to 
contact the investigator immediately if they experience signs and/or symptoms 
suspected to be PML between the 6-month telephone intervals. 
5.3
SAFETY PARAMETERS AND DEFINITIONS
Safety Assessments during Part 1 (OLE)
Safety assessments in Part 1 (OLE) will consist of monitoring and recording adverse 
events, including serious adverse events and adverse events of special interest; 
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 5.5.
Safety Assessments during Part 2 (SM)
Safety assessment in Part 2 (SM) will consist of only PML monitoring with use of the 
PML Subjective Checklist conducted by telephone at intervals of approximately 
6 months (see Appendix 3) during which any signs or symptoms suggestive of PML 
(see Appendix 8) will be documented and handled as described in Section 5.1.1.1 and 
Appendix 9 (Algorithm for the Evaluation of Progressive Multifocal 
Leukoencephalopathy). 
5.3.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation patient administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Sections 5.4.6.9 and 5.4.6.10


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
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.3.2
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 5.4.6.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, or according to National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) criteria; 
see Section 5.4.4); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.5.2 for 
reporting instructions).


5.3.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.5.2 for reporting instructions).  Adverse events of special interest for this 
study include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s
law (Section 5.4.6.7)

Suspected transmission of an infectious agent by etrolizumab, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product. This term 
applies only when a contamination of the study drug is suspected.

Adverse events of special interest specific to etrolizumab:
Systemic hypersensitivity reactions and anaphylactic and anaphylactoid 
reactions (see Section 5.1.1.2 and Clinical Criteria for Diagnosing Anaphylaxis 
in Appendix 10)
Neurological signs, symptoms, and adverse events that may suggest possible 
PML, on the basis of a positive finding on the PML Subjective Checklist that is 
accompanied by a positive finding on the PML Objective Checklist, or if there is 
strong clinical suspicion for PML (see Appendix 9 Algorithm for the Evaluation 
of Progressive Multifocal Leukoencephalopathy and Section 5.1.1.1)
5.4
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
5.4.1
Adverse Event Reporting Period for Part 1 (OLE)
After informed consent has been obtained, all adverse events, regardless of relationship 
to study drug, will be reported until the patient completes Part 1 (OLE).
During Part 1 (OLE), the investigator is responsible for ensuring that all adverse events 
(see Section 5.3.1 for definition) are recorded on the Adverse Event eCRF and reported 
to the Sponsor in accordance with instructions provided in this section and in 
Sections 5.5, 5.6, and 5.7.  The investigator is also responsible for reporting medical 
device complaints (see Section 5.5.4).
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.3.2 for seriousness criteria), severity 
(see Section 5.4.4), and causality (see Section 5.4.5).
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Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.  Past resolved 
adverse events will be recorded in the medical history according to their medical 
relevance.  Adverse events reported ongoing at the end of Study GA29144 will be stated 
unresolved in that study and also reopened in Study GA29145.  The adverse event will 
be reported with the start date and adverse event term identical to those in 
Study GA29144. Intensity should be evaluated by the investigator at the start of Part 1 
(OLE) with the intensity entered into the initial intensity field for the event in the eCRF for 
Study GA29145. Additionally, the most extreme NCI CTCAE grade for the event that 
occurs during Study GA29145 should also be recorded in the eCRF for Study GA29145.
All adverse events following patient informed consent to the study, regardless of 
relationship to study drug, will be reported until the patient completes Part 1 (OLE).  
Some patients may not enroll into Part 2 (SM), although all patients will be strongly 
encouraged to enter.  For those patients who do not enroll into Part 2 (SM) 
(i.e., withdraw consent from the study), the Sponsor should be notified if post-study the
investigators becomes aware of any serious adverse events that are believed to be 
related to prior study drug treatment (see Sections 5.7.1).  In addition, the Sponsor 
should be notified if the investigator becomes aware of any post-study events of 
confirmed or suspected PML, regardless of relationship to study drug, for up to 2 years 
after the patient’s last dose of study drug. 
5.4.2
Adverse Event Reporting Period for Part 2 (SM)
Part 2 (SM) of the OLE-SM study is focused on extended follow-up for PML.  During 
Part 2 (SM), the investigator will use the PML assessment interview to monitor for signs 
and symptoms of PML.  All adverse events suggestive of PML, regardless of relationship 
to study drug, should be expeditiously reported to the Sponsor as adverse events of 
special interest or serious adverse events, as appropriate, within 24 hours.  
The eCRF will be available during Part 2 (SM) to only report any adverse events of 
special interest or serious adverse events that may suggest possible PML or confirmed 
PML.  Refer to the eCRF help instructions for more details.  If the eCRF system is not 
available, then the process for submitting non-PML events (see below) should be 
followed.
The investigator is not required to actively monitor patients for other non-PML adverse 
events during Part 2 (SM); however, the investigator should notify the Sponsor if they 
become aware of any other non-PML serious adverse events that are believed to be 
related to prior study drug treatment.  The investigator should report such events directly 
to Roche or its designee either by faxing or by scanning and e-mailing the Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form using the fax number 
or e-mail address provided to investigators


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


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5.4.5
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly (see Table 3).  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

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 3
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
Adverse events will be considered related, unless they fulfill the criteria as specified 
below. 
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed two days after 
first dose of study drug).
5.4.6
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.


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PART 1 (OLE) 
All ongoing adverse events from Study GA29144 should be entered on the Adverse 
Event eCRF.
All new adverse events that occur during Part 1 (OLE) should be entered on the Adverse 
Event eCRF.
PART 2 (SM) 
Record on the Adverse Event eCRF ONLY event-related neurological abnormalities 
(signs/symptoms that may suggest possible PML) identified on both the PML Subjective 
AND PML Objective Checklist or if there is a strong clinical suspicion for PML as an 
adverse event of special interest or serious adverse event, as appropriate.  Each 
abnormality should be reported as a separate adverse event of special interest.  Do NOT 
report events as "Suspected PML" or "Rule out PML."  If there is a confirmed diagnosis 
of PML, report this diagnosis as a serious adverse event. 
In Part 2 of the study, all events that may suggest possible PML should be entered on 
the Adverse Event eCRF.  All other non-PML serious adverse events that the 
investigator becomes aware of and believes to be related to prior study drug treatment 
should be reported to the Sponsor via faxing/e-mailing the paper serious adverse event 
reporting form.
5.4.6.1
Injection-Site Reactions
Local cutaneous adverse events that occur at or around the injection site during or within 
24 hours after study drug injection should be captured as individual signs (e.g., erythema, 
induration/swelling at injection site) and symptoms (e.g., pain, pruritus at injection site) 
rather than a diagnosis of allergic reaction or injection site reaction.
5.4.6.2
Diagnosis versus Signs and Symptoms
For adverse events other than injection-site reactions (see Section 5.3.1), 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.


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5.4.6.3
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.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF.

If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.4.6.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported in this study.  For adverse events ongoing 
from the parent study, the current intensity of the event at this study start will be 
recorded as the initial intensity for the event in this study.  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 5.5.2 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 as a 
separate event on the Adverse Event eCRF.


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5.4.6.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5upper limit of normal [ULN] associated with 
cholestasis), only the diagnosis (i.e., cholestasis) 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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens (see Section 5.4.6.4 for 
more details).
5.4.6.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 


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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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens (see Section 5.4.6.4 for 
more details).
5.4.6.7
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 5.4.6.5) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.5.2).
5.4.6.8
Deaths
Part 1 OLE (including the 12-week safety follow-up period)
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.4.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.5.2).  This 
includes death attributed to progression of CD.
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 


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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 CD, "Crohn’s disease progression” should be 
recorded on the Adverse Event eCRF.
Part 2 (SM) 
During the 92-week safety monitoring for PML, all deaths due to PML, regardless of 
relationship to study drug, must be reported to the sponsor as a serious adverse event 
on the Adverse Event eCRF (see Section 5.4.6). 
If the investigator is made aware of a non-PML event of death, then it should be reported 
directly to Roche or its designee either by faxing or by scanning and e-mailing the 
Serious Adverse Event/Adverse Event of Special Interest Reporting Form using the fax 
number or e-mail address provided to investigators.
5.4.6.9
Preexisting Medical Conditions
Past resolved adverse events will be recorded in the medical history according to their 
medical relevance.  Adverse events reported ongoing at the end of Study GA29144 will 
be stated unresolved in those studies and also reported in Study GA29145.  
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”).
5.4.6.10
Lack of Efficacy or Worsening of Crohn’s Disease
Medical occurrences or symptoms of deterioration that are anticipated as part of CD 
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 CD on the Adverse Event eCRF, 
it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., “accelerated Crohn’s disease” or “worsening of Crohn’s 
disease”).
5.4.6.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.3.2), except as outlined 
below.  The duration of hospitalization should also be noted on the eCRF.


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The following hospitalization scenarios are not considered to be adverse events or 
serious adverse events:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease.
The patient has not suffered an adverse event.
The following hospitalization scenario is not considered to be a serious adverse event, 
but should be reported as an adverse event instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.4.6.12
Adverse Events Associated with an Overdose or Error in Drug 
Administration
Study drug overdose is the accidental or intentional use of the drug in an amount 
higher than the dose being studied.  An overdose or incorrect administration of study 
drug is not itself an adverse event, but it may result in an adverse event.
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF.
All adverse events associated with an overdose or incorrect administration of study 
drug should be recorded on the Adverse Event eCRF.  If the associated adverse event 
fulfills serious criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.5.2).
5.4.6.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from patient-reported outcome (PRO) data by 
the Sponsor, and safety analyses will not be performed using PRO data.  However, if 
any PRO responses suggestive of a possible adverse event are identified during site 
review of the PRO data, the investigator will determine whether the criteria for an 
adverse event have been met and, if so, will report the event on the Adverse Event 
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5.5
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR DURING PART 1 (OLE) AND 
PART 2 (SM)
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  See Section 5.5.2
for reporting requirements in Part 1 (OLE) and Part 2 (SM).
The following is a list of events that the investigator must report to the Sponsor within 
24 hours after learning of the event, regardless of relationship to study drug:

Serious adverse events (see Section 5.5.2 for more details)

Adverse events of special interest (see Section 5.5.2 for more details)

Pregnancies (see Section 5.5.3 for more 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 Institutional Review Board (IRB)/Ethics 
Committee (EC).
5.5.1
Emergency Medical Contacts
Medical Monitor Contact Information
Primary Contact
Medical Monitor:
, M.B., Ch.B. 
Primary:
1 973 659 6677
Secondary:
1 570 819 8565
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Quintiles Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Quintiles 
Medical Monitor, and track all calls. The Emergency Medical Call Center Help Desk will 
be available 24 hours per day, 7 days per week. A primary global contact number and 
additional back up number for the Help Desk and Medical Monitor contact information 


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will be distributed to all investigators (see "Protocol Administrative and Contact 
Information & List of Investigators").
5.5.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
Part 1 (OLE)
For reports of serious adverse events and adverse events of special interest, 
investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to the 
Sponsor by the EDC system.
In the event that the EDC system is unavailable, a paper Clinical Trial Serious Adverse
Event/Adverse Event of Special Interest Reporting Form and fax cover sheet should be 
completed and faxed to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the event), with use of the fax numbers provided to 
investigators (see "Protocol Administrative and Contact Information & List of 
Investigators").  Once the EDC system is available, all information will need to be 
entered and submitted via the EDC system.
Part 2 (SM)
Reports of all PML-related serious adverse events and adverse events of special interest 
(regardless of relationship) should be entered into the Adverse Event eCRF.  Events of 
related non-PML serious adverse events and pregnancies will be reported via faxing or 
by scanning and e-mailing the Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form using the fax number or e-mail address provided to investigators. 
5.5.3
Reporting Requirements for Pregnancies
5.5.3.1
Pregnancies in Female Patients
Part 1 (OLE)
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 24 weeks after the last 
dose of study drug. A paper Clinical Trial Pregnancy Reporting Form should be
completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than24 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.
Part 2 (SM)
The same approach (e.g., immediate reporting) as described below applies; however, 
pregnancies should be reported directly to the Sponsor by completion of the Clinical Trial 
Pregnancy Reporting Form and either by faxing or by scanning and e-mailing the form 
using the fax number or e-mail address provided to investigators.  Abortions or 
congenital anomalies/birth defects should be reported directly to the Sponsor with use of 
the Serious Adverse Event/Adverse Event of Special Interest Reporting Form as 
indicated in Section 5.5.2.
5.5.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
24 weeks after the last dose of study drug.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators. Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  When 
permitted by the site, the pregnant partner would need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
If the authorization has been signed, the investigator should submit a paper Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available. An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician.
5.5.3.3
Abortions
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant events), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.5.2).
5.5.3.4
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 5.5.2).


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5.5.4
Reporting Requirements for 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 immediately (i.e., no more than 24 hours after the 
investigator becomes aware of the event).  The 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 EDC system. 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 5.5.2. If 
the medical device complaint results in an adverse event to an individual other than the 
study patient, the device complaint must be reported on the PD103 IMP Deviation Form 
and the adverse event must be reported as a spontaneous adverse event to the 
Sponsor.
5.6
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.6.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or study-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  
All pregnancies reported during the study should be followed until pregnancy outcome.  
5.6.2
Sponsor Follow-Up
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case.


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5.7
POST-STUDY ADVERSE EVENTS
5.7.1
Post-Study Adverse Events Part 1 (OLE)
Patients Who Exit Part 1 (OLE) and Do Not Enter Part 2 (SM) 
All patients should be encouraged to enter Part 2 (SM) of this study to allow for 
long-term PML monitoring and timely assessment of any symptoms that could be related 
to PML. 
For those patients who do not enter Part 2 (SM) of this study, if investigators become 
aware of any serious adverse event after the end of the 12-week safety follow-up period 
that is believed to be related to prior study drug treatment, this should be reported to the 
Sponsor.  In addition, the Sponsor should be notified if the investigator becomes aware 
of any post-study events of confirmed or suspected PML, regardless of relationship to 
study drug, for up to 2 years after the patient’s last dose of study drug.
The investigator should report these events directly to Roche or its designee either by 
faxing or by scanning and e-mailing the paper Clinical Trial Serious Adverse
Event/Adverse Event of Special Interest Reporting Form using the fax number or e-mail
address provided to investigators.
Patients Who Exit Part 1 (OLE) and Enter Part 2 (SM)
Investigators should continue to provide follow-up data, if they receive it, to the Sponsor 
on unresolved adverse events.
5.7.2
Post-Study Adverse Events Part 2 (SM)
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.  
For patients who withdraw from the study, 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 e-mailing the Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form using the fax number or e-mail address provided to 
investigators.
5.8
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.


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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events for etrolizumab using the following reference 
document:

Etrolizumab Investigator's Brochure
Within the Investigator’s Brochure, the reference safety information is provided 
in Section 6.4 Identified Risks and Adverse Drug Reactions (Reference Safety 
Information).
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
All serious related (as assessed by the investigator and/or Sponsor) adverse events 
occurring in a patient administered etrolizumab at any time during the trial and assessed 
as unexpected per the reference safety information will be considered Suspected 
Unexpected Serious Adverse Reactions (SUSARs) for the purpose of regulatory 
reporting to all health authorities, with the exception of the U.S. Food and Drug 
Administration (FDA). For the FDA, SUSARs will be submitted as 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 maintain the blind, investigators will be informed of all unexpected serious adverse 
events satisfying local regulatory reporting criteria but regardless of study drug 
assignment (i.e., they may also receive reports of patients on placebo).
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Because of the non-comparative character of the study, no statistical tests are planned;
all efficacy parameters will be summarized descriptively.  Efficacy in Part 1 (OLE) will be 
assessed across visits using absolute values and change from baseline for continuous 
outcomes, and dichotomous data (e.g., CDAI remission, clinical remission) will be 
evaluated using frequency counts and proportions.  Demographic and baseline 
characteristics such as age, sex, race, region, use of corticosteroids and 
immunosuppressants, duration of disease, and CDAI, SF and AP scores will be 
summarized by use of descriptive statistics.


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6.1
NUMBER OF PATIENTS
The maximum number of patients enrolled in the OLE-SM study is approximately 1150
(i.e., all patients enrolled in Study GA29144).  No formal sample size calculations were 
performed.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enrolled in Part 1 (OLE) and Part 2 (SM) will be tabulated 
by country and study site.  The number of patients who discontinued early (early 
discontinuation of OLE treatment or early termination from the study) or completed the 
study will be tabulated.  Reasons for early discontinuation of treatment or early 
termination from the study will be listed and summarized.  Any eligibility criteria 
exceptions and other major protocol deviations will also be summarized.  
6.3
SAFETY ANALYSES FOR PART 1 (OLE)
The safety analyses will include all patients who received at least one dose of 
etrolizumab.
Safety will be assessed through descriptive summaries of adverse events, laboratory 
test results (serum chemistry, hematology including complete blood count with 
differential and platelet counts), and antibodies to etrolizumab.
6.3.1
Adverse Events
Verbatim descriptions of treatment-emergent adverse events will be coded and their 
incidence and observation time-adjusted rate will be summarized, as appropriate.  A 
treatment-emergent adverse event is defined as any new adverse event reported or any 
worsening of an existing condition on or after the first dose of study drug.  In addition, 
separate summaries will be generated for serious adverse events, deaths, and adverse 
events leading to discontinuation of etrolizumab.
Analyses will also be performed for:

Systemic hypersensitivity events
Specific analyses will be performed for anaphylactic reactions using both the 
anaphylactic reaction MedDRA SMQ and Sampson’s criteria (see Appendix 10
Clinical Criteria for Diagnosing Anaphylaxis).

Serious infections, in particular GI infections 

Opportunistic infections

Malignancies

Injection-site reactions


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6.3.2
Laboratory Tests
Descriptive summaries of laboratory values at baseline and throughout the study will be 
tabulated.  For selected parameters, changes from baseline and the proportion of 
patients experiencing clinically significant changes relative to baseline will be 
summarized.
The number and percentage of patients with positive serum antibodies to etrolizumab at 
baseline and during the study will be tabulated.
6.4
SAFETY ANALYSES FOR PART 2 (SM)
In Part 2 (SM), any suspected or confirmed PML events will be listed and described by 
means of safety narratives.
Serious adverse events (including serious infections) and deaths will also be described 
as narratives.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
Sponsor, contract research organization (CRO), and Data Management vendor will be 
responsible for the data management of this study, including quality checking of the data.  
Sites will be responsible for data entry into the eCRF via the EDC system.  In the event 
of discrepant data, data queries will be issued to the sites and resolved by the sites via 
the EDC system.  The Sponsor will produce an EDC Study Specification document that 
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, using the Sponsor’s 
standard procedures to handle and process the electronic transfer of these data.
7.2
ELECTRONIC CASE REPORT FORMS
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and have access to Help Text Medidata RAVE for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.


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7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
Patient-reported data may be collected electronically through use of electronic devices 
provided by an electronic patient-reported outcome (ePRO) vendor.  If an electronic 
device, such as an electronic diary (e-diary), is used, the electronic device will be 
designed for entry of data in a way that is attributable, secure, and accurate, in 
compliance with U.S. FDA regulations for electronic records (21 Code of Federal 
Regulations, Part 11).  The data will be transmitted to a centralized database at the 
ePRO vendor.  The data from the e-devices are available for view access only via 
secure access to a Web portal provided by the ePRO vendor.  Only identified and 
trained users may view the data, and their actions become part of the audit trail.  The 
Sponsor will have view access only.  Regular data transfers will occur from the 
centralized database at the vendor to the database at the Sponsor.
Once the study is complete, the ePRO data, audit trail, and trial and system 
documentation will be archived.  The Sponsor will receive all data entered by patient on 
the e-diary and tablet device and all the study documentation.
Details regarding patient reported data and the electronic device is available in the Study 
Reference Manual.  System backups for data stored by the Sponsor and records 
retention for the study data will be consistent with the Sponsor’s standard procedures.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include but are not limited to hospital records, 
clinical and office charts, laboratory notes, memoranda, evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, MRIs, ECGs, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.


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To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The investigational site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research.  An acceptable computerized data collection system allows 
preservation of the original entry of data.  If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, patient data (including PROs), Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 
study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the EU/EEA will comply 
with the EU Clinical Trial Directive (2001/20/EC).


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8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the “Consent Forms”) 
before IRB/EC submission.  The final IRB/EC-approved Consent Forms must be
provided to the Sponsor for health authority submission purposes according to local 
requirements.
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a patient's agreement to allow 
any remaining specimens to be used for exploratory research.  Patients who decline to 
participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each consent form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site utilizes a 


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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 only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.


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


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A central laboratory will be used for most laboratory assessments.  A selected group of 
assessments will be performed on site or by a local laboratory.
The eCRF data will be recorded via a Sponsor-designated EDC system.  An IxRS will be 
used for study drug inventory management.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
prior to submission.  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.
The Sponsor will comply with the requirements for publication of study results.  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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47-mediated adhesion to vascular cell adhesion molecule-1, mucosal adhesion 
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1994;153:384761.
Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012;380:1590605.
Best WR, Becktel JM, Singleton JW. Rederived values of the eight coefficients of the 
Crohn’s Disease Activity Index (CDAI). Gastroenterology 1979;77:8436.
Cepek KL, Parker CM, Madara JL, et al. Integrin E7 mediates adhesion of 
T lymphocytes to epithelial cells. J Immunol 1993;150:345970.
Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical 
response and remission in patients with Crohn’s disease: the CHARM trial. 
Gastroenterology 2007;132:5265.
Cosnes J, Nion-Larmurier I, Beaugerie L, et al. Impact of the increasing use of 
immunusuppressants in Crohn’s disease on the need for intestinal surgery. 
Gut 2005;54:23741.
de Vries HS, van Oijen MG, Driessen RJ, et al. Appropriate infliximab infusion dosage 
and monitoring: results of a panel meeting of rheumatologists, dermatologists and 
gastroenterologists. Br J Clin Pharmacol 2011;71:719.
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Crohn's and Colitis Organization, 17 February 2017 (unpublished).
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disease:  a meta-analysis of population-based studies. Inflamm Bowel Dis 
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intra-epithelial and lamina propria lymphocytes in patients with Crohn’s disease. 
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Gastroenterology 2001;121:25560.
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patchspecific lymphocyte homing receptor as an integrin molecule with an 
-chain homologous to human VLA-4-α. Cell 1989;56:3746.


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Hu M, Crowe DT, Weissman IL, et al. Cloning and expression of mouse integrin p(7): 
a functional role in Peyer's patch–specific lymphocyte homing. Proc Natl Acad Sci 
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Khanna R, Zou G, D’Haens G.D, et al.  A retrospective analysis: the development of 
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Lichtenstein GR, Hanauer SB, Sandborn WJ, et al. Management of Crohn’s disease in 
adults. Am J Gastroenterol 2009;104:46583.
Malchow H, Ewe K, Brandes JW, et al. European cooperative Crohn’s disease study 
(ECCDS): results of drug treatment. Gastroenterology 1984;86:24966.
Modigliani R, Mary JY, Simon JF, et al. Clinical, biological, and endoscopic picture of 
attacks of Crohn’s disease.  Evolution on prednisolone. Groupe d’Etudes 
Thérapeutiques des Affections Inflammatories du Tube Digestif (GETAID).  
Gastroenterology 1990;98:8118.
Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the 
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Peyrin-Biroulet L, Lémann M. Review article: remission rates achievable by current 
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Prefontaine E, Macdonald JK, Sutherland LR, et al. Azathioprine or 6-mercaptopurine for 
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Rosario M, Fox I, Milch C, et al.  Pharmacokinetic/pharmacodynamics relationship and 
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additional results from GEMINI 1 and 2 (abstract). Crohn’s and Colitis Foundation 
of America, Advances in Inflammatory Bowel Diseases 2013. Abstract P-140.
Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn’s
disease previously treated with infliximab: a randomized trial. Ann Intern Med 
2007:19;146(12):82938. Epub 2007 Apr 30.
Sandborn WJ, Colombel JF, D’Haens G, et al. One-year maintenance outcomes among
patients with moderately-to-severely active ulcerative colitis who responded to 
induction therapy with adalimumab: subgroup analyses from ULTRA 2. Aliment 
Pharmacol Ther 2013;37:20413.


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Sands BE, Feagan BG, Rutgeerts P, et al. Effects of Vedolizumab Induction Therapy for 
Patients With Crohn's Disease in Whom Tumor Necrosis Factor Antagonist 
Treatment Had Failed. Gastroenterology 2014;147:61827.
Siegal CA, Melmed GY. Predicting response to anti-TNF agents for the treatment of 
Crohn’s disease. Ther Adv Gastroenterol 2009;2(4):24551.
Silverberg MS, Satsangi J, Ahmad T, et al.  Toward an integrated clinical, molecular and 
serological classification of inflammatory bowel disease: report of a working party 
of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 
2005;19 Suppl A:5A-36A.
Summers RW, Switz DM, Sessions JT Jr, et al. National cooperative Crohn’s disease 
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Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric 
monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. 
Crohn’s Disease cA2 Study Group. N Engl J Med 1997;337:102935.
Van Assche G, Dignass A, Reinisch W, et al.  The second European evidence-based 
Consensus on the diagnosis and management of Crohn's disease: Special 
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van der Heijde D, Kivitz A, Schiff MH, et al.  Efficacy and safety of adalimumab in 
patients with ankylosing spondylitis: results of a multicenter, randomized, 
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Appendix 1
Open-Label Extension (OLE, Part 1) Schedule of Assessments
Assessment
Category
Part 1 (OLE)
In-Clinic Etrolizumab 
Administration 
Every 4 Weeks
At-Home Etrolizumab Administration Every 4 Weeks (or in-clinic 
administration if unable to perform at home)
Clinic Visit at Every 
4-Week Interval 
(3 days)
Clinic Visit at 
Every 12-Week 
Interval (starting 
at Week 24)
(7 days)
Clinic Visit 
at Every 
48-Week 
Interval c
(7 days)
Clinic Visit 
at Week 
108 d
(7 days)
Unscheduled 
Visit e
Study 
Completion 
or Early 
Withdrawal 
Visit f
0 a, b
4
8
12
Prior to entry 
into Part 1 
(OLE)
Informed consent
x
Review eligibility criteria
x
Study Drug 
Etrolizumab 
administration
x
x
x
x
x
Assessments 
during Part 1 
(OLE)
Concomitant medications
x
x
x
x
x
x
x
Adverse events g
x
x
x
x
x
x
x
Patient diary check
x
x
x
x h
Pregnancy test i
x
x
x
x
x
x
CDAI assessment
x j
x k
x k
x
x h
Weight
x
x
x
x h
PML neurologic 
examination l
x
x
x
x
x
Vital signs (BP, pulse 
rate)
x
x
x
x
Limited/symptom-driven 
physical examination, 
including GI
x
x
x
x
x
x


Appendix 1
Open-Label Extension (OLE, Part 1) Schedule of Assessments (cont.)
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Assessment
Category
Part 1 (OLE)
In-Clinic Etrolizumab 
Administration 
Every 4 Weeks
At-Home Etrolizumab Administration Every 4 Weeks (or in-clinic 
administration if unable to perform at home)
Clinic Visit at Every 
4-Week Interval 
(3 days)
Clinic Visit at 
Every 12-Week 
Interval (starting 
at Week 24)
(7 days)
Clinic Visit 
at Every 
48-Week 
Interval c
(7 days)
Clinic Visit 
at Week 
108 d
(7 days)
Unscheduled 
Visit e
Study 
Completion 
or Early 
Withdrawal 
Visit f
0 a, b
4
8
12
ECG
x
x
x
Ileocolonoscopy
x m
x
x n
Paired biopsy collection 
(optional; requires RCR 
consent) 
x
x
Laboratory 
Assessments
Hematology o
x
x
x
x
x p
Chemistry (including 
LFTs) q
x
x
x
x
x p
Serum (CRP)
x
x
x
x p
Hepatitis B DNA r
x
x
x
Anti-therapeutic antibody 
sample (serum) s
x b
x
x
x
x p
APabdominal pain; ATAanti-therapeutic antibody; BPblood pressure; CDAICrohn’s Disease Activity Index; CRPC-reactive protein; 
ECGelectrocardiogram; eCRFelectronic case report form; GIgastrointestinal; JCVJohn Cunningham virus; LFT liver function test; 
OLEopen-label extension; PMLprogressive multifocal leukoencephalopathy; RCR Roche Clinical Repository; SFstool frequency.
Note:  All assessments and blood draws are to be conducted prior to study medication administration.
a Day 1 of Week 0.
b Week 0 procedures and laboratory assessments that have been performed as part of the final visit for Study GA29144 do not need to be
repeated, with the exception of ATAs, which must be recollected at Week 0 if the Week 0 visit occurs 7 days after the final visit for 
Study GA29144.


Appendix 1
Open-Label Extension (OLE, Part 1) Schedule of Assessments (cont.)
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c Assessments in this column should be conducted in addition to the assessments conducted every 12 weeks.
d Assessments in this column should be conducted in addition to the assessments conducted every 12 weeks and every 48 weeks.
e
Unscheduled visit represents a visit that is not as per Schedule of Assessments and is required for an adverse event or for potential 
relapse assessment.  All indicated assessments are NOT performed at each unscheduled visit.  Assessments would be symptom driven 
(e.g., only perform PML neurologic examination if patient reports symptoms suspected to indicate PML).  Assessments corresponding to 
items noted in this column should be recorded on the eCRF.
f
Denotes the early withdrawal from treatment visit for the open-label treatment period.  To be performed within 30 days of last dose of 
study drug.  Study drug is not administered at the Early Withdrawal from Treatment visit.
g Patients will be given patient alert cards that provide information regarding the signs and symptoms of PML. Patients will be instructed to 
contact the study site at any time if they develop any new neurological signs or symptoms suggestive of PML.
h Patient diary check (including completion of abdominal pain questionnaire), CDAI assessment, and recording patient's weight are
required at study completion. Conduct CDAI assessment and record patient's weight at early withdrawal visit if diary-data captured prior 
to the early withdrawal visit are available.
i
For women of childbearing potential, including those who have had a tubal ligation.  Perform a urine pregnancy test; if the urine 
pregnancy test result is positive, perform a confirmatory serum pregnancy test.  Pregnancy test will be carried out at home once the 
patient starts etrolizumab administration at home.  Pregnancy test must be completed prior to etrolizumab administration.  Patient is to 
report the pregnancy test result in the patient diary.  Patients must be instructed at screening and reminded throughout the study that in 
case of a positive pregnancy test, they should stop self-administration of study drug and call the site immediately.  Do not administer 
etrolizumab unless the serum pregnancy test result is negative.
j
CDAI, SF, and AP scores will not be recalculated at the Week 0 visit; however, scores from the most recent visit in Study GA29144 (Week 10, 
Week 14, Week 74, or Early Withdrawal visit) should be entered into the database along with date of assessment.
k Patients are to complete the patient diary for stool frequency, abdominal pain, and general well-being for 10 days prior to the clinic visits when 
CDAI assessments are scheduled (every 12 weeks).
l
PML neurologic examination consists of the PML Subjective Checklist and the PML Objective Checklist.  Administered by a qualified HCP before 
other assessments, as per Appendix 8.
m The ileocolonoscopy should be conducted on the day of the clinic visit or within 10 days after the clinic visit was completed.
n An ileocolonoscopy will be performed at the Week 108 visit or early withdrawal visit if prior to Week 108.  If early withdrawal visit occurs after 
the Week 108 visit, then the ileocolonoscopy with biopsies should be conducted only at Week 108.
o Includes hemoglobin, hematocrit, platelet count, RBC count, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular 
hemoglobin concentration, red cell distribution width, WBC count, and differential.
p Not required if unscheduled visit leads to withdrawal and assessment previously conducted at unscheduled visit.


Appendix 1
Open-Label Extension (OLE, Part 1) Schedule of Assessments (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
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q Includes sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, creatinine, calcium, phosphorus, magnesium, total and direct 
bilirubin, total protein, albumin, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, creatine 
phosphokinase, and uric acid.
r
Only enrolled patients who were hepatitis B core antibody positive in Study GA29144 should have hepatitis B DNA measured at these 
timepoints.
s Samples are to be collected prior to dose administration at all timepoints indicated and whenever serum sickness is suspected.  If serum 
sickness or a clinically significant allergic drug reaction is suspected, the Sponsor should be notified, and serum for ATA analysis should be 
drawn and sent to the central laboratory.  ATA samples may also be utilized for assessment of etrolizumab serum concentrations.


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Appendix 2 12-Week Safety Follow-Up (OLE, Part 1)
Schedule of Assessments
Part 1 (OLE)
Week (7 days)
Unscheduled Visit c
6 a
12/Early Withdrawal Visit b
Concomitant medications
x
x
x
Adverse events
x
x
x
Urine pregnancy test d
x
Anti-therapeutic antibody 
sample (serum) e
x
PML assessment interview f
x
x g
Neurological examination f, h
x
x g
ATAanti-therapeutic antibody; JCVJohn Cunningham virus; OLEopen-label extension;
PMLprogressive multifocal leukoencephalopathy.
a Week 6 study assessments are to be made by telephone visit and not by clinic visit.
b If the patient discontinues prior to completion of the 12-week safety follow-up, the indicated 
assessments for the 12-week safety follow-up clinic visit should be performed as the Early 
Withdrawal visit of the safety follow-up period.
c Unscheduled visit for safety monitoring.
d For women of childbearing potential, including those who have had a tubal ligation, perform a 
urine pregnancy test; if the urine pregnancy test result is positive, confirm with a serum 
pregnancy test.
e If serum sickness or a clinically significant allergic drug reaction is suspected, Sponsor should 
be notified and serum for ATAs should be drawn and sent to the central laboratory.  ATA 
samples may be used for assessment of etrolizumab serum concentration.
f
Administer before other assessments.
g If clinically indicated.
h Neurologic examination consists of the PML Subjective Checklist and the PML Objective 
Checklist, as per Appendix 8.


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Appendix 3 Extended Progressive Multifocal Leukoencephalopathy Safety Monitoring (SM, Part 2) 
Schedule of Assessments
Part 2 (SM)
92-week Extended PML Monitoring Period a
24, 48, 68, and 92 Weeks after Patient Discontinuation from Study OR
Early Termination b
PML Subjective Checklist (Telephone Only) c
x
Adverse Event Reporting to Roche Safety Risk 
Management d
x
OLE-SMopen-label extensionsafety monitoring; PMLprogressive multifocal leukoencephalopathy; SMsafety monitoring.
Note:  The extended PML monitoring period is to be conducted for patients completing or discontinuing from Part 1 (OLE) of the 
OLE-SM study AND for patients entering OLE-SM Part 2 (SM) from Study GA29144 after completion of 12-week safety follow-up in 
Study GA29144.
a The total length of the PML monitoring period is 104 weeks after the patient discontinues from the study (12-week safety follow-up 
plus 92-week extended PML monitoring period).  During the extended PML monitoring period telephone visits will occur at the 
indicated timepoints for the 92-week extended PML monitoring period.  The extended PML monitoring will be conducted using a 
PML Subjective Checklist over the telephone.  PML monitoring should occur within 7 days of the specified day.
b If the patient discontinues after the 12-week safety follow-up visit but prior to study completion (end of extended PML monitoring 
period), the early termination visit from the extended PML monitoring period should be performed (a subjective checklist by 
telephone).
c If there are any signs or symptoms suggestive of PML during the telephone visit, the patient will be asked to come into the clinic for 
a neurologic examination (see Section 4.4.5).
d Investigators are not required to actively monitor patients for adverse events; however, if they become aware of any deaths, 
serious adverse events, or non-serious adverse events of special interest, these should be reported directly to the Sponsor via 
telephone or via fax machine using the Serious Adverse Event Reporting Form and fax cover sheet (see "Protocol Administrative 
and Contact Information & List of Investigators").


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Appendix 4
Childbearing Potential, Pregnancy Testing, and Contraception
All women of childbearing potential (including those who have had a tubal ligation) will 
have a serum pregnancy test at screening and a urine pregnancy test prior to 
administration of study drug at subsequent visits.  If a urine pregnancy test result is 
positive, study drug will not be administered that day.  The result must be confirmed by a 
serum pregnancy test (conducted by the central laboratory).  Refer to Section 5.5.3 of 
the protocol for management of a patient with a confirmed pregnancy.
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 months of amenorrhea with no identified cause 
other than menopause), and has not undergone surgical sterilization (removal of ovaries 
and/or uterus).
For women: patients are considered to be of childbearing potential unless they meet one 
of the following criteria:

The patient has been postmenopausal (nontherapy-induced amenorrhea) for at 
least 12 months

The patient had a surgical bilateral oophorectomy (with or without hysterectomy) 
more than 6 weeks prior to enrollment

The patient had a hysterectomy
Female patients of reproductive or childbearing potential who are unwilling to use a 
highly effective method of contraception or remain abstinent during the treatment period 
and for at least 24 weeks after the last dose of study drug will be excluded from study 
participation.
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of contraception.
Examples of highly effective contraception include the following:

Combined oral contraception pill

Contraceptive transdermal patch

Intrauterine device

Implants for contraception

Injections for contraception (with prolonged release)

Hormonal vaginal device

Sterilization, surgical tubal ligation

Sole sexual partner consisting of surgically sterilized male partner with appropriate 
postsurgical verification of the absence of spermatozoa in the ejaculate


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Appendix 4
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 as friction between the two can 
result in either product failing)
Patients may provide verbal confirmation that the partner completed appropriate 
follow-up after vasectomy.  Sites are not required to obtain partner medical records.
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined 
below:
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at 
least 24 weeks after the last dose of study drug.  Men must refrain from 
donating sperm during this same period. 
For men and women:  The reliability of sexual abstinence should be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception.


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Appendix 5
Crohn’s Disease Activity Index
Category
Count
Initial 
Total
Multiplication 
Factor
Total
Number of liquid or very 
soft stools
7-day total number of liquid or very 
soft stools (reported on the 7 days 
immediately prior to the study visit)
x 2
Abdominal pain
7-day total of daily abdominal pain 
scores on a 3-point scale: 0=none, 
1=mild, 2=moderate, 3=severe 
(reported on the 7 days 
immediately prior to the study visit)
x 5
General well being
7-day total of daily general well-
being scores on a 4-point scale: 
0=generally well, 1=slightly under 
par, 2=poor, 3=very poor, 4=terrible 
(reported on the 7 days 
immediately prior to the study visit)
x 7
Extra-intestinal 
manifestations of 
Crohn’s Disease
Total number of checked boxes 
(check all that apply):
☐Arthritis/arthralgia
☐Iritis/uveitis
☐Erythema nodosum/pyoderma 
gangrenosum/aphthous stomatitis
☐Anal fissure, fistula, or abscess
☐Other fistula
☐Fever over 37.8°C during past 
week
x 20
Lomotil/Imodium/opiates 
for diarrhea
Yes = 1
No = 0
x 30
Abdominal mass
None = 0
Questionable = 2
Definite = 5
x 10
Hematocrit (%)a
Males: subtract value from 47
Females: subtract value from 42
x 6
Body Weightb
(1- (Body weight/Standard Weight)) 
x 100
x 1
Final Score
Add totals:
a
b
If hematocrit subtotal <0, enter 0.
If body weight subtotal < -10, enter -10.
Adapted from: Best WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Crohn’s disease 
activity index. National Cooperative Crohn’s Disease Study. Gastroenterology 1976;70(3):43944.




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Appendix 7
Bristol Stool Form Scale


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Appendix 8
Worksheet for the PML Neurologic Examination
PML Subjective and Objective Checklists of neurologic assessments to monitor
for progressive multifocal leukoencephalopathy (PML) in the Etrolizumab Phase III
Studies
PML usually manifests with subacute, progressive neurologic deficits including:
Neurologic Domain
Signs/Symptoms
Relevant PML
Subjective/Objective
Checklist Question
Altered mental status
Can encompass a variety of presenting 
signs and symptoms including cognitive 
changes (confusion, difficulty 
concentrating, memory loss) and altered 
behavior (including personality changes)
Q2, Q5, Q6
Higher cortical dysfunction
Impaired comprehension and/or 
formulation of language (aphasia), loss of 
ability to recognize objects, persons, 
sounds, shapes, or smells (agnosia)
Q2, Q5, Q6
Visual changes
Loss of visual fields (homonymous 
hemianopsia), double vision (diplopia)
Q1
Motor deficits
Weakness (hemiparesis or monoparesis), 
seizures (generalized or partial), difficulties 
with speech (dysarthria) or swallowing 
(dysphagia)
Q2, Q3
Sensory deficits
Sensory loss (i.e. paresthesia)
Q7
Coordination
Difficulty walking and maintaining balance 
(ataxia), lack of voluntary coordination of 
limb movement (limb ataxia)
Q4
In order to monitor patients for PML, a neurologic exam (including evaluation of cranial
nerves, motor and sensory function, coordination, and mental status) will be performed as
per the Schedules of Assessments (see Appendix 1). 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 8
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
97/Protocol GA29145, Version 6
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
t
th (
l if
4. Have you noticed yourself
regularly bumping into things
or having difficulty writing?
Observe tandem
gait and finger to
nose.
5. Have you regularly been
experiencing difficulty
understanding others?
Test ability to
follow serial 
commands.
6. Have you had persistent
problems with your memory or
thinking?
Recall of 3
objects over 1 
minute with
distraction (only if
7. Have you been 
experiencing any persistent
numbness or other loss of
sensation?
Test sensation
side to side with
either pinprick or 
cold (only if


Appendix 8
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
98/Protocol GA29145, Version 6
PML Objective Checklist
Neurologic function 
being assessed
Instructions (bold text indicates
parts of exam required at each
visit, as specified in Schedule of
Assessments)
Abnormal 
exam?
If the answer is 
“Yes”, describe
the abnormal
objective exam
YES
NO
1. Visual fields and 
ocular motility

Visual Field Testing

Ocular Motility Testing
2. Speech

Observe the patient’s speech 
output for dysarthria or aphasia.
3. Strength

Pronator drift test (Barre 
maneuver)

Gait testing (normal, heel and 
toe walk)

ONLY if the patient has any 
subjective complaints of weakness,
test muscle strength of the relevant
muscle groups
4. Coordination

Observe tandem gait and 
finger to nose
5. Comprehension

Test ability to follow serial 
commands

“Take a piece of paper in your 
hand, fold it in half, and put it on the
floor.”
6. Memory and thinking

ONLY if the patient has
subjective complaints about their 
memory or thinking, test the ability
of the patient to recall 3 objects
over 1 minute with distraction
7. Sensation

ONLY if the patient has
subjective sensory complaints,
evaluate relevant areas based on
patient’s subjective complaints by 
comparing left vs. right side 
sensation to cold (e.g. alcohol swab
or cold stethoscope) or pinprick
(e.g. broken Q-tip)
Please refer to the PML Algorithm in the Protocol Appendix for details.

If there is an abnormal finding on the PML Subjective Checklist, this should be
appropriately documented on the worksheet and in the eCRF.


Appendix 8
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
99/Protocol GA29145, Version 6

If there is an abnormal finding on the PML Objective Checklist, this should be
appropriately documented on the worksheet and in the eCRF.

If there are any abnormalities found on the PML Subjective Checklist that are
accompanied by the corresponding abnormality on the PML Objective Checklist, or if
there is high clinical suspicion for PML (in the opinion of the investigator):
  This must be reported as an adverse event of special interest (AESI) within 
24 hours
  An urgent referral to a neurologist should be made.
  Dosing with study drug will be suspended until PML can be ruled out.
  Further evaluation will proceed according to the PML Algorithm in the 
Protocol Appendix.
   Any confirmed diagnosis of PML should be reported as a serious adverse 
event (SAE).
Please complete the PML eCRF.
Was the PML Subjective Checklist administered? (Yes/No)
If yes, date of administration of PML Subjective Checklist (Date)
If yes, were there any abnormalities on the PML Subjective Checklist? (Yes/No) 
Was the PML Objective Checklist administered? (Yes/No)
If yes, were there any abnormalities on the PML Objective Checklist? (Yes/No) 
Is PML suspected? (Yes/No)
More detailed instructions for the PML Objective Checklist Neurologic
Evaluations (please refer to the PML Neurologic Exam Video for more
information):
1.
Visual fields and ocular motility
Visual Field Testing:

Position yourself approximately 3 feet away from the patient, with eyes at the same
level.

Keeping both eyes open, ask the patient to cover one eye and ask if all parts of your
face and head are clear to them. Ask them to repeat, covering the other eye.


Appendix 8
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
100/Protocol GA29145, Version 6

Have the patient cover one eye and stare at your nose, and then ask them how
many fingers you are holding up, testing each of the 4 visual quadrants. Repeat with
the other eye covered.
Ocular Motility Testing:

Evaluate the patient for conjugate eye movement.

Starting about 3 feet from center, move in a big “H”, pausing at the center and at 
lateral gaze, and finishing with convergence (finger to their nose). Watch for
nystagmus in lateral gaze, smooth pursuits, and pupillary constriction with
convergence. Note: a couple of beats of nystagmus upon extreme lateral gaze is
considered normal.
2.
Speech

Observe the patient’s speech output for dysarthria or aphasia.

Dysarthria is a motor speech disorder. Findings can include “slurred” speech, 
decreased volume, slow rate of speech, limited tongue, lip, and jaw movement,
abnormal rhythm when speaking, changes in vocal quality, and drooling or poor 
control of saliva.

Aphasia is a disorder that results from damage to parts of the brain that control 
language, and can lead to problems with any or all of the following: speaking, 
listening, reading or writing.
3.
Strength
Pronator drift test (Barre maneuver):

Ask the patient to stand with their feet together and extend their arms out in front of 
them at 90 degrees (parallel to floor) with palms facing upwards toward the ceiling.

Ask the patient to close their eyes and keep their arms extended for 15 seconds.

If either arm drifts downward, upward, or starts to pronate (i.e. thumb turns up), this
is considered an abnormal exam.
Gait testing:

Ask the patient to walk across the room (~10 feet). The patient should have a
normal gait, with their left arm swinging forward when the right foot leads, and vice
versa. Be certain to note whether there is symmetric arm swinging, because a slight
decrease in arm swinging may be an indicator of upper extremity weakness.

Ask the patient to walk on their heels across the room (~10 feet). Carefully observe
whether they have any difficulty maintaining their toes off the ground or loss of
balance.


Appendix 8
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
101/Protocol GA29145, Version 6

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).
Finger to nose:

Hold your finger out so they need to reach out and lean. Start near the center, and
move your finger slowly so that they reach across their body. Make sure they
alternate touching your finger and their nose at a good speed. Inability to perform 
this accurately is considered an abnormal test.
5.
Comprehension

Test ability to follow serial commands

“Take a piece of paper in your hand, fold it in half, and put it on the floor.”


Appendix 8
Worksheet for the PML Neurologic Examination (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
102/Protocol GA29145, Version 6
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
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Appendix 9
Algorithm for the Evaluation of
Progressive Multifocal Leukoencephalopathy


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104/Protocol GA29145, Version 6
Appendix 10
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
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Appendix 11
Simple Endoscopic Score for Crohn’s Disease (SES-CD)
Table 1  Definitions of Simple Endoscopic Score for Crohn’s Disease
Simple Endoscopic Score for Crohn’s Disease values
Variable
0
1
2
3
Size of ulcers
None
Aphthous ulcers 
(Ø 0.1 to 0.5 cm)
Large ulcers 
(Ø 0.5 to 2 cm)
Very large ulcers 
(Ø2 cm)
Ulcerated 
surface
None
10%
1030%
30%
Affected surface
Unaffected 
segment
50%
5075%
75%
Presence of 
narrowings
None
Single, can be 
passed
Multiple, can be 
passed
Cannot be 
passed
Ø, Diameter.
Table 2  Example of SES-CD scoring form
Ileum
Right 
colon
Transverse 
colon
Left 
colon
Rectum
Total
Presence and size of ulcers 
(03)
Extent of ulcerated surface 
(03)
Extent of affected surface 
(03)
Presence and type of 
narrowings (03)
SES-CD
Adapted from: Daperno M, D’Haens G, Van Assche G, et al. Development and validation of a 
new, simplified endoscopic activity score for Crohn’s disease: the SES-CD. Gastrointestinal 
Endoscopy 2004;60:505512.

SAP_001.pdf: 
 
Official Title: 
An Open-Label Extension and Safety Monitoring Study of Patients 
With Moderately to Severely Active Crohn's Disease Previously 
Enrolled in the Etrolizumab Phase III Protocol GA29144 
NCT Number: 
NCT02403323 
Document Date: 
SAP Version 1: 27-September-2022 
 
 




 
Etrolizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GA29145 
2 
 
STATISTICAL ANALYSIS PLAN VERSION HISTORY 
This SAP was developed based on Roche SAP model document v2.0, Revised 28 Feb 
2022. 
SAP Version 
Approval Date 
Based on Protocol  
(Version, Approval Date) 
1 
see electronic date stamp 
on last page of the 
document 
v6, 29 April 2019 


 
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Statistical Analysis Plan GA29145 
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TABLE OF CONTENTS 
1. 
INTRODUCTION .......................................................................................... 7 
1.1 
OBJECTIVES AND ENDPOINTS ............................................ 9 
1.2 
STUDY DESIGN .................................................................... 10 
1.2.1 
Protocol Synopsis .................................................................. 10 
1.3 
OUTCOME MEASURES FOR GA29145 PART 1 
(OLE) ..................................................................................... 10 
1.3.1 
Efficacy Outcome Measures .................................................. 10 
1.3.2 
Safety Outcome Measures .................................................... 11 
1.3.3 
Exploratory Outcome Measures ............................................ 11 
1.4 
ANALYSIS TIMING ............................................................... 12 
2. 
STATISTICAL HYPOTHESES AND SAMPLE SIZE 
DETERMINATION ...................................................................................... 12 
2.1 
STATISTICAL HYPOTHESES .............................................. 12 
2.2 
SAMPLE SIZE DETERMINATION ........................................ 12 
3. 
ANALYSIS SETS ........................................................................................ 12 
4. 
STATISTICAL ANALYSES ......................................................................... 13 
4.1 
GENERAL CONSIDERATIONS ............................................ 13 
4.1.1 
Analysis of Study Conduct ..................................................... 13 
4.1.2 
Analysis of OLE Treatment .................................................... 14 
4.1.3 
Primary Efficacy Analysis ...................................................... 15 
4.1.3.1 
Endoscopic Improvement and Remission at 
Week 108 .............................................................................. 17 
4.1.3.2 
Simple Endoscopic Score for Crohn’s disease 
(SES-CD) score at Week 108 ................................................ 18 
4.1.3.3 
CDAI Remission and Clinical Remission Every 
12 Weeks ............................................................................... 19 
4.2 
SAFETY ANALYSES ............................................................. 19 
4.2.1 
Extent of Exposure ................................................................ 20 
4.2.2 
Adverse Events ..................................................................... 20 
4.2.3 
Additional Safety Assessments ............................................. 22 
4.2.3.1 
Laboratory Data ..................................................................... 22 
4.2.3.2 
Vital Signs .............................................................................. 22 


 
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Statistical Analysis Plan GA29145 
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4.2.3.3 
ECGs ..................................................................................... 22 
4.2.3.4 
Medical History ...................................................................... 22 
4.2.3.5 
Concomitant Medications ...................................................... 23 
4.2.4 
Open-Label Extension Timeframe ......................................... 23 
4.3 
INTERIM ANALYSES ............................................................ 23 
4.4 
CHANGES TO PROTOCOL-PLANNED 
ANALYSES ............................................................................ 23 
5. 
SUPPORTING DOCUMENTATION ............................................................ 23 
6. 
REFERENCES ........................................................................................... 24 
 
 
LIST OF TABLES 
Table 1 
Key Characteristics of GA29145 OLE-SM in CD (Juniper) ........... 9 
Table 2 
Efficacy Outcome Definitions ...................................................... 11 
Table 3 
Analysis Population ..................................................................... 12 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema for Part 1 (Open-Label Extension; OLE) of 
the OLE-SM Study ........................................................................ 8 
Figure 2 
Study Schema for Part 2 (Safety Monitoring; SM) of the 
OLE-SM Study .............................................................................. 8 
 


 
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Statistical Analysis Plan GA29145 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or Term 
Description 
5-ASAs 
5-aminosalicylic acid 
AE 
adverse event 
AEGT 
Adverse Events Group Terms 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AP 
abdominal pain 
AST 
aspartate aminotransferase 
ATA 
anti-therapeutic antibodies 
BMI 
body mass index 
CCOD 
clinical cutoff date 
CD 
Crohn’s Disease 
CDAI 
Crohn’s Disease Activity Index 
CD-PRO/SS 
Crohn’s Disease- Patient Reported Outcome/ Signs and Symptoms 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
Coronavirus Disease 2019 
CRP 
C-reactive protein 
CS 
corticosteroids 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
e-CRF 
electronic Case Report Form 
EQ-5D 
EuroQL 5 Dimension Questionnaire 
HLGT 
High Level Group Terms 
HLT 
High Level Term 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICE 
intercurrent event 
iDMC 
independent Data Monitoring Committee 
IS 
immunosuppressant 
IxRS 
interactive voice/Web based response system 
LOCF 
last-observation-carried-forward 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MICE 
multivariate imputation by chained equations 
mITT 
modified intent to treat 


 
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MMRM 
mixed models for repeated measures 
NRI 
non-responder imputation 
OLE 
open label extension 
PD 
pharmacodynamics 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PRO2 
patient-reported outcomes-2 
PT 
preferred term 
Q4W 
every 4 weeks 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
Subcutaneous 
SES-CD 
simplified endoscopic score for Crohn’s disease 
SF 
stool frequency 
SM 
safety monitoring 
SOC 
system organ class 
TNF 
tumor necrosis factor 
TNF-IR 
TNF-inadequate responder 
ULN 
upper limit of normal 
WOCF 
worst-observation-carried-forward 
 


 
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Statistical Analysis Plan GA29145 
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1. 
INTRODUCTION 
The analyses described in this Statistical Analysis Plan (SAP) will supersede those 
specified in Protocol GA29145 for the purposes of reporting. 
The purpose of this document is to describe the analyses for reporting out Part 1 of the 
Open-Label-Extension Safety Monitoring (OLE-SM) study for GA29145.  This SAP will 
solely focus on reporting data collected during Part 1 (OLE) of GA29145. 
This OLE-SM study is composed of two parts: 
1. 
Part 1 is the OLE for eligible patients, during which etrolizumab, 105 mg SC, will be 
administered Q4W followed by a 12-week safety follow-up post-treatment. 
2. 
Part 2 is the 92-week PML SM for all patients, during which no etrolizumab will be 
administered. 
Patients who are enrolled in Part 1 (OLE) should participate in Part 2 (SM). 
There may be patients from Study GA29144 who are ineligible for or choose not to 
participate in Part 1 (OLE) who will be asked to directly enroll in Part 2 (SM). 
Key characteristics of the GA29145 OLE-SM are provided in Table 1. Treatment arms 
and rollover of patients from induction/maintenance to GA29145 OLE-SM from parent 
CD studies are depicted in Figure 1 and Figure 2. 
The maximum number of patients enrolled in GA29145 OLE-SM is approximately 1150 
(i.e., all patients enrolled in Study GA29144).  No formal sample size calculations were 
performed.  


 
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Statistical Analysis Plan GA29145 
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Figure 1 Study Schema for Part 1 (Open-Label Extension; OLE) of the 
OLE-SM Study  
  
 
Figure 2 Study Schema for Part 2 (Safety Monitoring; SM) of the OLE-SM 
Study 
 
 
 
 


 
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Statistical Analysis Plan GA29145 
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Table 1 
Key Characteristics of GA29145 OLE-SM in CD (Juniper) 
Study 
GA29145 (Phase III) 
Treatment (Number 
Exposed) 
Open-label etrolizumab 105 mg SC Q4W (n  up to ~1150) 
Study Phases 
OLE up to 10 years from FPI 
12-week safety follow-up 
92-week PML monitoring 
Key Eligibility 
Criteria 
Part 1 (OLE) 
 
Part 2 (SM)** 
● 
Previously enrolled in Study 
GA29144 
● 
Starting at Week 10, CDAI > 
patient’s baseline CDAI 
● 
Not eligible for maintenance* 
● 
A clinical relapse during the 
Maintenance Phase^ 
● 
Complete the Maintenance 
Phase including the Week 66 
or Week 74 
● 
Previously enrolled in Study 
GA29144 and are not eligible 
or chose not to enroll in Part 
1 (OLE) and completed the 
12-week SFU 
● 
Participated in Part 1 (OLE) 
and completed the 12-week 
SFU 
CD= Crohn’s disease; CDAI =Crohn’s Disease Activity Index; FPI=first patient in; OLE=open- label 
extension; PML=progressive multifocal leukoencephalopathy; Q4W=every 4 weeks; 
SC=subcutaneous; SM=safety monitoring; SFU = safety follow-up. 
*Including patients who completed the Week 14 visit in Study GA29144 and could not subsequently 
enter the Maintenance Phase, because the sample size was achieved and enrollment into the 
Maintenance Phase was closed.  
**All patients must have completed the 12- week safety follow-up in either GA29144 or GA29145, Part 
1 (OLE), as applicable, prior to entering Part 2 (SM). 
^ A clinical relapse during the Maintenance Phase of Study GA29144 is defined as meeting at least 
one of the following criteria on two consecutive visits (may include unscheduled visits), with at least 
one of the two consecutive CDAI scores    220: CDAI score   the baseline (Week 0) score, or CDAI 
score  100 points higher than the Week 14 score 
Changes to the protocol-planned analyses are described in Section 4.4. 
1.1 
OBJECTIVES AND ENDPOINTS 
The objectives of this OLE-SM study are as follows: 
Part 1 (OLE) 
 
To assess the long-term safety and efficacy of etrolizumab in patients eligible for 
Part 1 (OLE) 


 
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Statistical Analysis Plan GA29145 
10 
 
Part 2 (SM) 
 
PML safety monitoring in patients who have stopped study treatment 
This SAP will only cover analyses for GA29145 Part 1 (OLE) objective. 
Other Safety Objectives 
 
To evaluate the incidence, rate per subject-year, and severity of infection-related 
adverse events 
 
To evaluate the incidence and rate per subject-year of malignancies 
 
To evaluate the incidence and severity of hypersensitivity reactions 
Exploratory Objectives 
 
To assess endoscopic appearance at Week 108 
The following endpoint was de-prioritised as a safety objective to an exploratory 
objective from Protocol GA29145, version 6.  Rationale for this is detailed in Section 4.4: 
 
To evaluate the incidence and the clinical significance of anti-therapeutic antibodies 
(ATAs) 
  
1.2 
STUDY DESIGN 
Details of the Part 1 (OLE) study design can be found in the Protocol Synopsis section, 
Section 3 and Study Schema in Figure 1 of Protocol Version 6. 
1.2.1 
Protocol Synopsis 
The Protocol Synopsis is in Protocol Synopsis Section of study GA29145 Protocol 
Version 6.  For additional details, see the Schedule of Assessments in Appendices 1 and 
2 of study GA29145 Protocol Version 6. 
 
1.3 
OUTCOME MEASURES FOR GA29145 PART 1 (OLE) 
1.3.1 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
 
Crohn’s Disease Activity Index (CDAI) remission assessed at 12-week intervals 
during GA29145 Part 1 (OLE) 
 
Clinical remission assessed at 12-week intervals during GA29145 Part 1 (OLE), as 
defined by a stool frequency (SF) mean daily score   3 and an abdominal pain (AP) 
mean daily score   1 with no worsening in either subscore compared to baseline, 
averaged over 7 days prior to visit 


 
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Statistical Analysis Plan GA29145 
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 
Simple Endoscopic Score for Crohn’s disease (SES-CD) score assessed at Week 
108 or at early withdrawal, if prior to Week 108, during GA29145 Part 1 (OLE) 
The efficacy outcome definitions are provided below. 
Table 2 
Efficacy Outcome Definitions 
Outcome Term 
Definition 
CDAI 
CDAI is a composite of eight assessments: number of liquid or soft stools, 
abdominal pain, general well-being, presence of complications, taking Lomotil 
(diphenoxylate/atropine) or other opiates for diarrhea, presence of an 
abdominal mass, hematocrit, and percentage deviation from standard weight 
SES-CD 
SES-CD is an endoscopic score derived from four variables (ulcers, ulcerated 
surface, inflamed surface, and presence of narrowing) that are scored in five 
ileocolonic segments. 
CDAI Remission 
CDAI Score < 150 
Clinical Remission 
An SF mean daily score ≤3 and an AP mean daily score ≤1 with no worsening 
in either subscore compared to baseline, where the average is taken over 7 
days prior to visit 
AP   abdominal pain; CDAI    Crohn’s Disease Activity Index; SES-CD   Simple Endoscopic 
Score for Crohn’s disease; SF   liquid/soft stool frequency. 
 
1.3.2 
Safety Outcome Measures 
The safety outcome measures for GA29145 Part 1 (OLE) of this study are as follows: 
 
Incidence and severity of adverse events 
 
Incidence of serious adverse events 
 
Incidence, rate per subject-year, and severity of infection-related adverse events 
 
Incidence of serious infection-related adverse events 
 
Incidence and severity of injection-site reactions 
 
Incidence of adverse events leading to etrolizumab discontinuation 
 
Incidence of laboratory abnormalities 
 
Incidence and rate per subject-year of malignancies 
 
Incidence and severity of hypersensitivity reactions 
  
1.3.3 
Exploratory Outcome Measures 
The exploratory outcome measures for GA29145 Part 1 (OLE) of this study are as 
follows: 


 
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 
SES-CD   4 (  2 for ileal patients), with no segment having a subcategory score 
(i.e., for ulceration size and extent, affected surface, or narrowing) that is   1, at 
Week 108 
 
Change in SES-CD score between Week 0 (Study GA29144) and Week 108 or 
early withdrawal (Study GA29145, Part 1; OLE) 
Incidence of ATAs to etrolizumab (de-prioritised from a safety outcome measure 
and will not be analysed or reported in primary Clinical Study Report [CSR] for 
GA29145 Part 1 (OLE). See Section 4.4 for details). 
 
1.4 
ANALYSIS TIMING 
GA29145 Part 1 (OLE) will be formally analyzed and reported in a primary CSR after the 
last patient has completed the 12-week safety follow up, following last dosing on 15th 
May 2022.  Note that a database snapshot rather than a database lock for reporting Part 
1 (OLE) of GA29145 will take place. 
2. 
STATISTICAL HYPOTHESES AND SAMPLE SIZE 
DETERMINATION 
2.1 
STATISTICAL HYPOTHESES 
Due to the non-comparative character of the study, no statistical tests or hypotheses are 
planned; all efficacy parameters will be summarized descriptively. 
2.2 
SAMPLE SIZE DETERMINATION 
The maximum number of patients that could be enrolled into the GA29145 OLE-SM 
study is approximately 1150 (i.e., all patients enrolled in Study GA29144).  No formal 
sample size calculations were performed. 
3. 
ANALYSIS SETS 
The analysis population for the purposes of analyses are presented in below: 
Table 3 
Analysis Population 
Open-Label 
Extension 
Patients who receive at least one dose of study drug in Study 
GA29145 Part 1 (OLE) 
Timeframe is from first dose of study drug in the GA29145 Part 1 
(OLE) to the patient’s last visit in GA29145 Part 1 (OLE), or safety 
follow-up, whichever is latest. Summaries will primarily focus on safety 
events arising after first dose of study drug in Study GA29145 Part 1 
(OLE) 
 


 
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4. 
STATISTICAL ANALYSES 
For reporting, a synoptic CSR will be reported.  Due to this synoptic nature, limited 
efficacy data will be reported and all safety outcome measures will be reported in the 
CSR. 
4.1 
GENERAL CONSIDERATIONS 
4.1.1 
Analysis of Study Conduct 
The number of patients who discontinued early (early discontinuation of OLE treatment 
or early termination from the study) or completed the study will be tabulated.  
Reasons for early discontinuation of treatment or early termination from the study will be 
listed and summarized.  Any eligibility criteria exceptions and other major protocol 
deviations will also be summarized. 
Since Part 1 (OLE) of GA29145 was terminated by the Sponsor on 15th February 2022, 
no patients are expected to reach treatment completion.  As a result of this, the end of 
Part 1 (OLE) of GA29145 is defined from the last dose date in GA29145 on 15th May 
2022. 
In summary, the following will be summarised for GA29145 Part 1 (OLE): 
 
Analysis populations 
 
Patient disposition 
 
Study treatment completion/discontinuation 
 
Study completion/discontinuation 
 
Major protocol deviations 
 
Exposure 
Treatment Labels 
For the OLE population, the only treatment arm to be summarized is: 
Group 
Patients Included 
OLE Etrolizumab 
Patients in the OLE population who receive at least one dose of 
etrolizumab in Study GA29145 Part 1 (OLE) 
All tables should be presented by treatment group only.  
Part 1 (OLE) Day 1 
OLE Study Day 1 is defined as the day patient has the first receipt of study drug in 
GA29145 Part 1 (OLE). 


 
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Baseline 
Baseline is defined as the last available assessment prior to first receipt of study drug in 
the Induction Phase of the parent study, GA29144. 
4.1.2 
Analysis of OLE Treatment 
The following variables collected at baseline will be summarized for the OLE population.  
No treatment comparisons will be made since GA29145 is a single-arm open-label 
study. 
For continuous variables, descriptive statistics including n, mean, median, standard 
deviation, minimum, and maximum will be calculated.  For categorical variables, number 
and percentage in each category will be displayed. 
Demography 
 
Age 
 
Age category (≥18 to < 40, ≥40 to < 65,  ≥65) 
 
Sex 
 
Race 
 
Ethnicity 
 
Region 
 
Smoking status history 
 
Body mass index 
 
Weight 
Disease Characteristics 
 
Duration of disease (years) 
 
Duration of disease (years) category (  3,   3 to < 8,   8) 
 
Disease location (Ileum only, Colon only, Ileum + Colon) 
 
Number of affected ileo-colonic segments 
 
Ulcerations at baseline 
 
Mean SF score 
 
Mean AP score (4-point scale) 
 
CDAI score 
 
CDAI Category (  330,   330) (IxRS and Rave) 
 
SES-CD score 
 
CD-PRO/SS – Functional score 


 
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 
CD-PRO/SS – Bowel score 
 
Inflammatory Bowel Disease Questionnaire (IBDQ) total score 
 
Fecal calprotectin (g/g) 
 
Fecal calprotectin category (<250 g/g,   250 < 500 g/g,   500 g/g) 
 
C-reactive protein (CRP) levels (mg/L) 
 
CRP category (  2.87 mg/L,   2 .87 to   10 mg/L,   10 mg/L) 
 
Albumin 
Baseline Treatments 
 
Use of oral CS at Baseline (yes vs. no) (IxRS and Rave) 
 
Use of IS at Baseline (yes vs. no) (IxRS and Rave) 
 
Prior anti-TNF exposure (yes vs. no) (IxRS and Rave) 
The patients with prior anti-TNF exposure at baseline will be further evaluated to include 
the number of TNFs previously received and status (e.g., primary non-responder, 
secondary non-responder, Intolerant, etc). 
 
4.1.3 
Primary Efficacy Analysis 
To evaluate the efficacy of etrolizumab during long-term open-label treatment, efficacy 
will be summarized within the population of patients who enroll into the Study GA29145.  
Both endoscopic improvement and clinical remission will be summarized in two separate 
analyses.  Due to the open-label nature of the study, no treatment comparisons will be 
made. 
Concerning missing data and treatment withdrawal imputation, there will be 3 strategies 
employed, described below. 
Hybrid LOCF 
Within this strategy, at each visit only patients who had the possibility of reaching the 
visit will be considered in the analysis for that specified visit.  Patients will be deemed 
evaluable at a visit if it was possible for them to have reached this visit based on their 
enrollment date and the date of the closure of Part 1 of the study. 
 
Patients for whom it is not possible to have reached the visit at the time of the 
clinical cut off are termed non-evaluable and will not be included in the analysis at 
that visit.  
 
For evaluable patients with missing data, Last Observation Carried Forward (LOCF) 
will be used from their most recent available data.  


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


 
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Simple Endoscopic Score for Crohn’s disease (SES-CD) score: Handling of 
Partially Available Segments 
Note that in the OLE study GA29145, no central adjudication took place and therefore 
only a local score will be available for the Week 108 assessment.  This differs from 
Study GA29144, which utilized central adjudication and up to 3 readers provided a 
score.  To overcome differences in reader availability between studies the following 
approach will be used: 
Baseline score will utilize data from all available readers with adjudication applied to 
determine the final total SES-CD score.  This aligns with the original Day 1 Baseline 
score in study GA29144 and ensures that the central readers are retained in the 
Baseline score derivation, as reported in the CSR analysis. 
The determination of segment availability will use the Local reader only for both the 
baseline and post-baseline time points, as follows: 
 
any segment(s) missing by the local reader at baseline will not be considered in 
the Week 108 visit total SES-CD total score calculation 
 
any segments(s) available at baseline that are not available at Week 108 will 
result in a non-responder status for the patient for endoscopic 
improvement/remission.  For continuous data the patient’s baseline segment 
score will be carried forward (BOCF) to impute the Week 104 segment score 
when calculating the total SESCD score. 
4.1.3.1 
Endoscopic Improvement and Remission at Week 108 
As endoscopy data is only collected at a common time point of Week 108 during the 
OLE Study GA21945, the endpoints of endoscopic improvement and endoscopic 
remission will be summarized only at this time point.  These endpoints will be examined 
overall and separated by their previous endoscopic improvement status at their latest 
visit prior to enrollment into GA29145 i.e., at the parent study’s (GA29144) Week 14 or 
Week 66. 
The handling of patients with partially available segments is detailed in Section 4.1.3, 
this is not considered as true missing data. 
Population:  All patients who enrolled into Part 1 of the OLE Study GA29145. 
Baseline:  The original baseline value from the parent study will be used to calculate 
improvement. 
Sub-groups:   


 
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 
All patients overall and split by prior endoscopic improvement status and their prior 
aTNF exposure status. 
 
Analysis 1 - Non-Responder 
Missing data: Patients who are non-evaluable at Week 108 (i.e., could not have 
reached the maximum visit if they had remained within the program as detailed in 
Section 4.1.3) will be removed from the analysis.  Patients who remain in Study 
GA29145 but are missing endoscopy scores (i.e., the assessment was not done) will be 
imputed as non-responders within the analysis, as LOCF is not appropriate when 
endoscopy data is not collected routinely.  
Intercurrent events:  Patients who withdraw during Study GA29145 will be set to non-
responders using the composite strategy if they could have reached OLE Week 108 at 
the time of the clinical cut-off date had they not withdrawn from treatment.  This excludes 
patients who withdrew from study drug on or after 15th February 2022. 
Analysis 2 - As Observed 
Missing data:  If a patient has missing data at a visit, they will be removed from the 
analysis and no imputation will be performed. 
Intercurrent events: No imputation will be performed for treatment withdrawals 
 
4.1.3.2 
Simple Endoscopic Score for Crohn’s disease (SES-CD) score 
at Week 108 
As endoscopy data is only collected at a common time point of Week 108 during the 
OLE Study GA21945, continuous SES-CD score will be summarized only at this time 
point and at parent study Baseline.  The handling of patients with partially available 
segments is detailed in Section 4.1.3, this is not considered as true missing data. 
Population:  All patients who enrolled into Part 1 of the OLE Study GA29145. 
Baseline:  The original baseline value from the parent study will be used as the baseline 
SES-CD score. 
Analysis 1 - BOCF 
Missing data: If a patient has missing data at a visit (i.e., the assessment was not 
done), they will be removed from the analysis and no imputation will be performed. 
Intercurrent events:  No imputation will be performed for treatment withdrawals 


 
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4.1.3.3 
CDAI Remission and Clinical Remission Every 12 Weeks 
The percentage of patients in CDAI remission or clinical remission as defined in the 
Efficacy Derivations Section 1.3.1 will be summarized for each OLE visit for patients who 
entered Study GA29145.  All OLE visits will be summarized until a minimum of 20 
evaluable patients overall remain within the analysis (i.e., an evaluable patient either 
reached the visit or could have reached the visit if they had remained within the OLE). 
Population:  Patients who enroll into Part 1 of Study GA29145. 
Baseline:  The original baseline value from the parent study will be used to calculate 
remission, where applicable. 
Sub-groups:  
 
Table outputs: All patients overall, split by aTNF exposure status and by OLE Day 1 
CDAI remission or clinical remission status, as appropriate. 
 
Figure outputs: All patients overall and split by OLE Day 1 CDAI remission or clinical 
remission status. 
Analysis 1 - Hybrid LOCF 
Missing data: If patients who remain in Study GA29145 at the specified visit are missing 
data then LOCF will be used to impute.  For visits where patients are non-evaluable (i.e. 
it is not possible for them to have reached the specified visit at the time of the clinical 
cut-off date) they will be removed from the analysis. 
Intercurrent Events:  Using the composite strategy in the case where patients have 
withdrawn from the Study GA29145, they will be set to non-responders for all visits 
where they are evaluable. This excludes patients who withdrew from study drug with 
reason being stated as “study terminated by sponsor” after 15th February 2022. 
Analysis 2 - As Observed 
Missing data:  If a patient has missing data at a visit, they will be removed from the 
analysis and no imputation will be performed. 
Intercurrent events: No imputation will be performed for treatment withdrawals 
 
4.2 
SAFETY ANALYSES 
Safety data will be assessed through descriptive summaries using the OLE population.  
All data available up until the clinical cut‑off date (CCOD) will be reported.   


 
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Safety evaluations for the OLE population will include data from the first dose of 
treatment in Part 1 (OLE) until the patient completes/withdraws from the Part 1(OLE) of 
the study GA29145, this includes any 12-week safety follow-up data. 
4.2.1 
Extent of Exposure 
Exposure to study treatment will be summarized by: 
 
treatment duration (weeks) 
 
number of patients receiving a dose at each visit 
 
number of doses received/missed for a patient 
 
4.2.2 
Adverse Events 
Verbatim descriptions of AEs will be mapped to the latest version of the Medical 
Dictionary for Regulatory Activities (MedDRA).   
Adverse events (AEs) will include all terms recorded on the AE Case Report Form (CRF) 
pages (except pregnancies).  For each recorded AE, the term entered by the investigator 
describing the event (the “reported term”) will be assigned a standardized term (the 
“preferred term”) and assigned to a superclass term on the basis of the Medical 
Dictionary for Regulatory Activities (MedDRA) World Health Organization (WHO) 
dictionary of terms.  All analyses of AE data will be performed using the preferred terms 
and system organ class unless otherwise specified. 
For the etrolizumab program, the adverse events of special interest (AESIs) are the 
following: 
 
Systemic hypersensitivity reactions and anaphylactic and anaphylactoid reaction 
which will be reported using the MedDRA anaphylactic reaction Standard MedDRA 
Query (SMQ) algorithmic and Hypersensitivity SMQ narrow. 
 
Neurological signs, symptoms, and AEs that may suggest possible progressive 
multifocal leukoencephalopathy (see Appendices 5 and 6 of Protocol) 
 
Suspected transmission of an infectious agent by the study drug 
 
Cases of potential drug-induced liver injury that include an elevated alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with 
either an elevated bilirubin or clinical jaundice, as defined by Hy’s Law 
Specific AEs listed below will also be reported: 
 
Serious infections 
 
Gastrointestinal Infections 
 
Opportunistic infections 
 
Malignancies 


 
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 
Injection site reactions 
A listing or, summary table (e.g., n > 10) of all AEs suspected or confirmed, and AEs 
associated with COVID-19 will be generated.  Associated AEs are defined as all AEs 
reported within a time window of 7 days prior and 30 days after the confirmed COVID-19 
start date (dates inclusive).  Additionally, a listing of patients experiencing ‘long 
COVID‑19’ will be generated.  This listing will include all AEs with a duration >30 days 
occurring after a confirmed COVID-19 infection or a positive PCR test. 
All AESIs and specific AEs will be determined using a selection of eCRF tick box or 
MedDRA SMQs, Adverse Events Group Terms (AEGTs), High Level Term (HLTs), High 
Level Group Terms (HLGTs), System Organ Class (SOC), as appropriate.  
Summary tables will be generated for AEs, serious adverse events (SAEs), deaths, AEs 
leading to discontinuation of study drug, and AESIs.  A listing will be generated for AEs, 
deaths, selected AESIs/specific AEs, and COVID-19 AEs.  Pregnancies will be reported 
as narratives in the study CSR. 
Summary tables of AEs will summarize the incidence of treatment-emergent AEs only.  
Treatment-emergent events are defined as any new AE reported on or after the first 
dose of OLE study drug or any worsening of an existing condition.  Note that worsening 
of existing conditions include AEs ongoing from the parent study, GA29144. Otherwise, 
only AEs reported on or after the first dose of OLE study drug are included. If the onset 
date of the AE is prior to the day of first dose, the AE will be considered treatment 
emergent only if the most extreme intensity is greater than the initial intensity (i.e., the 
intensity for a given AE increases and its end date is on or after the date of the first 
dose).  For all summary tables, the AEs will be sorted by SOC (in decreasing order of 
overall incidence) and then by preferred term (PT) (in decreasing order of overall 
incidence). 
For OLE etrolizumab treatment, the incidence count for each AE PT will be defined as 
the number of patients reporting at least one treatment-emergent occurrence of the 
event (multiple occurrences of the same AE in 1 patient will be counted only once).  The 
proportion of patients with an AE will be calculated as the incidence count divided by the 
total number of patients in the population.  Each table will also present the total number 
of AEs reported where multiple occurrences of the same AE in an individual are counted 
separately.  
Rate tables will be generated for selected AEs of interest.  The rate per 100 patient 
years and 95% CIs will be summarized by treatment group and will be calculated by: 
 𝐴𝐸 𝑅𝑎𝑡𝑒 (𝑝𝑒𝑟 100 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑦𝑒𝑎𝑟𝑠) = 
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝐴𝐸𝑠 (𝑖𝑛 𝑂𝐿𝐸 𝑜𝑛𝑙𝑦)
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑦𝑒𝑎𝑟𝑠 𝑎𝑡 𝑟𝑖𝑠𝑘 (𝑖𝑛 𝑂𝐿𝐸 𝑜𝑛𝑙𝑦) ×
100 


 
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where the total patient-years at risk is the sum over all patients of the time intervals (in 
years) from the first dose of study treatment in Part 1 (OLE) until the patient 
completes/withdraws from the study (including the 12-week safety follow-up, if 
applicable).  Only treatment emergent AEs with an onset date after the first dose of open 
label Etrolizumab in GA29145 will be included within these outputs.  
All summary tables and listings will report AEs using the OLE population.  
4.2.3 
Additional Safety Assessments  
4.2.3.1 
Laboratory Data 
Selected laboratory parameters for safety reporting will be described further in the OLE 
population by summarizing the marked abnormalities and shift tables.  Marked 
abnormalities will be identified according to a Sponsor-defined standard, which generally 
captures post- baseline laboratory values both outside a reference range and achieving 
a threshold percent change from baseline.  Where needed, laboratory values will be 
linearly transformed to a standard reference range in order to account for intrinsic 
differences between males and females or measurement differences between laboratory 
standards. 
Laboratory abnormalities and the patient’s worst Common Terminology Criteria for 
Adverse Events (CTCAE) grade during study will be summarized for hematology and 
serum chemistry parameters, in addition to change from Baseline summaries. 
Elevated liver enzyme tests will be summarized by the following upper limit of normal 
(ULN) categories as these are indicators of severe liver injury: 
 
ALT or AST>3ULN and total bilirubin>2 ULN as defined by Hy’s law 
 
ALT or AST>3 ULN 
 
4.2.3.2 
Vital Signs 
Vital signs will be summarized using summary statistics and change from baseline.  The 
proportion of patients experiencing clinically significant changes relative to baseline will 
be reported if appropriate. 
4.2.3.3 
ECGs 
A shift table for the qualitative ECG assessments will be produced, summarizing the 
Baseline and worst post-baseline results. 
4.2.3.4 
Medical History 
Medical history data collected in the electronic-CRF (eCRF) from OLE Day 1 will be 
summarized using summary statistics, reporting the proportion of patients with at least 
one medical condition and the total number of medical conditions.  The medical 
conditions will then be split out by type. 


 
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4.2.3.5 
Concomitant Medications 
Concomitant medications include any medication being used at any time from first dose 
of OLE study drug through to 7 days after last dose of OLE study drug.  The data will be 
summarized, and report the total number of patients taking at least one medication, and 
total number of medications.  Summaries will also be split by medication class and 
preferred medication.  Medication terms will be mapped and reported using the WHO 
drug dictionary.  
4.2.4 
Open-Label Extension Timeframe 
For the open-label extension population, the safety reporting timeframe is defined to 
capture safety information within the OLE treatment period only.  It begins at first dose of 
study drug in Study GA29145 Part 1 (OLE).  The end of the time-frame coincides with 
the last patient last visit, this includes safety follow-up in Study GA29145 Part 1 (OLE). 
4.3 
INTERIM ANALYSES  
There are no planned interim analyses for study GA29145. 
4.4 
CHANGES TO PROTOCOL-PLANNED ANALYSES  
The incidence of ATAs to etrolizumab was extensively evaluated in Ulcerative Colitis and 
Crohn’s Disease within the phase 3 program, where no obvious impact on injection site 
reactions or other relevant safety parameters such as hypersensitivity was found.  
Following this evaluation, ATAs has been de-prioritised from a safety objective and 
outcome measure in GA29145 to an exploratory objective and outcome measure. 
5. 
SUPPORTING DOCUMENTATION 
This section is not applicable, since there is no additional supporting document. 


 
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6. 
REFERENCES 
Not applicable. 


Signature Page for Statistical Analysis Plan - GA29145 - Published
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Scientific content approver
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