Clinical trial NCT02394028
Conditions: Crohn Disease
Sponsor: Hoffmann-La Roche
Start date: 2015-03-20; Completion date: 2021-09-07
Enrollment: 1035 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, Phase 3, double-blind, placebo-controlled study evaluating the efficacy, safety, and tolerability of etrolizumab compared with placebo during induction and maintenance treatment of moderately to severely active Crohn's Disease (CD). The target population includes participants with CD who are refractory or intolerant to corticosteroids (CS) and/or immunosuppressant (IS) therapy and who have either not received prior anti-tumor necrosis factor (anti-TNF) therapy (TNF-naive) or who have had prior exposure to anti-TNF therapies and demonstrated inadequate responses or intolerance to anti-TNFs.

The study period will consist of a Screening Phase (up to 35 days) plus (+) a 14-week Induction Phase + a 52-week Maintenance Phase + a 12-week Safety Follow-up Phase. At Week 14 (end of Induction Phase), participants achieving a decrease from baseline of at least 70 points in the Crohn's Disease Activity Index (CDAI) score (CDAI-70 response) without the use of rescue therapy will continue to the Maintenance Phase.

Detailed description:

Arms: arm 1: Cohort 1 enrolled participants first before Cohorts 2 and 3 in order to conduct an exploratory analysis on induction data. Participants randomized to this arm will receive one subcutaneous (SC) injection of etrolizumab (210 mg) at Weeks 0, 2, 4, 8, and 12 during the 14-week Induction Phase. In order to preserve the masking, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12. arm 2: Cohort 1 enrolled participants first before Cohorts 2 and 3 in order to conduct an exploratory analysis on induction data. Participants randomized to this arm will receive one SC injection of etrolizumab (105 mg) at Weeks 0, 4, 8, 12 and one SC injection of etrolizumab-matching placebo at Week 2 during the 14-week Induction Phase. In order to preserve the masking, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12. arm 3: Cohort 1 enrolled participants first before Cohorts 2 and 3 in order to conduct an exploratory analysis on induction data. Participants randomized to this arm will receive two SC injections of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12 (and one SC injection of etrolizumab-matching placebo at Week 2) during the 14-week Induction Phase, in order to preserve the masking. arm 4: Cohort 2 is enrolling participants after Cohort 1 and is considered a "feeder" cohort to help achieve the necessary sample size for the Maintenance Phase. Participants randomized to this arm will receive one SC injection of open-label etrolizumab (210 mg) at Weeks 0, 2, 4, 8, and 12 during the 14-week Induction Phase. In order to preserve the masking for the dose of etrolizumab, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12. arm 5: Cohort 2 is enrolling participants after Cohort 1 and is considered a "feeder" cohort to help achieve the necessary sample size for the Maintenance Phase. Participants randomized to this arm will receive one SC injection of open-label etrolizumab (105 mg) at Weeks 0, 4, 8, 12 and one SC injection of etrolizumab-matching placebo at Week 2 during the 14-week Induction Phase. In order to preserve the masking of the dose of etrolizumab, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12. arm 6: Cohort 3 is the last to enroll participants (after Cohort 2) and will be the pivotal cohort for the Induction Phase. Participants randomized to this arm will receive one SC injection of etrolizumab (210 mg) at Weeks 0, 2, 4, 8, and 12 during the 14-week Induction Phase. In order to preserve the masking, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12. arm 7: Cohort 3 is the last to enroll participants (after Cohort 2) and will be the pivotal cohort for the Induction Phase. Participants randomized to this arm will receive one SC injection of etrolizumab (105 mg) at Weeks 0, 4, 8, 12 and one SC injection of etrolizumab-matching placebo at Week 2 during the 14-week Induction Phase. In order to preserve the masking, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12. arm 8: Cohort 3 is the last to enroll participants (after Cohort 2) and will be the pivotal cohort for the Induction Phase. Participants randomized to this arm will receive two SC injections of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12 (and one SC injection of etrolizumab-matching placebo at Week 2) during the 14-week Induction Phase, in order to preserve the masking. arm 9: Participants who received placebo during the Induction Phase (from Cohorts 1 and 3) and achieved a CDAI-70 response at Week 14 will undergo a sham randomization into the Maintenance Phase. Placebo responders from induction will receive blinded maintenance treatment with an SC injection of placebo once every 4 weeks (q4w) from Week 16 to Week 64. arm 10: Participants who received etrolizumab during the Induction Phase (from Cohorts 1-3) and achieved a CDAI-70 response at Week 14 without the use of rescue therapy will be re-randomized into the Maintenance Phase. Etrolizumab responders from induction who are re-randomized to this arm will receive blinded maintenance treatment with an SC injection of placebo q4w from Week 16 to Week 64. arm 11: Participants who received etrolizumab during the Induction Phase (from Cohorts 1-3) and achieved a CDAI-70 response at Week 14 without the use of rescue therapy will be re-randomized into the Maintenance Phase. Etrolizumab responders from induction who are re-randomized to this arm will receive blinded maintenance treatment with an SC injection of etrolizumab (105 mg) q4w from Week 16 to Week 64.
Interventions: intervention 1: Etrolizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Etrolizumab will be administered as per regimen specified in individual arms. intervention 2: Etrolizumab-matching placebo will be administered as per regimen specified in individual arms.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A Phase III, Randomized, Double-Blind, Placebo-Controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of Etrolizumab 
as an Induction And Maintenance Treatment For Patients With 
Moderately to Severely Active Crohn's Disease 
NCT Number: 
NCT02394028 
Document Date: 
Protocol Version 7: 24-April-2019 
 
 
 










Etrolizumab—F. Hoffmann-La Roche Ltd
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4.3.5
Destruction of the Investigational Medicinal 
Product/Comparator .............................................................. 72
4.3.6
Reporting of Prefilled Syringe Complaints/Events ................. 73
4.3.7
Post-Trial Access to Etrolizumab........................................... 73
4.4
Concomitant Therapy ............................................................ 73
4.4.1
Management of Concomitant Crohn’s Disease 
Medication in the Induction Phase......................................... 73
4.4.2
Management of Immunosuppressants throughout 
the Study ............................................................................... 73
4.4.3
Management of Concomitant Crohn’s Disease 
Medication in the Maintenance Phase................................... 74
4.4.4
Permitted Rescue Therapy.................................................... 74
4.4.4.1
Rescue Therapy in the Induction Phase................................ 74
4.4.4.2
Rescue Therapy in the Maintenance Phase.......................... 74
4.4.5
Prohibited Therapy ................................................................ 75
4.5
Study Assessments ............................................................... 75
4.5.1
Informed Consent Forms and Screening Log........................ 75
4.5.2
Screening .............................................................................. 76
4.5.2.1
Re-Screening......................................................................... 76
4.5.3
Study Assessments during Induction and 
Maintenance.......................................................................... 77
4.5.4
Assessments at Study Completion........................................ 77
4.5.5
Early Withdrawal from Study ................................................. 78
4.5.6
Assessments at Unscheduled Visits...................................... 78
4.5.7
Description of Visit Activities.................................................. 78
4.5.7.1
Medical History and Demographic Data ................................ 78
4.5.7.2
Physical Examinations........................................................... 78
4.5.7.3
Fistula Examinations ............................................................. 79
4.5.7.4
Vital Signs, Height, and Weight ............................................. 79
4.5.7.5
Crohn’s Disease Activity Assessments.................................. 79
4.5.7.6
Ileocolonoscopy with Biopsies............................................... 80
4.5.7.7
Neurological Examination...................................................... 83
4.5.7.8
Progressive Multifocal Leukoencephalopathy 
Assessment........................................................................... 83
4.5.7.9
Electrocardiograms................................................................ 84


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4.5.7.10
Patient-Reported Outcomes .................................................. 84
4.5.7.11
Study Drug and Compliance.................................................. 87
4.5.7.12
Concomitant Medications ...................................................... 87
4.5.7.13
Adverse Events ..................................................................... 87
4.5.7.14
Tuberculosis Screening ......................................................... 87
4.5.7.15
Chest X-ray............................................................................ 88
4.5.7.16
Pregnancy Testing................................................................. 88
4.5.7.17
Laboratory Assessments ....................................................... 88
4.5.7.18
Samples for Roche Clinical Repository.................................. 92
4.5.8
Safety Follow-Up Assessments............................................. 95
4.5.9
Eligibility for Entry to Open-Label 
Extension-Safety Monitoring Study........................................ 96
4.5.9.1
Inclusion Criteria for Part 1 (OLE) of Study 
GA29145 ............................................................................... 96
4.5.9.2
Exclusion Criteria for Part 1 (OLE) of Study 
GA29145 ............................................................................... 96
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 97
4.6.1
Patient Discontinuation.......................................................... 97
4.6.1.1
Withdrawal from Study........................................................... 97
4.6.2
Discontinuation from Study Drug........................................... 97
4.6.3
Study and Site Discontinuation.............................................. 98
5.
ASSESSMENT OF SAFETY....................................................................... 98
5.1
Safety Plan ............................................................................ 98
5.1.1
Potential Risks for Etrolizumab.............................................. 98
5.1.1.1
Serious Infections.................................................................. 99
5.1.1.2
Hypersensitivity Reactions................................................... 102
5.1.1.3
Hepatic Effects .................................................................... 103
5.1.1.4
Local Injection-Site Reactions ............................................. 103
5.1.1.5
Malignancies........................................................................ 103
5.1.1.6
Immunogenicity ................................................................... 104
5.1.1.7
Decreased Effectiveness of Immunizations......................... 104
5.1.2
Risks Associated with Worsening of Crohn’s 
Disease................................................................................ 104


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5.1.3
Data Monitoring Committee................................................. 105
5.2
Safety Parameters and Definitions ...................................... 105
5.2.1
Adverse Events ................................................................... 105
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 106
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 107
5.2.4
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 107
5.2.5
Adverse Event Reporting Period ......................................... 107
5.2.6
Eliciting Adverse Event Information..................................... 108
5.2.7
Assessment of Severity of Adverse Events ......................... 108
5.2.8
Assessment of Causality of Adverse Events ....................... 109
5.2.9
Procedures for Recording Adverse Events.......................... 110
5.2.9.1
Injection-Site Reactions....................................................... 110
5.2.9.2
Diagnosis Versus Signs and Symptoms.............................. 110
5.2.9.3
Adverse Events That Are Secondary to Other 
Events.................................................................................. 111
5.2.9.4
Persistent or Recurrent Adverse Events.............................. 111
5.2.9.5
Abnormal Laboratory Values ............................................... 111
5.2.9.6
Abnormal Vital Sign Values ................................................. 112
5.2.9.7
Abnormal Liver Function Tests............................................ 113
5.2.9.8
Deaths ................................................................................. 113
5.2.9.9
Preexisting Medical Conditions............................................ 113
5.2.9.10
Lack of Efficacy or Worsening of Crohn’s 
Disease................................................................................ 114
5.2.9.11
Hospitalization or Prolonged Hospitalization........................ 114
5.2.9.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 114
5.2.9.13
Patient-Reported Outcome Data ......................................... 115
5.3
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 115
5.3.1
Emergency Medical Contacts.............................................. 115
5.3.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 116


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5.3.2.1
Events That Occur Prior to Study Drug Initiation ................. 116
5.3.2.2
Events That Occur after Study Drug Initiation...................... 116
5.3.3
Reporting Requirements for Pregnancies............................ 116
5.3.3.1
Pregnancies in Female Patients.......................................... 116
5.3.3.2
Pregnancies in Female Partners of Male Patients............... 117
5.3.3.3
Abortions ............................................................................. 117
5.3.3.4
Congenital Anomalies/Birth Defects .................................... 117
5.3.4
Reporting Requirements for Prefilled Syringe 
Complaints/Events............................................................... 118
5.4
Follow-Up of Patients after Adverse Events ........................ 118
5.4.1
Investigator Follow-Up......................................................... 118
5.4.2
Sponsor Follow-Up .............................................................. 118
5.5
Post-study Adverse Events.................................................. 119
5.6
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 119
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 120
6.1
Determination of Sample Size ............................................. 121
6.1.1
Induction Phase................................................................... 121
6.1.2
Maintenance Phase............................................................. 122
6.2
Summaries of Conduct of Study.......................................... 123
6.3
Summaries of Treatment Group Comparability ................... 123
6.4
Efficacy Analyses ................................................................ 123
6.4.1
Induction Phase................................................................... 124
6.4.1.1
Cohort 1............................................................................... 124
6.4.1.2
Cohort 2............................................................................... 124
6.4.1.3
Cohort 3............................................................................... 124
6.4.2
Maintenance Phase............................................................. 125
6.4.3
Co-Primary Efficacy Endpoints............................................ 126
6.4.4
Secondary Efficacy Endpoints............................................. 126
............................................ 127
6.5
Safety Analyses................................................................... 127
6.5.1
Adverse Events ................................................................... 127
6.5.2
Laboratory Tests.................................................................. 128


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6.6
Pharmacokinetic, Pharmacodynamic, 
 
 Analyses............................................................. 128
6.7
Optional Interim Analysis..................................................... 129
7.
DATA COLLECTION AND MANAGEMENT ............................................. 129
7.1
Data Quality Assurance....................................................... 129
7.2
Electronic Case Report Forms............................................. 130
7.3
Electronic Patient-Reported Outcome Data......................... 130
7.4
Source Data Documentation................................................ 130
7.5
Use of Computerized Systems ............................................ 131
7.6
Retention of Records........................................................... 131
8.
ETHICAL CONSIDERATIONS.................................................................. 132
8.1
Compliance with Laws and Regulations .............................. 132
8.2
Informed Consent................................................................ 132
8.3
Institutional Review Board or Ethics Committee.................. 133
8.4
Confidentiality...................................................................... 133
8.5
Financial Disclosure ............................................................ 134
9.
STUDY DOCUMENTATION, MONITORING, AND
ADMINISTRATION ................................................................................... 134
9.1
Study Documentation .......................................................... 134
9.2
Protocol Deviations.............................................................. 134
9.3
Site Inspections ................................................................... 134
9.4
Administrative Structure....................................................... 135
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 135
9.6
Protocol Amendments ......................................................... 136
10. REFERENCES ......................................................................................... 137




Etrolizumab—F. Hoffmann-La Roche Ltd
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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER STUDY 
TO EVALUATE THE EFFICACY AND SAFETY OF 
ETROLIZUMAB AS AN INDUCTION AND 
MAINTENANCE TREATMENT FOR PATIENTS 
WITH MODERATELY TO SEVERELY ACTIVE 
CROHN’S DISEASE
PROTOCOL NUMBER:
GA29144
VERSION NUMBER:
7
EUDRACT NUMBER:
2014-003824-36
IND NUMBER:
119725
TEST PRODUCT:
Etrolizumab (RO5490261)
MEDICAL MONITOR:
, M.D., M.S.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please 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
12/Protocol GA29144, Version 7
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF 
ETROLIZUMAB AS AN INDUCTION AND MAINTENANCE 
TREATMENT FOR PATIENTS WITH MODERATELY TO 
SEVERELY ACTIVE CROHN’S DISEASE
PROTOCOL NUMBER:
GA29144
VERSION NUMBER:
7
EUDRACT NUMBER:
2014-003824-36
IND NUMBER:
119725
TEST PRODUCT:
Etrolizumab (PRO145223)
PHASE:
Phase III
INDICATION:
Crohn's Disease
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Co-Primary Efficacy Objectives
The co-primary efficacy endpoints for this study are the following:

Clinical remission, defined as a liquid/soft 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 the 7 days prior to visit

Endoscopic improvement, defined as a 50% reduction from the baseline Simple
Endoscopic Score for Crohn’s Disease (SES-CD)
Primary efficacy objectives for this study will be analyzed separately for the Induction and 
Maintenance Phases as outlined below.
Induction Phase:  To independently evaluate the efficacy of etrolizumab dose regimens 
compared with placebo in inducing clinical remission and endoscopic improvement at the end of 
the Induction Phase (Week 14)
Maintenance Phase:  To independently evaluate the efficacy of etrolizumab compared with 
placebo in achieving clinical remission and endoscopic improvement at 1 year of maintenance 
treatment (Week 66), for patients who achieved a Crohn’s Disease Activity Index (CDAI)70 
response (defined as a decrease of at least 70 points from baseline CDAI) at Week 14
Secondary Efficacy Objectives
Induction Phase

To evaluate the efficacy of etrolizumab compared with placebo in achieving clinical
remission at Week 6

To evaluate the efficacy of etrolizumab compared with placebo in achieving an 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 14






Etrolizumab—F. Hoffmann-La Roche Ltd
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enter an extended PML-monitoring phase Part 2 (SM) of Study GA29145 for 92 weeks.  An 
independent Data Monitoring Committee (iDMC) will monitor safety and study conduct on an 
ongoing basis.
Patients in all cohorts will be required to provide blood samples for population PK analysis and 
PD characterization.  Patients will also have an option to consent and participate in a PK/PD 
substudy.  The objective of the substudy is to determine the relationship between etrolizumab 
exposure and receptor occupancy in peripheral blood in patients with CD.  To achieve this 
objective, it is planned that approximately 150 evaluable patients will be enrolled in the substudy.  
Blood sampling for the PK/PD substudy will continue in the Maintenance Phase.
Moderate to severely active CD will be defined at baseline by clinical signs and symptoms that 
result in a CDAI score between 220 and 480, as well as either an average SF ≥6 or an 
average SF 3 and average AP 1, calculated on the day of randomization using electronic 
diary (e-diary) PRO data from the 7 days prior to randomization.  In conjunction, the presence of 
active inflammation, defined as a SES-CD of 7, or 4 in cases of isolated ileitis or 
post-ileocecal resection, is required and will be determined by a screening ileocolonoscopy 
scored using the central read model.  
The study population will consist of patients who are refractory or intolerant to one or more of 
the following therapies:  1) corticosteroid (CS), 2) immunosuppressant (IS), or 3) anti- tumor 
necrosis factor (TNF) (or inadequate response to anti-tumor necrosis factor [TNF-IR]).  Patients 
who enroll on the basis of refractory or intolerance to CS and/or IS may have been previously 
exposed to ant-TNFs or be naïve to anti-TNFs.
Approximately 1150 patients will be randomized into the study from approximately 420 global 
investigational sites via enrollment into one of three cohorts.  The enrollment will be sequential, 
first into Cohort 1, then Cohort 2, and lastly Cohort 3.
Overview of Screening Phase
Patients will be evaluated for eligibility in the 35-day Screening Phase.  Assessments for 
eligibility are noted in the protocol.
During the Screening Phase, patients taking CS therapy must have been on a stable dose of 
20 mg/day prednisone or equivalent or 6 mg/day oral budesonide for at least 2 weeks
immediately prior to their randomization.  Similarly, eligible patients requiring background IS
therapy (e.g., azathioprine [AZA] [or equivalent], 6-mercaptopurine [6-MP] [or equivalent], or
methotrexate [MTX]) must be receiving a stable IS dose regimen for at least 8 weeks
immediately prior to their randomization.  Patients who have been treated with anti-TNF therapy
must have discontinued this treatment for at least 8 weeks prior to their randomization.
The ileocolonoscopy should be performed during the Screening Phase and at least 9 days prior 
to randomization to allow sufficient time for a central reader scoring and determination of 
eligibility, and to avoid the ileocolonoscopy bowel preparation influencing the patient reported 
outcomes used in the determination of baseline SF, AP, and CDAI scores (i.e., abdominal pain, 
general well-being, and stool frequency)
Overview of Induction Phase
Eligible patients will be enrolled sequentially into one of three cohorts for the 14-week Induction 
Phase.
Patients enrolled in Cohort 1 (double-blind, placebo-controlled, exploratory cohort; n 300) will 
be randomized in a 1:2:2 ratio to receive placebo, etrolizumab 105 mg subcutaneously (SC)
every 4 weeks (Q4W) (low dose), or etrolizumab 210 mg SC (high dose) at Weeks 0, 2, 4, 8, 
and 12 within a 14-week Induction Phase (note that patients randomized to low-dose 
etrolizumab and patients randomized to placebo will receive one placebo injection at Week 2,
see below).  Patients enrolled in Cohort 2 (etrolizumab doseblind, active-treatment cohort; 
n 350) will be randomized in a 1:1 ratio to receive low-dose or high-dose regimens of 
etrolizumab.  Patients enrolled in Cohort 3 (double-blind, placebo-controlled, pivotal cohort; 
n 500) will be randomized in a 2:3:3 ratio to receive placebo or etrolizumab low-dose or high-
dose.  Because the low dose and high dose of etrolizumab are in syringes of different volumes, 
in order to preserve the blind, patients in all three cohorts will receive two injections at Weeks 0, 
4, 8, and 12.  Patients randomized to low-dose etrolizumab will receive one placebo (matching 
high-dose prefilled syringe) and one low-dose etrolizumab injection at each administration 
except at Week 2, when they will receive one placebo injection.  Patients randomized to 


high-dose etrolizumab will receive one placebo and one high-dose etrolizumab injection at each 
administration, except at Week 2 where they will receive one high-dose injection.  Finally, 
patients randomized to placebo will receive two placebo injections at every administration, 
except at Week 2 where they will receive one placebo injection.
The randomization in all cohorts will be stratified by concomitant oral CS treatment (yes vs. no), 
concomitant IS treatment (yes vs. no), baseline CDAI 330 (yes vs. no), and prior anti-TNF 
exposure (yes vs. no).  The enrollment will be managed to ensure that the proportion of the 
TNF-exposed patients in Cohort 3 does not exceed approximately 60% and that the proportion 
of patients with a CDAI score between 450 and 480 does not exceed approximately 10% in 
each cohort.
During the Induction Phase, patients in all cohorts should keep their dose(s) of CS and IS 
therapy stable (if requiring CS/IS at baseline).  Increase in dose of these medications will be 
considered rescue therapy.  Also, every attempt should be made to keep anti-diarrheal 
medication at a fixed dose, if required.  The impact of titrating anti-diarrheal medication on the 
placebo response rate for SF and AP has not been studied in a moderate to severely active CD 
population; dose adjustments may confound the data interpretation.  Changes to any 
concomitant medications must be documented in the electronic Case Report Form (eCRF).
Between and including Weeks 10 and 14, there is an optional escape to Part 1 (OLE) of Study 
GA29145, where patients can receive open-label etrolizumab.  This can only be exercised if a 
patient experiences disease worsening, defined as a CDAI Week 10 score greater than the 
patient’s baseline (Week 0) score.
At Week 14, patients achieving CDAI-70 response without the use of rescue therapy will 
continue to the Maintenance Phase until a sample size of approximately 480 patients enrolled 
in the Maintenance Phase has been achieved.  Patients not eligible for the Maintenance Phase 
may be eligible for Part 1 (OLE) of Study GA29145.
Patients who are in the Induction Phase after closure of enrollment into the Maintenance 
Phase may enroll in Part 1 (OLE) of Study GA29145, if eligible, upon completion of the 
Induction Phase at Week 14 or in the event of disease worsening, as specified above, between 
Weeks 10 and 14
Patients who require surgical intervention for CD at any time during the Induction Phase will 
stop study treatment, enter the Safety Follow-Up Phase, and will be asked to enter Part 2 (SM) 
of Study GA29145 for PML monitoring.  Patients who self-withdraw from the Induction Phase 
and do not meet the eligibility criteria for OLE treatment will also enter the Safety Follow-Up 
Phase and be asked to enter Part 2 (SM) of Study GA29145 for PML monitoring.
Concomitant CD Therapy in the Induction Phase
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by a patient from 4 weeks prior 
to screening to the study completion/early termination visit.  
Anti-diarrheal medications are permitted if used to manage chronic diarrhea but every attempt 
should be made to keep the dose/regimen stable.  Any changes in the dose/regimen after 
baseline (Week 0) must be captured by the investigator and/or patient. 
Occasional use of nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen is 
permitted for pain relief (e.g., in the case of headache, arthritis, myalgia, etc.).  Prophylactic 
aspirin use up to 325 mg/day is also permitted.
Patients should not be treated for continuing signs and symptoms of CD with any medication 
that is prohibited to be taken concomitantly with etrolizumab; these include but are not limited 
to: anti-integrins, anti-adhesion molecules (e.g., anti-MAdCAM-1), T- or B- cell-depleting agents 
with the exception of AZA and 6-MP (or equivalent), TNF antagonists, antagonists of 
IL-23 IL-12 (e.g., ustekinumab), anti-metabolites, cyclosporine, and tacrolimus.
CS enemas/suppositories and/or topical (rectal) 5-aminosalicylate (5-ASA) preparations are 
also prohibited medications.  Patients taking these medications will be considered non-
responders for the purpose of any endoscopic analyses. These treatments must be 
discontinued, but patients may continue to receive etrolizumab and may still be eligible for 
Part 1 (OLE) of Study GA29145.
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Management of Concomitant CD Therapy in the Maintenance Phase
During the Maintenance Phase, corticosteroid dose should be tapered starting at Week 14 
according to the following schedule:

20 mg/day prednisone (or equivalent):  titrated via dose reduction of 2.5 mg/week until
discontinuation

6 mg/day oral budesonide:  titrated via dose reduction of 3 mg every 2-weeks until
discontinuation
If needed, patients may increase their corticosteroid dose up to their baseline dose (i.e., dose at 
randomization), but the dose-tapering regimen should be re-initiated within 2 weeks.  
Patients who are taking concomitant IS therapy (AZA, 6-MP, MTX) must remain on stable doses 
throughout the study unless dose reduction or discontinuation is required because of a toxicity 
related to the medication.  
Doses of anti-diarrheal medication should also be kept stable.  
Generally accepted criteria for discontinuation of IS due to toxicity include, but are not limited to, 
acute pancreatitis, severe leukopenia, severe thrombocytopenia, or significant elevations of the 
liver-associated enzymes from baseline, especially in the presence of an elevated total bilirubin.  
The ultimate decision to discontinue IS remains at the discretion of the Investigator. 
Rescue Therapy in the Maintenance Phase
This is defined as medication prescribed for new or worsening CD symptoms, and includes: 

Any new CS or IS therapy for CD

Increase in dose of IS therapy above the baseline (Week 0) dose

Increase in the dose of CS therapy above a patient’s baseline (Week 0) dose (applicable to
patients requiring CS at baseline)
Antibiotics, 5-ASAs, anti-diarrheals, probiotics, herbal/ayurvedic, nutritional, and homeopathic 
supplements are not considered as rescue therapies.  
Patients who require rescue therapy during the Maintenance Phase may be offered early 
access to the OLE (Study GA29145, Part 1), if eligible, and will be required to complete the 
Early Withdrawal visit assessment. 
Prohibited therapies are as described for the Induction Phase.
Study Drug Administration
Patients will receive etrolizumab or placebo by SC injection according to their treatment 
assignment, as described below in “Investigational Medicinal Products”.  Patients and study 
personnel will be blinded to study drug assignment (or the etrolizumab dose assignment for 
Cohort 2 patients in the Induction Phase) for the entire study. 
In the Induction Phase, study medication will be administered at the investigational site and 
patients will be trained to self-administer.  A health care professional (HCP) will administer the 
first two doses, with the patient or their caregiver administering subsequent doses under HCP 
supervision.  In the Maintenance Phase after completing Week 16, patients have the option to 
return to the investigational site or to self-administer/have a caregiver administer their dose 
Q4W at home within 3 days of their scheduled dose unless a PK blood draw is planned, in 
which case the dose must be administered after the blood draw on the day of visit or within 
3 days after the visit.
Schedule of Assessments
A schedule of study assessments is provided in Appendix 1 and a schedule of PK and PD 
assessments is provided in Appendix 1 and 3. 
Number of Patients
Approximately 1150 patients will be randomized into the Induction Phase of the trial via 
enrollment into one of three cohorts. 
Patients receiving etrolizumab in the Induction Phase who achieve a CDAI-70 response at 
Week 14 without the use of rescue therapy will be randomized into the Maintenance Phase of 




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
Meets the following surveillance colonoscopy requirements:
Surveillance was undertaken at screening or 12 months prior in patients with
colonic disease for > 10 years (regardless of any risk factors for bowel cancer).
Surveillance was undertaken at screening or 5 years prior in patients with colonic 
disease for 10 years who have risk factors for bowel cancer.
(Notelocal colonic surveillance guidelines can be followed if patients have no risk 
factors and colonic disease for 10 years.)

Have experienced intolerance, refractory disease, or no response (as defined below) to at
least one of the following therapies within 5 years from screening:
CS Therapy
Refractory:
Has signs/symptoms of persistently active disease despite a history of at least 
one 4-week induction regimen including a dose equivalent to 30 mg/day 
prednisone for 2 weeks if oral or 1 week if IV or 9 mg/day oral budesonide
Intolerance to CS therapy:
History including, but not limited to, Cushing’s syndrome, 
osteopenia/osteoporosis, hyperglycemia, insomnia, and infection 
IS Therapy
Refractory: 
Has signs/symptoms of persistently active disease despite a history of at least 
one 12-week regimen of oral AZA (or equivalent) (1.5 mg/kg) or 6-MP (or 
equivalent) (0.75 mg/kg) or MTX (15 mg/week)
Intolerance to 6-MP (or equivalent), AZA (or equivalent), or MTX:
History of intolerance to AZA (or equivalent), 6-MP (or equivalent), and/or MTX
(including, but not limited to, infection, nausea/vomiting, abdominal pain, 
pancreatitis, liver function test abnormalities, lymphopenia, and thiopurine 
methyltransferase genetic polymorphism)
Anti-TNF Therapy:
Inadequate primary non-response:
Did not respond (as evidenced by persistent signs/symptoms related to CD after 
receiving 2 induction doses of either infliximab [5 mg/kg] or adalimumab 
[160 mg/80 mg or 80 mg/40 mg] or certolizumab pegol [400 mg])
Inadequate secondary non-response:
Initially responded to induction therapy with infliximab (5 mg/kg) or adalimumab 
(40 mg) or certolizumab pegol (400 mg), but experienced signs/symptoms
related to recurrence of CD during maintenance
Intolerance: 
Experienced a significant injection-site reaction, congestive heart failure, 
infection, or other condition that precluded continuing use of anti-TNF therapy at 
any time 
Patients who have not previously demonstrated inadequate response or intolerance to one 
or more anti-TNF therapies are eligible to participate in the study provided they are 
intolerant or refractory to corticosteroid or immunosuppressant therapy.
Exclusion Criteria
Exclusion Criteria Related to Gastrointestinal Health

Has undergone subtotal colectomy with ileorectal anastomosis or has undergone total
colectomy

Short-bowel syndrome

Has an ileostomy or colostomy


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
Has evidence of fixed stenosis or small-bowel stenosis with prestenotic dilation that
precludes adequate endoscopic assessment of the bowel

Diagnosis of UC or indeterminate colitis

Suspicion of ischaemic colitis, radiation colitis, or microscopic colitis

Evidence of abdominal or perianal abscess

Sinus tract with evidence for infection (e.g., purulent discharge) in the clinical judgment of
the investigator.  Fistulas related to Crohn’s disease are not exclusionary.

Expected to require surgery to manage CD-related complications during the study

A history or evidence of adenomatous colonic polyps that have not been removed

Past or present disease-related colonic mucosal dysplasia
Exclusion Criteria Related to Prior or Concomitant Therapy

Any of the following treatments for CD within 8 weeks prior to randomization:
Adalimumab
Certolizumab pegol
Infliximab

Any prior treatment with ustekinumab within 14 weeks prior to randomization

Any prior treatment with etrolizumab or other anti-integrin agents (including vedolizumab,
natalizumab, and efalizumab)

Any prior treatment with anti-adhesion molecules (e.g., anti-MAdCAM-1)

Prior treatment with T cellor B celldepleting agents (e.g., rituximab, alemtuzumab, or
visilizumab) within 12 months prior to randomization, with the exception of AZA and 6-MP
(or equivalent).

Any investigational treatment that included investigational vaccines within 12 weeks prior to
randomization in the study or five half-lives of the investigational product, whichever is
greater

History of moderate or severe allergic or anaphylactic/anaphylactoid reactions to chimeric,
human, or humanized antibodies, fusion proteins, or murine proteins or hypersensitivity to
etrolizumab (active drug substance) or any of the excipients (L-histidine, L-arginine,
succinic acid, polysorbate 20)

Treatment with corticosteroid enemas/suppositories and/or topical (rectal)
5-aminiosalicylate (5-ASA) preparations 2 weeks prior to randomization

Continued tube feeding, defined formula diets, and/or parenteral alimentation/nutrition as
treatment for CD 3 weeks prior to randomization

Expectation of tube feeding, defined formula diets, and/or parenteral alimentation/nutrition
as treatment for CD during the study

Any live or attenuated vaccines 4 weeks prior to randomization

Use of IV steroids during screening, with the exception of a single IV steroid dose
administered in the Emergency Department

Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil 4 weeks prior to
randomization

Chronic use of NSAIDs.  Prophylactic aspirin use up to 325 mg/day is permitted, as is
occasional use of NSAIDs for conditions such as headache, arthritis, myalgia, and
menstrual cramps.

If receiving oral CSs, patients will be excluded unless the dose is stable at 20mg/day
prednisone or equivalent for 2 weeks immediately prior to randomization.

If receiving ongoing treatment with oral 5-ASA, patients will be excluded if the dose is not
stable for 2 weeks immediately prior to randomization.


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
If receiving ongoing treatment with probiotics (e.g., Culturelle, Saccharomyces boulardii) or
over-the-counter supplements (e.g., N-acetyl glucosamine, curcumin), patients will be
excluded if the dose is not stable for 2 weeks immediately prior to randomization.

If receiving ongoing treatment with ISs (e.g., 6-MP, AZA, or MTX), patients will be excluded
if the dose is not stable for 8 weeks immediately prior to randomization.

If receiving ongoing treatment with antibiotics for the treatment of CD, patients will be
excluded if the dose is not stable for 2 weeks immediately prior to randomization.
Patients may continue to receive ongoing treatment with anti-diarrheals (e.g., loperamide or 
diphenoxylate with atropine), preferably achieving a stable dose for 2 weeks prior to 
randomization.  However, if the patient and/or the treating physician decides to change the dose 
or course of anti-diarrheals at any time during screening, these patients will be allowed to 
participate in study.
Exclusion Criteria Related to Infection Risk

Congenital or acquired immune deficiency

Patients must undergo screening for HIV and test negative for preliminary and confirmatory
tests

Positive hepatitis C virus (HCV) antibody test result, unless the patient (1) has undetectable
HCV RNA levels for 6 months after completing a successful course of HCV antiviral
treatment and an undetectable HCV RNA at screening or (2) has a known history of HCV
antibody positivity with history of undetectable HCV RNA and undetectable HCV RNA at
screening in the absence of history of HCV anti-viral treatment

In the screening hepatitis B assessment (which consists of testing for hepatitis B surface
antigen [HBsAg], hepatitis B core anti-body [HBcAb], and if required, hepatitis B virus [HBV]
DNA), patients who test positive for HBsAg are excluded from the study.  Patients who test
positive for HBcAb but negative for HBsAg must have a confirmed negative HBV DNA test
result to be eligible for the study and will be required to undergo periodic monitoring for HBV
DNA during the study.

Positive stool test result for ova or parasites or positive stool culture for pathogens at time of
screening

Evidence of infection with and/or treatment for Clostridium difficile or other intestinal
pathogen treatment within 8 weeks prior to randomization.

A history of active or latent tuberculosis (TB) confirmed by one of the following screening
tests:
Positive tuberculin (purified protein derivative-PPD) skin test
Or
Positive QuantiFERONTB Gold test
Patients with a documented history of BCG vaccination must have a negative 
QuantiFERON test result and negative chest radiograph (see below) to be eligible. 

Suspicion of active TB on chest radiograph (X-ray, posteroanterior and lateral) taken within
3 months of randomization.

History of recurrent opportunistic infections and/or history of severe or disseminated viral
infections

Any serious opportunistic infections that occurred 6 months prior to screening

Any current or recent signs or symptoms (8 weeks before screening) of infection, except
for the following:
Minor infections (e.g., common cold) that have, in the investigator’s judgment, 
completely resolved prior to randomization
Fungal infections of the nail beds
Oral or vaginal candidiasis that has resolved with or without treatment prior to 
randomization


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
Any major episode of infection requiring treatment with IV antibiotics 8 weeks prior to
screening or oral antibiotics 4 weeks prior to screening.  Treatment with antibiotics as
adjunctive therapy for CD in the absence of documented infection is not exclusionary.
Exclusion Criteria Related to General Safety

Pregnancy or lactation

Lack of peripheral venous access

Hospitalization (other than for elective reasons) within 4 weeks prior to randomization

Inability to comply with study protocol, in the opinion of the investigator

Significant uncontrolled comorbidity such as neurological, cardiac (e.g., moderate to severe
heart failure New York Heart Association Class III/IV), pulmonary, renal, hepatic, endocrine,
or GI disorders (other than CD)

Neurological conditions or diseases that may interfere with monitoring for PML

Clinically significant abnormalities on screening neurologic examination

History of demyelinating disease

History of major neurological disorders, including stroke, MS, brain tumor,
neurodegenerative disease, or poorly controlled epilepsy

History of alcohol, drug, or chemical abuse 6 months prior to screening

Conditions other than CD that could require treatment with 20 mg/day of prednisone
(or equivalent) during the course of the study

History of cancer, including hematologic malignancy, solid tumors, and carcinoma in situ
within 5 years before screening
Non-serious basal cell or squamous cell carcinoma of the skin that has been excised 
and is considered cured is not exclusionary.
A history of chronic myelogenous leukemia, hairy cell leukemia, melanoma, renal cell 
carcinoma, or Kaposi sarcoma is exclusionary irrespective of the duration of time 
before screening.

History of cervical smear result at any time that indicated the presence of adenocarcinoma
in situ (AIS), high-grade squamous intraepithelial lesions (HSIL), or cervical intraepithelial
neoplasia (CIN) of Grade 1

History of organ transplant or cell transplantation

Presence of metal in the body that could a pose hazard during any potential scanning in
patients for whom a magnetic resonance imaging (MRI) scan is considered unsafe
Exclusion Criteria Related to Laboratory Values (at Screening)

Serum creatinine 2 times the upper limit of normal (ULN)

Impaired hepatic function defined by one of the following:
Serum transaminases 3 ULN
Alkaline phosphatase 3 ULN
Total bilirubin 2.5 ULN (excluding inherited deficiencies such as Gilbert’s disease)

Platelet count 100,000/L

Hemoglobin 8 g/dL

Absolute neutrophil count 1500/L

Absolute lymphocyte count 500/L
Length of Study
The study duration, from screening to end of study participation for a given eligible patient, will 
be up to 82 weeks (4-week screening period 14-week Induction Phase 52-week Maintenance 








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Secondary Efficacy Endpoints
Induction Phase

Proportion of patients who achieve clinical remission at Week 6

Proportion of patients who achieve 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 14

Changes from baseline to Week 14 in CD-PRO/SS score
Maintenance Phase

Proportion of patients in clinical remission at Week 66 among patients who achieve clinical 
remission at Week 14

Proportion of patients who achieve corticosteroid-free clinical remission at Week 66 

Proportion of patients who maintain endoscopic improvement at Week 66 among patients 
achieving endoscopic improvement at Week 14

Proportion of patients achieving 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 66 

Proportion of patients achieving durable remission 

Proportion of patients achieving corticosteroid-free clinical remission for 24 weeks at 
Week 66 

Change from baseline to Week 66 in CD-PRO/SS score
Secondary endpoints for the Maintenance Phase will be assessed in the group of patients who 
were randomized into the Maintenance Phase, unless otherwise specified.
The primary induction study endpoint-analysis for Cohort 3 will evaluate the difference between 
each etrolizumab arm and placebo using the Cochran-Mantel-Haenszel (CMH) test statistic 
stratified by the factors used at randomization.  The absolute treatment difference will be 
provided along with the 95% two-sided CI estimate.
The primary maintenance study endpoint-analysis will evaluate the difference in proportions 
between the two treatment arms using the CMH test statistic stratified by the factors used at
randomization into the Maintenance Phase.  The absolute treatment difference will be provided 
along with the 95% two-sided CI estimate.  Detailed specifications of the statistical methods 
used for all analyses will be described in the SAP. 
Determination of Sample Size  
Induction Phase
A total of approximately 1150 patients will be randomized into one of three induction cohorts.
The pivotal analysis for induction phase will be performed using only patients from Cohort 3.  In 
this pivotal induction cohort, patients will be randomized to receive either placebo, etrolizumab 
105 mg or etrolizumab 210 mg in a 2:3:3 ratio.  The co-primary endpoint will be tested using a 
CMH test at the 5% significance level, where both clinical remission and endoscopy 
improvement are required to be significant.  The sample size for Cohort 3 is expected to provide 
85% power to detect a 15% difference in rates of clinical remission (SF mean daily score 3 
and AP mean daily score 1) between each etrolizumab arm and placebo under the assumption 
of a placebo remission rate of 15% and a two-sided test performed at a significance level of 
5%.   Additionally, Cohort 3 will provide 80% power to detect a 10% difference in proportions 
for each etrolizumab arm versus placebo for endoscopic improvement, under the assumption of 
placebo response rate of 5% and a two-sided test at the 5% significance level. The 2 test was 
used to confirm the power calculations.


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Maintenance Phase
A total of approximately 480 patients achieving CDAI-70 response at Week 14 will be eligible 
to enroll into the Maintenance Phase.
A co-primary endpoint will be used for the analysis of the Maintenance Phase: clinical remission 
(SF mean daily score 3 and AP mean daily score 1) and endoscopic improvement at 
Week 66.  The maintenance co-primary analysis will be performed on all patients re-randomized 
into the Maintenance Phase who were randomized to etrolizumab (105 mg or 210 mg) in the 
Induction Phase.  The co-primary endpoint will be tested using a CMH test at the 5% 
significance level, where both clinical remission and endoscopy improvement are required to be 
significant.  Note that to maintain the blind, patients randomized to placebo in the Induction 
Phase will undergo a sham randomization and will receive placebo in the Maintenance Phase.  
These patients will not form part of the pivotal maintenance analysis.
Of the approximately 480 patients projected to be enrolled in the Maintenance Phase, 
approximately 420 patients will undergo re-randomization to receive either placebo or 
etrolizumab, and approximately 60 patients will undergo a sham randomization to placebo.  
These projections are based on the assumption that 50% of patients receiving etrolizumab and 
40% of patients receiving placebo during the Induction Phase will be eligible for the 
Maintenance Phase.
Assuming a maintenance sample size of 210 patients per arm using a 1:1 allocation to receive 
either placebo or etrolizumab 105 mg, the maintenance analyses conducted at the 5% 
significance level will provide the following power:

Clinical remission at Week 66 (SF mean daily score 3 and AP mean daily score 1):  at 
least 90% power to detect a 15% treatment difference assuming a placebo Week 66 
remission rate of up to 20%

Endoscopic improvement:  approximately 90% power to detect a 15% treatment difference 
assuming a placebo Week 66 improvement rate of up to 30%
Furthermore, the study is designed to provide sufficient power for the following secondary 
analyses:

Clinical remission at Week 66 among patients achieving clinical remission at Week 14:  a 
sample size of N 186 (i.e., 93 per arm) will provide 80% power to detect a 20% treatment 
difference assuming a placebo rate of up to 30%.  This assumes a Week 14 clinical 
remission rate of ≥22% among etrolizumab patients.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
5-ASA
5-aminosalicylate
6-MP
6-mercaptopurine
AIS
adenocarcinoma in situ
ANCOVA
analysis of covariance
AP
abdominal pain
APQ
Abdominal Pain Questionnaire
ATA
anti-therapeutic antibody
AUC
area under the serum concentration-time curve
AZA
azathioprine
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
CDEIS
Crohn's Disease Endoscopic Index of Severity
CDPRO/SS
Crohn’s DiseasePatient-Reported Outcome Signs and 
Symptoms
CIN
cervical intraepithelial neoplasia
Cmax
maximum serum drug concentration
CMH
Cochran-Mantel-Haenszel
Cmin
minimum serum drug concentration
CS
corticosteroid
CSF
cerebrospinal fluid 
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
e-diary
electronic diary
EMA
European Medicines Agency
ePRO
electronic patient-reported outcome
FDA
U.S. Food and Drug Administration
GI
gastrointestinal
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen 
HBV
hepatitis B virus
HCP
health care professional
HCV
hepatitis C virus


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Abbreviation
Definition
HIPAA
U.S. Health Insurance Portability and Accountability Act
HSIL
high-grade squamous intraepithelial lesion
IBD
inflammatory bowel disease
ICH
International Council for Harmonisation
iDCC
independent data coordinating center
iDMC
independent Data Monitoring Committee
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IR
inadequate responder
IRB
Institutional Review Board
IS
immunosuppressant
IV
intravenous
IxRS
interactive voice or Web-based response system
JCV
John Cunningham virus
LD
loading dose
mAb
monoclonal antibodies
MAdCAM-1
mucosal addressin cell adhesion molecule
mITT
modified intent to treat
MOA
mechanism of action
MS
multiple sclerosis
MRI
magnetic resonance imaging
MTX
methotrexate
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NSAIDs
nonsteroidal anti-inflammatory drugs
OLE
open-label extension
PD
pharmacodynamics
PFS
prefilled syringe
PK
pharmacokinetic
PML
progressive multifocal leukoencephalopathy
PPD
purified protein derivative
PRO
patient-reported outcome
PRO2
Patient-Reported Outcome-2 
Q4W
every 4 weeks


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Abbreviation
Definition
QOL
quality of life
qPCR
quantitative polymerase chain reaction
RCR
Roche Clinical Repository
SC
subcutaneous
SESCD
Simple Endoscopic Score for Crohn’s Disease
SF
liquid/soft stool frequency
SM
safety monitoring
SUSAR
suspected unexpected serious adverse reaction
TB
Tuberculosis
TNF
tumor necrosis factor
TNFIR
inadequate response to anti-tumor necrosis factor
UC
ulcerative colitis
ULN
upper limit of normal


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1.
BACKGROUND
1.1
BACKGROUND ON CROHN’S DISEASE
Crohn’s disease (CD) is a chronic, relapsing form of inflammatory bowel disease (IBD) 
that can affect any portion of the gastrointestinal (GI) 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 fistulas and abscesses (penetrating).  
Clinical signs and symptoms include chronic diarrhea, abdominal pain, cachexia, 
abdominal mass, or tenderness as well as the overt signs of fistulas. The disease 
course is variable; patients can experience a severe initial flare followed by few 
symptoms over the next 10 years (43%) or 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 (CSs) 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 CS 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.


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Immunosuppressants (ISs) (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 
quiescent CD.  Immunosuppressants are given with or without a steroid bridge, 
depending on a patient’s symptoms during the 24-month onset of IS 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 IS 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, thromobocytopenia, 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)(anti-TNFs) 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 lower than 35% and, among patients who respond 
to induction therapy, fewer than 50% have achieved 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 a biological escape 
mechanism that may benefit from a therapy with a different pharmacological target.  
Anti-TNFs are also associated with significant side effects, including serious infection, 
opportunistic infection, lupus-like reactions, and an increased risk of lymphoma 
(Siegal and Melmed 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 U.S. only for the treatment of moderate 
to severely active CD. The use of natalizumab, which blocks both 41 and 47 has 


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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 T-lymphocyte binding to the 
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 which, unlike 
vedolizumab, targets both the 47 and E7 receptors that regulate trafficking and 
retention of T-cell subsets in the intestinal mucosa, respectively.  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, which 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 studies (see Etrolizumab Investigator’s Brochure).
It is important to note that, unlike natalizumab, etrolizumab does not bind to 41 or 
inhibit the interaction of 41 and VCAM-1 and 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.  However, 
in any clinical trial of etrolizumab, signs or symptoms suggestive of PML would be 
carefully monitored through regular neurological examinations.  Safety assessments for 
etrolizumab have been completed in adult Phase I and Phase II studies, in which 
patients with moderate to severely active UC received either single or multiple doses of 
IV or subcutaneous (SC) etrolizumab.  A total of 158 patients have been exposed to 
etrolizumab in the Phase I and II studies, with no significant adverse safety signals, 


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including any evidence of increased rates of serious or opportunistic infections that might 
be associated with etrolizumab treatment.  Acknowledging that the clinical experience 
with etrolizumab is limited, no events of PML have been reported in patients treated with 
etrolizumab.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
The purpose of this study is to assess the efficacy and safety of etrolizumab, a novel 
anti-integrin with a unique MOA that has been shown to inhibit the trafficking and 
retention of inflammatory T-cells in the intestinal mucosa via a disruption of 
47/MAdCAM-1 and E7/E-cadherin binding.
Although 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 suggests that expression levels are similar between both diseases.  The reported 
efficacy of vedolizumab, an anti-47 mAb, in CD demonstrates a role for 47 in the 
pathobiology of this disease (Sandborn et al. 2013) and suggests that etrolizumab will be 
efficacious.  In addition, because E7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, the dual MOA of etrolizumab may bring 
enhanced efficacy in CD without generalized immunosuppression compared with
available anti-integrin and anti-TNF therapies.  
In a global Phase II study (Study ABS4986g; EUCALYPTUS), etrolizumab was 
efficacious in treating moderate to severe UC and achieved a placebo-corrected clinical 
remission rate of 20.5% (p0.058) and an endoscopic remission rate of 10.3% 
(p0.004) at 10 weeks after treatment initiation (105 mg every 4 weeks [Q4W]) in an 
all-comers population (Vermeire et al. 2013).  In addition, etrolizumab had an acceptable 
safety profile with no clinically significant safety signals observed.  There is no known 
safety risk identified for etrolizumab at this time, but as an investigational medicinal 
product (IMP) with limited Phase II data, the full safety profile for etrolizumab will be 
further characterized as Phase III clinical development progresses.  A safety plan is 
provided in Section 5, describing potential risks for etrolizumab and the risk-mitigation 
strategies to minimize risks for the patients in this study.
To address potential risks to participating patients, the clinical experience with 
etrolizumab in patients with UC and information on the mechanism of action was 
considered in the clinical design and safety management plan of the proposed Phase III
study to address potential risks to participating patients.  The planned induction and 
maintenance dose regimens are expected to be safe and efficacious and were selected 
based on the observed safety, pharmacokinetic (PK), and pharmacodynamic (PD) profile 
of etrolizumab in UC, with consideration given to potential differences in exposure 
related to the transmural and patchy presentation of inflammation in CD.  Only patients 
who have undergone a sufficient washout of prior biological therapy for CD will be 


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eligible to participate and patients with a history of moderate allergic reactions to mAbs 
will be excluded.  As described in Section 1.2, etrolizumab is selective for intestinal 
mucosal tissue and does not impact peripheral lymphoid populations.  Consequently, the 
risk of PML is expected to be lower with etrolizumab compared with other 
non-gut-selective biologics, with no events of PML reported in the UC Phase II or OLE
studies. Patients at risk of severe infections (including PML and opportunistic infections) 
will be excluded from this study.  The potential risk of severe infections associated with 
concomitant IS therapy has been carefully considered.  On the basis of data from the UC 
Phase II study and the recent vedolizumab Phase III program, which showed that 
concomitant IS use did not impact the infection rates, concomitant IS use will not be 
prohibited in this study (see Section 3.3.3 for a more detailed assessment of this risk).
Patient safety will be monitored throughout the study via assessment of vital signs, 
safety laboratory assessments, neurological exams, and continuous review of adverse 
events.  Should any patients become pregnant, develop anaphylaxis, develop PML, 
specific malignancy, colonic mucosal dysplasia, or certain specific serious infections 
(see Section 5.1.1.1), they will be permanently discontinued from the study treatment 
(see Section 4.6.2).  Patients will not be eligible to enter the Induction Phase of the study 
if requiring a CS dose 20mg/day prednisone or equivalent, or6 mg/day oral 
budesonide.  In addition, the dose must have remained stable for 2 weeks prior to 
patient randomization into the Induction Phase.  During the Maintenance Phase of the 
study, patients who experience a clinical relapse in their CD status will have the option to 
enroll into an open-label study of etrolizumab.  During the Induction Phase, when 
concomitant CD treatments must remain stable, patients will not be allowed to 
participate if they require a CS dose 20mg/day prednisone or equivalent.
An independent Data Monitoring Committee (iDMC) will review all safety data twice 
yearly during the study or more frequently based on the emerging safety data.  Refer to 
Section 5 for additional details. 
Given the significant clinical and non-clinical data generated to date for etrolizumab, 
there is a strong rationale and a positive benefit-risk assessment for studying 
etrolizumab in a Phase III clinical trial in CD, supported by:

Studies of an anti-47 mAb, vedolizumab, approved for the treatment of patients 
with moderate to severe CD

Completed studies with etrolizumab in UC demonstrating clinically meaningful 
benefit, as well as a full characterization of the PK/PD profile in UC and, importantly, 
an acceptable safety profile in previous etrolizumab studies

Data that implicate 47 receptors in the pathobiology of CD with the possibility that 
inhibition of the E7/E-cadherin interaction by etrolizumab could bring enhanced 
efficacy

An acceptable safety profile in the ongoing clinical development program, and a 
carefully designed Phase III CD program with robust safety monitoring


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2.
OBJECTIVES
2.1
EFFICACY OBJECTIVES
Analyses of clinical remission will be made on the basis of patient-reported values for 
liquid/soft stool frequency (SF) and abdominal pain (AP) (derived from the 7-day 
average scores), and centrally read, clinician-reported values for endoscopic 
improvement, as assessed by the Simple Endoscopic Score for Crohn’s Disease 
(SESCD), the summed score of four endoscopic variables that are rated in 5 ileocolonic 
segments of the bowel (Daperno et al. 2004).
2.1.1
Co-Primary Efficacy Objectives 
The co-primary efficacy endpoints for this study are the following:

Clinical remission, defined as a SF mean daily score 3 and an AP mean daily 
score 1 with no worsening in either subscore compared to baseline, averaged over 
the 7 days prior to visit

Endoscopic improvement, defined as a 50% reduction from the baseline SES-CD
Primary efficacy objectives for this study will be analyzed separately for the Induction 
and Maintenance Phases as outlined below.  

Induction Phase:  To independently evaluate the efficacy of etrolizumab dose 
regimens compared with placebo in inducing clinical remission and endoscopic 
improvement at the end of the Induction Phase (Week 14) 

Maintenance Phase:  To independently evaluate the efficacy of etrolizumab 
compared with placebo in achieving clinical remission and endoscopic improvement 
at 1 year of maintenance treatment (Week 66), for patients who achieved a Crohn’s 
Disease Activity Index (CDAI)70 response (defined as a decrease of at least 
70 points from baseline CDAI) at Week 14
2.1.2
Secondary Objectives
Induction Phase

To evaluate the efficacy of etrolizumab compared with placebo in achieving clinical 
remission at Week 6

To evaluate the efficacy of etrolizumab compared with placebo in achieving an 
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 14

To evaluate the reduction in CD signs and symptoms achieved by etrolizumab dose 
regimens compared with placebo at Week 14 as assessed by the Crohn’s Disease 
Patient-Reported Outcome Signs and Symptoms (CDPRO/SS) measure


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Maintenance Phase
All secondary Maintenance endpoints are for patients who achieved CDAI-70 at 
Week 14, unless otherwise stated.

To evaluate the efficacy of etrolizumab compared with placebo in maintaining 
clinical remission at Week 66 for patients who achieved clinical remission at 
Week 14

To evaluate the efficacy of etrolizumab compared with placebo in achieving 
corticosteroid-free clinical remission at Week 66 among patients who were receiving 
corticosteroids at baseline

To evaluate the efficacy of etrolizumab compared with placebo in maintaining 
endoscopic improvement at Week 66 for patients who achieved endoscopic 
improvement at Week 14

To evaluate the efficacy of etrolizumab compared with placebo in achieving a 
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 66 

To evaluate the efficacy of etrolizumab compared with placebo in achieving durable 
clinical remission during 1 year of maintenance therapy (i.e., at 4 of the 6 in-clinic 
assessment visits that are conducted during the Maintenance Phase at Weeks 24, 
28, 32, 44, 56, and 66) 

To evaluate corticosteroid-free clinical remission at Week 66 (off corticosteroid for at
least 24 weeks prior to Week 66) in patients who were receiving corticosteroids at 
baseline

To evaluate change in CD signs and symptoms from baseline to Week 66 as
assessed by the CD-PRO/SS measure
 
 
 






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Moderate to severely active CD will be defined at baseline by clinical signs and 
symptoms that result in a CDAI score between 220 and 480, as well as either an 
average SF ≥6 or an average SF 3 and average AP 1, calculated on the day of 
randomization using electronic diary (e-diary) PRO data from the 7 days prior to 
randomization.  In conjunction, the presence of active inflammation, defined as a 
SES-CD of 7, or 4 in cases of isolated ileitis or post-ileocecal resection, is required 
and will be determined by a screening ileocolonoscopy scored using the central read 
model.
The study population will consist of patients who are refractory or intolerant to one or 
more of the following therapies:  1) CS, 2) IS, or 3) anti-TNFs (or TNF-IR). Patients who 
enroll on the basis of refractory or intolerance to CS and/or IS may have been previously 
exposed to ant-TNFs or be naïve to anti-TNFs (as defined in Section 4.1.1).
Approximately 1150 patients will be randomized into the study from approximately 
500 global investigational sites via enrollment into one of three cohorts 
(see Section 3.1.3).  The enrollment will be sequential, first into Cohort 1, then Cohort 2, 
and lastly Cohort 3.
3.1.2
Overview of Screening Phase
Patients will be evaluated for eligibility in the 35-day Screening Phase (see Figure 1).  
Assessments for eligibility are noted in Appendix 1a.
During the Screening Phase, patients taking CS therapy must have been on a stable 
dose of 20 mg/day prednisone or equivalent or 6 mg/day oral budesonide for at least 
2 weeks immediately prior to their randomization.  Similarly, eligible patients requiring 
background IS therapy (e.g., AZA [or equivalent], 6-MP [or equivalent], or MTX) must 
be receiving a stable IS dose regimen for at least 8 weeks immediately prior to their 
randomization.  Patients who have been treated with anti-TNF therapy must have 
discontinued this treatment for at least 8 weeks prior to their randomization.
The ileocolonoscopy should be performed during the Screening Phase and at least 
9 days prior to randomization to allow sufficient time for a central reader scoring and 
determination of eligibility, and to avoid the ileocolonoscopy bowel preparation 
influencing the patient reported outcomes used in the determination of baseline SF, AP,
and CDAI scores (i.e., abdominal pain, general well-being, and stool frequency).
Refer to Section 4.5.2.1 for requirements related to re-screening a patient.
3.1.3
Number of Patients
Approximately 1150 patients will be randomized into the Induction Phase of the trial via 
enrollment into one of three cohorts (see Section 3.1.3 and Table 4 for details regarding 
sample size for each cohort).


Patients receiving etrolizumab in the Induction Phase who achieve a CDAI-70 response 
at Week 14 without the use of rescue therapy will be randomized into the Maintenance 
Phase of the trial until a sample size of approximately 480 patients enrolled in the 
Maintenance Phase is achieved.  Of the approximately 480 patients enrolled in the 
Maintenance Phase, approximately 420 patients are estimated to be CDAI-70 
responders who received etrolizumab during the Induction Phase and will be 
re-randomized to either etrolizumab 105 mg SC Q4W or placebo in the Maintenance 
Phase.  The remaining approximately 60 patients are CDAI-70 responders who received 
placebo during the Induction Phase and will undergo a sham randomization to blinded 
placebo treatment during the Maintenance Phase.
3.1.4 
Overview of Induction Phase
Eligible patients will be enrolled sequentially into one of three cohorts for the 14-week 
Induction Phase (see Appendix 1a).
Patients enrolled in Cohort 1 (double-blind, placebo-controlled, exploratory cohort; 
n 300) will be randomized in a 1:2:2 ratio to receive placebo, etrolizumab 105 mg SC 
Q4W (low dose), or etrolizumab 210 mg SC (high dose) at Weeks 0, 2, 4, 8, and 
12 within a 14-week Induction Phase (note that patients randomized to low-dose 
etrolizumab and patients randomized to placebo will receive one placebo injection at 
Week 2, see below).  Patients enrolled in Cohort 2 (etrolizumab doseblind, 
active-treatment cohort; n 350) will be randomized in a 1:1 ratio to receive low-dose or 
high-dose regimens of etrolizumab.  Patients enrolled in Cohort 3 (double-blind, 
placebo-controlled, pivotal cohort; n 500) will be randomized in a 2:3:3 ratio to receive 
placebo or etrolizumab low-dose or high-dose.  Because the low dose and high dose of 
etrolizumab are in syringes of different volumes, in order to preserve the blind, patients 
in all three cohorts will receive two injections at Weeks 0, 4, 8, and 12.  Patients 
randomized to low-dose etrolizumab will receive one placebo (matching high-dose 
prefilled syringe) and one low-dose etrolizumab injection at each administration except 
at Week 2, when they will receive one placebo injection.  Patients randomized to 
high-dose etrolizumab will receive one placebo and one high-dose etrolizumab injection 
at each administration, except at Week 2 where they will receive one high-dose 
injection.  Finally, patients randomized to placebo will receive two placebo injections at 
every administration, except at Week 2 where they will receive one placebo injection.
The randomization in all cohorts will be stratified by concomitant oral CS treatment 
(yes vs. no), concomitant IS treatment (yes vs. no), baseline CDAI 330 (yes vs. no), 
and prior anti-TNF exposure (yes vs. no). The enrollment will be managed to ensure that 
the proportion of the TNF-exposed patients in Cohort 3 does not exceed approximately 
60% and that the proportion of patients with a CDAI score between 450 and 480 does 
not exceed approximately 10% in each cohort. 
During the Induction Phase, patients in all cohorts should keep their dose(s) of CS and 
IS therapy stable (if requiring CS/IS at baseline).  Increase in dose of these medications 
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Figure 1
Study Schema Induction Phase
Anti-TNFanti-tumor necrosis factor; CDCrohn’s disease; ETROEtrolizumab; ISimmunosuppressants, 
SCsubcutaneous; Wkweek.


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Figure 2
Study Schema Maintenance Phase
CScorticosteroids; ETROEtrolizumab; OLEopen label extension phase; PBOplacebo; q4wevery 4 weeks; Re-Rxre-randomized; Wkweek.




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The primary clinical endpoint is based on previous FDA recommendations, the evolving 
global regulatory environment (new EMA new medicinal products guideline for CD 
released July 2018; CHMP 2016), and the results generated from the exploratory 
induction of Cohort 1 in this study. Both FDA and EMA in its new guideline discouraged 
the use of CDAI as primary endpoint for CD registration studies due to the limitations of 
the index. Instead, co-primary endpoint composed of patient-reported signs/symptoms 
and endoscopic measure is encouraged. 
The use of SF and AP addresses the FDA’s recommendation to use 7-day scores of SF 
and AP that correlate with CDAI remission.  Defining clinical remission and response 
that use unweighted measures of AP and SF are more easily interpretable by clinicians, 
patients, and caregivers and are more likely to represent clinically meaningful 
improvements in symptoms and disease activity for moderate to severe CD patients 
experiencing different degrees of SF and AP during a flare. 
Endoscopic improvement, defined as a change in SES-CD 50% from the baseline 
score (Ferrante et al. 2013), is a co-primary endpoint.
The SESCD consists of four endoscopic variables (ulcers, ulcerated surface, inflamed 
surface, and presence of narrowings) that are scored in five ileocolonic segments.  The 
SESCD was prospectively developed and validated in patients with mild to severe CD 
(according to CDAI) by Daperno et al. (2004).  This scoring system was recommended 
by the FDA and is generally preferred by physicians to other measures because of 
quantification of ulcer size (rather than a qualitative assessment of ulcer characteristics), 
determination of the percent ulceration in a segment (rather than determination by a 
visual analogue scale), and for better inter-rater reliability (inter-class correlation 
coefficients were 0.83 and 0.71 for SESCD and Crohn's Disease Endoscopic Index of 
Severity (CDEIS), respectively; Khanna et al. 2014).  Because the score does not adjust 
for the number of visible segments, only segments visualized at baseline will be included 
in the endpoint assessment.  This means any new narrowing due to inflammation that 
renders a segment not evaluable for scoring after study treatment will qualify the patient 
as not achieving endoscopic improvement for the secondary endpoint analysis.  Similarly, 
any improvement in inflammation that renders a segment evaluable for scoring after 
study treatment will not be reflected in the endpoint assessment.  The Statistical 
Analysis Plan will describe any sensitivity analysis which are planned to assess the 
impact of these missing data on the endpoint.  Given the limited experience with 
endoscopic scoring systems in general gastroenterology practice, all ileocolonoscopies 
in the study will be recorded at the investigational site, but central readers will determine 
the SESCD.
Published studies have used multiple endoscopic endpoints to assess efficacy, which 
appear to be arbitrarily defined.  Mucosal healing, defined qualitatively as an absence of 
mucosal ulcers, has been studied as a primary or secondary endpoint in a number of 
Phase IV studies (Rutgeerts et al. 2004 [natalizumab]; Rutgeerts et al. 2006 [infliximab]; 


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Colombel et al. 2010 [infliximab and azathioprine]; Hebuterne et al. 2013 [certolizumab]; 
Rutgeerts et al. 2012 [adalimumab]).  Some studies have defined endoscopic thresholds 
that represent endoscopic remission without clarity on the clinical significance of these 
scores (Hebuterne et al. 2013 [certolizumab]; Rutgeerts et al. 2012 [adalimumab]).  In 
this study, endoscopic improvement is defined as the proportion of patients 
demonstrating a 50% reduction in SES-CD versus their pretreatment baseline score.  
For induction, this endpoint will be measured at Week 14 and, for maintenance, at Week 
66 among patients who achieved a clinical response at Week 14.  The endpoint is based 
on recent post hoc analyses of the SONIC trial which determined a 50% reduction in 
SESCD score to be predictive of CS-free CDAI remission following 50 weeks of 
treatment with biologic therapy (Ferrante et al. 2013).  This definition is also appropriate
when considering the large variability in SESCD change at the end of a 6-week 
Induction Phase measured in a sample of 24 placebo patients (with moderate to 
severely active CD) who were participating in one of two trials of novel biologic agents 
(Ferrante et al. 2010).  The dataset showed that 6 patients achieved both 50% reduction 
in either SESCD or CDEIS score, and at least a 5-point reduction in either SESCD or 
CDEIS score.
3.3.2
Rationale for Patient Population
Patients with uncontrolled, moderate to severely active CD are at risk for developing 
stricturing or penetrating complications of inflammation, as well as symptoms that are 
debilitating to quality of life.  The treatment goals for CD are to induce and maintain 
symptom improvement, induce mucosal healing, and improve quality of life.  However, 
for a significant proportion of patients, these goals are not met by current therapies 
(see Section 1.1).  As such, the study population will include patients who are refractory 
to one or more of the following therapies: 1) CS, 2) IS, or 3) anti-TNFs (or TNF-IR). 
Patients who enroll on the basis of refractory or intolerance to CS and/or IS may have 
been previously exposed to ant-TNFs or be naïve to anti-TNFs.  Data from the 
etrolizumab Studies ABS4986g and GA27927 in UC (see Etrolizumab Iinvestigator’s 
Brochure) and the vedolizumab GEMINI 2 and 3 studies (Sandborn et al. 2013; Sands et 
al. 2014) have demonstrated the favorable efficacy of the anti-47 mechanism of action 
in these patient subgroups.  Patients belonging to each subgroup will be identified on the 
basis of refractory and inadequate-response criteria agreed upon with the EMA and FDA.
Patients with moderate to severely active CD between the ages of 18 and 80 years of 
age will be studied.  This age range is typical of patients enrolled in clinical trials of new 
investigational agents for CD and reflects the observation that adult CD can become or 
persist as moderate to severely active disease at any age.  Given that the primary 
clearance mechanism for etrolizumab is neither renal elimination nor first-pass 
metabolism, the risk of accumulation in patients 65 years of age is considered low and 
is also mitigated by laboratory exclusions related to poor renal and hepatic function.


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In line with EMA guidelines, eligible patients must have an established diagnosis of CD 
for at least 3 months, with moderately to severely active disease corroborated by 
endoscopic evidence of inflammation.  This is expected to improve the specificity of the 
CDAI, SF, and AP assessments and to allow the evaluation of endoscopic improvement 
endpoint.  On the basis of the construction of the SES-CD, patients with isolated ileitis or 
post-ileocecal resection can be expected to have a lower baseline score compared with 
patients with ileocolonic disease, regardless of whether the extent of inflammation and 
ulceration is the same in affected segments.  As such, different SES-CD entry scores 
are proposed for these subgroups of patients.  It is acknowledged that patients with 
fistulizing disease are not well served by therapeutic options. 
 
3.3.3
Rationale for the Design of Induction and Maintenance Phases
Patient randomization into the Induction Phase will be stratified by disease activity on the 
basis of CDAI score 330 or 330 (predictive of CDAI response and remission rates 
with biologic therapy; Sandborn et al. 2013; Sands et al. 2014), CS use, IS use, and 
prior anti-TNF failure (all indicators of disease activity). These factors are considered 
sufficient to mitigate the risk of imbalance in disease severity across treatment arms. 
Assessment of the induction of clinical remission and endoscopic improvement at 
Week 14 is justified on the basis of the observation that anti-integrin therapies have a 
slower onset of action compared with anti-TNF therapies (Sandborn et al. 2005, 2013), 
as well as the clinical consensus that the onset of endoscopic improvement is typically 
observed 1624 weeks after induction therapy, particularly in treatment refractory 
patients (a consensus supported by observed data showing that Mayo Clinic Score 
remission with etrolizumab took up to 14 weeks in TNFIR patients with UC, see 
Etrolizumab Investigator’s Brochure).  A challenge of the 14-week Induction Phase is the 
requirement to keep concomitant CD therapies stable for the duration, so as not to 
confound the endpoint analysis.  This is problematic in the context of patients who 
require rescue therapy to treat a flare and patients who are responding to treatment but 
unable to taper their CS dose.  The study design addresses this by allowing use of 
rescue therapy in case of disease worsening, in which case patients would be classified 
as non-responders for the primary analysis, and restricting the maximum baseline CS to 
20mg/day prednisone-equivalent dose.  Although not prohibited therapeutic adjustment, 
increasing the dose of anti-diarrheal drugs should be avoided.  Patients should keep 
their dose of anti-diarrheal medication stable as much as possible because the effect of 
titrating anti-diarrheal medication on the placebo-response rate on clinical remission is 
unknown.
The Induction Phase includes an exploratory cohort (Cohort 1) that is adequately sized 
to assess effect size and accuracy of statistical planning assumptions for the new 
endpoints in pivotal cohort (Cohort 3), the clinical validity of the dichotomous endpoint 
definitions, and the testing hierarchy of the endpoints.  An active-treatment induction 


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cohort (Cohort 2) is also included in this study to generate a sufficient number of 
remitters for assessment of endpoints in the Maintenance Phase.  The final cohort 
(Cohort 3) is a pivotal induction cohort, which will generate data for the endpoint analysis 
of the induction study.
Patients achieving a CDAI-70 response at Week 14 without rescue therapy will be 
re-randomized into the Maintenance Phase until a sample size of approximately 
480 patients in the Maintenance Phase is achieved.  Based on expert clinical opinion, 
patients achieving clinical remission and endoscopic improvement at Week 14 are 
expected to be a subpopulation within this group.  Randomization into the Maintenance 
Phase will be stratified by the use of disease activity (described for the Induction Phase, 
except CDAI-remission [score 150] at both Weeks 10 and 14 will be used instead of 
CDAI 330 or 330).  In addition, the randomization will be stratified by assignment to 
low- or high-dose etrolizumab (allowing an assessment of the impact of low- or high-
dose induction therapy on the maintenance endpoints).  Given the large number of strata, 
any potential imbalance in the proportion of endoscopic improvers at Week 14 will be 
handled using a covariate-adjusted analysis for the Week 66 endoscopic-improvement 
endpoint.
The duration of the Maintenance Phase (52 weeks) is considered an appropriate period 
by the FDA and EMA to establish the benefit of long-term therapy.  During the first 
8 weeks of the Maintenance Phase, patients receiving CS during the Induction Phase 
should undergo weekly dose reductions aligned with recommendations for CS tapering 
in the current American College of Gastroenterology and European Crohn’s and Colitis 
Organization guidelines and following the EMA recommendation to avoid a rapid taper.  
The tapering schedule will allow patients to be assessed for the key secondary outcome 
of achieving corticosteroid-free clinical remission at Week 66 among patients who enter 
into maintenance phase.
An analysis of data from Study ABS4986g in patients with UC, which compared 
etrolizumab induction therapy with placebo (Vermeire et al. 2013), showed that infection 
rates were similar between etrolizumab and placebo in the subgroups of patients taking 
concomitant IS or CS therapy and the subgroups not taking these concomitant 
treatments (see Etrolizumab Investigator’s Brochure).  Although this is a small dataset 
with limited duration of exposure, more data for a longer duration of concomitant 
exposure are available for vedolizumab.  A recent analysis of the vedolizumab 
development program demonstrated a modest increase in infection rates in patients 
using IS regardless of whether they received vedolizumab or placebo. In addition, the 
rates of infection and serious infection in the vedolizumab treatment group were similar 
in patients who were taking concurrent IS and those who were not 
(Colombel et al. 2016).
The risk of PML is expected to be lower with etrolizumab compared with other 
non-gut-selective biologics, with no events of PML reported in the UC Phase II or OLE 


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studies.  However, the potential risk of PML and other severe infections has been
carefully considered.  Patient safety will be monitored throughout the study via 
assessment of vital signs, safety laboratory assessments, neurological exams, and 
continuous review of adverse events.  Should any patients have anaphylaxis, develop 
PML, specific malignancy, colonic mucosal dysplasia, or certain specific serious 
infections, they will be permanently discontinued from the study treatment 
(Section 4.6.2).  During the Maintenance Phase of the study, patients who experience a 
clinical relapse in their CD status will have the option to enroll into an open-label study of 
etrolizumab.  
After the final visit in the treatment period, patients not participating in the OLE study will 
be assessed for safety for an additional 12 weeks starting after the last dose of study 
drug (see Section 4.5.8).  This period reflects an adequate timeframe for washout of 
etrolizumab based on the estimated elimination half-life of 11 days (see Etrolizumab 
Investigator’s Brochure).  
3.3.4
Rationale for Etrolizumab Dose and Schedule
The PK profiles of several biologics are shown to be similar in UC and CD patient 
populations (Ternant et al. 2008, Fasanamde et al. 2009, Awni et al. 2013, 
Feagan et al. 2013; Sandborn et al. 2013).  With these similarities, most biologic agents 
(e.g., anti-TNF or anti-integrin agents) have been successful in managing either UC or 
CD with use of the same dosing regimen (Feagan et al. 2013, Sandborn et al. 2013, 
Infliximab Package Insert; Adalimumab Package Insert).  Because etrolizumab has been 
evaluated in patients with moderate to severely active UC in a Phase II study 
(Study ABS4986g; Eucalyptus) in which clinically meaningful induction of disease 
remission was achieved at a nominal dose of 100 mg (0.7 mL 150 mg/mL etrolizumab 
formulation) Q4W (three doses at Weeks 0, 4, and 8) and a nominal dose of 300 mg 
Q4W loading dose(LD [LD of 420 mg at Week 0, 300 mg at Weeks 2, 4, and 8]) without 
significant safety concerns, the dose regimen (105 mg SC Q4W) of etrolizumab is also 
proposed as one of the doses to be tested in this study.
3.3.4.1
Rationale for Dose Ranging in the Induction Phase
In the Induction Phase, patients will be randomized to receive placebo, low-dose 
etrolizumab, or high-dose etrolizumab.  Low-dose etrolizumab (105 mg) will be 
administered Q4W SC (Weeks 0, 4, 8, and 12). 
A low dose regimen of 105 mg SC at Q4W is specified for dose ranging in the Induction 
Phase on the basis of the following considerations:

In the Phase II UC trial, a nominal dose of 100 mg (0.7 mL of 150 mg/mL solution 
via vial and syringe), administered Q4W SC, showed a clinically meaningful 
induction of remission in patients with UC and had a favorable safety profile in the 
Phase II trial. 


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
The exposure of 100 mg, administered Q4W SC, was shown to be sufficient for 
maximal 7-receptor occupancy in both blood and colonic tissue from all patients 
who provided evaluable samples in the Phase II trial. 

Population PK/PD modeling predicts that a dose lower than the 100-mg SC Q4W 
regimen (e.g., 50 mg Q4W SC) will result in the loss of maximal 7-receptor 
occupancy during the Q4W dosing interval in approximately 44% of patients, and 
exposure is likely to be in the nonlinear PK range. 
In addition to the 105-mg Q4W dose, a higher dose regimen of 210 mg SC at Weeks 0, 
2, 4, 8, and 12 is specified for dose ranging in the Induction Phase on the basis of the 
following considerations:

Despite the similarities in pathogenesis to UC, CD exhibits a more complex 
anatomical disease presentation throughout the gastrointestinal (GI) tract 
(i.e., transmural inflammation, patchy distribution, and strictures) when compared 
with UC.  A positive exposure-response relationship was reported recently for 
vedolizumab, an in-class, anti-integrin antibody, following the Induction Phase of a 
Phase III clinical trial in patients with CD.  Results showed the induction dose is 
sufficient to reach a complete receptor occupancy in all patients 
(Rosario et al. 2013), yet an increase in clinical response/remission was observed in 
patients with higher drug concentrations (Sandborn et al. 2013; Rosario et al. 2014).  
These observations from vedolizumab studies suggest that higher etrolizumab 
exposure may have the potential to offer more clinical benefit in this patient 
population.

In addition to Q4W dose of 210 mg, the additional 210-mg dose at Week 2 is 
intended to load the etrolizumab exposure upfront to allow exposure achieving 
steady state faster.  Earlier loading dose of anti-TNF agents or anti-integrins 
antibodies (Rutgeerts et al. 2004) were found to be effective in inducing clinical 
remission (CDAI score <150), and such a loading dose strategy was also 
implemented in this study.

The proposed higher dose of 210 mg5 doses SC (at Weeks 0, 2, 4, 8, and 12) in 
patients with CD will result in a 2.5-fold total dose separation from the 105 mg 
Q4W 4 dose regimen and is predicted to achieve an exposure level 30% lower 
than that from the 300 mg420 mg LD cohort studied in the UC Phase II trial, which 
had an acceptable safety/tolerability profile.
In summary, given the favorable safety profile and positive clinical outcomes observed in 
the nominal 100-mg Q4W cohort in etrolizumab UC Phase II study, it is appropriate to 
evaluate the 105-mg Q4W dose, the same regimen studied in the UC Phase III trials for 
CD induction therapy.  In addition, given the complex pathophysiology of CD, an 
observed positive exposure-efficacy relationship for vedolizumab treatment despite a full 
receptor saturation in the blood, the available safety coverage and an acceptable safety 
profile of etrolizumab, it is scientifically sound to evaluate a higher dose regimen of 
210 mg (Weeks 0, 2, 4, 8, and 12) to understand the dose-response relationship in 
patients with CD during the Induction Phase.


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3.3.4.2
Rationale for Maintenance Dose Regimen
Patients who respond to etrolizumab treatment in the Induction Phase (see Table 1 for 
definition of CDAI-70 response) will be re-randomized to receive 105 mg etrolizumab or 
placebo Q4W in the Maintenance Phase; patients who respond to placebo in the 
Induction Phase will continue to receive placebo in the Maintenance Phase. 
With the assumption that the PK profiles of mAbs (anti-TNF or anti-integrins) are similar 
in UC and CD patient populations (Ternant et al. 2008; Fasanamde et al. 2009; 
Awni et al. 2013; Feagan et al. 2013; Sandborn et al. 2013), the lower regimen of 
105 mg SC at Q4W is specified in the Maintenance Phase on the basis the following 
considerations:

The 105-mg Q4W SC dose planned for the Phase III study in CD is anticipated (by 
population modeling) to maintain full 7receptor occupancy at all times in 85% of 
patients.  The nominal dose of 100 mg Q4W SC 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).
3.3.5
Rationale for Control Group
A placebo-treated control group will be used in this study to assess the differences in 
efficacy, safety, and tolerability in patients who receive etrolizumab and background CD 
therapy compared with patients who receive placebo and background CD therapy.  The 
use of a control group is necessary given the inherent variability in disease flares and 
the use of subjective assessments, such as the PROs.  Patients in the control group will 
undergo the same study assessments as the etrolizumab-treated patients.  The 1:1 ratio 
for etrolizumab to placebo treated patients is necessary to achieve a statistically 
powered comparison of primary endpoint between these treatment arms.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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3.4
OUTCOME MEASURES
3.4.1
Efficacy Outcome Measures
Table 1 contains definitions for the efficacy outcome measures.
3.4.1.1
Co-Primary Efficacy Outcome Measures
Induction Phase

Clinical remission at Week 14

Endoscopic improvement at Week 14
Maintenance Phase, among patients who achieve CDAI-70 response at Week 14

Clinical remission at Week 66

Endoscopic improvement at Week 66 
3.4.1.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures for the Induction and Maintenance Phases 
are listed below.  
Induction Phase

Clinical remission at Week 6

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 14

Change in CD signs and symptoms from baseline to Week 14 as assessed by the 
CD-PRO/SS measure
Maintenance Phase

Clinical remission at Week 66 among patients who achieved clinical remission at 
Week 14

Corticosteroid-free clinical remission at Week 66 among patients who were 
receiving corticosteroids at baseline

Endoscopic improvement at Week 66 among patients who achieved endoscopic 
improvement at Week 14

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 66 

Durable clinical remission

Corticosteroid-free clinical remission for 24 weeks at Week 66 among patients who 
were receiving corticosteroids at baseline

Change in CD signs and symptoms from baseline to Week 66 as assessed by the 
CD-PRO/SS measure 




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
Incidence of adverse events leading to study drug discontinuation

Incidence of specific laboratory abnormalities

Incidence of malignancies

Incidence of ATAs to etrolizumab
3.4.4
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are:

Etrolizumab serum concentrations at specified timepoints throughout the Induction 
and Maintenance Phases
The PK outcome measures for the PK/PD substudy are:

Observed Cmax after the first and final doses during the Induction Phase

Time to Cmax after the first and final doses during the Induction Phase

Area under the serum concentrationtime curve (AUC) within a dose interval after 
the first and final doses during the Induction Phase

Apparent clearance

Apparent volume of distribution

Elimination half-life
 
 
 
 
 




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
For women who are not postmenopausal (at least 12 months of 
nontherapy-induced amenorrhea) or surgically sterile (e.g., absence of ovaries 
and/or uterus):  agreement to remain abstinent or use a highly effective method of 
contraception (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 for the duration of the study [i.e., during the 
treatment period and for at least 24 weeks after the last dose of study drug] 
see Appendix 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 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 for the partner) and withdrawal are not acceptable 
methods of contraception.

Diagnosis of CD based on clinical, histopathological, and endoscopic evidence 
established 3 months prior to screening visit.
The Medical Monitor should be consulted in cases where CD was established 
at least 6 months prior to screening and a histopathology report is not available. 
The eligibility of the patient will be considered based on the weight of evidence 
supporting diagnosis and excluding other potential diagnoses.

Moderately to severely active disease defined in the Screening Phase by: 
Clinical signs and symptoms resulting in a CDAI score of 220 to 480 
calculated on the day of randomization, requiring a minimum of 4 days of 
e-diary PRO data from the 7 days prior to randomization AND
A mean daily SF score ≥6 OR a mean daily SF > 3 and a mean daily AP 
score > 1 calculated on the day of randomization, requiring a minimum of 
4 days of e-diary PRO data from the 7 days prior to randomization (applicable
to Cohort 3, the pivotal cohort, only) AND
The presence of active inflammation on screening ileocolonoscopy defined as 
a SES-CD of 7 or 4 in cases of isolated ileitis or post-ileocecal resection as 
determined by the central read model

Involvement of ileum and/or colon with at least four colonic segments traversable by 
a pediatric endoscope or three segments (colon and/or ileum) for patients who have 
undergone a bowel resection for CD


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
Meets the following surveillance colonoscopy requirements:  
Surveillance was undertaken at screening or 12 months prior in patients with
colonic disease for >10 years (regardless of any risk factors for bowel cancer).
Surveillance was undertaken at screening or 5 years prior in patients with 
colonic disease for 10 years who have risk factors for bowel cancer. 
(Notelocal colonic surveillance guidelines can be followed if patients have no 
risk factors and colonic disease for 10 years.) 

Have experienced intolerance, refractory disease, or no response (as defined below) 
to at least one of the following therapies within 5 years from screening: 
CS Therapy
Refractory:
Has signs/symptoms of persistently active disease despite a history of at 
least one 4-week induction regimen including a dose equivalent to 
30 mg/day prednisone for 2 weeks if oral or 1 week if IV or 9 mg/day 
oral budesonide
Intolerance to CS therapy:
History including, but not limited to, Cushing’s syndrome, 
osteopenia/osteoporosis, hyperglycemia, insomnia, and infection 
IS Therapy
Refractory: 
Has signs/symptoms of persistently active disease despite a history of at 
least one 12-week regimen of oral AZA (or equivalent) (1.5 mg/kg) or 
6-MP (or equivalent) (0.75 mg/kg) or MTX (15 mg/week)
Intolerance to 6-MP (or equivalent), AZA (or equivalent), or MTX:
History of intolerance to AZA (or equivalent), 6-MP (or equivalent), and/or 
MTX (including, but not limited to, infection, nausea/vomiting, abdominal 
pain, pancreatitis, liver function test abnormalities, lymphopenia, and 
thiopurine methyltransferase genetic polymorphism)
Anti-TNF Therapy
Inadequate primary non-response:
Did not respond (as evidenced by persistent signs/symptoms related to CD 
after receiving 2 induction doses of either infliximab [5 mg/kg] or 
adalimumab [160 mg/80 mg or 80 mg/40 mg] or certolizumab pegol 
[400 mg])
Inadequate secondary non-response:
Initially responded to induction therapy with infliximab (5 mg/kg) or 
adalimumab (40 mg) or certolizumab pegol (400 mg), but experienced 
signs/symptoms related to recurrence of CD during maintenance 


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Intolerance: 
Experienced a significant injection-site reaction, congestive heart failure,
infection, or other condition that precluded continuing use of anti-TNF 
therapy at any time 
Patients who have not previously demonstrated inadequate response or intolerance 
to one or more anti-TNF therapies are eligible to participate in the study provided 
they are intolerant or refractory to corticosteroid or immunosuppressant therapy.
4.1.2
Exclusion Criteria
Patients meeting any of the following criteria will be excluded from study entry.
Exclusion Criteria Related to Gastrointestinal Health

Has undergone subtotal colectomy with ileorectal anastomosis or has undergone
total colectomy

Short-bowel syndrome 

Has an ileostomy or colostomy

Has evidence of fixed stenosis or small-bowel stenosis with prestenotic dilation that 
precludes adequate endoscopic assessment of the bowel

Diagnosis of UC or indeterminate colitis

Suspicion of ischaemic colitis, radiation colitis, or microscopic colitis

Evidence of abdominal or perianal abscess

Sinus tract with evidence for infection (e.g., purulent discharge) in the clinical 
judgment of the investigator.  Fistulas related to Crohn’s disease are not 
exclusionary.

Expected to require surgery to manage CD-related complications during the study

A history or evidence of adenomatous colonic polyps that have not been removed

Past or present disease-related colonic mucosal dysplasia 
Exclusion Criteria Related to Prior or Concomitant Therapy

Any of the following treatments for CD within 8 weeks prior to randomization:
Adalimumab
Certolizumab pegol
Infliximab

Any prior treatment with ustekinumab within 14 weeks prior to randomization

Any prior treatment with etrolizumab or other anti-integrin agents (including 
vedolizumab, natalizumab, and efalizumab) 

Any prior treatment with anti-adhesion molecules (e.g., anti-MAdCAM-1)


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
Prior treatment with T cellor B celldepleting agents (e.g., rituximab, alemtuzumab, 
or visilizumab) within 12 months prior to randomization, with the exception of AZA 
and 6-MP (or equivalent)

Any investigational treatment that included investigational vaccines within 12 weeks 
prior to randomization in the study or five half-lives of the investigational product, 
whichever is greater

History of moderate or severe allergic or anaphylactic/anaphylactoid reactions to 
chimeric, human, or humanized antibodies, fusion proteins, or murine proteins or 
hypersensitivity to etrolizumab (active drug substance) or any of the excipients 
(L-histidine, L-arginine, succinic acid, polysorbate 20)

Treatment with corticosteroid enemas/suppositories and/or topical (rectal) 
5-aminiosalicylate (5-ASA) preparations 2 weeks prior to randomization

Continued tube feeding, defined formula diets, and/or parenteral 
alimentation/nutrition as treatment for CD 3 weeks prior to randomization

Expectation of tube feeding, defined formula diets, and/or parenteral 
alimentation/nutrition as treatment for CD during the study

Any live or attenuated vaccines 4 weeks prior to randomization

Use of IV steroids during screening, with the exception of a single IV steroid dose 
administered in the Emergency Department

Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil 4 weeks prior 
to randomization

Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs).  Prophylactic aspirin 
use up to 325 mg/day is permitted, as is occasional use of NSAIDs for conditions 
such as headache, arthritis, myalgia, and menstrual cramps. 

If receiving oral CSs, patients will be excluded unless the dose is stable at 
20mg/day prednisone or equivalent for 2 weeks immediately prior to 
randomization.

If receiving ongoing treatment with oral 5-ASA, patients will be excluded if the dose 
is not stable for 2 weeks immediately prior to randomization.  

If receiving ongoing treatment with probiotics (e.g., Culturelle, Saccharomyces 
boulardii) or over-the-counter supplements (e.g., N-acetyl glucosamine, curcumin), 
patients will be excluded if the dose is not stable for 2 weeks immediately prior to 
randomization.  

If receiving ongoing treatment with ISs (e.g., 6-MP, AZA, or MTX), patients will be 
excluded if the dose is not stable for 8 weeks immediately prior to randomization.  

If receiving ongoing treatment with antibiotics for the treatment of CD, patients will 
be excluded if the dose is not stable for 2 weeks immediately prior to 
randomization.
Patients may continue to receive ongoing treatment with anti-diarrheals (e.g., loperamide 
or diphenoxylate with atropine), preferably achieving a stable dose for 2 weeks prior to 


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randomization.  However, if the patient and/or the treating physician decides to change 
the dose or course of anti-diarrheals at any time during screening, these patients will be 
allowed to participate in study.
Exclusion Criteria Related to Infection Risk

Congenital or acquired immune deficiency

Patients must undergo screening for HIV and test negative for preliminary and 
confirmatory tests

Positive hepatitis C virus (HCV) antibody test result, unless the patient (1) has 
undetectable HCV RNA levels for 6 months after completing a successful course 
of HCV antiviral treatment and an undetectable HCV RNA at screening or (2) has a 
known history of HCV antibody positivity with history of undetectable HCV RNA and 
undetectable HCV RNA at screening in the absence of history of HCV anti-viral 
treatment

In the screening hepatitis B assessment (which consists of testing for hepatitis B 
surface antigen [HBsAg], hepatitis B core anti-body [HBcAb], and if required, 
hepatitis B virus [HBV] DNA), patients who test positive for HBsAg are excluded 
from the study.  Patients who test positive for HBcAb but negative for HBsAg must 
have a confirmed negative HBV DNA test result to be eligible for the study and will 
be required to undergo periodic monitoring for HBV DNA during the study.

Positive stool test result for ova or parasites or positive stool culture for pathogens 
at time of screening

Evidence of infection with and/or treatment for Clostridium difficile or other intestinal 
pathogen treatment within 8 weeks prior to randomization.

A history of active or latent tuberculosis (TB) confirmed by one of the following 
screening tests:
Positive tuberculin (purified protein derivative-PPD) skin test
Or
Positive QuantiFERONTB Gold test
Patients with a documented history of BCG vaccination must have a negative 
QuantiFERON test result and negative chest radiograph (see below) to be 
eligible. 

Suspicion of active TB on chest radiograph (X-ray, posteroanterior and lateral) taken 
within 3 months of randomization.

History of recurrent opportunistic infections and/or history of severe or disseminated 
viral infections

Any serious opportunistic infections that occurred 6 months prior to screening


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
Any current or recent signs or symptoms (8 weeks before screening) of infection, 
except for the following:
Minor infections (e.g., common cold) that have, in the investigator’s judgment, 
completely resolved prior to randomization
Fungal infections of the nail beds
Oral or vaginal candidiasis that has resolved with or without treatment prior to 
randomization

Any major episode of infection requiring treatment with IV antibiotics 8 weeks prior 
to screening or oral antibiotics 4 weeks prior to screening. Treatment with 
antibiotics as adjunctive therapy for CD in the absence of documented infection is 
not exclusionary.
Exclusion Criteria Related to General Safety

Pregnancy or lactation

Lack of peripheral venous access

Hospitalization (other than for elective reasons) within 4 weeks prior to 
randomization

Inability to comply with study protocol, in the opinion of the investigator

Significant uncontrolled comorbidity such as neurological, cardiac (e.g., moderate to 
severe heart failure New York Heart Association Class III/IV), pulmonary, renal, 
hepatic, endocrine, or GI disorders (other than CD)

Neurological conditions or diseases that may interfere with monitoring for PML

Clinically significant abnormalities on screening neurologic examination

History of demyelinating disease

History of major neurological disorders, including stroke, MS, brain tumor, 
neurodegenerative disease, or poorly controlled epilepsy

History of alcohol, drug, or chemical abuse 6 months prior to screening

Conditions other than CD that could require treatment with 20 mg/day of 
prednisone (or equivalent) during the course of the study

History of cancer, including hematologic malignancy, solid tumors, and carcinoma 
in situ within 5 years before screening
Non-serious basal cell or squamous cell carcinoma of the skin that has been 
excised and is considered cured is not exclusionary.
A history of chronic myelogenous leukemia, hairy cell leukemia, melanoma, 
renal cell carcinoma, or Kaposi sarcoma is exclusionary irrespective of the 
duration of time before screening.

History of cervical smear result at any time that indicated the presence of 
adenocarcinoma in situ (AIS), high-grade squamous intraepithelial lesions (HSIL), or 
cervical intraepithelial neoplasia (CIN) of Grade 1


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
History of organ transplant or cell transplantation

Presence of metal in the body that could a pose hazard during any potential 
scanning in patients for whom a magnetic resonance imaging (MRI) scan is 
considered unsafe
Exclusion Criteria Related to Laboratory Values (at Screening)

Serum creatinine 2 times the upper limit of normal (ULN)

Impaired hepatic function defined by one of the following: 
Serum transaminases 3ULN
Alkaline phosphatase 3ULN
Total bilirubin 2.5ULN (excluding inherited deficiencies such as Gilbert’s 
disease)

Platelet count 100,000/L

Hemoglobin 8 g/dL

Absolute neutrophil count 1500/L

Absolute lymphocyte count 500/L
4.2
METHOD OF TREATMENT ASSIGNMENT, RANDOMIZATION,
AND BLINDING
4.2.1
Induction Phase
Following completion of the screening period and after all patient eligibility requirements 
are confirmed, patients will be randomized to either placebo or etrolizumab low-dose or 
etrolizumab high-dose (Cohort 1 and Cohort 3) or to etrolizumab low-dose or 
etrolizumab high-dose (Cohort 2). 
The randomization in all cohorts will be stratified by concomitant oral CS treatment 
(yes vs. no), concomitant IS treatment (yes vs. no), baseline CDAI 330 (yes vs. no), 
and TNFIR patient status (yes vs. no).  A permuted blocks randomization method will 
be used to obtain an approximately 1:2:2 ratio among the placebo, low-dose etrolizumab, 
and high-dose etrolizumab arms in Cohort 1, an approximately 1:1 ratio between the 
low-dose etrolizumab and high-dose etrolizumab arms in Cohort 2, and an 
approximately 2:3:3 ratio among the placebo, low-dose etrolizumab, and high-dose
etrolizumab arms in Cohort 3.
During the Induction Phase, the interactive voice or Web-based response system (IxRS) 
will make etrolizumab low-dose, etrolizumab high-dose, or placebo study treatment kit 
assignments.  To preserve the blind to study drug assignment in the Induction Phase, all 
patients will receive injections from two separate kits at Weeks 0, 4, 8, and 12.  One kit 
will consist of a 1-mL prefilled syringe with needle safety device (hereafter referred to as 
PFS) with a 0.7-mL injection volume (delivering placebo or 105 mg of etrolizumab), and 
one kit will consist of a 2.25-mL PFS with a 1.4-mL injection volume (delivering placebo 


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or 210 mg of etrolizumab).  Depending on dose assignment, one PFS (patients assigned 
to active drug) or both PFSs (patients assigned to placebo) will contain placebo.  At 
Week 2, all patients will receive a study drug injection from one kit that consists of a 
2.25-mL PFS with a 1.4-mL injection volume (delivering placebo or 210 mg of 
etrolizumab) (see Section 4.3.1).  The PFS will contain placebo for patients in the low-
dose etrolizumab and placebo arms and active drug for patients in the high-dose 
etrolizumab arm.  The placebo and active drug PFSs are filled and packaged to look 
identical (other than the difference in volume for the 1-mL PFS vs. the 2.25-mL PFS).
4.2.2
Maintenance Phase
At Week 16, patients treated with etrolizumab who achieved a CDAI-70 response at 
Week 14 without rescue therapy will undergo a second randomization into the 
Maintenance Phase in a 1:1 ratio to treatment with placebo or etrolizumab 105 mg 
SC Q4W (until n approximately 480, see Section 3.1.3).  The randomization will be 
stratified by CDAI remission at both Weeks 10 and 14 (yes vs. no), induction dose 
regimen (low dose vs. high dose), concomitant oral CS treatment (yes vs. no), and prior 
TNFIR patient (yes vs. no).
Patients who received placebo in either Cohort 1 or 3 and who are eligible for the 
Maintenance Phase will continue to receive blinded placebo during the Maintenance 
Phase to keep the blind and avoid any performance bias from the Induction Phase that 
confounds the Maintenance Phase.
As in the Induction Phase, during the Maintenance Phase, the IxRS will make
etrolizumab low-dose/placebo study treatment kit assignments. One treatment kit will be 
assigned for each visit.  Each kit will consist of a 1-mL PFS with 0.7 mL injection volume
(delivering placebo or 105 mg of etrolizumab).  The placebo and active drug kits are 
filled and packaged to look identical.  Patients performing study drug administration at 
home may receive two or three kits at a time beginning at Week 16 in order to allow 
sufficient supply until their next in-clinic visit.
4.2.3
Blinding/Unblinding
Patients, all study site personnel, and the Sponsor and its agents will be blind to 
treatment assignment throughout the 14-week induction and 52-week maintenance 
treatment periods of the pivotal studies (i.e., blind to the treatment assignments for 
induction Cohort 3, and for the maintenance cohort).  The IxRS service provider and 
personnel responsible for performing PK assays (in order to identify appropriate dilutions 
of PK samples to be analyzed) will be unblinded to patients’ randomized treatment 
assignments.  As described in Section 6, treatment assignment will be unblinded to the 
Sponsor (this does not include representatives of the Sponsor such as Site Monitors) for 
Cohort 1 at the end of the Induction Phase, or earlier, in the event of an optional interim 
analysis as described in Section 6.7. However, patients and all study site personnel will 
remain blinded to individual treatment assignment until after the study is completed (after 


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all patients have either completed the treatment and safety follow-up period or
discontinued early from the study) and the database is locked.  Because of the 
exploratory nature of active-treatment Cohort 2, the Sponsor (including personnel 
performing PK/PD 
 analysis) will not be blinded to dose arm assignments 
to enable performing
 analyses, if required.  These personnel will 
have no involvement in the Sponsor’s oversight of the study conduct.  Patients and all 
study site personnel will remain blinded to individual dose assignment until after the 
study is completed.  The Sponsor, patients, and all study site personnel will remain 
blinded to individual treatment assignments for patients enrolled in the pivotal Cohort 3.
If unblinding is necessary for patient management, the investigator will be able to break 
the treatment code by contacting the IxRS. Treatment codes should not be broken 
except in emergency situations when knowledge of the study drug assignment is critical 
to the clinical management of a patient.  The Investigator must make reasonable 
attempts to first discuss the case with the Sponsor’s representative Medical Monitor 
before breaking the treatment code.  If the investigator wishes to know the identity of the 
study drug for any other reason, he or she must contact the Medical Monitor.  The 
investigator should document and provide an explanation for any premature unblinding 
(e.g., accidental unblinding, unblinding because of a serious adverse event as per 
Health Authority reporting requirements).  The Sponsor Safety Reporting Department 
(independent from the study team) will break the treatment code for all unexpected 
serious adverse events (see Section 5.2.2) considered by the investigator to be related 
to study drug for the purpose of regulatory reporting.  The study team will remain blind to 
study treatment.
4.3
STUDY TREATMENT
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Etrolizumab and Placebo
Etrolizumab will be supplied by the Sponsor as a single-use PFS containing 150 mg/mL 
etrolizumab for SC administration.  To preserve the blind to study drug assignment in the 
Induction Phase, all patients will receive injections from two PFSs at Weeks 0, 4, 8, and 
12:  a 1-mL PFS with a 0.7-mL injection volume (delivering placebo or 105 mg of 
etrolizumab) and a 2.25-mL PFS with a 1.4-mL injection volume (delivering placebo or 
210 mg of etrolizumab).  Depending on dose assignment, one PFS (patients assigned to 
active drug) or both PFSs (patients assigned to placebo) will contain placebo.  At 
Week 2, all patients will receive a study drug injection from a 2.25-mL PFS with a 1.4-mL 
injection volume (delivering placebo or 210 mg of etrolizumab).  The PFS will contain 
placebo for patients in the low-dose etrolizumab and placebo arms and active drug for 
patients in the high-dose etrolizumab arm.  In the Maintenance Phase, patients will 
receive injections from a 1-mL PFS with a 0.7-mL injection volume (delivering placebo or 
105 mg of etrolizumab). 


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Etrolizumab is formulated as 150 mg/mL in 20 mM histidine, 0.2 M arginine succinate, 
and 0.04% (weight/volume) polysorbate 20, pH 5.8.  Each PFS is for single-dose 
parenteral administration and contains no preservatives.
Drug product composition for the placebo is exactly the same as that of active drug 
product without the presence of etrolizumab.
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, 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.  The drug 
label indicates the storage temperature.  PFSs of study medication should be 
refrigerated at 2°C8°C (35.6F46.4F) and protected from excessive light and heat.  
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 
(up to 30C [86F]).  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 for a replacement.
Used PFS with study drug will be stored at room temperature in designated sharps 
containers and returned to the site for disposal per local schedule.
Under no circumstances is the investigator to allow study medication to be used other 
than as directed by the protocol.
Details about the packaging and labeling of the study drug will be provided in the 
protocol supporting documents.
For further details, see the current Investigator's Brochure.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Etrolizumab and Placebo
In the Induction Phase, all patients receive one 0.7-mL injection and one 1.4-mL injection 
with use of a PFS at Weeks 0, 4, 8, 12 and one 1.4-mL injection at Week 2 
(see Appendix 1a).  In the Maintenance Phase, all patients will receive one 0.7-mL 


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injection with use of a PFS Q4W (see Appendix 1b). For the 0.7-mL injection, the device 
includes a 1-mL long glass syringe with a staked-in stainless steel needle (27G ½‘’
thin-wall design).  For the 1.4-mL injection, the device includes a 2.25 mL glass syringe 
with a staked-in stainless steel needle (27G ½” thin-wall design). The PFS is a standard
design, and the device is fitted with a custom-designed plunger rod and an extended 
finger flange.  A part of the needle cap of the PFS may contain natural rubber latex that 
may cause allergic reactions in latex-sensitive individuals.
Study site health care professionals (HCPs) will be trained on the use of the PFS and 
SC administration of study medication into the thigh, abdomen, or upper arm.  Patients 
will in turn be trained in the use of the device by an HCP and an “Instruction for Use” 
leaflet.  In the event that a caregiver will ultimately administer study drug to the patient in 
the home setting, the caregiver is to be trained.  The upper arm site is to be used for 
caregiver and is not a site to be used for patient self-administration of study treatment.
During the Induction Phase, study medication is to be administered under close 
supervision of the HCP in a setting where medications and resuscitation facilities are 
available.  The first two treatments (Week 0 [Day 1] and Week 2) will be administered by 
the HCP and observed by the patient (and/or caregiver).  The subsequent treatments in 
the Induction Phase may be administered by the patient (or caregiver) and observed by 
the HCP in the clinic setting.  Following treatment administrations, patients will be 
monitored for acute hypersensitivity reactions for at least 1 hour 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 will not be eligible to receive open-label etrolizumab in 
Part 1 (OLE) of Study GA29145 and are to enter the 12-week safety follow-up in this 
study, followed by PML monitoring in Part 2 (SM) of Study GA29145.
All adverse events of systemic hypersensitivity reactions or anaphylactoid or anaphylaxis 
reactions (see Appendix 7) 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).
During the Maintenance Phase, patients will have the option to return to the 
investigational site or self-administer/have a caregiver administer their treatments at 
home, upon completion of the training for self-administration and deemed competent by 
the investigator.  Patients and/or the caregiver will be provided with contact information 
for questions related to self-administration between clinic visits.  Competence of the 
patient or caregiver to administer at home will be documented.  Compliance in the home
setting is to be monitored with use of an e-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 shall carry at all 


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times.  These alert cards 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, then the 
patient should administer study medication within a window of 3 days from the 
scheduled dosing date, unless a PK blood draw is planned, in which case the dose must 
be administered within 3 days of the blood draw within 3 days after the visit. 
If necessary, patients or their HCP may choose to continue administration of study 
medication in the clinic.
The recommended injection sites are the front of the middle thighs and the lower part of 
the abdomen below the navel except for the 2 inch area directly around the navel.  It is 
recommended that patients be in a comfortable position to self-administer study drug.  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 cannot administer the injection in their upper arm.  Injections should 
never be given into areas where the skin is not intact or is tender, bruised, red, or hard.  
During Weeks 0, 4, 8, and 12 of the Induction Phase when 2 injections are administered 
(0.7 mL and 1.4 mL), study drug should be injected in two separate injection sites 
(e.g., middle thigh and lower abdomen). Injecting both doses of study drug in the same 
area is not recommended. Site personnel will inspect the injection sites at each clinic 
visit.  Record any injection-site reactions, including those following an injection in the 
home setting (see Section 5.1.1.4), as adverse events.
Guidelines for treatment interruption or discontinuation are provided in Section 4.6.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study, etrolizumab and etrolizumab placebo, are 
provided by the Sponsor.  The study site will acknowledge receipt of IMPs with use of 
the IxRS to confirm the shipment condition and content.  Any damaged shipments will be 
replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.


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4.3.4
Assessment of Compliance
Patient compliance will be assessed by maintaining adequate drug dispensing logs, the 
patient e-diary, and return records.
An e-diary will be provided to patients to record home injections.
Patients will return all unused PFSs in the provided boxes at each visit as a measure of 
drug accountability and patient compliance.  Site personnel will monitor the medication 
records from the e-diary via an online portal.  
Sharps containers for any used PFSs will be provided locally to patients for home usage.  
After home injections, the used syringes must be placed into the sharps containers 
immediately.  The sharps containers should be returned to sites.  Sharps containers will 
be discarded by the site staff at the frequency set by local schedule.
A Drug Dispensing Log must be kept as described in Section 4.3.3.  The investigator is 
responsible for ensuring that study drug is administered in compliance with the protocol.  
Delegation of this task must be clearly documented and approved by the investigator.  
Upon study completion, 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 Monitors, 
unless alternate destruction has been authorized by the Sponsor or required by local or 
institutional regulations (Section 4.3.3).  The investigator's copy of the Drug Return 
Record(s) must accurately document the return of all study drug supplies to Sponsor.
4.3.5
Destruction of the Investigational Medicinal 
Product/Comparator
Any used PFSs will be placed into 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 patient numbers) of IMP(s) destroyed

Quantity of IMP(s) destroyed

Date of destruction

Method of destruction

Name and signature of responsible person who destroyed investigational product(s)
In case of device failure or if there are any issues with the drug, the PFS should not be 
destroyed and instead should be returned to the investigator site in the packaging 
provided for this purpose.  The device is to be sent from the investigator site to the 
appropriate Sponsor clinical trial supplies department for further assessment.


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4.3.6
Reporting of Prefilled Syringe Complaints/Events
For reporting of PFS complaints or events, see Section 5.3.4.
4.3.7
Post-Trial Access to Etrolizumab
For post-trial access to etrolizumab, see Section 4.5.9.
4.4
CONCOMITANT THERAPY
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
4 weeks prior to screening to the study completion/early withdrawal visit.  
Anti-diarrheal medications are permitted if used to manage chronic diarrhea, but every 
attempt should be made to keep the dose/regimen stable.  Any changes in the 
dose/regimen after baseline (Week 0) must be captured by the investigator and/or 
patient. 
Occasional use of NSAIDs or acetaminophen is permitted for pain relief (e.g., in the case 
of headache, arthritis, myalgia, etc.).  Prophylactic aspirin use up to 325 mg/day is also 
permitted.
All medications used must be reported to the investigator and recorded on the 
Concomitant Medications eCRF.
4.4.1
Management of Concomitant Crohn’s Disease Medication 
in the Induction Phase
During the Induction Phase, in all cohorts, concomitant CSs will be maintained at a 
stable dose of 20 mg/day prednisone or equivalent or 6 mg/day oral budesonide.
4.4.2
Management of Immunosuppressants throughout the Study
Patients must remain on stable doses of ISs (e.g., AZA (or equivalent), 6-MP (or 
equivalent), MTX) throughout the study unless dose reduction or discontinuation is 
required because of a toxicity related to the medication.  Generally accepted criteria for 
discontinuation of IS due to toxicity include, but are not limited to, acute pancreatitis, 
severe leukopenia, severe thrombocytopenia, or significant elevations of the liver-
associated enzymes from baseline, especially in the presence of an elevated total 
bilirubin.  The ultimate decision to discontinue IS remains at the discretion of the 
Investigator.


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4.4.3
Management of Concomitant Crohn’s Disease Medication in 
the Maintenance Phase
The CS dose should be tapered starting at Week 14 according to the following schedule:

20 mg/day prednisone (or equivalent):  titrated via dose reduction of 2.5 mg/week 
until discontinuation

6 mg/day oral budesonide:  titrated via dose reduction of 3 mg every 2 weeks until 
discontinuation
For patients who cannot tolerate the dose tapering without recurrence of clinical 
symptoms, the CS dose may be increased but should not exceed the baseline dose 
(i.e., dose at Week 0 of the study), and the dose-tapering regimen should be re-initiated 
within 2 weeks.  
Patients taking concomitant IS therapy (AZA (or equivalent), 6-MP (or equivalent), or 
MTX) must remain on stable doses throughout the study unless dose reduction or 
discontinuation is required because of a toxicity related to the medication.
4.4.4
Permitted Rescue Therapy
4.4.4.1
Rescue Therapy in the Induction Phase
This is defined as medication prescribed for new or worsening CD symptoms and 
includes:

Any new CS or IS therapy for CD

Any increase in dose or regimen of baseline Crohn’s medications
Antibiotics, 5-ASAs, anti-diarrheals, probiotics, herbal/ayurvedic, nutritional and 
homeopathic supplements are not considered as rescue therapies.
Patients requiring rescue therapy during the Induction Phase will be considered 
non-responders for the primary analysis and will not be eligible for the Maintenance 
Phase.  
4.4.4.2
Rescue Therapy in the Maintenance Phase
This is defined as medication prescribed for new or worsening CD symptoms and 
includes: 

Any new CS or IS therapy for CD

Increase in dose of IS therapy above the baseline (Week 0) dose

Increase in the dose of CS therapy above a patient’s baseline (Week 0) dose 
(applicable to patients requiring CS at baseline) 
Antibiotics, 5-ASAs, anti-diarrheals, probiotics, herbal/ayurvedic, nutritional, and
homeopathic supplements are not considered as rescue therapies.  


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4.4.5
Prohibited Therapy
Patients should not be treated for continuing signs and symptoms of CD with any 
medication that is prohibited to be taken concomitantly with etrolizumab; these include,
but are not limited to, anti-integrins, anti-adhesion molecules (e.g., anti-MAdCAM-1),
T- or B-celldepleting agents with the exception of 6-MP and AZA (or equivalent), 
TNF antagonists, antagonists of IL-23 IL-12 (e.g., ustekinumab), anti-metabolites, 
cyclosporine, and tacrolimus.  Any patient treated with a prohibited medication in the 
Induction or Maintenance Phase will be considered a non-responder for the purpose of 
the primary analysis.  These patients must be immediately discontinued from 
etrolizumab; they will not be eligible for Part 1 (OLE) of Study GA29145 and must enter 
the 12-week safety follow-up period.  They will then be asked to enroll in an extended 
PML-monitoring phase (Part 2 [SM] of Study GA29145) for 92 weeks.
CS enemas/suppositories and/or topical (rectal) 5-ASA preparations are also prohibited 
medications. Patients taking these medications will be considered non-responders for 
the purpose of any endoscopic analyses. These treatments must be discontinued, but 
patients may continue to receive etrolizumab and may still be eligible for Part 1 (OLE) of 
Study GA29145.
4.5
STUDY ASSESSMENTS 
The description of the study assessments for the Screening, Induction, and Maintenance 
Phases are described in Sections 4.5.2, and 4.5.3 and the Schedule of Assessments is 
provided in Appendix 1a and Appendix 1b.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled (e.g., screen 
failures, eligible patients who choose not to enroll) will be maintained at the study site.
A separate informed consent is required for patients participating in the optional PK/PD 
substudy.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.


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4.5.2
Screening
The screening period should not exceed 35 calendar days. 
All screening tests and evaluations (see Appendix 1a for screening tests and evaluations 
and Section 4.5.7 for description of test and evaluations) will be performed within 
35 days prior to Day 1 except for the ileocolonoscopy, which should be performed during 
the screening and at least 9 days prior to the date of randomization (see Section 4.5.7.6).  
Laboratory samples should be collected from the patient early in the screening period to 
allow time for the laboratory results to be available for review by the site for eligibility.  
The ECG and chest X-ray can be obtained any time before Day 1 (see Section 4.5.7.9
and Section 4.5.7.15).  All screening evaluations must be completed and reviewed to 
confirm that patients meet all eligibility criteria before Day 1.  The investigator will 
maintain a screening log to record details of all patients screened as described in 
Section 4.5.1.
4.5.2.1
Re-Screening
If a patient does not meet all the eligibility criteria within 35 days after the original 
screening visit, re-screening is permitted.  Patients found to be ineligible for entry into 
the study may be re-screened only once (e.g., if the patient develops additional 
manifestations of CD, a worsening of existing manifestations at a later time, if patient’s 
clinical status has changed such that the abnormal laboratory value may be directly 
affected [e.g., transfusion], or if there is evidence that the central laboratory sample may 
have degraded during transport) with the exception of certain laboratory testing 
(described below).  Each patient must re-consent before re-screening occurs.
Re-screening is not required for the following assessments provided the results are 
available from the initial screening, and the date of the initial screening assessment 
was6 weeks prior to the re-screening randomization visit.

HIV preliminary and confirmatory tests

Hepatitis C virus (HCV) antibody test

Hepatitis B assessment (i.e., surface antigen [HBsAg] core anti-body [HBcAb], and if 
required, hepatitis B virus [HBV] DNA)
If, in the investigator’s judgment, the patient is deemed to have been at risk of any of the 
above infections (based on medical history, or geographical or social circumstance) the 
patient should be re-screened with the above tests. 
Patients who are classified as screen failures due to the presence of C. difficile may be 
re-screened 60 days after the end of successful treatment. Full re-screening will be 
required.
As described in Section 4.5.7.14, if a negative TB screening test result has been 
documented within 3 months before screening, or re-screen, no new test is needed.


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Patients who met the SESCD eligibility criterion during their first screen do not need to
repeat the ileocolonoscopy procedures as long as date of the ileocolonoscopy during the 
initial screening assessment was 4 weeks prior to the scheduled randomization visit 
after re-screen.
Patients who have been hospitalized (other than elective reasons) 5 weeks prior to the 
scheduled randomization visit after re-screen are not eligible for the study.
4.5.3
Study Assessments during Induction and Maintenance
Visits for the Induction and Maintenance Phases should occur within 3 days of the 
specified time, except for CD assessment visits at Weeks 10, 14, 66, and early 
withdrawal (i.e., visits not associated with study drug administration), which may occur 
within 7 days of the specified time.  
During the Induction Phase, all visits take place in the clinic; however, in the 
Maintenance Phase, patients are contacted by telephone (a telephone visit) for the 
purpose of study assessment rather than making a clinic visit for prespecified visits 
(indicated in Appendix 1a and Appendix 1b).  Blood draws for the PK/PD substudy may 
be collected by appropriately qualified personnel in the patient’s home or other suitable 
location away from the clinic.  If samples are not collected at the clinic, samples will be 
sent on the day of collection to a central laboratory for storage until analysis begins.
All assessments are performed on the day of the specified visit, except where a time 
window is specified.  Assessments scheduled on the day of study drug administration 
(e.g., blood draws, pregnancy tests) should be performed prior to dosing, unless 
otherwise noted. 
When study drug administration in the home (or the clinic, if applicable) is required on 
the same day as clinic assessments, drug is to be administered at home after the clinic 
visit. 
4.5.4
Assessments at Study Completion
Patients who complete the treatment phase will be asked to visit the clinic for Week 66
assessments.  The end of study treatment (Week 66 or the early withdrawal from 
treatment visit) is followed by a 12-week Safety Follow-Up Phase (telephone visit at 
Week 6 and clinic visit at Week 12; see Appendix 1a, Appendix 1b, and Appendix 2).  
Patients who are eligible and consent to receive open-label etrolizumab will enroll 
directly into Part 1 (OLE) of Study GA29145 after the Week 66 visit is completed; these 
patients will not enter the 12-week Safety Follow-Up Phase of the study.  Ineligible 
patients or those who choose not to enroll in Part 1 (OLE) of Study GA29145 will be 
asked to enroll in Part 2 (SM) of Study GA29145 for extended PML follow-up after 
completion of the 12-week Safety Follow-Up Phase of the study.


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4.5.5
Early Withdrawal from Study
It is critical to the integrity of this study that patients adhere to the visit schedule outlined 
in the protocol.  As such, every reasonable effort should be made to convey to the 
patients the importance of remaining on the study.  All patients withdrawing from the 
study prior to Week 66 should complete an early withdrawal visit, including those 
patients who are enrolling in Part 1 (OLE) of Study GA29145 at the end of the Induction 
Phase or prior to completion of the Maintenance Phase.  Assessments are specified in 
the Schedule of Assessments in Appendix 1a and Appendix 1b.
The early withdrawal visit should take place 4 weeks (7 days) after the last dose of 
study drug.  Patients who wish to withdraw from the study during the Safety Follow-Up 
Phase should also complete an early withdrawal visit.
4.5.6
Assessments at Unscheduled Visits
An unscheduled visit may occur at any time during the study (i.e., because of relapse of 
disease or an adverse event).  Patients who are seen by the investigator or site staff at a 
time point not required by the protocol should undergo symptom-driven assessments 
(e.g., undergo a PML assessment interview and neurological examination only if patient 
reports symptoms suspected of PML).  
See Appendix 1a and Appendix 1b for assessments that if performed in case of an 
unscheduled visit should be recorded on the eCRF. 
4.5.7
Description of Visit Activities
4.5.7.1
Medical History and Demographic Data
Medical history includes clinically significant diseases, procedures, and all medication 
taken in the 4 weeks prior to screening (including prescription, over-the-counter, and 
herbal/homeopathic remedies and therapies).  A detailed history of medication used for 
CD is required for the 5 years prior to screening. 
Demographic data, including age, sex, whether the patient is a fraternal or identical twin, 
and self-reported race/ethnicity, will be collected during screening.
4.5.7.2
Physical Examinations
A complete physical examination will be performed at screening and should include the 
evaluation of head, eye, ear, nose, and throat, and cardiovascular, dermatological, 
musculoskeletal, respiratory, GI, and neurological systems, including administration of 
the PML Subjective Checklist and the PML Objective Checklist by the investigator 
(see Section 4.5.7.8 for PML assessment details and Appendix 6 for PML algorithm).  
Clinically significant findings from the physical examination should be recorded as 
medical history during screening.


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Symptom-driven physical examinations will be performed at Weeks 14, 24, 32, 44, 56, 
and 66 (or Early Withdrawal Visit).  New or worsened abnormalities from screening 
should be recorded as adverse events, if appropriate.  
 
 
 
 
 
 
 
4.5.7.4
Vital Signs, Height, and Weight
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 at screening and at 
Weeks 0, 4, 8, 12, 16, 24, 32, 44, 56, and 66 (or Early Withdrawal Visit).  Record vital 
signs before study drug administration at clinic visits only.
Height should be measured at screening only.
Weight should be measured during screening and at Weeks 0, 10, 14, 24, 28, 32, 44, 56, 
and 66 (or Early Withdrawal Visit).
4.5.7.5
Crohn’s Disease Activity Assessments
Collect a detailed history of CD, including date of diagnosis, disease severity, 
hospitalizations, and extraintestinal manifestations at screening.
Disease severity will be evaluated using the CDAI, SF, AP, and SESCD.  The CDAI, 
SF, and AP are described in Appendix 9.  The SESCD is assessed 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. 
The CDAI, SF, and AP scores will be calculated at Weeks 0, 10, 14, 24, 28, 32, 44, 56, 
and 66 (or Early Withdrawal Visit). SESCD assessments will take place at screening 
and Weeks 14 and 66 (or Early Withdrawal Visit). 
Abdominal pain will be additionally assessed throughout the study with the Abdominal 
Pain Questionnaire (APQ) recorded daily on an e-diary (see Appendix 11).


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For the Week 14 and 66 visits, the ileocolonoscopy should be scheduled on the day of 
the visit. If this is not possible, the ileocolonoscopy should be performed no later than 
5 days after the visit.  
4.5.7.6
Ileocolonoscopy with Biopsies
The ileocolonoscopy will be performed within the screening period and at least 9 days 
prior to randomization and at Weeks 14 and 66 and/or withdrawal from study 
(Early Withdrawal visit; see Appendix 1a and Appendix 1b).
Patients are to prepare their bowel prior to the ileocolonoscopy procedures.  Medications 
used for bowel preparation should be reported on the concomitant medications pages of 
eCRF.
 
.
A full colonoscopy is required to guard against enrolling patients with colonic carcinoma 
and dysplasia. Depending on a patient’s risk factor for bowel cancer and their last 
surveillance colonoscopy, the surveillance can be done in combination with this 
screening ileocolonoscopy.  Refer to Section 4.1.1 regarding surveillance colonoscopy 
requirements for inclusion into this study.
For each patient, a video recording the entire ileocolonoscopy procedure is performed 
using a recording device issued or recommended by the central read vendor. All video 
recordings will be edited by the central read vendor to produce video clips that are 
representative of each segment of the colon visualized up to the terminal ileum.  The 
video clips will be read centrally for mucosal lesions and endoscopic severity by an 
independent gastroenterologist experienced in IBD who is blind to the patient’s clinical 
activity and treatment allocation.  When scoring the SESCD, please use the worst 
affected portion of each segment.
In all cases, video recordings should be performed prior to biopsy.  Technical 
instructions for making the video recording will be provided separately (these instructions 
will include how to capture the depth of insertion and how to mark bowel segments 
during the recording).
Each patient entered into the study will have biopsy sample collections performed during 
the ileocolonoscopy at Screening, Week 14, and Week 66 as follows:


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At Screening: a total of 9 pairs (18 biopsy samples)

Two pairs of biopsies (4 biopsy samples) taken from an area that is within 2040 cm 
from the anal verge (sigmoid colon) and one pair of biopsies (2 biopsy samples) 
should be taken from the transverse colon.  The three pairs of biopsies should be 
placed in formalin at the sites.
–
If the colon segment is normal, random biopsies should be obtained and
labeled as "non-inflamed" along with the location (i.e., transverse colon, sigmoid 
colon) on the central laboratory requisition form.
–
If the colon segment has macroscopic disease but no discrete lesion 
(e.g., ulcers), the biopsies should be taken from the most severely affected area 
and labeled as "inflamed" along with the location (i.e., transverse colon, sigmoid 
colon) on the central laboratory requisition form.
–
If the colon segment has discrete lesion (e.g., ulcers), the biopsies should be 
taken perpendicular to the edge of the largest lesion present and labeled as 
"inflamed" along with the location (i.e., transverse colon, sigmoid colon) on the 
central laboratory requisition form.  Obtaining biopsies from the base of the 
ulcer should be avoided.

Six pairs of biopsies (12 biopsy samples) preferentially from the inflamed terminal 
ileum or if necessary the inflamed ileocecal valve or another more distal inflamed 
region of the colon.
–
Patients with active disease of the terminal ileum (Montreal location category L1 
or L3; Silverberg et al. 2005) will have biopsies taken of inflamed mucosa from 
this region if it is accessible during endoscopy.  These biopsy samples will be 
identified as ileum samples.
o
Four pairs of biopsies (8 biopsy samples) should be placed in formalin at 
the sites.
o
Each of the remaining two pairs of biopsies (4 biopsy samples) should be 
placed in separate stabilization buffer (RNAlater) and shipped to a central 
laboratory for storage at 80°C.
–
If the terminal ileum is not accessible in patients with L1 or L3 disease, the 
biopsies will be taken either from an inflamed region of the ileocecal valve or 
another more distal inflamed region of colon. These biopsy samples will be 
identified as colonic samples.
o
Four pairs of biopsies (8 biopsy samples) should be placed in formalin at 
the sites.
o
Each of the remaining two pairs of biopsies (4 biopsy samples) should be 
placed in separate stabilization buffer (RNAlater; one pair per tube) and 
shipped to a central laboratory for storage at 80°C.


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At Weeks 14 and 66 (or Early Withdrawal Visit):  a total of 6 pairs (12 biopsy 
samples) at each timepoint

Two pairs of biopsies (4 biopsy samples) taken from an area that is within 20-40 cm 
from the anal verge (sigmoid colon) and one pair of biopsies (2 biopsy samples) 
should be taken from the transverse colon.  The three pairs of biopsies should be 
placed in formalin at the sites.
–
If the colon segment is normal, random biopsies should be obtained and 
labeled as "non-inflamed" along with the location (i.e. transverse colon, sigmoid 
colon) on the central laboratory requisition form.
–
If the colon segment has macroscopic disease but no discrete lesion 
(e.g., ulcers), the biopsies should be taken from the most severely affected area 
and labeled as "inflamed" along with the location (i.e. transverse colon, sigmoid 
colon) on the central laboratory requisition form.
–
If the colon segment has discrete lesion (e.g., ulcers), the biopsies should be 
taken perpendicular to the edge of the largest lesion present and labeled as 
"inflamed" along with the location (i.e. transverse colon, sigmoid colon) on the 
central laboratory requisition form.  Obtaining biopsies from the base of the 
ulcer should be avoided.

Three pairs of biopsies (6 biopsy samples) preferentially from the inflamed terminal 
ileum or if necessary the inflamed ileocecal valve or another more distal inflamed 
region of the colon.
–
Patients with active disease of the terminal ileum (Montreal location category L1 
or L3; Silverberg et al. 2005) will have biopsies taken of inflamed mucosa from 
this region if it is accessible during endoscopy.  These biopsy samples will be 
identified as ileum samples.
o
Two pairs of biopsies (4 biopsy samples) should be placed in formalin at the 
sites.
o
One pair of biopsies (2 biopsy samples) should be placed in a stabilization 
buffer (RNAlater) and shipped to a central laboratory for storage at 80°C.
–
If the terminal ileum is not accessible in patients with L1 or L3 disease, the 
biopsies will be taken either from an inflamed region of the ileocecal valve or 
another more distal inflamed region of colon.  These biopsy samples will be 
identified as colonic samples.
o
Two pairs of biopsies (4 biopsy samples) should be placed in formalin at the 
sites.
o
One pair of biopsies (2 biopsy samples) should be placed in a stabilization 
buffer (RNAlater) and shipped to a central laboratory for storage at 80°C.


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  Samples will be sent to the central 
laboratory to be paraffin embedded and for further storage or distribution (unless 
analysis is to be performed locally, as indicated).
4.5.7.7
Neurological Examination
A neurological examination including assessments of cranial nerves, motor and sensory 
function, coordination, and mental status will be performed by a qualified HCP 
(e.g., investigator, physician assistant, nurse, nurse practitioner; a neurology 
consultation is not required) prior to any other assessment during screening and at 
Weeks 4, 14, 24, 32, 44, 56, and 66 (or Early Withdrawal Visit).
Clinically significant findings from the neurological examination should be recorded as 
medical history during screening, and new clinically significant findings should be 
recorded as adverse events after the first dose of study drug.
4.5.7.8
Progressive Multifocal Leukoencephalopathy Assessment
Study site personnel and patients will be educated regarding the signs and symptoms 
of PML.
Patients will be closely monitored during the course of the study for any new symptoms 
or signs suggestive of PML through regular neurological examinations and 
administration of the PML Subjective Checklist (symptom assessment; see Appendix 5) 
and the PML Objective Checklist (neurologic evaluation; see Appendix 5).  The PML 
assessment should be performed prior to any other assessment along with the 
neurological examination (see Section 4.5.7.7) by a qualified HCP (e.g., investigator, 
physician assistant, nurse, nurse practitioner; a neurology consultation is not required) 
during in-clinic visits at screening and at Weeks 4, 14, 24, 32, 44, 56, and 66 (or Early 
Withdrawal Visit).
A blood sample to test for antibodies to JCV will be taken and stored for possible later 
assessment of how widespread the JCV infection is in the study population.  Sample 
testing for the presence of JCV antibodies is not helpful in predicting risk for PML or for 
evaluating neurologic symptoms.  The sample may be tested if there is a strong belief 
that this information will be helpful in managing a patient's condition.
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 a strong clinical 
suspicion for PML, the event should be reported expeditiously as an adverse event of 
special interest within 24 hours (see Section 5.2.1 and Appendix 6 for the Algorithm for 
Evaluation of PML).  If PML is suspected, dosing with study treatment for that patient 
should be suspended and the patient should be promptly referred to a neurologist to rule 


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out PML.  Following formal evaluation by a neurologist, further work-up may include 
brain MRI performed with and without contrast.  If PML cannot be ruled out, the case will
be referred to an expert PML adjudication committee.  If there remains any suspicion of 
PML, the PML adjudication committee may recommend performing a lumbar puncture 
with cerebrospinal fluid (CSF) analysis for JCV by PCR.  If JCV is detected, the patient 
should be treated as a PML case, permanently discontinued from study drug, and 
transferred to safety follow-up. 
Dosing with study treatments can be resumed only if PML has been ruled out 
(see Appendix 6 for the Algorithm for Evaluation of PML).
After completing the Maintenance Phase, patients not enrolling in Part 1 (OLE) of 
Study GA29145 to receive treatment with open-label etrolizumab will enter the 12-week 
Safety Follow-Up Phase (see Appendix 2).  The PML assessment interview and 
neurologic examination are to be performed at Week 12 of the safety follow-up.
Following the 12-week safety follow-up, all patients will be requested to continue 
monitoring for PML for an additional 92 weeks by enrolling in Part 2 (SM) of 
Study GA29145, giving a total of 2 years PML follow-up after the last dose of study 
medication.  No study drug will be administered to patients during Part 2 (SM).
4.5.7.9
Electrocardiograms
ECGs will be performed during screening or prior to randomization at Week 0, Week 16, 
and Week 66 (or Early Withdrawal Visit).
A 12-lead ECG with formal readings should be obtained for each patient 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.  ECGs should be obtained 
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 to be kept as part of the patient's permanent study 
file at the site.  ECG outputs are to be stored at the site.
4.5.7.10
Patient-Reported Outcomes
PROs (
, APQ and the loose stool frequency, abdominal pain, 
and general well-being components of the CDAI) will be collected to help characterize 
the patient-reported clinical profile of etrolizumab.  The instruments will be translated as 
required into the local language.
PRO data are collected electronically with the use of electronic PRO (ePRO) devices 
(i.e., e-diary and tablet).  The investigator staff will provide the patient with an e-diary 


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and instructions for completing the PRO questionnaires electronically for those PROs 
that need to be completed outside of the clinic.  Patients will also be instructed to contact 
the site promptly if they have any questions about the use of the e-diary during 
screening or at any time during the study.  For instances when PROs are to be 
completed at the clinic, the patient will fill them out on a tablet.
Review electronic data captured by the patient since the previous study visit with the 
patient at each clinic visit.  ePRO data is collected and assessed at visits as outlined 
below and noted in the Schedule of Assessments (see Appendix 1a and Appendix 1b). 
During screening, patients will be instructed on how to appropriately use and complete 
questions on the e-diary.  The signs and symptoms of CD, specifically, number of liquid 
or soft stools, abdominal pain, and general well-being, must be recorded daily 
throughout the study, including the screening period.  
To ensure instrument validity and that data standards meet Health Authority 
requirements, the PROs completed at the sites (
) must be administered 
at the investigational site prior to the completion of other non-PRO assessments and 
before the patient receives any disease-status information or study drug during that visit.  
Crohn’s Disease Activity Index 
The CDAI quantifies the signs and symptoms of patients with CD (see Appendix 9).  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 on the 
e-diary on a daily basis.  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 (Types 6 and 7 on the 
Bristol Stool Scale; see Appendix 8).  Because the ileocolonoscopy preparations can 
interfere with the assessment of other clinical parameters, e-diary entries used to 
calculate the complete CDAI should not correspond to day(s) of bowel preparation, 
endoscopy, or the day after endoscopy.
Stool Frequency and Abdominal Pain
Two patient reported factors will be evaluated:  the frequency of liquid or soft stools and 
abdominal pain.  The score is calculated using the unweighted mean number of 




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4.5.7.11
Study Drug and Compliance
During the Induction Phase, patients will receive placebo, low-dose etrolizumab, or 
high-dose etrolizumab at Weeks 0, 2, 4, 8, and 12.  
During the Maintenance Phase, patients will receive placebo or low-dose etrolizumab at 
Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64.  After completing Week 16, 
patients have the option to return to the investigational site or to self-administer/have a 
caregiver administer their subsequent doses at home within 3 days of their scheduled 
dose unless a PK blood draw is planned (see Appendix 1b and Appendix 3), in which 
case the dose must be administered after the blood draw on the day of visit or within 3 
days after the visit.
If the patient chooses to administer drug at home during the Maintenance Phase, the 
patient is to record the location of each injection and whether the injection was 
successfully administered following each home dose administration.
4.5.7.12
Concomitant Medications
Concomitant medications are monitored beginning at the Screening Phase and reviewed 
at each study visit, including any unscheduled visit(s).
4.5.7.13
Adverse Events
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsy sample collection, discontinuation of medications) should be 
reported.  All adverse events will be monitored beginning at Week 0 and will be reviewed 
at each study visit including any unscheduled visit(s).  See Section 5.2.1 for more details 
about adverse events and safety reporting.
4.5.7.14
Tuberculosis Screening
Patients will be evaluated for TB at screening.  The PPD skin test and 
QuantiFERON-TB Gold are acceptable screening assays for latent Mycobacterium TB 
infection.
If a negative TB screening test result has been documented within 3 months before 
screening, no new test is needed.
A positive PPD tuberculin skin test reaction is considered 5 mm.


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Patients with a history of bacille Calmette-Guérin vaccination should be screened only 
with use of the QuantiFERON-TB Gold test.  
An indeterminate QuantiFERON-TB Gold test should either be repeated or followed up 
with a PPD tuberculin skin test in patients who are eligible to have a PPD tuberculin skin 
test performed.

The patient is considered to have a positive diagnostic test for TB if at least one of 
the following circumstances applies:
Positive QuantiFERON-TB Gold test
Two successive indeterminate QuantiFERON-TB Gold tests
Positive PPD tuberculin skin test

The patient is considered to have a negative diagnostic test for TB if at least one of 
the following circumstances applies:
Negative QuantiFERON-TB Gold test
Negative PPD tuberculin skin test
If a negative TB screening test has been documented within 3 months of screening, no 
new test is needed.
4.5.7.15
Chest X-ray
A chest X-ray will be conducted at screening and used to detect TB.  If a chest X-ray has 
been documented within the previous 3 months and has shown no clinically significant 
abnormalities, no additional chest X-ray is required.
4.5.7.16
Pregnancy Testing
All women of childbearing potential (including those who have had a tubal ligation) will 
have a serum pregnancy test at screening.
Urine pregnancy tests are performed at Weeks 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 
44, 48, 52, 56, 60, and 64 (or Early Withdrawal visit).  A urine pregnancy test is also 
performed at Week 12 (or Early Withdrawal visit) of the 12-Week Safety Follow-up 
Phase. During the period where telephone visits are conducted, patients can take a 
urine pregnancy test at home and report the test result via e-diary.
For a positive urine pregnancy test result, confirm by a serum pregnancy test.
4.5.7.17
Laboratory Assessments
Laboratory assessments are performed at Screening, Induction, and Maintenance as 
indicated on the Schedule of Assessments (see Appendix 1a and Appendix 1b and 
described below). 


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Guidelines for Laboratory Assessments
General Guidelines:

All laboratory investigations will be sent to one or more central laboratories for 
analysis. 

Laboratory sample handling and shipment are outlined in the Study Manual.
Screening Phase Guidelines

All patient laboratory samples required for screening should be collected early in the 
screening period to allow time for laboratory results to be available for review by the 
site for eligibility. 

Patients may be re-screened for laboratory inclusion and exclusion criteria up to two 
times, with the exception of C. difficile infection.  Patients who are classified as 
screen failures because of the presence of C. difficile infection may be re-screened
60 days after successful treatment.  For all other laboratory inclusion and exclusion 
criteria, if a patient fails to meet the criteria a third time, he or she becomes a screen 
failure.

Laboratory testing repeated because of administrative or technical issues 
(e.g., breakage of a sample vial during transit to the central laboratory or 
degradation of a sample during transportation) is not considered re-screening.

Laboratory samples should be drawn prior to the initiation of bowel preparation.

Test results that are borderline or indeterminate may be repeated within the 
Screening Phase.
Induction and Maintenance Phase Guidelines

On days of study drug administration, take laboratory samples before the 
administration of study drug.
Laboratory assessments include the following:
Hematology and Clinical Chemistry

Hematology (hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
absolute differential count [neutrophils, eosinophils, lymphocytes, monocytes, 
basophils, other cells], mean corpuscular volume, mean corpuscular hemoglobin, 
mean corpuscular hemoglobin concentration, and RBC distribution width)
Collected during screening and at Weeks 0, 10 (hematocrit only), 14, 24, 28 
(hematocrit only), 32 (hematocrit only), 44, 56 (hematocrit only), and 66 (or 
Early Withdrawal visit)


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
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 during screening and at Weeks 0, 14, 24, 44, and 66 (or Early 
Withdrawal visit)
 

HIV, hepatitis B, and hepatitis C 
Collected during screening only
Patients who are HBV antibody positive should have HBV DNA measured at 
Weeks 14, 24, 32, 44, 56, and 66.

JCV antibodies
A blood sample to test for antibodies to JCV will be taken and stored for 
possible later assessment of how widespread the JCV infection is in the study 
population.  Sample testing for the presence of JCV antibodies is not helpful in 
predicting risk for PML or for evaluating neurologic symptoms.  The sample 
may be tested if there is a strong belief that this information will be helpful in 
managing a patient's condition.
 
 
 
 
 
 
Anti-Therapeutic Antibody Assessments

Anti-therapeutic antibody (ATA) serum samples will be collected for the detection 
and characterization of antibodies against etrolizumab in all patients.  Samples are 
analyzed using validated assays.  For ATA samples without matched PK 
determinations, etrolizumab concentrations may be measured for the purpose of 
helping interpret ATA data.  
 
. ATA samples are to be collected before dosing at Weeks 0, 4, 14, 24, 
32, 44, 66 (or Early Withdrawal visit), and unscheduled visit.


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Population Pharmacokinetic Assessments

PK serum samples will be collected for determination of etrolizumab concentrations 
and are to be analyzed using a validated assay.  PK serum samples are to be 
collected before dosing (if specified sample collection timepoint is a dosing date) at 
Weeks 0, 10, 14, 16, 24, 28, 32, 44, and 66 (or Early Withdrawal visit).
Optional Whole-Blood DNA 

Whole-blood DNA may be collected and processed for genetic analysis from 
consenting patients at randomization.  These samples may be assayed for mRNA 
expression, genetic variation, and other biomarker(s) to predict response or toxicity 
to etrolizumab.
Optional PK/PD Substudy Assessments

The following samples will be collected only from all patients consenting to 
participate in the PK/PD substudy (see Appendix 3 for additional substudy sampling 
schedule) in addition to the PK/PD samples collected from all patients in the main 
study. 
Receptor Occupancy: Whole-blood samples will be collected during screening, 
Day 1 before dosing, Days 3, 4, or 5 (only one of these days), and at Weeks 4, 
10, 14, 16, 20, 24, 28 (all predose) 
PK serum samples will be collected on Days 3, 4, or 5 (only one of these days), 
Weeks 2, 4, 12 (all predose), Days 3, 4, or 5 post Week 12 dose (only one of 
these days), and predose on Week 20 (or Early Withdrawal visit).
Substudy PD serum samples will be collected at Days 3, 4, or 5 (only one of 
these days) and at predose on Weeks 2, 4, and 20 (or Early Withdrawal visit).
Urinalysis

Collected during screening and at Week 0 (before the first dose of study drug)
Stool Samples
 
 

Collected during screening and at Weeks 14, 66, and early withdrawal prior to the 
prep for the ileocolonoscopy
 
Biopsies

Collected during screening and at Weeks 14 and 66 (see Section 4.5.7.6)


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4.5.7.18
Samples for Roche Clinical Repository
Overview of the Roche Clinical Repository
The Roche Clinical Repository (RCR) is a centrally administered group of facilities for 
the long-term storage of human biologic specimens, including body fluids, solid tissues, 
and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens facilitates the rational design of new pharmaceutical agents 
and the development of diagnostic tests, which may allow for individualized drug therapy 
for patients in the future.
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  In addition, any residual biopsy and blood samples 
for biomarkers left over at the end of the study and analyses will be transferred to the 
RCR for consenting patients.  RCR specimens are used to achieve the following 
objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
Approval by the Institutional Review Board or Ethics Committee
Sampling for the RCR is contingent upon the review and approval of the 
 
research and the RCR portion of the Informed Consent Form by each site's Institutional 
Review Board or Ethics Committee (IRB/EC) and, if applicable, an appropriate 
regulatory body.  If a site has not been granted approval for RCR sampling, this section 
of the protocol will not be applicable at that site.
Sample Collection
Whole blood (DNA) will be collected for genetic analysis from consenting patients (RCR 
ICF).
Samples obtained 
 but not utilized or 
not entirely consumed are to be transferred to the RCR.


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Specimen types include:


 

Ileum/Colon biopsy samples (formalin and stabilization buffer [such as RNAlater or a 
similar buffer]; see for specific collection timepoints)

Stool samples
Potential applications of RCR samples include these samples being assayed for mRNA 
expression, genetic variation, histology, and other biomarker(s) that change or predict 
response or toxicity to etrolizumab.
For all samples, dates of consent should be recorded on the associated RCR page of
the eCRF.  For sampling procedures, storage conditions, and shipment instructions, see 
the Reference Manual or Laboratory Manual.
RCR specimens are destroyed no later than 15 years after the date of final closure of the 
associated clinical database.  The RCR storage period is in accordance with the 
IRB/ECapproved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
The dynamic biomarker specimens are subject to the confidentiality standards described 
in Section 8.4.  The genetic biomarker specimens undergo additional processes to 
ensure confidentiality, as described below.
Confidentiality
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable.
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities and Roche monitors, 
representatives, and collaborators, as appropriate.


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Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators.  The aggregate results of any research conducted using 
RCR specimens will be available in accordance with the effective Roche policy on study 
data publication.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise.
Consent to Participate in the Roche Clinical Repository
A separate signature for consent is required for participation in the RCR.  The 
investigator or authorized designee will explain to each patient the objectives, methods, 
and potential hazards of participation in the RCR.  Patients will be told that they are free 
to refuse to participate and may withdraw their specimens at any time, and for any 
reason, during the storage period.  A separate, specific signature is required to 
document a patient's agreement to provide optional RCR specimens.  Patients who 
decline to participate do not provide a separate signature.
The investigator should document whether the patient has given consent to participate 
by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes with use of the RCR Subject Withdrawal Form 
and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 
from Study GA29144 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
Study GA29144.


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Monitoring and Oversight
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples.
4.5.8
Safety Follow-Up Assessments
Safety follow-up is conducted in this study for a period of 12 weeks after the last dose of 
study drug for patients not enrolling in Part 1 (OLE) of Study GA29145 (see Appendix 2).  
Patients are assessed at 6-week intervals during this period, one assessment by phone 
and one in-person clinic visit.  The visits should be scheduled on the basis of the date of 
the last dose of study drug (i.e., the Week 6 telephone visit should take place 6 weeks 
after the last dose of study drug and the Week 12 in-person clinic visit should take place 
12 weeks after the last dose of study drug).  Adverse events should be followed as 
outlined in Section 5.3.
Following the 12-week safety monitoring period, patients will be asked to enroll in Part 2
(SM) of Study GA29145, where they are monitored for PML for an additional 92 weeks.  
Patients enrolling in Part 2 (SM) for the extended PML monitoring will NOT receive 
treatment with open-label etrolizumab.  During the extended PML follow-up period in
Part 2 (SM), patients will have telephone visits every 6 months to assess for any 
emergence of symptoms and signs of PML.  In total, follow-up for the development of 
any signs or symptoms of PML will be conducted for a period of 2 years after last dose 
of study drug.
Patients who discontinue from the study will be asked to return to the clinic within 
4 weeks (3 days) after the last dose of study drug or last scheduled visit for an early 
withdrawal visit (see Appendix 2).
See for the Schedule of Assessments performed at the study completion/early 
withdrawal from treatment visit.
After the study completion, adverse events should be followed as outlined in 
Sections 5.4 and 5.5.  See Appendix 2 for the schedule of 12-week safety follow-up 
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4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
The investigator has the right to discontinue a patient from study drug or withdraw a 
patient from the study at any time.  In addition, patients have the right to voluntarily 
discontinue study drug or withdraw from the study at any time for any reason.  Reasons 
for discontinuation of study drug or withdrawal from the study may include, but are not 
limited to:

Patient withdrawal of consent at any time

Any medical condition the investigator or Sponsor determines may jeopardize the 
patient’s safety if he or she continues in the study

The investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance, specifically defined as missing scheduled visits or 
non-adherence with background medications
4.6.1.1
Withdrawal from Study
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients will not be followed for any reason after withdrawing 
consent.  Patients who withdraw from the study will not be replaced.
4.6.2
Discontinuation from Study Drug
Patients must discontinue study drug if they experience any of the following:

Pregnancy

Anaphylaxis or other severe hypersensitivity reaction

Develop colonic mucosal dysplasia

Malignancy (with the exception of local, resected basal or squamous cell carcinoma 
of the skin) or cervical Pap test with AIS, HSIL, or CIN of Grade 1

Specific serious infection (see Section 5.1.1.1 for details on serious infection):
Any patient who experiences a de novo or reactivated serious viral infection, 
such as HBV, HCV, HIV, should discontinue study medication.
Any patient who develops life-threatening infections during the study should 
discontinue study medication.

Any medication for rescue outside defined limits of the protocol (see Section 4.4.5)
Patients who discontinue study drug prematurely for the reasons listed above will be 
asked to return to the clinic for an early withdrawal visit, which should take place within 
4 weeks after the last dose (see Section 4.5.4 and Section 4.5.5) and will continue to 
undergo safety follow-up assessments for 12 weeks within this study.  Patients should 
then enroll in Part 2 (SM) of Study GA29145 for 92 weeks of monitoring for PML 
(see Section 4.5.8).  The primary reason for premature study drug discontinuation 


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should be documented on the appropriate eCRF.  Patients who discontinue study drug 
prematurely will not be replaced.
4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the study is placed on hold or if the Sponsor 
decides to discontinue the study or development program.
The Sponsor has the right to replace a site at any time.  Reasons for replacing a site 
may include, but are not limited to:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for this study is designed to ensure patient safety and mitigate potential 
risks. The principles of the safety plan include education of investigators and patients 
regarding all identified and potential safety risks, specific eligibility criteria to screen out 
at-risk patients, monitoring to ensure timely identification and management of a safety 
event, and management strategy such as guidelines for treating an event and for 
withholding or discontinuing study treatment, as appropriate.  These principles are to be 
applied for all safety risks in the clinical program.  
5.1.1
Potential Risks for Etrolizumab
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.


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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.
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.  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, efalizumab, 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 are not eligible 
for this study (see Section 4.1.2).
A blood sample to test for antibodies to JCV will be taken and stored for possible later 
assessment of how widespread the JCV infection is in the study population.  Sample 


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testing for the presence of JCV antibodies is not helpful in predicting risk for PML or for 
evaluating neurologic symptoms.  The sample may be tested if there is a strong belief 
that this information will be helpful in managing a patient's condition.
Study site personnel and patient participants should be educated regarding the signs
and symptoms of PML.  Patients and partners/caregivers should be issued with alert 
cards to remind them of these and to advise them to contact the investigator right away if 
they notice any new or worsening neurological abnormalities.
See Appendix 5 for details of assessments regarding PML.
PML Monitoring
During the study, patients should be closely monitored for any signs and symptoms of 
PML via regular 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 1a).  The PML Subjective Checklist (symptom assessment) and the PML 
Objective Checklist (neurologic evaluation) will be administered (Appendix 5; Worksheet 
for the PML Neurologic Examination).
If a patient has a positive finding on the PML Subjective Checklist that is accompanied 
by a positive finding on the PML Objective Checklist or if there is strong clinical suspicion 
for PML, the event should be expeditiously reported to the sponsor as adverse events of 
special interest or serious adverse events, as appropriate, within 24 hours 
(see Section 5.1.1.1.1 and Appendix 6 for the Algorithm for Evaluation of PML).  
If PML is suspected, dosing with study drug 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 drug can only be resumed in patients where PML has been ruled out.  
Refer to Appendix 6 for the Algorithm for Evaluation of PML.
PML Treatment
There is no known effective treatment for PML.  Plasmapheresis has been employed in 
some patients in an effort to promote clearance of a suspected causative agent 
(Tan et al. 2011).  If an event of PML occurs, subsequent management of PML will be at 
the direction of the consulting neurologist. 


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Additional information for the management of this potential risk is provided in Appendix 5
(Worksheet for the PML Neurologic Examination) and Appendix 6 (Algorithm for the 
Evaluation of PML).
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 because of 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, are not eligible for this study 
(see Section 4.1.2).  
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 
antibody (anti-HBc) and test negative for HBV DNA test are eligible for the study; 
however, these patients must undergo periodic monitoring for HBV DNA during the study.
Patients with active or latent TB (not including patients who have prior vaccination with 
Bacille Calmette-Guerin [BCG]) will be excluded from the study.  Any 
immunosuppressed patient with a strong suspicion of TB exposure and no prior 
vaccination with BCG should be considered at risk for having latent TB infection.
Patients at risk for TB exposure include:

Patients who have household contact with a person with active TB

Patients living in areas with high incidence of TB

Patients who frequently visit areas with high prevalence of active TB

Patients who meet these criteria should be evaluated per local practice to exclude 
latent TB.
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.  


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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.  
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.  
5.1.1.2
Hypersensitivity Reactions
Background
In completed Phase I/II clinical trials of etrolizumab in ulcerative colitis, one serious 
adverse event of hypersensitivity (Grade 2) has been reported.  No anaphylactic, 
anaphylactoid, or severe hypersensitivity reactions were observed; however, 
anaphylaxis and hypersensitivity reactions will be closely monitored during the study.  
Patient Selection
Patients who have a history of moderate or severe allergic or anaphylactic/anaphylactoid 
reactions to chimeric, human, or humanized antibodies, fusion proteins, or murine 
proteins or hypersensitivity to etrolizumab (active drug substance) or any of the 
excipients (L-histidine, L-arginine, succinic acid, polysorbate 20) are not eligible for 
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.  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.  
Patients should be instructed to recognize the symptoms of any anaphylactic, 
anaphylactoid, or hypersensitivity reaction and to contact a HCP or seek immediate care 
in case of any such symptoms.  Patients are to be provided with alert cards to remind 
them and a caregiver or partner of the above.
If the patient develops any systemic hypersensitivity or anaphylactic or anaphylactoid 
reaction, the event should be expeditiously reported to the Sponsor as an adverse event 
of special interest or serious adverse event, as appropriate, within 24 hours.
If a patient has symptoms of anaphylaxis or severe hypersensitivity, the administration of 
etrolizumab must be discontinued permanently. 
Refer to Appendix 7 (Clinical Criteria for Diagnosis Anaphylaxis).


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5.1.1.3
Hepatic Effects
Background
Liver toxicity has been reported with other drugs that target 4 integrins (natalizumab) 
and 47 integrins (vedolizumab).  Therefore, this potential risk is being monitored in all 
etrolizumab studies.  In nonclinical chronic toxicology studies, no abnormalities 
indicating liver toxicity with etrolizumab were observed.  The risk in humans is currently 
unknown.
Patient Selection
Patients with significant liver function test abnormalities should be excluded from the 
etrolizumab clinical studies (see Section 4.1.2).
Education, Monitoring, and Management
Patients should receive guidance on reporting liver problems if they occur.  Liver function 
tests should continue to be monitored according to the schedule of assessments and as 
clinically indicated. Significant hepatic events should be evaluated promptly and 
managed accordingly.
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 
malignancy in this patient population a priori, the trial includes selection criteria and 
additional information to minimize any hypothetical risk. 
Patient Selection
Patients who have a history of cancer within 5 years prior to screening (with the 
exception of local resected basal or squamous cell carcinoma of the skin), including AIS, 
HSIL, or CIN of Grade 1 or colonic dysplasia, are to be excluded from the study. 
Monitoring and Management
Investigators should remain vigilant for signs or symptoms of cancer in scheduled study 
assessments, including those of potential lymphoma.


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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 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 1a, Appendix 1b, 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 within 4 weeks prior randomization are 
not eligible for 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.
5.1.2
Risks Associated with Worsening of Crohn’s Disease
The worsening of CD may result in the use of rescue therapies.  In severe cases, 
worsening of CD may lead to hospitalization or requiring surgery.
At any time during the study, patients who have worsening of their CD will be permitted 
to receive additional therapy with steroids (i.e., IV, oral, or topical).  Addition of or 
increases in doses of immunosuppressants (i.e., AZA, 6-MP, or MTX) will also be 
allowed in the Maintenance Phase if clinically indicated in the opinion of the investigator.
Rescue therapy with anti-TNF agents, cyclosporine, tacrolimus, sirolimus, MMF, 
natalizumab, vedolizumab, efalizumab, rituximab, other lymphocyte depleting agents, or 


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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 therapies are not to receive 
further treatment with etrolizumab.
See Section 4.5.6, Appendix 1a, and Appendix 1b 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 on an ongoing basis.  Members of the iDMC will be external to the Sponsor and 
will follow a charter that outlines the iDMC roles and responsibilities.  The iDMC will 
meet at a minimum every 6 months (frequency adjustable as required) to review 
unblinded safety and study conduct data prepared by an independent data coordinating 
center (IDCC).  If the iDMC deems a risk-benefit assessment necessary, the iDMC may 
also review unblinded efficacy data.  The iDMC may recommend stopping the study 
early for safety reasons.  However, the iDMC may not recommend stopping the trial 
early for positive efficacy or solely for futility.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments 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 5.3.
5.2.1
Adverse Events
According to the International Council for Harmonisation (ICH) guideline for Good 
Clinical Practice, an adverse event is any untoward medical occurrence in a clinical 
investigation subject administered a pharmaceutical product, regardless of causal 
attribution.  An adverse event can 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 5.2.9.9 and 5.2.9.10

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline


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
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)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Fatal (i.e., the adverse event actually causes or leads to death)

Life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.2.9.11)

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 (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] criteria; 
see Section 5.2.7); 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.
The investigator must report serious adverse events to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.3.2 for reporting 
instructions).


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5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.3.2 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 as 
defined by Hy’s law (see Section 5.2.9.7). 

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product. This term 
applies only when a contamination of the study drug is suspected.

Adverse events of special interest specific to etrolizumab:
Systemic hypersensitivity reactions and anaphylactic and anaphylactoid 
reactions (see Section 5.1.1.2 and Sampson’s Criteria in Appendix 7)
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 5 and Section 5.1.1.1.1)
5.2.4
Methods and Timing for Capturing and Assessing 
Safety Parameters
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.3, 5.4, and 5.5. 
The investigator is also responsible for reporting medical device complaints 
(see Section 5.3.4).
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.2.7), and causality (see Section 5.2.8).
5.2.5
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.


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After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsy sample collections, discontinuation of medications) should be 
reported (see Section 5.3.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until the patient completes his or her last study visit (in the Safety 
Follow-Up Phase). After the Safety Follow-Up Phase, the investigator should report any 
serious adverse events that are believed to be related to prior study drug treatment 
(see Section 5.5).  In addition, the Sponsor should be notified if the investigator becomes 
aware of any post-study events of confirmed or suspected PML, regardless of 
relationship to study drug, for up to 2 years after the patient’s last dose of study drug 
(see Section 5.5).
5.2.6
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.2.7
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.


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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 oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.2.8
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration as well as
Table 3.

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 (as 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


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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 rechallenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after first 
dose of study drug).
5.2.9
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF; use of colloquialisms and abbreviations should be 
avoided.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.2.9.1
Injection-Site Reactions
Local cutaneous adverse events that occur at or around the injection site during or within
24 hours following study drug injection should be captured as individual signs (e.g., 
erythema, induration/swelling at injection site) or symptoms (e.g., pain, pruritus at
injection site) rather than a diagnosis of allergic reaction or injection-site reaction.
5.2.9.2
Diagnosis Versus Signs and Symptoms
For adverse events other than injection-site reactions (see Section 5.2.9.1), 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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5.2.9.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are 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 gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent 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.
5.2.9.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, 
between patient evaluation timepoints.  Such events should be recorded only once on 
the Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported. If a persistent adverse event becomes 
more severe, the most extreme severity should be recorded on the Adverse Event eCRF.  
If the event becomes serious, it should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning that the event became serious; see Section 5.3.2 for 
reporting instructions.  The Adverse Event eCRF should be updated by changing the 
event from “non-serious” to “serious,” providing the date that the event became serious 
and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF.
5.2.9.5
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:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)


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
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with 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.  Refer to Section 5.2.9.4.
5.2.9.6
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:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Clinically significant in the investigator’s judgment
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 


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changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.  Refer to Section 5.2.9.4.
5.2.9.7
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 5.2.9.2) 
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 adverse event of special interest 
(see Section 5.3.2).
5.2.9.8
Deaths
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.2.5), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.3.2).  
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
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, "CD progression" should be recorded on 
the Adverse Event eCRF.  
5.2.9.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 


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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").
5.2.9.10
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 CD” or “worsening of CD”).
5.2.9.11
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 5.2.2), except as outlined 
below.  The duration of hospitalization should also be noted on the eCRF.
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease.
The patient has not suffered an adverse event.
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient
care outside of normal outpatient clinic operating hours
5.2.9.12
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 
an adverse event unless it results in untoward medical effects.
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF.




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To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Quintiles and Roche Genentech Medical Emergency List, escalate 
emergency medical calls, provide medical translation service (if necessary), connect the 
investigator with a Quintiles Medical Monitor, and track all calls.  The Emergency 
Medical Call Center Help Desk will be available 24 hours per day, 7 days per week.  A 
primary global contact number and additional back up number for the Help Desk and 
Medical Monitor contact information will be distributed to all investigators (see "Protocol 
Administrative and Contact Information & List of Investigators").
5.3.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.3.2.1
Events That Occur Prior to Study Drug Initiation
After informed consent has been obtained but prior to the initiation of the study drug, 
only serious adverse events caused by a protocol-mandated intervention should be 
reported.  The Serious Adverse Event/Adverse Event of Special Interest Reporting Form 
provided to investigators should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the event), either by 
faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators.
5.3.2.2
Events That Occur after Study Drug Initiation
After initiation of the study drug, all serious adverse events and adverse events of 
special interest will be reported until 12 weeks after the last dose of study drug (i.e., until 
the end of the 12-Week Safety Follow-up Phase).  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, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.
Instructions for reporting post-study adverse events are provided in Section 5.5. 
5.3.3
Reporting Requirements for Pregnancies
5.3.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 24 weeks after the last 
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 


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the form using the fax number or email address provided to investigators. Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.
5.3.3.2
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 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.
5.3.3.3
Abortions
Any therapeutic or spontaneous abortion should be classified as a serious adverse event 
(because the Sponsor considers any such 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 5.3.2).
5.3.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly or birth defect in a child born to a female patient exposed to 
study drug or 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 5.3.2).


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5.3.4
Reporting Requirements for Prefilled Syringe 
Complaints/Events
In this study, the prefilled syringe is considered a medical device. The investigator must 
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 (i.e., no 
more than 24 hours) after learning of the event (refer to the pharmacy manual for further 
details). 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 results in an adverse event to the study patient, the event must be 
reported on the Adverse Event eCRF and submitted through the EDC system. If the 
event is serious, the Adverse Event eCRF must be completed and submitted 
immediately (i.e., no more than 24 hours after learning of the event), as outlined in 
Section 5.3.2.  If the medical device results in an adverse event to an individual other 
than the study patient, the device complaint must be reported on the PD103 form and 
the adverse event must be reported as a spontaneous adverse event to the Sponsor.
5.4
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.4.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, the adverse event outcome should be updated at Study Discontinuation.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.4.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, 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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5.5
POST-STUDY ADVERSE EVENTS
Patients who enter the OLE-SM study (GA29145 Parts 1 and/or 2) should follow the 
adverse event reporting requirements for that study.
Post-study, if the patient does not enter the OLE-SM study (GA29145 Parts 1 and/or 2), 
the Sponsor should be notified if the investigator becomes aware of any serious adverse 
event that occurs after the end of the adverse event reporting period (until 12 weeks 
after the last dose of study drug) if the event is believed to be related to prior study drug 
treatment.  In addition, the Sponsor should be notified if the investigator becomes aware 
of any post-study events of confirmed or suspected PML, regardless of relationship to 
study drug, for up to 2 years after the patient’s last dose of study drug. 
The investigator should report these events directly to Roche or its designee either by 
faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators.
5.6
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events for etrolizumab using the following reference 
document:

Etrolizumab Investigator's Brochure
Within the Investigator’s Brochure, the reference safety information is 
provided in Section 6.4 (Identified Risks and Adverse Drug Reactions 
[Reference Safety Information]).
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study, with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
All serious related (as assessed by the investigator and/or sponsor) adverse events 
occurring in a patient administered etrolizumab at any time during the 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 


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to all health authorities, with the exception of the FDA.  For the FDA, SUSARs will be 
submitted as Investigational New Drug (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
For the purpose of statistical analyses, the Induction and Maintenance Phases will be 
treated as independent studies.
Per the protocol, the planned analysis of induction data for Cohort 1 was performed in 
March 2017 after the last patient in cohort 1 completed 14 weeks of treatment, and prior 
to the commencement of the pivotal induction cohort 3.  The induction data from Cohort 
1 was unblinded and evaluated in an exploratory manner to provide an early assessment 
of efficacy, and is treated as an independent phase II readout.  The analysis provided 
the first data available for etrolizumab in treating Crohn’s disease, and was used to
confirm the statistical assumptions for the pivotal induction cohort (Cohort 3), to confirm 
the re-randomization rates and thus expected sample size for maintenance, and to
inform the development of the Statistical Analysis Plan.  Only a small number of Sponsor 
personnel close to the data analysis were unblinded and have knowledge of patient-level 
treatment assignment for Cohort 1.  All remaining Sponsor personnel (including those 
involved in oversight of study conduct) and sites remain blinded to patient-level 
treatment assignment.  The Sponsor remains blinded to maintenance data for all 
patients in the study (including cohort 1) until the maintenance database is formally 
cleaned, verified, and locked.
The open-label Cohort 2 serves as a feeder cohort to provide sufficient sample size for 
the maintenance analysis. Induction data from Cohort 2 will also be considered 
exploratory and may be analyzed to inform decision making and development of the 
Statistical Analysis Plan.


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6.1
DETERMINATION OF SAMPLE SIZE
6.1.1
Induction Phase
A total of approximately 1150 patients will be randomized into one of three induction 
cohorts.  The sample size of each cohort is summarized in Table 4 and described below.
Table 4
Sample Size for Each Cohort
Cohort
No. of Patients
Total
Placebo
Low-Dose 
(105 mg)
High-Dose 
(210 mg)
Exploratory induction 
cohort 
(Cohort 1)
~300
~60
~120
~120
Active-treatment 
induction cohort
(Cohort 2)
~350
NA
~175
~175
Pivotal induction 
cohort 
(Cohort 3)
~496
~124
~186
~186
NAnot applicable; No.number.
The sample size for Cohort 1 (see Table 4) was determined to provide approximately 90% 
power to detect a 20% difference in PRO2 or CDAI remission rates between each 
etrolizumab arm and placebo (under the assumption of placebo remission rate of 15%, 
similar to results reported in the GEMINI 2 trial of vedolizumab in patients with CD; 
Sandborn et al. 2013) and approximately 80% power to detect a 15% difference versus 
placebo in endoscopic response (under the assumption of placebo response rate of 
10%) and a two-sided 2 test at the 10% significance level.
The pivotal analysis for induction phase will be performed using only patients from 
Cohort 3.  In this pivotal induction cohort, patients will be randomized to receive either 
placebo, etrolizumab 105 mg or etrolizumab 210 mg in a 2:3:3 ratio.  The co-primary 
endpoint will be tested using a CMH test at the 5% significance level, where both clinical 
remission and endoscopy improvement are required to be significant.  The sample size 
for Cohort 3 is expected to provide 85% power to detect a 15% difference in rates of 
clinical remission (SF mean daily score 3 and AP mean daily score 1) between each 
etrolizumab arm and placebo under the assumption of a placebo remission rate of 15% 
and a two-sided test performed at a significance level of 5%.  Additionally, Cohort 3 will 
provide 80% power to detect a 10% difference in proportions for each etrolizumab arm 
versus placebo for endoscopic improvement, under the assumption of placebo response 
rate of 5% and a two-sided test at the 5% significance level. The 2 test was used to 
confirm the power calculations.


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Cohort 2 is sized at approximately 350 patients to achieve a sufficient number of patients 
for the Maintenance Phase analyses. 
6.1.2
Maintenance Phase
A total of approximately 480 patients achieving CDAI-70 response at Week 14 will be 
eligible to enroll into the Maintenance Phase.
A co-primary endpoint will be used for the analysis of the Maintenance Phase: clinical 
remission (SF mean daily score 3 and AP mean daily score 1) and endoscopic 
improvement at Week 66.  The maintenance co-primary analysis will be performed on all 
patients re-randomized into the Maintenance Phase who were randomized to 
etrolizumab (105 mg or 210 mg) in the Induction Phase.  The co-primary endpoint will be 
tested using a CMH test at the 5% significance level, where both clinical remission and 
endoscopy improvement are required to be significant.  Note that to maintain the blind, 
patients randomized to placebo in the Induction Phase will undergo a sham 
randomization and will receive placebo in the Maintenance Phase.  These patients will 
not form part of the pivotal maintenance analysis. 
Of the approximately 480 patients projected to be enrolled in the Maintenance Phase, 
approximately 420 patients will undergo re-randomization to receive either placebo or 
etrolizumab, and approximately 60 patients will undergo a sham randomization to 
placebo.  These projections are based on the assumption that 50% of patients receiving 
etrolizumab and 40% of patients receiving placebo during the Induction Phase will be 
eligible for the Maintenance Phase.
Assuming a maintenance sample size of 210 patients per arm using a 1:1 allocation to 
receive either placebo or etrolizumab 105 mg, the maintenance analyses conducted at 
the 5% significance level will provide the following power:

Clinical remission at Week 66 (SF mean daily score 3 and AP mean daily
score 1):  at least 90% power to detect a 15% treatment difference assuming a 
placebo Week 66 remission rate of up to 20%

Endoscopic improvement: approximately 90% power to detect a 15% treatment 
difference assuming a placebo Week 66 improvement rate of up to 30%
Furthermore, the study is designed to provide sufficient power for the following 
secondary analyses:

Clinical remission at Week 66 among patients achieving clinical remission at 
Week 14:  a sample size of N186 (i.e., 93 per arm) will provide 80% power to 
detect a 20% treatment difference assuming a placebo rate of up to 30%.  This 
assumes a Week 14 clinical remission rate of ≥22% among etrolizumab patients


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Table 5
Power Estimates for Primary and Key Secondary Efficacy 
Analysis in the Pivotal Induction Phase and Maintenance Phase
Study
Endpoint
Power
Assumed Response 
Rates
Sample Size per Group
Induction
Clinical remission ≥85%
Placebo15%
Etrolizumab30%
Placebo124
Etrolizumab 105 mg 186
Etrolizumab 210 mg 186
Endoscopic 
improvement
≥80%
Placebo5%
Etrolizumab15%
Placebo124
Etrolizumab 105 mg186
Etrolizumab 210 mg186
Maintenance
Clinical remission ≥90% a
Placebo≤20%
Etrolizumab≤35%
Placebo210
Etrolizumab 105 mg210
Endoscopic 
improvement
~90% a Placebo ≤30%
Etrolizumab45%
Placebo210
Etrolizumab 105 mg210
All analyses powered using type I error, 5.0%.
a Analysis conducted on all patients in Maintenance Phase who were randomized to 
etrolizumab in the Induction Phase.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients randomized and re-randomized will be tabulated by study site 
and treatment arm.  Patient disposition (the number of patients randomized, treated, and 
completing each study period) will be tabulated by treatment arm.  Reasons for 
premature study drug discontinuation or withdrawal from study, any eligibility criteria 
deviations, and other major protocol deviations will be summarized by treatment arm.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics such as age, sex, race, region, use of
corticosteroids and immunosuppressants, anti-TNF therapy, duration of disease, extent 
of disease, average daily SF, average daily AP, CDAI, SES-CD, 
 and 
 will be summarized for all randomized patients by treatment arm with use of 
descriptive statistics for both the Induction and Maintenance Phases.  Exposure to study 
drug (number of study treatments and duration of treatment) will be summarized by 
treatment arm.
6.4
EFFICACY ANALYSES
For the purpose of statistical analyses, the Induction and Maintenance Phases will be 
treated as independent studies.
Patients who are non-evaluable for efficacy at a specific time point, because of missing 
data, will be considered non-responders for all categorical endpoints.  In addition, 
patients requiring rescue therapy, and/or surgical intervention for CD, and/or took 
prohibited medications (see Section 4.4.5), will be considered non-responders for the 


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analysis.  Non-responder definitions will be further detailed and finalized in the Statistical 
Analysis Plan for the study.
In addition to the analyses described in Section 6.4.1 and Section 6.4.2, the following 
analyses will be performed for the co-primary efficacy endpoint and key secondary 
efficacy endpoints. Details of these analyses will be described in the SAP:

Subgroup analyses to evaluate the consistency of results across prespecified 
subgroups (including baseline antiTNF-status, baseline CS status, baseline IS 
status, age, sex, 
, Region

Sensitivity analyses to evaluate the robustness of results to the primary analysis 
methods (e.g., handling of dropouts, adjusting for cohort)
6.4.1
Induction Phase
Efficacy analyses for the Induction Phase will be performed separately for each cohort, 
and will include all patients who were randomized and received at least one dose of 
study drug (modified intent-to-treat population [mITT]).  Patients will be grouped 
according to the treatment assigned at randomization.
6.4.1.1
Cohort 1
An exploratory analysis was conducted when all patients in Cohort 1 (n = 300) 
completed the Week 14 visit or, discontinued early from the study.  At this point, the 
Sponsor was unblinded to patient level data and treatment assignments for patients in 
Cohort 1 Induction Phase only.  Patients, site monitors, and investigators remain blinded
to patient-specific treatment assignments.  The induction data from Cohort 1 was 
exploratory in nature and was evaluated prior to the commencement of enrollment to the 
pivotal Induction Phase of Cohort 3.  Maintenance phase data from Cohort 1 patients will 
form part of the pivotal maintenance phase analysis and remains blinded to all Sponsor 
personnel and sites until the database lock.
6.4.1.2
Cohort 2
Cohort 2 is considered a “feeder” cohort to help achieve the necessary sample size for 
the maintenance study.  All primary and secondary efficacy parameters will be 
summarized descriptively for each treatment arm.  Demographic and baseline 
characteristics such as age, sex, race, region, use of corticosteroids and 
immunosuppressants, duration of disease, and CD activity scores will be summarized for 
each treatment group by use of descriptive statistics.
6.4.1.3
Cohort 3
The co-primary endpoint analysis will compare for each etrolizumab dose arm versus the 
placebo arm the proportion of patients who achieve clinical remission or endoscopic 
improvement at Week 14.


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The difference between each etrolizumab arm and placebo arm will be evaluated using 
the CMH test statistic stratified by the factors used at randomization.  The absolute 
treatment difference will be provided along with the 95% two-sided CI estimate.
All categorical secondary endpoints will be analyzed using the same methodology as the 
primary endpoint.  For all efficacy endpoints, descriptive summary statistics will be 
provided for each treatment arm.
Continuous endpoints will be analyzed using an ANCOVA model with the stratification 
variables used at randomization and the baseline value of the studied measure as a 
covariate.
The co-primary endpoints will each be tested at the 5% significance level, with both 
required to be significant for the co-primary endpoints to be deemed significant.  The 
overall type I error rate will be maintained at 5% using a hierarchical model for testing of 
the two etrolizumab doses versus placebo and corresponding key secondary endpoints.  
The hierarchical model specifications will be detailed in the Statistical Analysis Plan 
before unblinding.  The remaining secondary endpoints 
 will 
be considered to provide supportive information and no adjustments for multiple
comparisons will be performed.
6.4.2
Maintenance Phase
Efficacy analyses for the Maintenance Phase will include all etrolizumab induction 
patients who were randomized into the Maintenance Phase and received at least one 
dose of study drug (mITT population).  Patients will be grouped according to the 
treatment assigned at randomization into the Maintenance Phase.
For all categorical endpoints, the difference in proportions between the two treatment 
arms will be evaluated using the CMH test.  The CMH test will include important 
stratification factors such as those used to randomize patients into the Maintenance 
Phase.  The stratification factors used for re-randomization into the maintenance phase 
include sustained CDAI remission at Weeks 10 and 14.  As a result of the changes to 
endpoints introduced in Protocol Version 6, this stratification factor in the analysis will be 
replaced with clinical remission at Week 14 for the clinical remission at Week 66 
analysis, and endoscopic improvement at Week 14 for the endoscopic improvement at 
Week 66 analysis.  A sensitivity analysis will be conducted to include the sustained CDAI 
stratification factor used at randomization.  The test will be performed at the two-sided 
5% significance level.  The absolute treatment difference will be provided along with the 
95% two-sided CI estimate.  All categorical secondary endpoints will be analyzed using 
the same methodology as for the primary endpoint. 
Continuous endpoints will be analyzed using an ANCOVA model with the stratification 
variables used at randomization and the baseline value of the studied measure as a 
covariate.


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If the primary endpoint is statistically significant, key secondary endpoints will be tested 
sequentially.  Details will be specified in the Statistical Analysis Plan before unblinding.
Patients who are non-evaluable for efficacy at a specific timepoint (e.g., because of 
missing data or early enrollment into Part 1 [OLE] of Study GA29145) will be considered 
non-responders for all categorical endpoints.  
6.4.3
Co-Primary Efficacy Endpoints
Induction Phase

Proportion of patients in clinical remission at Week 14

Proportion of patients achieving endoscopic improvement at Week 14
Maintenance Phase, among patients who achieve CDAI-70 response at Week 14

Proportion of patients in clinical remission at Week 66

Proportion of patients achieving endoscopic improvement at Week 66 
6.4.4
Secondary Efficacy Endpoints
The secondary endpoints are as follows:
Induction Phase 

Proportion of patients who achieve clinical remission at Week 6

Proportion of patients who achieve 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 14

Changes from baseline to Week 14 in CD-PRO/SS score
Maintenance Phase 

Proportion of patients in clinical remission at Week 66 among patients who achieve 
clinical remission at Week 14

Proportion of patients who achieve corticosteroid-free clinical remission at Week 66 
among patients who were receiving corticosteroids at baseline

Proportion of patients who maintain endoscopic improvement at Week 66 among 
patients achieving endoscopic improvement at Week 14

Proportion of patients achieving 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 66 

Proportion of patients achieving durable remission 

Proportion of patients achieving corticosteroid-free clinical remission for 24 weeks at 
Week 66 among patients who were receiving corticosteroids at baseline

Change from baseline to Week 66 in CD-PRO/SS score




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existing condition on or after the first dose of study drug.  In addition, separate 
summaries will be generated for serious adverse events, deaths, and adverse events 
leading to discontinuation of study drug.
Analyses will also be performed for:

Systemic hypersensitivity events
Specific analyses will be performed for anaphylactic reactions.

Serious infections
The frequency of serious infections, in particular GI infections, will be 
summarized for each treatment arm.

Opportunistic infections
The occurrence of opportunistic infections will be summarized for each 
treatment arm.

Malignancies
Events of malignancy will also be summarized for each treatment arm.

Injection-site reactions
The frequency of injection-site reactions will be summarized for each treatment 
arm.

Surgery for CD
The time to onset of surgery for CD complications will be summarized for each 
treatment arm. 
6.5.2
Laboratory Tests
Descriptive summaries of laboratory values at baseline and throughout the study will be 
tabulated by treatment arm.  For selected parameters, changes from baseline and the 
proportion of patients experiencing clinically significant changes relative to baseline will 
be summarized by treatment arm.
The number and percentage of patients with positive serum antibodies to etrolizumab at 
baseline and during the study will be tabulated by treatment arm.
6.6
PHARMACOKINETIC, PHARMACODYNAMIC,
 
 ANALYSES
Serum concentration at various specified timepoints during the Induction and 
Maintenance Phases will be listed and summarized by descriptive summary statistics 
including means, geometric means, ranges, standard deviations, and coefficients of 
variation.  Individual and mean concentration-versus-time data will be tabulated and 
plotted.


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All drug concentration data collected from this study will be included in a modelbased 
analysis that uses a non-linear mixed effect modelbased approach to further 
characterize the PK and relevant influential factors.  The modelbased analysis will be 
reported separately from the main clinical study report.
 
 
 
6.7
OPTIONAL INTERIM ANALYSIS
The Sponsor may choose to conduct an interim analysis.  The interim analysis will 
involve unblinding of treatment assignments to the Sponsor for purposes of data 
analysis and interpretation. Patients and all study site personnel will remain blind to 
individual patient-level treatment assignments until completion of the trials.  The interim 
analysis will be performed and interpreted by members of the Sponsor study team and 
appropriate senior management personnel, who will be unblinded at the treatment group 
level.
The decision to conduct an optional interim analysis and the timing of the analysis will be 
documented in the Sponsor’s trial master file prior to the conduct of the interim analysis.  
Access to treatment assignment information will follow the Sponsor’s standard 
procedures.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor, CRO, and Data Management vendor will be responsible for data 
management of this study, including quality checking of the data.  Sites will be 
responsible for data entry into the EDC system with use of eCRFs.  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 a data quality plan that will describe the quality 
checking to be performed on the data.  eCRFs and correction documentation will be 
maintained in the EDC system’s audit trail. 
Central laboratory data will be transferred directly to the Sponsor, with use of the 
Sponsor’s standard procedures to handle and process the electronic transfer of these 
data.


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7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and have access to Help Text in the Medidata RAVE system for appropriate 
eCRF completion.  eCRFs will be submitted electronically to the Sponsor and should be 
handled in accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
Patient-reported data will be collected using an electronic devices provided by an ePRO 
vendor.  The devices (i.e., e-diary and tablet) are designed for entry of data in a way that 
is attributable, secure, and accurate, in compliance with FDA regulations for electronic 
records (21 CFR Part 11).  The ePRO device data 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.  System backups for data stored by the Sponsor 
and records retention for the study data will be consistent with the Sponsor’s standard 
procedures.  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 investigator will receive patient data for the site in 
both human- and machine-readable formats on an archival-quality compact disc that 
must be kept with the study records as source data.  Acknowledgement of receipt of the 
compact disc is required.  In addition, the Sponsor will receive all patient data in a 
machine-readable format on a compact disc.
Details regarding patient-reported data and the electronic devices are available in the 
Study Reference Manual.  System backups for data stored by the Sponsor and records 
retention for the study data will be consistent with the Sponsor’s standard procedures.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 


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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, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study 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, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results and medication inventory records must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.


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8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the International Council for
Harmonisation (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 an IND will comply with FDA regulations and applicable 
local, state, and federal laws.  Studies conducted in the European Union or European 
Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "consent forms") before IRB/EC submission.  
The final IRB/ECapproved consent forms must be provided to the Sponsor for health 
authority submission purposes according to local requirements.
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a patient's agreement to allow 
any remaining specimens to be used for exploratory research.  Patients who decline to 
participate will not provide a separate signature.
The consent forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The consent forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved consent forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the consent forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 


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


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Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient last visit).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including 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 


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permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial is sponsored by F. HoffmannLa Roche Ltd.  Approximately 500 global 
investigator sites will participate in this study to enroll approximately 1150 patients.
A contract research organization will be contracted to manage the study and perform 
monitoring activities.
Centralized facilities (vendors) will be used to collect PRO data and endoscopy reading 
and interpretation; however, the investigator or a designee will also read the endoscopy 
if required for clinically indicated safety reasons.
A central laboratory (i.e., Roche or a vendor) will be used for most laboratory 
assessments, including possible histologic grading of biopsies as per the laboratory 
manual.  A selected group of assessments will be performed on site or by a local 
laboratory.
The eCRF data will be recorded via a Sponsor-designated EDC system.  An IxRS will be 
used for study drug inventory management and to randomize patients to study drug.
An iDMC will be established to perform regular review of the safety data to ensure the 
ongoing safety of participating patients.  Members of the iDMC will be external to the 
Sponsor and will follow a charter that outlines the iDMC roles and responsibilities. The 
iDMC will meet approximately every 6 months (frequency adjustable as required) to 
review unblinded safety and study conduct data prepared by an independent data 
coordinating center (iDCC).  If the iDMC deems a benefitrisk assessment necessary, 
the iDMC may also review unblinded efficacy data.  The iDMC may recommend stopping 
the study early for safety reasons.  However, the iDMC may not recommend stopping 
the trial early for positive efficacy or solely for futility.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 


Etrolizumab—F. Hoffmann-La Roche Ltd
136/Protocol GA29144, Version 7
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
 data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission.  This allows the Sponsor to protect proprietary information and to provide 
comments on the basis of information from other studies that may not yet be available to 
the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


Etrolizumab—F. Hoffmann-La Roche Ltd
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10.
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Appendix 1a
Schedule of Assessments:  Screening and Induction Phase
Assessment 
Category
Assessments
Screening Day a
35 to 1
Study Week (3 days for Weeks 2, 4, 8, 
and 12; 7 days for Weeks 10 and 14)
UV c
Early WD
(7 days)
0 b
2
4
8
10
12
14
Screening only 
Assessments
Informed consent
x
Demographic data
x
Height
x
Medical History
x
Chest x-ray d
x
TB screen e
x
Hepatitis C serology
x
HIV test
x
Plasma sample (Storage for
JCV antibody testing) 1
x
Study Drug
Initial randomization
x
Study drug administration f
x
x
x
x
x


Appendix 1a
Schedule of Assessments:  Screening and Induction Phase (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
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Assessment 
Category
Assessments
Screening Day a
35 to 1
Study Week (3 days for Weeks 2, 4, 8, 
and 12; 7 days for Weeks 10 and 14)
UV c
Early WD
(7 days)
0 b
2
4
8
10
12
14
Assessments at 
Screening and 
Induction
Review eligibility criteria
x
x g
Concomitant medications
x
x
x
x
x
x
x
x
x
x
Adverse events h
x
x
x
x
x
x
x
x
x
x
e-Diary check i
x
x
x
x
x
x
x
x
x
x
Pregnancy test j
x
x g
x
x
x
x
x
CDAI assessment
x
x k
x
x
x
x l
Weight
x
x
x
x
x
x
PML assessment interview m
x
x
x
x
x
Neurological examination m
x
x
x
x
x
Vital signs (BP and pulse)
x
x g
x
x
x
x
Physical examination n
x
x
x
Fistula examination o
x
x
x
ECG
x
x p
x
q
x
x
x
 q
x
x
Stool sample 
x r, s
x s
x s, t
Ileocolonoscopy u
x
x
x
x t, v
Ileum/colon biopsies 
(formalin) 
x w
x x
x t, v, x
Ileum/colon biopsies 
(RNAlater)
x w
x x
x t, v, x




Appendix 1a
Schedule of Assessments:  Screening and Induction Phase (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
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a All assessments must be performed after obtaining informed consent.
b Day 1 of Week 0. Visit window of 3 days does not apply.
c An unscheduled visit is required for an adverse event, serious adverse event or can be undertaken to evaluate a patient for ongoing 
signs and symptoms of CD that potentially require rescue therapy, or can be used to evaluate potential clinical relapse.  All the listed 
assessments do NOT have to be performed at an unscheduled visit; assessments should be symptom-driven (e.g., perform PML 
assessment interview and neurological examination only if patient reports symptoms suspected of PML).  Assessments 
corresponding to items noted in this column should be recorded on the eCRF.
d Not required if normal chest X–ray result within 3 months prior to screening.
e The following tests are acceptable screening assays for latent TB in this study:  PPD (a tuberculin skin test reaction; e.g., Mantoux 
test), INF-based test (e.g., QuantiFERON-TB Gold).  Only one of these screening assays is required. 
f
All patients will receive one 0.7-mL injection and one 1.4-mL injection of Weeks 0, 4, 8, and 12. On Week 2, all patients will receive 
one 1.4-mL injection. 
g Perform prior to randomization.
h After informed consent has been obtained but prior to the initiation of study drug, only serious adverse events cause by a protocol-
mandated intervention (e.g., invasive procedure such as biopsy sample collections, discontinuation of medications) should be 
reported. After initiation of study drug, all adverse events, regardless of relationship to study drug, will be reported until the patient 
completes his or her last visit.
i
Patients are to complete the e-diary daily for frequency of loose/liquid stools, abdominal pain (including the APQ), and general well-
being.  Patients will complete the CDPRO/SS measure for at least 9 consecutive days around each visit as programmed in the e-
diary. In order to allow for the visit window to account for early or delayed visits, patients may complete the CDPRO/SS up to 12 
days, except for the Week 0 visit in which patients are to complete the CD-PRO/SS on a daily basis for the 9 days before the 
Week 0 visit.
j
Serum screening test for all females except those who are 1-year postmenopausal or surgically sterile; perform a urine test at 
other visits.  If urine test result is positive, perform confirmatory serum test. Patients must be instructed at screening and reminded 
throughout the study that in case of positive pregnancy test result they must call the site immediately.  Do not administer etrolizumab 
unless the serum test result is negative.
k The patient will complete the PRO components of the CDAI on the e-diary daily during the screening phase. The blood draw for the 
hematocrit component can occur at any time during screening and the screening hematocrit value will be used for the Week 0 CDAI 
calculation. The physician assessment components of the CDAI score will be assessed at the Week 0 visit. The CDAI score for 
eligibility will be calculated at the Week 0 visit prior to randomization.




Appendix 1a
Schedule of Assessments:  Screening and Induction Phase (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
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z Enrolled patients who are HBV core antibody positive should have HBV DNA measured at Week 14.
cc At all timepoints indicated and whenever serum sickness or a clinically significant allergic drug reaction is suspected.  
 
1 A blood sample to test for antibodies to JCV will be taken and stored for possible later assessment of how widespread the JCV 
infection is in the study population.  Sample testing for the presence of JCV antibodies is not helpful in predicting risk for PML or for 
evaluating neurologic symptoms.  The sample may be tested if there is a strong belief that this information will be helpful in 
managing a patient's condition.










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Appendix 2 Schedule of Assessments for 12-Week Safety 
Follow-Up
Assessment
Week (3 days)
Unscheduled 
Visit c
6 a
12/Early Withdrawal b
PML assessment interview d
x
x e
Neurological examination d
x
x e
Anti-therapeutic antibody sample (serum) f
x
Urine pregnancy test g
x
Medication changes
x
x
x
Adverse events
x
x
x
ATAanti-therapeutic antibody sample; PMLprogressive multifocal leukoencephalopathy.
a Week 6 study assessments are to be made by telephone visit and not by clinic visit.
b Denotes early withdrawal visit from safety follow-up period.
c Unscheduled visit for safety monitoring.
d Administer before other assessments.
e If clinically indicated.
f
At all timepoints indicated and whenever serum sickness is expected.  
 
g Urine pregnancy test.  If urine test is positive, perform confirmatory serum test.


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Appendix 3 Schedule of Assessments: All Optional PK/PD Substudy Samples
Assessments
Screening 
Day a
35 to 1
Study Week (3 days)
Unscheduled 
Visit
Early 
Withdrawal
0 b
2 4 8 10
12
14
16
20 c 24
28
32 36 c
40 c 44 48 c 52c 56 60c
64c
66
Substudy PK 
sample d, e  
(Serum)
x f
Baseline 
not 
required. 
Sample to 
be taken 
on one of 
Days 3/4/5
post-visit
x x
x e, f 
At visit 
AND 
one of 
Days 
3/4/5 
post 
visit
x
x
Substudy PD 
sample d, e  
(whole blood, 
FACS tube)
x
x f 
Baseline 
AND one 
of Days 
3/4/5 post 
visit
x
x
x
x
x
x
x
Substudy PD 
sample d, e
(serum)
x f 
Baseline 
not 
required. 
Sample to 
be taken 
on one of 
Days 3/4/5
post-visit
x x
x
x


Appendix 3 Schedule of Assessments:  All Optional PK/PD Substudy Samples
(cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
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FACSfluorescence-activated cell sorting; PDpharmacodynamics; PKpharmacokinetic.
These samples are to be collected only in those patients who consent for the PK/PD substudy, in addition to the samples collected for the main 
study (see Appendix 1). 
Samples for PK/PD sub-study will be collected in approximately 150 evaluable patients participating in the PK/PD substudy (see footnote f, 
below)
a All assessments must be performed after obtaining informed consent.  
b Day 1 of Week 0.
c Telephone visit:  Blood draws may be collected by appropriately qualified personnel in the patient’s home or other suitable location away from 
the clinic. If samples are not collected at the clinic, samples will be sent on the day of collection to a central laboratory for storage until 
analysis begins.
d Only for patients who consent to participate in PK/PD substudy. 
e Samples are to be collected prior to dose administration (if specified sample collection timepoint is a dosing date.
f
For patients participating in the PK/PD substudy, an additional blood draw will be required; this can take place 3, 4, or 5 days after the 
baseline visit with the first dose and after the dose on Week 12 visit.  The additional blood draws should be collected by appropriately 
qualified personnel in the patient’s home or other suitable location away from the clinic.  If samples are not collected at the clinic, samples 
should be sent on the day of collection to a central laboratory for storage until analysis begins.


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Appendix 4 Childbearing Potential, Pregnancy Testing, and 
Contraception
All women of childbearing potential (including those who have had a tubal ligation) will 
have a serum pregnancy test at screening and a urine pregnancy test prior to 
administration of study drug at subsequent visits.  If a urine pregnancy test result is 
positive, study drug will not be administered until pregnancy is ruled out.  The result 
must be confirmed by a serum pregnancy test (conducted by the central laboratory).  
Refer to Section 5.3.3 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 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.
Examples of highly effective contraception include the following:

Combined oral contraceptive pill

Contraceptive transdermal patch

Intrauterine device

Implants for contraception

Injections for contraception (with prolonged release)

Hormonal vaginal device

Sterilization, surgical tubal ligation

Sole sexual partner consisting of surgically sterilized male partner with appropriate 
postsurgical verification of the absence of spermatozoa in the ejaculate

Double-barrier methods:  condom and occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository (Note:  a female condom 
and male condom should not be used together because friction between the two 
can result in either product failing)
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:


Appendix 4 Childbearing Potential, Pregnancy Testing, and 
Contraception (cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
156/Protocol GA29144, Version 7
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 12 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


Etrolizumab—F. Hoffmann-La Roche Ltd
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Appendix 5 Worksheet for the PML Neurologic Examination
PML SUBJECTIVE AND OBJECTIVE CHECKLISTS OF NEUROLOGIC
ASSESSMENTS TO MONITOR FOR PROGRESSIVE MULTIFOCAL
LEUKOENCEPHALOPATHY (PML) IN THE ETROLIZUMAB PHASE III STUDIES
PML usually manifests with subacute, progressive neurologic deficits including:
Neurologic Domain
Signs/Symptoms
Relevant PML
Subjective/Objective
Checklist Question
Altered mental status
Can encompass a variety of presenting signs
and symptoms including cognitive changes
(confusion, difficulty concentrating, memory loss) 
and altered behavior (including personality
changes)
Q2, Q5, Q6
Higher cortical dysfunction
Impaired comprehension and/or formulation of
language (aphasia), loss of ability to recognize
objects, persons, sounds, shapes, or smells
(agnosia)
Q2, Q5, Q6
Visual changes
Loss of visual fields (homonymous 
hemianopsia), double vision (diplopia)
Q1
Motor deficits
Weakness (hemiparesis or monoparesis), 
seizures (generalized or partial), difficulties with
speech (dysarthria) or swallowing (dysphagia)
Q2, Q3
Sensory deficits
Sensory loss (i.e. paresthesias)
Q7
Coordination
Difficulty walking and maintaining balance 
(ataxia), lack of voluntary coordination of limb
movement (limb ataxia)
Q4
To monitor patients for PML, a neurologic exam (including evaluation of cranial nerves, 
motor and sensory function, coordination, and mental status) will be performed as per
the schedule of assessments (see Appendix 1). This neurologic exam will consist of
administration of the PML Subjective Checklist and the PML Objective Checklist.
At screening, the PML Subjective Checklist and the PML Objective Checklist (including
the components listed as optional, e.g. muscle group strength testing, recall of 3 objects
in 1 minute, and sensory testing) should be performed.
At all other visits, the PML Subjective Checklist and the PML Objective Checklist
(bolded items) should be performed, and the optional items should only be performed 
when there is an abnormal finding on the corresponding PML Subjective Checklist (i.e.
complaints of focal weakness or focal sensory change would prompt a more detailed
objective neurologic evaluation).


Appendix 5 Worksheet for the PML Neurologic examination 
(cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
158/Protocol GA29144, Version 7
PML Subjective Checklist
Symptoms
“Compared to
how you usually
feel, have you 
had a significant 
change in any of
the following?”
If the answer is “Yes”,
obtain a description of
the symptom(s) with 
examples
Applicable Objective
Test(s): Document result 
on PML Objective 
Checklist Worksheet
YES
NO
1. Have you been 
experiencing any persistent
difficulty with your vision such
as loss of vision or double 
vision? Have you been having
trouble with reading?

Test visual fields and 
ocular motility
2. Have you been 
experiencing any persistent
difficulty speaking or having
your speech understood by 
others?

Casual observation of 
speech output for 
dysarthria or aphasia.
3. Have you been 
experiencing any persistent
weakness in an arm or a leg?

Test for pronator drift 
(Barre maneuver).

Assess gait.

Test muscle strength
(only if indicated).
4. Have you noticed yourself
regularly bumping into things
or having difficulty writing?

Observe tandem gait
and finger to nose.
5. Have you regularly been
experiencing difficulty
understanding others?

Test ability to follow 
serial commands.
6. Have you had persistent
problems with your memory or
thinking?

Recall of 3 objects over 
1 minute with distraction 
(only if indicated).
7. Have you been 
experiencing any persistent
numbness or other loss of
sensation?

Test sensation side to 
side with either pinprick
or cold (only if
indicated).


Appendix 5 Worksheet for the PML Neurologic examination 
(cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
159/Protocol GA29144, Version 7
PML Objective Checklist
Neurologic function 
being assessed
Instructions
(bold text indicates parts of exam
required at each visit, as specified in
Schedule of Assessments)
Abnormal
exam?
If the answer is
“Yes”, describe the 
abnormal objective 
exam finding
YES
NO
1. Visual fields and 
ocular motility

Visual Field Testing 

Ocular Motility Testing
2. Speech

Observe the patient’s speech 
output for dysarthria or aphasia.
3. Strength

Pronator drift test (Barre 
maneuver)

Gait testing (normal, heel and 
toe walk)

ONLY if the patient has any 
subjective complaints of weakness,
test muscle strength of the relevant 
4. Coordination

Observe tandem gait and finger 
to nose
5. Comprehension

Test ability to follow serial 
commands

“Take a piece of paper in your 
hand, fold it in half, and put it on 
the floor.”
6. Memory and thinking

ONLY if the patient has subjective 
complaints about their memory or 
thinking, test the ability of the 
patient to recall 3 objects over 1 
minute with distraction
7. Sensation

ONLY if the patient has subjective 
sensory complaints, evaluate 
relevant areas based on patient’s 
subjective complaints by comparing
left vs. right side sensation to cold
(e.g. alcohol swab or cold
stethoscope) or pinprick (e.g. 
broken Q-tip)


Appendix 5 Worksheet for the PML Neurologic examination 
(cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
160/Protocol GA29144, Version 7
Please refer to the PML Algorithm in the Protocol Appendix for details.

If there is an abnormal finding on the PML Subjective Checklist, this should be
appropriately documented on the worksheet and in the eCRF.

If there is an abnormal finding on the PML Objective Checklist, this should be
appropriately documented on the worksheet and in the eCRF.

If there are any abnormalities found on the PML Subjective Checklist that are
accompanied by the corresponding abnormality on the PML Objective Checklist, or if
there is high clinical suspicion for PML (in the opinion of the investigator):

This must be reported as an adverse event of special interest (AESI) within 
24 hours

An urgent referral to a neurologist should be made.

Dosing with study drug will be suspended until PML can be ruled out.

Further evaluation will proceed according to the PML Algorithm in the 
Protocol Appendix.

Any confirmed diagnosis of PML should be reported as a serious adverse 
event (SAE).
Please complete the PML eCRF.
Was the PML Subjective Checklist administered? (Yes/No)
If yes, date of administration of PML Subjective Checklist (Date)
If yes, were there any abnormalities on the PML Subjective Checklist? (Yes/No) 
Was the PML Objective Checklist administered? (Yes/No)
If yes, were there any abnormalities on the PML Objective Checklist? (Yes/No) 
Is PML suspected? (Yes/No)
More detailed instructions for the PML Objective Checklist Neurologic Evaluations 
(please refer to the PML Neurologic Exam Video for more information):
1. Visual fields and ocular motility
Visual Field Testing:

Position yourself approximately 3 feet away from the patient, with eyes at the same
level.

Keeping both eyes open, ask the patient to cover one eye and ask if all parts of your
face and head are clear to them. Ask them to repeat, covering the other eye.


Appendix 5 Worksheet for the PML Neurologic examination 
(cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
161/Protocol GA29144, Version 7

Have the patient cover one eye and stare at your nose, and then ask them how
many fingers you are holding up, testing each of the 4 visual quadrants. Repeat with
the other eye covered.
Ocular Motility Testing:

Evaluate the patient for conjugate eye movement.

Starting about 3 feet from center, move in a big “H”, pausing at the center and at 
lateral gaze, and finishing with convergence (finger to their nose). Watch for
nystagmus in lateral gaze, smooth pursuits, and pupillary constriction with
convergence. Note: a couple of beats of nystagmus upon extreme lateral gaze is
considered normal.
2. Speech

Observe the patient’s speech output for dysarthria or aphasia.

Dysarthria is a motor speech disorder. Findings can include “slurred” speech, 
decreased volume, slow rate of speech, limited tongue, lip, and jaw movement,
abnormal rhythm when speaking, changes in vocal quality, and drooling or poor 
control of saliva.

Aphasia is a disorder that results from damage to parts of the brain that control 
language, and can lead to problems with any or all of the following: speaking, 
listening, reading or writing.
3. Strength
Pronator drift test (Barre maneuver):

Ask the patient to stand with their feet together and extend their arms out in front of 
them at 90 degrees (parallel to floor) with palms facing upwards toward the ceiling.

Ask the patient to close their eyes and keep their arms extended for 15 seconds.

If either arm drifts downward, upward, or starts to pronate (i.e. thumb turns up), this
is considered an abnormal exam.
Gait testing:

Ask the patient to walk across the room (~10 feet).  The patient should have a
normal gait, with their left arm swinging forward when the right foot leads, and vice
versa.  Be certain to note whether there is symmetric arm swinging, because a
slight decrease in arm swinging may be an indicator of upper extremity weakness.

Ask the patient to walk on their heels across the room (~10 feet). Carefully observe
whether they have any difficulty maintaining their toes off the ground or loss of
balance.

Ask the patient to walk on their toes across the room (~10 feet). Carefully observe if
they have any difficulty maintaining their heels off the ground or loss of balance.


Appendix 5 Worksheet for the PML Neurologic examination 
(cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
162/Protocol GA29144, Version 7
Additional strength testing (ONLY if the patient has any subjective complaints of 
weakness):

Test muscle strength of the relevant muscle groups based on the patient’s
subjective complaints.

General guidelines for a basic muscle strength exam:

Upper extremity:
o
Finger grip strength
o
Flexion at elbow
o
Extension at elbow
o
Deltoid strength:  Maintain bent arms up (perpendicular to floor) and
resist while investigator pushes down
o
Shoulder shrug against resistance

Lower extremity: (examine while patient is sitting down)
o
Raise thigh (while bent)
o
Straighten leg
o
Flex leg
o
Flex foot
o
Extend foot
4. Coordination
Tandem gait:

As the patient is looking at his feet, ask them to walk 8 steps with one foot touching
in front of the other (demonstrate for them).
Finger to nose:

Hold your finger out so they need to reach out and lean. Start near the center, and
move your finger slowly so that they reach across their body. Make sure they
alternate touching your finger and their nose at a good speed. Inability to perform 
this accurately is considered an abnormal test.
5. Comprehension

Test ability to follow serial commands

“Take a piece of paper in your hand, fold it in half, and put it on the floor.”


Appendix 5 Worksheet for the PML Neurologic examination 
(cont.)
Etrolizumab—F. Hoffmann-La Roche Ltd
163/Protocol GA29144, Version 7
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 7 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) 

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) 
2.
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 8 Bristol Stool Form Scale


Etrolizumab—F. Hoffmann-La Roche Ltd
167/Protocol GA29144, Version 7
Appendix 9
Crohn’s Disease Activity Index (CDAI)


Etrolizumab—F. Hoffmann-La Roche Ltd
168/Protocol GA29144, Version 7
Appendix 10
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.


































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SAP_001.pdf: 
 
Official Title: 
A Phase III, Randomized, Double-Blind, Placebo-Controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of Etrolizumab 
as an Induction And Maintenance Treatment For Patients With 
Moderately to Severely Active Crohn's Disease 
NCT Number: 
NCT02394028 
Document Date: 
SAP Version 3: 20-Sep-2021 
 
 
 


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Etrolizumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan GA29144
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF 
ETROLIZUMAB AS AN INDUCTION AND MAINTENANCE 
TREATMENT FOR PATIENTS WITH MODERATELY TO 
SEVERELY ACTIVE CROHN’S DISEASE
PROTOCOL NUMBER:
GA29144
STUDY DRUG:
Etrolizumab (RO5490261)
VERSION NUMBER:
3
IND NUMBER:
119725
EUDRACT NUMBER:
2014-003824-36
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
 M.Sc.
 Ph.D.
DATE FINAL:
Version 1: 19 December 2019
DATE AMENDED:
Version 2: 14 December 2020
Version 3: See electronic date stamp below
Date and Time(UTC)        Reason for Signing                              Name
Company Signatory
20-Sep-2021 16:30:29


Etrolizumab—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan GA29144
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE

Added Section 2.2 (Trial Objective):
–
Section added to clearly define trial objective for estimands

Changes to Section 2.3.2 (Secondary Efficacy Outcome Measures):
–
Added Crohn’s Disease Activity Index (CDAI) remission as secondary endpoint (not 
included in protocol)

Changes to Section 2.4.1 (Sample Size):
–
Included statement that Cohort 3 Induction closed early.

Changes to Section 4.4.3 (Intercurrent Events):
–
Clarified wording for COVID-19 specific Intercurrent Events (ICEs)
–
Added treatment strategy

Changes to Sections 4.4.4.1 and 4.4.4.2 (Induction Co-Primary Efficacy Endpoints)
and Section 4.4.9 (Maintenance Co-Primary Efficacy Endpoints):
–
Clarified wording for coronavirus disease of 2019 (COVID-19) specific ICEs 
between endoscopy and clinical remission
–
Added treatment strategy

Changes to Section 4.4.6 (Sensitivity Analyses for Induction Co-Primary Endpoints)
and Section 4.4.11 (Sensitivity Analyses for Maintenance Co-Primary Endpoints):
–
Added tipping point analysis and included Multiple Imputation (MI) as sensitivity 
for clinical remission (further details added in Section 4.10) 

Changes to Section 4.4.8 (Induction Secondary Efficacy Endpoints) and Section 4.
4.13 (Maintenance Secondary Efficacy Endpoints):
–
Added treatment strategy for estimand definitions
–
Clarified handling approach for COVID-19 related ICE for CDAI and clinical 
remission endpoints

Changes to Section 4.4.12 (Supplementary Analyses):
–
Added supplementary analysis which changes population attribute in primary 
estimand i.e., perform analysis among CDAI-100 responders at Week 14

Removed Section 4.4.14.8 (Histology) from Statistical Analysis Plan (SAP) (and 
Clinical Study Report [CSR])

Changes to Section 4.9.3 (Adverse Events):
–
Added long COVID analyses

Changes to Section 4.10 (Missing Data):
–
Added additional wording and section 4.10.2 on a “well-justified” imputation 
model and strategy as per FDA feedback. Individual sections have also been 
added for each endpoint (4.10.2.1, 4.10.2.2 and 4.10.2.3) 


Etrolizumab—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan GA29144
–
Added multiple imputation as sensitivity analysis (Section 4.10.1) for CDAI and 
clinical remission endpoints
–
Added wording on performing tipping point analysis (Section 4.10.1)
Additional minor changes have been made to improve clarity and consistency.


Etrolizumab—F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan GA29144
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE............................. 2
1.
BACKGROUND .......................................................................................... 11
2.
STUDY DESIGN......................................................................................... 11
2.1
Protocol Synopsis.................................................................. 12
2.2
Trial Objective........................................................................ 12
2.3
Outcome Measures ............................................................... 12
2.3.1
Co-Primary Efficacy Outcome Measures............................... 12
2.3.2
Secondary Efficacy Outcome Measures................................ 12
2.4
Determination of Sample Size ............................................... 13
2.4.1
Sample Size .......................................................................... 13
2.5
Analysis Timing ..................................................................... 15
3.
STUDY CONDUCT..................................................................................... 15
3.1
Randomization....................................................................... 15
3.1.1
Induction Phase..................................................................... 15
3.1.2
Maintenance Phase............................................................... 16
3.2
Independent Review Facility.................................................. 16
3.3
Data Monitoring ..................................................................... 16
4.
STATISTICAL METHODS .......................................................................... 16
4.1
Analysis Populations ............................................................. 17
4.1.1
Induction Phase..................................................................... 17
4.1.1.1
Modified Intent-to-Treat Population ....................................... 17
4.1.1.2
Safety Population .................................................................. 17
4.1.1.3
Pharmacokinetic-Evaluable Population ................................. 17
4.1.2
Maintenance Phase............................................................... 17
4.1.2.1
Modified Intent-to-Treat Population ....................................... 17
4.1.2.2
Safety Population .................................................................. 17
4.1.2.3
Pharmacokinetic-Evaluable Population ................................. 17
4.2
Analysis of Study Conduct..................................................... 17
4.3
Analysis of Treatment Group Comparability .......................... 18
4.4
Efficacy Analysis.................................................................... 19


Etrolizumab—F. Hoffmann-La Roche Ltd
5/Statistical Analysis Plan GA29144
4.4.1
Analysis Methods .................................................................. 20
4.4.2
Covariate Adjustment ............................................................ 21
4.4.3
Intercurrent Events ................................................................ 21
4.4.4
Induction Co-Primary Efficacy Endpoints............................... 23
4.4.4.1
Definition of Co-Primary Estimand: Clinical 
Remission.............................................................................. 23
4.4.4.2
Definition of Co-Primary Estimand: Endoscopic 
Improvement.......................................................................... 24
4.4.5
Missing Data Handling Methods for Induction Co-
Primary Endpoints ................................................................. 25
4.4.6
Sensitivity Analyses for Induction Co-Primary 
Endpoints............................................................................... 26
4.4.7
Supplementary Analyses....................................................... 26
4.4.8
Induction Secondary Efficacy Endpoints................................ 26
4.4.8.1
Control of Type I Error ........................................................... 26
4.4.8.2
Estimand Definitions for Induction Secondary 
Efficacy Endpoints................................................................. 28
4.4.8.3
Crohn’s Disease Activity Index Remission at 
Week 14 ................................................................................ 29
4.4.8.4
Endoscopic Remission at Week 14 ....................................... 29
4.4.8.5
Clinical Remission at Week 6 ................................................ 29
4.4.8.6
Crohn’s Disease-Patient Reported 
Outcome/Signs and Symptoms Score at Week 
14-Functional Domain............................................................ 29
4.4.8.7
Crohn’s Disease-Patient Reported 
Outcome/Signs and Symptoms Score at Week 
14-Bowel Domain .................................................................. 30
4.4.9
Maintenance Co-Primary Efficacy Endpoints......................... 30
4.4.9.1
Definition of Co-primary Estimand: Clinical 
Remission.............................................................................. 30
4.4.9.2
Definition of Co-primary Estimand: Endoscopic 
Improvement.......................................................................... 31
4.4.10
Missing Data Handling Methods for Maintenance 
Co-Primary Endpoints............................................................ 32
4.4.11
Sensitivity Analyses for Maintenance Co-Primary 
Endpoints............................................................................... 33
4.4.12
Supplementary Analyses....................................................... 33






Etrolizumab—F. Hoffmann-La Roche Ltd
8/Statistical Analysis Plan GA29144
LIST OF TABLES
Table 1
Planned Sample Sizes for Induction Phase ................................ 14
Table 2
Planned Sample Sizes for Maintenance Phase .......................... 14
Table 3
Planned Power Estimates for Primary and Key Secondary 
Efficacy Analyses in Induction Cohort 3 and Maintenance 
Phase.......................................................................................... 15
LIST OF FIGURES
Figure 1
Multiple Testing Procedures for Induction Endpoints.................. 28
Figure 2
Multiple Testing Procedure for Maintenance Endpoints.............. 35
LIST OF APPENDICES
Appendix 1
Outcome Measures Definitions................................................... 57
Appendix 2
Summary of Imputation Methods for Intercurrent Events 
(ICE) and Missing Data............................................................... 58


Etrolizumab—F. Hoffmann-La Roche Ltd
9/Statistical Analysis Plan GA29144
GLOSSARY OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AP
abdominal pain
AST
aspartate aminotransferase
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
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
MMRM
mixed models for repeated measures
NRI
non-responder imputation
PD
pharmacodynamics


Etrolizumab—F. Hoffmann-La Roche Ltd
10/Statistical Analysis Plan GA29144
Abbreviation
Definition
PK
pharmacokinetic
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
SOC
system organ class
TNF
tumor necrosis factor
ULN
upper limit of normal
WOCF
worst-observation-carried-forward


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1.
BACKGROUND
Study GA29144 (IND119725) is a multicenter, Phase III, double-blind, 
placebo-controlled study evaluating the efficacy, safety, and tolerability of etrolizumab 
compared with placebo during Induction and Maintenance treatment phases for patients 
with moderate to severely active Crohn’s disease (CD).
Patients are enrolled sequentially into one of the three Induction cohorts, as described 
below:

Cohort 1 (N300): placebo, etrolizumab 105 mg, etrolizumab 210 mg (1:2:2) 

Cohort 2 (N350): etrolizumab 105 mg, etrolizumab 210 mg (1:1)

Cohort 3 (N496): placebo, etrolizumab 105 mg, etrolizumab 210 mg (2:3:3)
Cohorts 1 and 2 are exploratory Induction cohorts, whilst Cohort 3 serves as the pivotal, 
confirmatory cohort for the Induction phase analysis.
Patients achieving Crohn’s Disease Activity Index70 (CDAI-70) responses at Week 14, 
without the use of rescue treatment are eligible to enter the Maintenance Phase.  
Patients who received etrolizumab (high or low dose) during the Induction Phase will be 
randomized into the Maintenance Phase in a 1:1 ratio to placebo or etrolizumab 105 mg 
subcutaneous (SC) every 4 weeks (Q4W).  To maintain the blind, patients receiving 
placebo during the Induction Phase will undergo a sham randomization, and will receive 
blinded placebo treatment during the Maintenance Phase.
The Maintenance Phase analysis will include patients from all three Induction cohorts.
This Statistical Analysis Plan (SAP) describes the data and analysis methods that will be 
reported in the GA29144 final Clinical Study Report (CSR).  The following data will be 
evaluated independently:

Induction Phase – Cohorts 1, 2, and 3

Maintenance Phase
Data will be reported based on the final protocol and final database, using the analysis 
methods as described in this SAP.
It is noted that Cohort 1 data were unblinded and analyzed in 2017 to inform the design 
of the pivotal Induction cohort, prior to its commencement.  Topline results from this 
preliminary analysis will be summarized in the CSR.
2.
STUDY DESIGN
Details of the study design can be found in the Protocol Synopsis section of Protocol 
Version 7 and Study Schema in Figure 1 and Figure 2 of the Protocol Version 7.


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2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Protocol Synopsis Section of Protocol Version 7.  For 
additional details, see the Schedule of Assessments in Appendices 1A, 1B, 2 and 3 of 
the Protocol Version 7.
2.2
TRIAL OBJECTIVE
Primary efficacy objectives for this study will be analyzed separately for the Induction
and Maintenance Phases as outlined below:

Induction Phase: To independently evaluate the efficacy of etrolizumab dose
regimens compared with placebo in inducing clinical remission and endoscopic
improvement at the end of the Induction Phase (Week 14)

Maintenance Phase: To independently evaluate the efficacy of etrolizumab
compared with placebo in achieving clinical remission and endoscopic improvement
at 1 year of maintenance treatment (Week 66), for patients who achieved a Crohn’s
Disease Activity Index (CDAI)-70 response (defined as a decrease of at least 70 
points from baseline CDAI) at Week 14, without the use of rescue therapy.
2.3
OUTCOME MEASURES
Full definitions of all the outcome measures to be analyzed during the Induction and 
Maintenance Phases, as specified in the protocol, are included in Appendix 1.
 
 
However, as a result of evolving regulatory guidelines, CDAI 
remission is now considered as a secondary endpoint for the Induction and Maintenance 
Phases.
2.3.1
Co-Primary Efficacy Outcome Measures
Induction: 

Clinical remission (Stool Frequency [SF] mean daily score3 and Abdominal Pain 
(AP) mean daily score1, with no worsening in either sub-score compared to 
baseline, averaged over the 7 days prior to visit) at Week 14

Endoscopic improvement (50% reduction from baseline in the Simplified 
Endoscopic Score for Crohn’s Disease [SES-CD]) at Week 14
Maintenance: 

Clinical remission at Week 66, for patients achieving a CDAI-70 response (decrease 
of at least 70 points from baseline CDAI) at Week 14

Endoscopic improvement at Week 66, for patients achieving a CDAI-70 response at 
Week 14
2.3.2
Secondary Efficacy Outcome Measures
Induction: 

Clinical remission at Week 6


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
CDAI remission at Week 14

Endoscopic remission (see Appendix 1) at Week 14

Change from baseline to Week 14 in CD signs and symptoms, as assessed by the 
Crohn’s Disease-Patient Reported Outcome/Signs and Symptoms (CD-PRO/SS) 
functional domain score

Change from baseline to Week 14 in CD signs and symptoms, as assessed by the 
CD-PRO/SS bowel domain score
Maintenance: 
As above, all the following are for patients achieving a CDAI-70 response at Week 14 
unless otherwise stated:

Clinical remission at Week 66 among patients achieving clinical remission at 
Week 14

CDAI remission at Week 66

Corticosteroid-free clinical remission at Week 66 among patients who were 
receiving corticosteroids at baseline

Endoscopic improvement at Week 66 among patients achieving endoscopic 
improvement at Week 14

Endoscopic remission (see Appendix 1) at Week 66

Durable clinical remission (see Appendix 1)

Corticosteroid-free clinical remission at Week 66 (off corticosteroid for at least 
24 weeks prior to Week 66) in patients who were receiving corticosteroids at 
baseline

Change from baseline to Week 66 in CD-PRO/SS bowel domain score

Change from baseline to Week 66 in CD-PRO/SS functional domain score
2.4
DETERMINATION OF SAMPLE SIZE
2.4.1
Sample Size
The planned sample size and power for each phase specified in the protocol are 
presented in Table 1, 2 and 3.


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Table 1
Planned Sample Sizes for Induction Phase
Cohort
No. of Patients
Total
Placebo
etrolizumab 105mg
etrolizumab 210mg
Cohort 1
(Exploratory)
300
60
120
120
Cohort 2
(Exploratory)
350
NA
175
175
Cohort 3
(Pivotal)
496
124
186
186
Table 2
Planned Sample Sizes for Maintenance Phase
No. of Patients
Total
Placebo/
Placebo
etrolizumaba /
Placebo
etrolizumaba /
etrolizumab 105 mg
Maintenance 
Phase
480
~60
~210
~210
a Patients randomized to either dose of etrolizumab (i.e., 105 mg or 210 mg) during Induction 
Phase.


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Table 3 Planned Power Estimates for Primary and Key Secondary Efficacy 
Analyses in Induction Cohort 3 and Maintenance Phase
At the time of study closure a total of 1035 patients were randomized into the Induction 
Phase across cohorts 1-3, and the sample size of N480 for Maintenance Phase was 
met. The protocol specified sample size for Cohort 3 for the pivotal Induction Phase was 
not met as the study was closed at N 385. Details surrounding the early closure and 
impact on power will be discussed in the final CSR.
2.5
ANALYSIS TIMING
The trial will be formally unblinded, analyzed and reported in the final CSR after the last 
patient has completed or withdrawn early from the Induction or Maintenance Phase, 
whichever comes first.
3.
STUDY CONDUCT
3.1
RANDOMIZATION
An independent interactive voice/Web-based response system (IxRS) vendor was used 
to perform all kit assignments, using a stratified permuted block randomization method.
An independent unblinded statistician from an independent data coordinating center 
(iDCC) performed periodic reviews to confirm that the randomization schema has been 
implemented correctly for the study.
3.1.1
Induction Phase
Following screening and baseline assessments, patients who fulfil the 
inclusion/exclusion criteria to enter the study will be enrolled sequentially into one of the 
three Induction Cohorts.  Randomization into each cohort in the Induction Phase is 
stratified by:

Concomitant oral corticosteroids (CS) treatment (yes vs. no)
Study
Endpoint
Power
Assumed Response Rates 
(placebo vs. active)
Induction 
(Cohort 3)
Clinical Remission at Week 14
85%
15% vs. 30%
Endoscopic Improvement at 
Week 14
80%
5% vs. 15%
Maintenance
Clinical Remission at Week 66
90%
20% vs. 35%
Endoscopic Improvement at 
Week 66
~90%
30% vs. 45%
Clinical Remission at Week 66 
among patients achieving clinical 
remission at Week 14
80%
30% vs. 50%
Based on assumption that 22% 
patients will achieve clinical 
remission at Week 14


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
Concomitant immunosupressants (IS) treatment (yes vs. no)

Baseline CDAI 330 (yes vs. no)

Prior anti-tumor necrosis factor (TNF) exposure (yes vs. no) 
A stratified permuted block randomization method will be used.
3.1.2
Maintenance Phase
Patients are only eligible to enter the Maintenance Phase if they achieved a CDAI-70 
response at Week 14 without the use of rescue therapy.  Patients in Cohort 1 or 
Cohort 3 who were randomized to placebo during the Induction Phase will undergo a 
sham randomization in order to maintain the blind; these patients will receive placebo 
during the Maintenance Phase.  Patients in Cohort 1-3 who were randomized to 
etrolizumab (either 105 mg or 210 mg dose) in Induction Phase will be re-randomized 
into the Maintenance Phase, where randomization is stratified by:

CDAI Remission at both Week 10 and Week 14 (yes vs. no)

Induction Dose Regimen (high vs. low)

Concomitant oral CS (yes vs. no)

Prior anti-TNF exposure (yes vs. no) 
A stratified permuted block randomization method will be used.
3.2
INDEPENDENT REVIEW FACILITY
An independent review facility will provide an independent central review of 
ileocolonoscopy videos to determine the SES-CD.  Details of the review process are 
described in the central review charter.
3.3
DATA MONITORING
An independent Data Monitoring Committee (iDMC) was incorporated in the study 
design to monitor safety and study conduct on a twice yearly basis during the study, or 
more frequently based on the emerging safety data.  Members of the iDMC are external 
to the Sponsor and follow a charter that outlines the iDMC roles and responsibilities.
4.
STATISTICAL METHODS
The statistical methods described in this SAP are based on the final protocol and pertain 
to the following:

Induction Phase – Cohorts 1, 2, and 3 separately

Maintenance Phase
Induction data will be presented separately for Cohorts 13.
The Maintenance Phase analysis will include all patients re-randomized into the 
Maintenance Phase; this includes patients across Cohorts 1-3 from the Induction Phase.


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4.1
ANALYSIS POPULATIONS
4.1.1
Induction Phase
4.1.1.1
Modified Intent-to-Treat Population
All patients randomized who received at least one dose of study drug in the Induction 
Phase.  Patients will be grouped according to the randomized treatment group at 
Induction.
4.1.1.2
Safety Population
All patients who received at least one dose of study drug during the Induction Phase.  
Patients will be grouped by the treatment most frequently received during the Induction 
Phase.
4.1.1.3
Pharmacokinetic-Evaluable Population
All patients who have received at least one dose of etrolizumab and have had at least 
one quantifiable concentration measured during the Induction Phase.
4.1.2
Maintenance Phase
4.1.2.1
Modified Intent-to-Treat Population
All patients re-randomized or enrolled into Maintenance who received at least one dose 
of study drug in the Maintenance Phase and were treated with etrolizumab as induction 
therapy across Cohorts 1-3. 
The placebo/placebo treatment arm will be included in the modified intent to treat (mITT) 
population but the data will be treated as exploratory.
4.1.2.2
Safety Population
All patients who received at least one dose of study drug during the Maintenance Phase.  
Patients will be grouped by the treatment most frequently received during the 
Maintenance Phase.
4.1.2.3
Pharmacokinetic-Evaluable Population
All patients who have received at least one dose of etrolizumab, and have had at least 
one quantifiable concentration measured during Maintenance Phase.
4.2
ANALYSIS OF STUDY CONDUCT
The following will be summarized by treatment arm(s) for both Induction and 
Maintenance Phases:

Analysis populations

Patient disposition

Study treatment completion/discontinuation

Study completion/discontinuation

Major protocol deviations


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
Exposure
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
To review treatment group comparability, a number of variables collected at baseline 
(see Section 4.6.2) will be summarized and compared across treatment groups.
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.
Demographics and baseline characteristics for the Maintenance Phase will use the data 
collected from their Induction baseline visit.
Demography

Age (18 to < 40, ≥40 to 65, ≥65) 

Sex

Race

Ethnicity

Region

Smoking status history

Body mass index

Weight
Disease Characteristics

Duration of disease

Duration of disease 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)

SES-CD score

CD-PRO/SS – Functional score

CD-PRO/SS – Bowel score


 


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


 
Baseline Treatments

Use of oral CS at Baseline (yes vs. no)

Use of IS at Baseline (yes vs. no)

Prior anti-TNF exposure (yes vs. no) 
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).
4.4
EFFICACY ANALYSIS
The Induction and Maintenance Phases will be analyzed and reported as separate 
studies.
Induction Phase
Cohort 1 statistical analyses will be carried out at the 10% significance level.  No control 
for type I error will be performed; all p-values will be nominal and for exploratory 
purposes only.
Cohort 2 involves treatment with open label etrolizumab and has no control arm; data 
will be summarized descriptively only for all efficacy endpoints.  Confidence intervals will 
be reported at the 5% significance level.
Cohort 3 will serve as the pivotal, confirmatory analysis for the Induction phase and will 
be analyzed using a 5% significance level.  The co-primary endpoint and all key 
secondary endpoints will undergo a multiple testing procedure to provide strong control 
for type I error, as described in Section 4.4.8.1 and Section 4.4.13.1.
Data for the Induction Phase will be presented separately for Cohorts 1-3 in the study 
CSR, with Cohort 3 serving as pivotal, confirmatory analysis.  Pooling of data across 
cohorts and pooled treatment comparisons may be undertaken to provide additional 
supportive information for the Induction Phase; details of such analyses will be 
documented in a separate SAP (e.g., Summary of Clinical Efficacy SAP).
Maintenance Phase
The Maintenance Phase analysis will include all patients re-randomized into the 
Maintenance Phase; this includes patients across cohorts 1-3 from the Induction Phase.  
The pivotal analysis for Maintenance will be performed on patients receiving etrolizumab 
during the Induction Phase.  Patients receiving placebo during the Induction Phase and 


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who undergo a sham randomization to receive continued treatment with blinded placebo 
will be reported as exploratory only.
4.4.1
Analysis Methods
Statistical hypotheses for the primary and key secondary endpoints for the Induction 
Cohort 3 and Maintenance Phases will be evaluated using a multiple testing procedure 
to ensure an overall type I error rate no greater than 5%.  Details of the multiplicity 
strategies are described separately for the Induction Phase (Section 4.4.8) and 
Maintenance Phase (Section 4.4.13).  All hypothesis testing pertaining to these pivotal 
analyses will take place using a two-sided 5% significance level.  Cohort 1 will be tested 
using a 10% significance level, no control will be undertaken for multiple testing.
Binary endpoints undergoing formal statistical testing described in this SAP will be 
analyzed using the Cochran-Mantel-Haenszel (CMH) test as the primary analysis 
method. The difference between proportions will be presented along with 95% 
confidence intervals for the pivotal Induction and Maintenance analyses, and 90% for the 
Cohort 1 Induction analysis, and will be constructed using the Newcombe method. The 
confidence intervals for the treatment group proportions will be constructed using the 
Wilson method.
Continuous endpoints undergoing formal statistical testing described in this SAP will be 
evaluated using a Mixed Model for Repeated Measures (MMRM) as the primary analysis 
method.  The model will include covariates as described in Section 4.4.2, along with 
terms for treatment, baseline value, visit, and a visit-by-treatment interaction term.  
Within each participant, the model will incorporate an unstructured variance-covariance 
matrix for the random error terms.  Parameters will be estimated using the restricted 
maximum likelihood, and the Kenward-Roger method will be used for calculating the 
denominator degrees of freedom.  In the event that the model fails to converge, the 
spatial variance-covariance matrix will be used.
After accounting for intercurrent events (ICE) according to each endpoint’s respective 
estimand definition (see Section 4.4.2), missing data handling methods for any patient 
with missing data are detailed in Section 4.10, in addition to Section 4.4.4 and 
Section 4.4.8 for the co-primary endpoints in Induction and Maintenance.
Approaches for all endpoints (primary, secondary 
) on handling ICE 
according to each strategy, and the imputation method for true missing data (after 
accounting for ICE) are summarized in Appendix 2.


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4.4.2
Covariate Adjustment
Unless otherwise stated, analyses of efficacy endpoints (co-primary, secondary, 
) will be adjusted for the IxRS stratification factors described below.
Induction

Concomitant oral CS treatment (yes vs. no)

Baseline CDAI330 (yes vs. no)

Prior anti-TNF exposure (yes vs. no) 
An investigation using Cohort 1 induction data revealed that the analysis was over-
stratified using all 4 stratification factors used at randomization, leading to multiple strata 
with small sample sizes (e.g.,5), and some strata being excluded from the CMH 
analysis.  Simulations project that Cohort 3 will also be over-stratified.  For this reason, 
the 4th stratification factor of Immunosuppressant use (yes vs. no) will be dropped from 
the primary reporting methods for both Cohort 1 and 3.
Maintenance

Induction Dose Regimen (high vs. low)

Concomitant oral CS (yes vs. no)

Prior anti-TNF exposure (yes vs. no) 
The fourth stratification factor of “CDAI Remission status at Week 10 and Week 14” used 
for the Maintenance randomization will be dropped from the primary analysis methods to 
avoid over-stratification that would otherwise results in too many strata with small 
(i.e.,5) sample sizes.
4.4.3
Intercurrent Events
In alignment with the addendum to ICH E9, estimands are described for the co-primary 
efficacy endpoints in Induction and Maintenance Phase in Section 4.1.1 and 
Section 4.1.2 respectively.  The estimand attributes include the following ICE along with 
their respective strategy approach:
1.
Patient/Treatment Discontinuation:  The investigator has the right to discontinue a 
patient from treatment/the study at any time and patients have the right to voluntarily 
discontinue from treatment/the study for any reason at any time.  Patients must 
discontinue from treatment if any of the following (but not limited to) occur:  
pregnancy, anaphylaxis or other severe hypersensitivity reaction, development of 
colonic mucosal dysplasia, malignancy or specific serious infections (more 
information can be found in the Study GA29144 Protocol).  Any patient discontinuing 
from treatment/study for any reason will not be replaced.  If a patient discontinues 
treatment prematurely, then this patient will be considered as being unsuccessfully 
treated and will be evaluated under the composite strategy.  Therefore, for binary 
endpoints, these patients will be treated as non-responders.  Similarly, for 
continuous endpoints, as an unfavorable outcome that would reflect a composite 


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endpoint equivalent to a non-responder, the patient’s worst-post-baseline-value for 
the endpoint will be carried forward, i.e., worst-observation-carried-forward (WOCF) 
imputation. 
2.
Use of rescue therapy (or prohibited medication):  Rescue therapy is defined as 
medication prescribed for new or worsening CD symptoms and includes any new 
CS or IS therapy for CD and any increase in dose or regimen of baseline Crohn’s 
medications.  For patients in Maintenance Phase, increase in the dose of CS 
therapy above a patient’s baseline dose (applicable to patients requiring CS at 
baseline) is also classed as rescue therapy. Antibiotics, 5-aminosalicylate, anti-
diarrheals, probiotics, herbal/ayurvedic, nutritional and homeopathic supplements 
are not considered as rescue therapies.  Patients requiring rescue therapy (or 
prohibited medication) will be considered as a failure of study drug which is 
synonymous with the composite strategy.  Therefore, for binary endpoints, these 
patients will be treated as non-responders.  Similarly, for continuous endpoints, as 
an unfavorable outcome that would reflect a composite endpoint equivalent to a 
non-responder, the patient’s worst-post-baseline-value for the endpoint will be 
carried forward i.e., WOCF imputation. 
3.
Deaths:  Any instance of death will be treated as a failure of study treatment.  
Therefore, for binary endpoints, these patients will be treated as non-responders.  
Similarly, for continuous endpoints, as an unfavorable outcome that would reflect a 
composite endpoint equivalent to a non-responder, the patient’s 
worst-post-baseline-value for the endpoint will be carried forward i.e., WOCF 
imputation.
4.
Coronavirus disease -19-related:  Corona virus disease 2019 (COVID-19) related 
events are defined as any systematic disruptions such as:

Visit attended but key assessments not performed at Week 14 or 66 due to logistical 
constraints, or restrictions put in place by the government, hospital or investigator 
(e.g., ileocolonoscopy cancelled due to not qualifying as an ‘urgent’ medical 
procedure)

Treatment discontinuation with COVID-19 cited as a reason 

Visit not done, leading to key endpoint evaluations not performed (e.g., 
ileocolonoscopy at Weeks 14 and 66, and CDAI assessments at Weeks 14 and 66).  
Reasons for missing the visit include logistical constraints at site, restrictions that 
impede a patient/investigator from carrying out the visit, or due to patient’s fear of 
the pandemic.
A hypothetical strategy will be employed in order to estimate the treatment effect in the 
hypothetical world in the absence of COVID-19.  It is determined that COVID-19 is only 
likely to impact collection of data from site-based assessments and endoscopy 
procedures. Therefore, COVID-19 is not considered to have a major impact on a 
patient’s ability to complete eDiary data.  Any missing eDiary data will be considered as 
“true missing” and handled according to the missing data handling method as detailed in 
Section 4.4.5.  For site based assessments, data from the previous site visit will be used 
(i.e., last-observation-carried-forward [LOCF] imputation).  For endoscopy data, i.e.,


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SES-CD score, where intermediate data collection isn’t available, a multiple imputation 
(MI) approach will be used.  For continuous endpoints where MMRM is used for 
analysis, MMRM will also be used to impute data missing due to COVID-19-related ICE 
under the hypothetical strategy.
4.4.4
Induction Co-Primary Efficacy Endpoints
The Induction Phase of Study GA29144 has two co-primary efficacy endpoints:  Clinical 
remission and endoscopic improvement, both measured at Week 14.
No type I error control will be undertaken for treatment comparisons in Cohort 1.  
Cohort 2 involves treatment with open label etrolizumab and has no control arm, data 
will be summarized descriptively.
For Cohort 3, to control for multiple testing the primary efficacy treatment comparison will 
take place for placebo vs. etrolizumab 210 mg, where both endpoints need to be 
statistically significant at the 5% significance level.  The testing for the etrolizumab 
105 mg dose group will follow thereafter, and is described further in Section 4.4.5.
The estimands for the pivotal Cohort 3 primary analysis is described below.
4.4.4.1
Definition of Co-Primary Estimand: Clinical Remission
The estimand corresponding to clinical remission at Week 14 is described by the 
following attributes:
a)
Population:  Adult patients with moderate to severely active CD who have 
experienced intolerance, refractory disease or no response to one of CS therapy, IS 
therapy or anti-TNF therapy.  See Protocol Synopsis section of Protocol Version 7 
for the full list of inclusion/exclusion criteria.
b)
Variable:  Clinical remission at Week 14, measured using stool frequency and 
abdominal pain scores averaged over 7 days.
c)
Intercurrent Events Strategy:  Patients with an ICE due to treatment 
discontinuation, use of rescue therapy, or death as highlighted in Section 4.4.3, will 
be considered as treatment failures and therefore, non-responders under the 
composite strategy.  COVID-19 is not considered an ICE for this endpoint as it is not 
likely to impact a patient’s ability to enter eDiary data.
d)
Treatment: The treatment of interest is etrolizumab 210mg, which will be compared 
to a placebo treatment group.
e)
Population-Level Summary:  Difference in the proportion of patients in clinical 
remission at Week 14 between placebo and etrolizumab 210 mg in Cohort 3.
Definition:
Clinical remission is defined as a SF mean daily score3 and AP mean daily score1, 
with no worsening in either sub-score compared to baseline, averaged over 7 days.  For 
details of calculations, see Section 4.6.


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Analysis Methods:
The following hypothesis will be tested:
Null hypothesis H0: etrolizumab 210 mg Placebo0; the proportion of patients 
achieving clinical remission at Week 14 in the placebo arm is the same as the proportion 
of patients achieving clinical remission in the etrolizumab 210 mg arm.
Alternative hypothesis H1: etrolizumab 210 mg Placebo ≠ 0; the proportion of 
patients achieving clinical remission at Week 14 in the placebo arm is not the same as 
the proportion of patients achieving clinical remission in the etrolizumab 210 mg arm.
Clinical remission at Week 14 will be analyzed as described in Section 4.4.1.
4.4.4.2
Definition of Co-Primary Estimand: Endoscopic Improvement
The estimand corresponding to endoscopic improvement at Week 14 is described by the 
following attributes:
a)
Population:  Adult patients with moderate to severely active CD who have 
experienced intolerance, refractory disease or no response to one of CS therapy, IS 
therapy or anti-TNF therapy.  See Protocol Synopsis section of Protocol Version 7 
for the full list of inclusion/exclusion criteria.
b)
Variable:  Endoscopic improvement at Week 14, as measured by the SES-CD 
score.
c)
Intercurrent Events Strategy:  ICE are outlined in Section 4.4.3 and the strategy 
described for binary endpoints will be employed i.e., a composite strategy.  In other 
words, patients with an ICE due to treatment discontinuation, use of rescue therapy, 
or death, will be considered as treatment failures and therefore, non-responders.  
For COVID-19 related ICE, since no additional data are collected at time-points 
other than Weeks 14 and 66, a multiple imputation approach will be used as detailed 
in Section 4.10.
d)
Treatment: The treatment of interest is etrolizumab 210 mg, which will be compared 
to a placebo treatment group.
e)
Population-Level Summary:  Difference in proportion of patients achieving 
endoscopic improvement at Week 14 between placebo and etrolizumab 210 mg in 
Cohort 3.
Definition:
Endoscopic improvement is defined as a 50% reduction in the baseline SES-CD score.  
For details of the scoring methodology and handling of partial scores, see Section 4.6.


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Analysis Methods:
The following hypothesis will be tested:
Null hypothesis H0: etrolizumab 210 mg Placebo 0; the proportion of patients 
achieving endoscopic response at Week 14 in the placebo arm is the same as the 
proportion of patients achieving endoscopic response in the etrolizumab 210 mg arm.
Alternative hypothesis H1: etrolizumab 210 mg Placebo ≠ 0; the proportion of 
patients achieving endoscopic response at Week 14 in the placebo arm is not the same 
as the proportion of patients achieving endoscopic response in the etrolizumab 210 mg 
arm.
Endoscopic response at Week 14 will be analyzed as described in Section 4.4.1.
4.4.5
Missing Data Handling Methods for Induction Co-Primary 
Endpoints
The handling of ICE explained in Section 4.4.2 will be applied before using the missing 
data handling approaches in this Section.  The handling of ICE will be applied in the 
order that the ICE occurs within the study. 
Patients with insufficient daily diary entries (fewer than 4 out of the 7 days) for 
calculation of the weekly average will be flagged.  For these patients, the 7-day window 
will be extended to up to 3 additional days to a maximum of a 10-day window until there 
are at least 4 diary entries available.  For example, if diary entries are only available for 3 
out of the 7 days prior to the visit, the 4th entry will be used from either the 8th, 9th, or 
10th day, depending on when the 4th entry is first observed.  Clinical remission will then 
be determined as defined in Section 4.4.4.1.  If at least 4 diary entries are not available 
using the extended 10 day window, patients will be set to non-responders.  Patients will 
be flagged if their clinical remission is calculated using the extended 10 window, and 
separate sensitivity analyses will be performed to assess robustness under alternative 
data handling methods, see Section 4.4.6.
Missing data on endoscopic improvement at Week 14 will be assumed to be missing at 
random (MAR) and imputed using Multivariate Imputation by Chained Equations (MICE) 
as described by White et. al. (2011).  This is a popular Multiple Imputation (MI) approach 
and is detailed in Section 4.10.       Details for the handling of partially available data are 
described in Section 4.6, here the method of adjusting for segments available at 
baseline will be used as the main analysis method.


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4.4.6
Sensitivity Analyses for Induction Co-Primary Endpoints
Sensitivity analyses will be carried out on both co-primary endpoints using the following 
methods:

A logistic regression model using the same stratification factors used in the CMH 
test for the primary analysis as covariates. The adjusted rates and differences will 
be reported.  

CMH test using stratification factors obtained from the electronic Case Report Form
instead of IxRS, if data is discrepant between the two data sources (e.g.,10% 
discrepancy for a stratification factor)

A Fisher’s Exact test will also be performed on both co-primary endpoints. For 
endoscopic improvement, this will be performed on non-responder imputed data 
only and for clinical remission it will be performed on the data imputed using the 
extended 10 day window.
Additionally, to assess the robustness of analyses and sensitivity to departures from the 
missing data assumptions, the following analyses will be produced.  

Non-responder imputation (replacing widening the window to 10 days for clinical 
remission, and replacing MI for endoscopic improvement). 

Multiple imputation for imputing missing data in clinical remission without widening 
the window.

A tipping point analysis will be conducted to explore the impact of independently 
varying the MAR assumptions about missing outcomes on the two treatments arms 
of interest i.e., etrolizumab 210mg and placebo. This will be performed as a 
sensitivity to the missing data handling methods for both co-primary endpoints. The 
handling of ICEs corresponding to the composite strategy (i.e., withdrawal, rescue 
therapy, death) will remain unchanged in the tipping point analysis and patients will 
be set to non-responders. For endpoints with COVID-19 as an ICE, these will be 
included in the tipping point analysis along with the patients with otherwise missing 
data to test the MAR assumptions. The tipping point analysis is described further in 
Section 4.10.1
4.4.7
Supplementary Analyses
The following analysis will be carried out for the endoscopic endpoints:

Endoscopic 50% improvement/remission using all available data (i.e., no adjustment 
for segments available at Baseline
4.4.8
Induction Secondary Efficacy Endpoints
4.4.8.1
Control of Type I Error
The testing of the co-primary and key secondary endpoints will undergo a multiple 
testing procedure to ensure that the family-wise control for type I error does not exceed 
5%.  For the context of multiple testing, the etrolizumab 210 mg dose will be considered 
as the co-primary endpoint, where testing of the etrolizumab 105 mg dose and all other 
secondary endpoints will be gated on success of the etrolizumab 210 mg co-primary.


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A hierarchical gatekeeping method will be employed, involving a mixture of serial and 
parallel testing.  A serial test will be applied to the endpoints of clinical remission and 
endoscopic improvement (Families 1 and 4 in Figure 1) and will therefore require 
statistical significance of both endpoints in order to proceed to the next family.
[Technical note: to achieve this, the two endpoints within the family will be treated as two 
sub-families, which will be ordered by the p-values where the sub-family with the lowest 
p-value will be considered first. The two sub-families will be tested using a truncated 
Hommel procedure with a truncation parameter of 1. The single endpoint of clinical 
remission at Week 6 (Families 3 and 6) will require statistical significance in order to 
proceed to the next family as only hypothesis is tested. For all other endpoints (Families 
2,5,7), testing of endpoints within a family will occur in parallel using a truncated Hommel 
procedure with a truncation value of 0.8, except for the last family (Family 7) which will 
use a regular Hommel test (truncation parameter of 1).  At each level of testing, the 
truncation parameter of 0.8 prioritizes power for the endpoints within a family, at the cost 
of a substantial drop in power to subsequent families in the event that at least one non-
significant result is obtained within the family.  Where testing occurs in parallel, the order 
of the endpoints for testing will be based on their raw p-values, and continuation to the 
next family may only take place if at least one endpoint is statistically significant, 
otherwise testing will stop.  After the hierarchy has stopped, any remaining secondary 
endpoints 
 will be considered as supportive information, 
and no claims of statistical significance will be made.  An ‘overview of efficacy results’ 
table will be generated that will show the adjusted and raw p-values to help guide
interpretation.  


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Figure 1
Multiple Testing Procedures for Induction Endpoints
CDAICrohn’s disease activity index; CD-PROCrohn’s disease patient reported outcome; 
Etroetrolizumab.
4.4.8.2
Estimand Definitions for Induction Secondary Efficacy 
Endpoints
For the secondary efficacy endpoints described in the proceeding sections, we define 
the following:

Population: Adult patients with moderate to severely active CD who have 
experienced intolerance, refractory disease or no response to one of CS therapy, IS 
therapy or anti-TNF therapy.  See Protocol Synopsis Section of Protocol Version 7 
for the full list of inclusion/exclusion criteria.

Intercurrent Events strategy: Patients with an ICE due to treatment 
discontinuation, use of rescue therapy, or death, as highlighted in Section 4.4.3, will 
be considered as treatment failure under the composite strategy and treated with an 
unfavorable outcome, i.e., non-responders for binary endpoints and WOCF for 
continuous endpoints.  Any COVID-related ICE (where relevant) will be handled
according to the hypothetical strategy.  The imputation approach will be dependent 
on the nature and frequency of collected data as detailed in Section 4.4.2.     

Treatment: The treatments of interest are the etrolizumab 105 mg and 210 mg 
treatment arms. These arms will be compared to the placebo treatment arm 
separately i.e., etrolizumab 105 mg vs placebo and etrolizumab 210 mg vs placebo
The remainder of attributes, namely, the variable and population-level summary, are 
defined for each secondary efficacy endpoint in the sections below.


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4.4.8.3
Crohn’s Disease Activity Index Remission at Week 14
The proportion of patients achieving CDAI remission at Week 14, as defined in
Appendix 1.  CDAI remission is measured using 8 weighted sub-scores.  Details of the 
scoring method and handling of missing sub-scores can be found in Section 4.6 and 
Section 4.10.
This will be analyzed as described in Section 4.4.1 for binary endpoints.  Patients in the 
placebo treatment arm will be compared with the etrolizumab 105 mg and 210 mg 
treatment arms separately using the difference in proportions of patients in CDAI 
remission at Week 14 in Cohort 3. 
COVID-19-related events are not to be considered as an ICE for the eDiary component 
of the CDAI score.
4.4.8.4
Endoscopic Remission at Week 14
The proportion of patients achieving endoscopic remission at Week 14, as defined in
Appendix 1.
This will be analyzed as described in Section 4.4.1 for binary endpoints.  Patients in the 
placebo treatment arm will be compared with the etrolizumab 105 mg and 210 mg 
treatment arms separately using the difference in proportions of patients in endoscopic 
remission at Week 14 in Cohort 3.  Patients with SES-CD scores that are not available
from any reader for Week 14 will be treated as missing and handled according to the 
approach outlined in Section 4.10.  Details for the handling of partially available data are 
described in Section 4.6, here the method of adjusting for segments available at 
Baseline will be used as the main analysis method.
4.4.8.5
Clinical Remission at Week 6
The proportion of patients achieving clinical remission at Week 6, as defined in
Appendix 1.  Clinical remission at Week 6 is measured using SF and AP averaged over 
at least 4 out of the 7 days prior to the visit. 
This will be analyzed as described in Section 4.4.1 for binary endpoints.  Patients in the 
placebo treatment arm will be compared with the etrolizumab 105 mg and 210 mg 
treatment arms separately using the difference in proportions of patients in clinical 
remission at Week 6 in Cohort 3.  If less than 4 days diary entries are available out of the 
7 days prior to the visit, then the data will be flagged and handled according to the 
approach outlined in Section 4.10. 
COVID-19-related events are not to be considered as an ICE for the eDiary data.
4.4.8.6
Crohn’s Disease-Patient Reported Outcome/Signs and 
Symptoms Score at Week 14-Functional Domain
The change from baseline at Week 14 in CD-PRO/SS score for the functional domain.


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This will be analyzed as described in Section 4.4.1 for continuous endpoints.  The mean 
change from baseline to Week 14 CD-PRO/SS score for the functional domain will be 
estimated in Cohort 3 for each of the etrolizumab 105 mg and 210 mg treatment arms 
and compared to the placebo treatment arm separately using difference of means.  
Missing CD-PRO/SS score for the functional domain at Week 14 will be imputed using 
the MMRM as described in Section 4.10.
4.4.8.7
Crohn’s Disease-Patient Reported Outcome/Signs and 
Symptoms Score at Week 14-Bowel Domain
The change from baseline at Week 14 in CD-PRO/SS score for the bowel domain.
This will be analyzed as described in Section 4.4.1 for continuous endpoints.  The mean 
change from baseline to Week 14 CD-PRO/SS score for the bowel domain will be 
estimated in Cohort 3 for each of the etrolizumab 105 mg and 210 mg treatment arms 
and compared to the placebo treatment arm using difference of means.  Missing 
CD-PRO/SS score for the bowel domain at Week 14 will be imputed using the MMRM as 
described in Section 4.10.
4.4.9
Maintenance Co-Primary Efficacy Endpoints
The Maintenance Phase of Study GA29144 has two co-primary efficacy endpoints:  
clinical remission and endoscopic improvement, both measured at Week 66.  To control 
for multiple testing, both endpoints will need to be statistically significant for the co-
primary endpoint to be deemed as significant.
4.4.9.1
Definition of Co-primary Estimand: Clinical Remission
The estimand corresponding to clinical remission at Week 66 is described by the 
following attributes:
a)
Population:  Adult patients that achieved a CDAI-70 response at Week 14 without 
the use of rescue therapy, and who were randomized to etrolizumab 105 mg or 
210 mg in Cohorts 13 as Induction therapy.  See Protocol Synopsis Section of 
Protocol Version 7 for the full list of inclusion/exclusion criteria.
b)
Variable:  Clinical remission at Week 66, measured using stool frequency and 
abdominal pain averaged over 7 days.
c)
     Intercurrent Events Strategy:  ICE are outlined in Section 4.4.3 and the 
strategy described for binary endpoints will be employed i.e., a composite strategy.  
In other words, patients with an ICE due to treatment discontinuation, use of rescue 
therapy, or death, will be considered as treatment failures and therefore, non-
responders.  COVID-19 is not considered to be an ICE for this endpoint as it is not 
likely to impact a patient’s ability to enter eDiary data.
d)
Treatment: The treatment of interest is etrolizumab/etrolizumab 105 mg, which will 
be compared to the etrolizumab/placebo treatment group.


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e)
Population-Level Summary:  Difference in proportion of patients in clinical 
remission at Week 66 between etrolizumab/etrolizumab 105 mg and 
etrolizumab/placebo in the Maintenance Phase.
Definition:
Clinical remission is defined as a SF mean daily score3 and AP mean daily score1, 
with no worsening in either sub-score compared to baseline, averaged over the 7 days 
prior to visit.  For details of calculations, see Section 4.6.
Analysis Methods:
The following hypothesis will be tested:
Null hypothesis H0:  etrolizumab/etrolizumab 105 mg etrolizumab/Placebo0; the 
proportion of patients achieving clinical remission at Week 66 in the etrolizumab/placebo 
arm is the same as the proportion of patients achieving clinical remission in the 
etrolizumab/etrolizumab 105 mg arm.
Alternative hypothesis H1:  etrolizumab/etrolizumab 105 mg etrolizumab/Placebo 
≠ 0; the proportion of patients achieving Clinical Remission at Week 66 in the 
etrolizumab/placebo arm is not the same as the proportion of patients achieving Clinical 
Remission in the etrolizumab/etrolizumab 105 mg arm.
Clinical remission at Week 66 will be analyzed as described in Section 4.4.1.
4.4.9.2
Definition of Co-primary Estimand: Endoscopic Improvement
The estimand corresponding to endoscopic improvement at Week 66 is described by the 
following attributes:
a)
Population:  Adult patients that achieved a CDAI-70 response at Week 14 without 
the use of rescue therapy, and who were randomized to etrolizumab 105 mg or 
210 mg in Cohorts 1-3 as Induction therapy.  See protocol synopsis from Protocol 
Version 7 for the full list of inclusion/exclusion criteria.
b)
Variable:  Endoscopic improvement at Week 66, as measured by the SES-CD 
score.
c)
Intercurrent Event Strategy:  Patients with an ICE due to treatment 
discontinuation, use of rescue therapy, or death, as highlighted in Section 4.4.3, will 
be considered as treatment failures and therefore, non-responders under the 
composite strategy.  For COVID-19 related ICE, under the hypothetical strategy, 
since no additional data are collected at time-points other than Weeks 14 and 66, a 
MI approach will be used as detailed in Section 4.10.
d)
Treatment: The treatment of interest is etrolizumab/etrolizumab 105mg, which will 
be compared to the etrolizumab/placebo treatment group.
e)
Population-Level Summary:  Difference in proportion of patients achieving 
endoscopic improvement at Week 66 between etrolizumab/etrolizumab 105mg and 
etrolizumab/placebo in the Maintenance Phase.


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Definition
Endoscopic improvement is defined as a 50% reduction in the baseline SES-CD score.  
For details of calculations, see Section 4.6.
Analysis Methods
The following hypothesis will be tested:
Null hypothesis H0: etrolizumab/etrolizumab 105 mg etrolizumab/Placebo0; the 
proportion of patients achieving endoscopic response at Week 66 in the 
etrolizumab/placebo arm is the same as the proportion of patients achieving endoscopic 
response in the etrolizumab/etrolizumab 105 mg arm.
Alternative hypothesis H1: etrolizumab/etrolizumab 105 mg etrolizumab/Placebo 
≠ 0; the proportion of patients achieving endoscopic response at Week 66 in the 
etrolizumab/placebo arm is not the same as the proportion of patients achieving 
endoscopic response in the etrolizumab/etrolizumab 105 mg arm.
Endoscopic response at Week 66 will be analyzed as described in Section 4.4.1.
4.4.10
Missing Data Handling Methods for Maintenance Co-Primary 
Endpoints
The handling of ICE explained in Section 4.4.3 will be applied before using the missing 
data handling approaches in this section.  The handling of ICE will be applied in the 
order that the ICE occurs within the study. 
Patients with insufficient daily diary entries (less than 4 out of the 7 days) for calculation 
of the weekly average will be flagged.  For these patients, the 7-day window will be 
extended to up to 3 additional days to a maximum of a 10-day window until there are at 
least 4 diary entries available.  For example, if diary entries are only available for 3 out of 
the 7 days prior to the visit, the 4th entry will be used from either the 8th, 9th, or 10th 
day, depending on when the 4th entry is first observed.  Clinical remission will then be 
determined as defined in Section 4.4.4.1.  If at least 4 diary entries are not available
using the extended 10 day window, patients will be set to non-responders.  Patients will 
be flagged if their clinical remission is calculated using the extended 10 window, and 
separate sensitivity analyses will be performed to assess robustness under alternative 
data handling methods, see Section 4.4.11.  Missing data on endoscopic improvement 
at Week 66 will be assumed to be MAR and imputed using MICE as described by 
White et. al. (2011). This approach is detailed in Section 4.10.  Details for the handling 
of partially available data are described in Section 4.6, here the method of adjusting for 
segments available at baseline will be used as the main analysis method.


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4.4.11
Sensitivity Analyses for Maintenance Co-Primary Endpoints
Sensitivity analyses will be carried out on both co-primary endpoints using:

A logistic regression model using the same stratification factors used in the CMH 
test for the primary analysis as covariates. The adjusted rates and differences will 
be reported.

A Fisher’s Exact test will also be performed on both co-primary endpoints. For 
endoscopic improvement, this will be performed on non-responder imputed data 
only and for clinical remission it will be performed on the data imputed using the 
widened windows.
Additionally, to assess the robustness of analyses and sensitivity to departures from the 
missing data assumptions, the following analyses will be produced:

Non-responder imputation (replacing widening the window for clinical remission, and 
MI for endoscopic improvement). 

Multiple imputation for imputing missing data in clinical remission without widening 
the window.

A tipping point analysis will be conducted to explore the impact of independently 
varying the assumptions about missing outcomes on the two treatments arms of 
interest i.e., etrolizumab/etrolizumab 105 mg and etrolizumab/placebo. This will be 
performed as a sensitivity to the missing data handling methods for both co-primary 
endpoints (handling of ICE will remain unchanged). The tipping point analysis is 
described further in Section 4.10.1.
4.4.12
Supplementary Analyses
The following analysis will be carried out for the endoscopic endpoints:

Endoscopic 50% improvement/remission using all available data (i.e., no adjustment 
for segments available at baseline
In addition, a supplementary analysis will be done on each Maintenance co-primary 
endpoint with an alternative estimand with the following change to the population 
attribute:

Population:  Adult patients that achieved a CDAI-100 response at Week 14 without 
the use of rescue therapy, and who were randomized to etrolizumab 105 mg or 
210 mg in Cohorts 13 as Induction therapy.  See Protocol Synopsis Section of 
Protocol Version 7 for the full list of inclusion/exclusion criteria.
All other attributes will remain the same.
4.4.13
Maintenance Secondary Efficacy Endpoints
4.4.13.1
Control of Type 1 Error
The testing of the co-primary and key secondary endpoints will undergo a multiple 
testing procedure to ensure that the family-wise control for type I error does not exceed 
5%.


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The study for the Maintenance Phase will be considered positive if both clinical 
remission and endoscopic improvement endpoints at Week 66 demonstrate statistical 
significance at the 5% significance level. 
A hierarchical gatekeeping method will be employed for the key secondary endpoints, 
involving a mixture of serial and parallel testing.  A serial test will be applied to the
endpoints of clinical remission at Week 66 and endoscopic improvement at Week 66 
(Family 1 in Figure 2) and will therefore require statistical significance of both endpoints 
in order to proceed to the next family.  To achieve this, Family 1 will be treated as two 
sub-families, which will be ordered by the p-values where the sub-family with the lowest 
p-value will be considered first. The two sub-families will be tested using a truncated 
Hommel procedure with a truncation parameter of 1. The endpoint of durable remission 
(Family 4) will require statistical significance in order to proceed to the next family since 
there is only one hypothesis being tested.  For all other endpoints (Families 2,3,5), 
testing of endpoints within a family will occur in parallel using a truncated Hommel 
procedure; Families 2 and 3 will involve a truncated test using a truncation value of 0.5, 
and Family 5 will use a regular Hommel test (with a truncation parameter of 1).  For 
Families 2, 3, and 5, the order of the endpoints for testing will be based on their raw p-
values, and continuation to the next family (if applicable) may only take place if at least 
one endpoint is significant, otherwise testing will stop.  A truncation parameter of 0.5 
preserves power for endpoints in families lower down the hierarchy, with the trade-off for 
a reduction in power for endpoints within families higher up the hierarchy.  After the 
hierarchy has stopped, any remaining secondary endpoints 
 
will be considered as supportive information, and no claims of statistical significance will 
be made. 
The secondary endpoints of corticosteroid-free (24 weeks) clinical remission and 
endoscopic improvement among Week 14 endoscopic improvers will not be formally 
controlled for type I error; nominal p-values will be presented.


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Figure 2
Multiple Testing Procedure for Maintenance Endpoints
CDAICrohn’s Disease Activity Index; CD-PRO/SSCrohn’s Disease-Patient Reported 
Outcome/Signs and Symptoms.
4.4.13.2
Estimand Definitions for Maintenance Secondary Efficacy 
Endpoints
For the secondary efficacy endpoints described in the proceeding sections, we define 
the following:

Population:  Adult patients that achieved a CDAI-70 response at Week 14 without 
the use of rescue therapy, and who were randomized to etrolizumab 105 mg or 
210 mg in Cohorts 13 as Induction therapy.  See Protocol Synopsis of Protocol
Version 7 for the full list of inclusion/exclusion criteria.

Intercurrent Event strategy:  Patients with an ICE due to treatment 
discontinuation, use of rescue therapy, or death, as highlighted in Section 4.4.3, will 
be considered as treatment failure under the composite strategy and treated with an 
unfavourable outcome i.e., non-responders for binary endpoints and WOCF for 
continuous endpoints.  Any COVID-related ICE (where relevant) will be handled 
according to the hypothetical strategy.  The imputation approach will be dependent 
on the frequency of collected data as detailed in Section 4.4.2.

Population-Level Summary:  Difference between etrolizumab/etrolizumab 105mg 
and etrolizumab/placebo in the Maintenance Phase.

Treatment: The treatment of interest is etrolizumab/etrolizumab 105mg, which will 
be compared to a etrolizumab/placebo treatment group.


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The remainder of the attributes, namely, the variable and population-level summary are 
defined for each secondary efficacy endpoint in the sections below, including any other 
more refined definition of the patient population.
4.4.13.3
Crohn’s Disease Activity Index Remission at Week 66
The proportion of patients in CDAI remission at Week 66, as defined in Appendix 1.  
CDAI remission is measured using 8 weighted sub-scores.  Details of the scoring 
method and handling of missing sub-scores can be found in Section 4.6 and
Section 4.10.
This will be analyzed as described in Section 4.4.1 for binary endpoints.  Patients in the 
etrolizumab/placebo treatment arm will be compared with the etrolizumab/etrolizumab 
105 mg treatment arm using the difference in proportions.
COVID-19-related events are not to be considered as an ICE for the eDiary component 
of the CDAI score.
4.4.13.4
Clinical Remission at Week 66 among Patients in Clinical 
Remission in Week 14
The proportion of patients in clinical remission (as defined in Appendix 1) at Week 66, 
among the subset of Maintenance mITT population achieving clinical remission at 
Week 14.  Clinical remission is measured using SF and AP averaged over at least 4 out 
of the 7 days prior to the visit.
This will be analyzed as described in Section 4.4.1 for binary endpoints.  Patients in the 
etrolizumab/placebo treatment arm will be compared with the etrolizumab/etrolizumab 
105 mg treatment arm using the difference in proportions.  If less than 4 days diary 
entries are available out of the 7 days prior to the visit, then the data will be flagged and 
handled according to the approach outlined in Section 4.10.
COVID-19-related events are not to be considered as an ICE for eDiary data.
4.4.13.5
Corticosteroid-free Clinical Remission at Week 66 among 
Patients Receiving Corticosteroids at Baseline
The proportion of patients achieving clinical remission and are not taking oral 
corticosteroids at Week 66, among the subset of Maintenance mITT population receiving 
oral corticosteroids at baseline.
This will be analyzed as described in Section 4.4.1 for binary endpoints, except the oral 
corticosteroid stratification factor will be dropped.  Patients in the etrolizumab/placebo 
treatment arm will be compared with the etrolizumab/etrolizumab 105 mg treatment arm 
using the difference in proportions.  If less than 4 days diary entries are available out of 
the 7 days prior to the visit, then the data will be flagged and handled according to the 
approach outlined in Section 4.10.


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4.4.13.6
Endoscopic Remission at Week 66
The proportion of patients achieving endoscopic remission at Week 66, as defined in
Appendix 1.
This will be analyzed as described in Section 4.4.1 for binary endpoints.  Patients in the 
etrolizumab/placebo treatment arm will be compared with the etrolizumab/etrolizumab 
105 mg treatment arm using the difference in proportions. Patients with SES-CD scores 
that are not available from any reader for Week 66 will be treated as missing and 
handled according to the approach outlined in Section 4.10.  Details for the handling of 
partially available data are described in Section 4.6, here the method of adjusting for 
segments available at Baseline will be used as the main analysis method.
4.4.13.7
Endoscopic Improvement at Week 66 among Patients 
Achieving Endoscopic Improvement at Week 14
The proportion of patients achieving endoscopic improvement at Week 66, among the 
subset of Maintenance mITT population achieving endoscopic improvement at Week 14. 
Patients with no available SES-CD score at Week 14 are excluded and not considered.
This will be analyzed as described in Section 4.4.1 for binary endpoints.  Patients in the 
etrolizumab/placebo treatment arm will be compared with the etrolizumab/etrolizumab 
105 mg treatment arm using the difference in proportions.  Patients with SES-CD scores 
that are not available from any reader will be treated as missing and handled according 
to the approach outlined in Section 4.10.  Details for the handling of partially available 
data are described in Section 4.6, here the method of adjusting for segments available at 
baseline will be used as the main analysis method.
4.4.13.8
Durable Clinical Remission
The proportion of patients achieving durable clinical remission during the Maintenance 
Phase, defined as achieving clinical remission in at least 4 of the 6 in-clinical 
assessment visits (Weeks 24, 28, 32, 44, 56, and 66), which must include the Week 66 
visit.
This will be analyzed as described in Section 4.4.1 for binary endpoints.  Patients in the 
etrolizumab/placebo treatment arm will be compared with the etrolizumab/etrolizumab 
105 mg treatment arm using the difference in proportions.  If less than 4 days diary 
entries are available out of the 7 days prior to the visit at Weeks 24, 28, 32, 44, and 56, 
then the data will be considered missing and handled according to the approach outlined 
in Section 4.10.
4.4.13.9
Corticosteroid-Free Clinical Remission for 24 Weeks at 
Week 66 among Patients Receiving Corticosteroids at Baseline
The proportion of patients achieving clinical remission at Week 66 and are not taking 
oral CS for at least 24 weeks prior to Week 66.  This analysis will be performed among 
the subset of Maintenance mITT population who were receiving oral corticosteroids at 
baseline.


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This will be analyzed as described in Section 4.4.1 for binary endpoints.  Patients in the 
etrolizumab/placebo treatment arm will be compared with the etrolizumab/etrolizumab 
105 mg treatment arm using the difference in proportions.  If less than 4 days diary 
entries are available out of the 7 days prior to the visit, then the data will be considered 
missing and handled according to the approach outlined in Section 4.10.
4.4.13.10
Crohn’s Disease-Patient Reported Outcome/Signs and 
Symptoms Score at Week 66-Functional Domain
The change from baseline at Week 66 in CD-PRO/SS score for the functional domain.
This will be analyzed as described in Section 4.4.1 for continuous endpoints.  The mean 
change from baseline to Week 66 CD-PRO/SS score for the functional domain will be 
estimated for the etrolizumab/etrolizumab 105 mg treatment arm and compared to the 
etrolizumab/placebo treatment arm using difference of means.  Missing CD-PRO/SS 
score for the functional domain at Week 66 will be imputed using the MMRM as 
described in Section 4.10.
4.4.13.11
Crohn’s Disease-Patient Reported Outcome/Signs and 
Symptoms Score at Week 66 – Bowel Domain
The change from baseline at Week 66 in CD-PRO/SS score for the bowel domain.  
This will be analyzed as described in Section 4.4.1 for continuous endpoints.  The mean 
change from baseline to Week 66 CD-PRO/SS score for the bowel domain will be 
estimated for the etrolizumab/etrolizumab 105 mg treatment arm and compared to the 
etrolizumab/placebo treatment arm using difference of means.  Missing CD-PRO/SS 
score for the bowel domain at Week 66 will be imputed using the MMRM as described in
Section 4.10.
 
 
 
 
 
 
 




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4.4.15
Subgroup Analyses
The following subgroup analyses will be conducted on the co-primary endpoints for both 
the Induction and Maintenance Phase. 

TNF status 

CS at baseline

IS at baseline 

CDAI score at baseline

Age

Gender 

Region 

ADA status

Disease location 

Disease duration

Induction dose – Maintenance only
Subgroup categories may be combined if numbers are too low (e.g., n10) to ensure a 
meaningful assessment.
4.5
INTERIM ANALYSIS
The GA29144 study contains distinct patient cohorts for the Induction phase, where the 
cohorts are independent of each other.  Cohorts 1 and 2 are exploratory Induction 
cohorts that have been unblinded and analyzed previously by the Sponsor to support 
decision making for Cohort 3.  In particular, Cohort 1 was considered to be a Phase II 
study within the GA29144 Phase III trial, and Cohort 2 is open-label etrolizumab without 
a placebo control arm. 
After all patients in Cohort 1 completed the Week 14 visit (or withdrew early), a 
preliminary, exploratory analysis was performed that led to the Protocol being amended 
in global version 6 for the following: 

Primary endpoint for Induction and Maintenance

Inclusion criteria

Reduced sample size for Cohort 3 due to changes in type I error control strategy for 
testing of the two etrolizumab doses 
The protocol amendment took place prior to enrollment of any patients in Cohort 3.
A summary of the preliminary results for key endpoints will be included in the CSR for 
background and context.  The CSR main results section however will report data from 
Cohorts 1 and 2 using the final locked database.  It is acknowledged that data may 


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change slightly between the preliminary and final analysis, although these are expected 
to be minimal.  Further, it is acknowledged that the analysis methods may differ.
No interim analysis is planned for the pivotal Induction Phase (i.e., Cohort 3) or for the 
pivotal Maintenance Phase analysis.
No type I error adjustment for evaluating multiple Induction cohorts will be undertaken 
since the pivotal analysis for Induction will take place on an independent set of patients 
(Cohort 3).  Furthermore, no analyses have been conducted on the Maintenance Phase 
data, and treatment assignment for the pivotal treatment arms in Maintenance Phase 
(i.e., etrolizumab/placebo and etrolizumab/etrolizumab 105 mg) remains blinded to the 
Sponsor until formal database lock.
4.6
EFFICACY DERIVATIONS
4.6.1
Study Day 1 Definition
Study Day 1 is defined as the day of first receipt of study drug.
4.6.2
Baseline Definition
Baseline is defined as the last available assessment prior to first receipt of study drug.
4.6.3
Abdominal Pain and Liquid/Soft Stool Frequency
Patients are to report their symptoms daily throughout the duration of study using the e-
diary devices provided by the Sponsor.  The AP and SF scores will be determined 
weekly, as follows:
The score will be taken as the average of 4-7 daily scores within a 7-day window.  Since 
the endoscopy procedure and associate bowel preparations will affect outcomes, the 
selected scores used in the calculation will exclude the days surrounding such 
procedures.  Therefore, the 7 days will be taken prior to the earliest of the following 
dates:

Visit date or projected date (if visit date unavailable/not applicable)

Endoscopy date - 1

Bowel preparation date
At least 4 (not necessarily consecutive) non-missing scores will need to be available to 
calculate the average; otherwise the patient’s score will be flagged as missing.
The abdominal pain is reported on a 0-3 ordinal scale (0none, 1mild, 2moderate, 
3severe), stool frequency denotes the number of loose or liquid stools passed by the 
patient.  A higher score indicates worse disease activity for both abdominal pain and 
stool frequency.


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4.6.4
Crohn’s Disease Activity Index
The CDAI score is a composite endpoint of 8 sub-scores that are weighted and summed 
together, as shown in Appendix 9 of the Protocol, Version 7.  Sub-scores 1-3 consist of 
patient reported outcomes, as reported daily using e-diaries provided by the Sponsor.  
Sub-scores 4-8 are assessed by the investigator at site visits.  The CDAI score ranges 
from 0-600, where higher scores indicate worse disease activity.
CDAI Remission is defined as an absolute CDAI score150. 
CDAI-70 response is defined as a decrease from CDAI baseline score of at least 
70 points.
CDAI-100 response is defined as a decrease from CDAI baseline score of at least 
100 points.
4.6.5
Simplified Endoscopic Score for Crohn’s Disease
The SES-CD assessment consists of 20 individual component scores, where 
4 characteristics are measured across 5 segments of the intestine.  Each score can take 
a value between 0-3, giving rise to an overall SES-CD total score of 0-60, with higher 
scores indicating worse disease.
The endoscopic assessment will undergo an independent central reading process, 
where up to 3 readers (local reader, central reader 1, and central reader 2) will 
determine a SES-CD score via an adjudication model.  It should be noted that during 
Cohort 1 Induction phase, all three readers were always required, and a fixed 2 point 
scale adjudication model was used to determine subject eligibility.  This later changed to 
a sliding scale adjudication model, and the 2nd central reader was only requested if 
required (i.e., non-agreement of the first two readers).  For analysis purposes to ensure 
consistent handling across cohorts, the sliding scale adjudication model will be used for 
all endoscopic outcomes described in this SAP.  Details of the adjudication process can 
be found in the Bioclinica Independent Review Charter, latest Version this includes 
details for both the 2 point scale and sliding scale models.
Partial scores may arise when less than 20 individual scores are available for evaluation.  
In particular, scores for an entire segment may be missing due narrowing, video quality 
(applicable to central reads only), or procedural reasons at site.  Three data handling 
methods will be used and are described below; this will take place at a reader level when 
determining the total SES-CD score for a given reader, unless specified otherwise.




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4.7
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Patients in all cohorts will be required to provide blood samples for population 
pharmacokinetic (PK) analysis and pharmacodynamics (PD) characterization. 


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Patients had the option to consent and participate in a PK/PD sub study to collect 
samples at additional time points.
4.7.1
Pharmacokinetic Analyses
Serum concentrations at various times during Induction and Maintenance Phases will be 
listed and summarized by descriptive summary statistics including means, geometric 
means, ranges, standard deviation and coefficients of variation.  Analyses will be split by 
treatment group and cohort as appropriate.
Individual and mean concentration versus time data will be tabulated and plotted if more 
than two post dose time points are available.
The PK data from each Cohort will be combined to form a population PK analysis, 
details of which will be documented in a separate PK analysis plan.  Population typical 
value of PK parameters will be estimated for the entire study population, along with 
estimates of intra/interpatient variance and estimation of random error.  Individual patient 
parameter estimates will be computed using the post hoc analysis procedure. Impacts 
of covariates on relevant PK parameters will also be evaluated.
4.7.2
Pharmacodynamic Analyses
PD biomarkers to be analyzed are as follows:

Serum concentrations of sMAdCAM-1 (in all study enrolled patients)

7 receptor occupancy on peripheral blood “intestinal” homing beta7high T and B 
lymphocyte subsets as measured by flow cytometry (data from patients enrolled in 
the PKPD sub-study only)
Data will be evaluated based on availability, and expressed as percentage of pre-dose 
baseline value over time.  Absolute value and/or percentage change from baseline will 
be listed and summarized by descriptive summary statistics at each study time point, 
including but not limited to means, standard deviation, medians, minimum and 
maximum.  Analyses will be split by treatment group and cohort as appropriate.
Additional 
 analyses or modelling may be conducted as appropriate.
4.8
BIOMARKER ANALYSES
Additional biomarker strategies and analyses will be detailed in the Biomarker Analysis 
Plan (BAP).
4.9
SAFETY ANALYSES
Safety data will be assessed through descriptive summaries using the Induction and 
Maintenance Safety populations respectively.  All data available up until the clinical 
cut-off date (CCOD) will be reported.  No formal statistical comparisons between 
treatment groups will be conducted.


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Safety evaluations for the Induction Safety population will include data from first dose of 
treatment in the Induction Phase until the earliest of the following: withdrawal during the 
Induction treatment period (including withdrawal at Week 14 for patients not eligible for 
Maintenance), first Maintenance dose, withdrawal or completion of Safety Follow-Up.  
Safety evaluations for the Maintenance Safety Population will include data from first 
dose of treatment in the Induction Phase (i.e., data from the Induction Phase will be 
included) until the latest of the following: withdrawal from the Maintenance treatment 
period, completion of Maintenance treatment period, withdrawal or completion of Safety 
Follow-Up.
4.9.1
Exposure to Study Drug
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
A listing of any dosing errors (i.e., incorrect treatment received) will be produced, if 
applicable.
In the event that a treatment group cannot be attributed to a Kit ID, it will be assumed 
that the patient received the planned (i.e., randomized) treatment.
4.9.2
Adverse Events
Adverse events (AEs) will include all terms recorded on the AE Case Report Form (CRF) 
pages (except pregnancies).  For each recorded AE, the term entered by the investigator 
describing the event (the “reported term”) will be assigned a standardized term (the 
“preferred term”) and assigned to a superclass term on the basis of the Medical 
Dictionary for Regulatory Activities (MedDRA) World Health Organization (WHO) 
dictionary of terms.  All analyses of AE data will be performed using the preferred terms 
unless otherwise specified.
For 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


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
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

Injection site reactions
A listing and if applicable, summary table (e.g., n10) of all AEs suspected, confirmed or 
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 each individual 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 or any worsening of an 
existing condition on or after the first dose of study drug.  If the onset date of the AE is 
prior to the day of first dose, the AE will be considered treatment emergent only if the 
most extreme intensity is greater than the initial intensity (i.e., the intensity for a given AE 
increases and its end date is on or after the date of the first dose).  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 each treatment group, 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.


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To account for potential exposure differences between arms during the Maintenance 
phase (e.g., due to differences in drop-out rate), 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:
 	 (	 100 	 	) =
   !"#
   $% &#  %#' ( 100
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 the Induction phase up until the patient 
completes/withdraws from the study.
All summary tables and listings will report AEs using the safety population split by 
treatment arm. For the Induction phase, cohorts will be summarized separately.  
In addition to evaluations on the Maintenance Safety Population which include AEs 
during the Induction phase, evaluations will also be made on the Maintenance Safety 
Population that only include AEs that occur during the Maintenance Phase (i.e., AEs 
occurring during Induction will be excluded).
4.9.3
Laboratory Data
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2ULN as defined by Hy’s law

ALT or AST3 ULN
4.9.4
Immunogenicity
The number and percentage of patients with positive serum antibodies to etrolizumab at 
baseline and during the study will be summarized by treatment arm.
4.9.5
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.
4.9.6
Electrocardiogram
A shift table for the qualitative ECG assessments will produced, summarizing the 
Baseline and worst post-baseline results.


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4.9.7
Medical History
Medical history data collected in the electronic-CRF (eCRF) 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.
4.9.8
Concomitant Medications
Concomitant medications include any medication being used at any time from first dose 
of study drug through to 7 days after last dose of study drug, or medication being used at 
any time up to the start of study treatment.  The data will be summarized, and report the 
total number of patients taking at least one medication, and total number of medications.  
Summaries will also be split by medication class and preferred medication.  Medication 
terms will be mapped and reported using the WHO drug dictionary.
4.10
MISSING DATA
Missing data for longitudinal continuous endpoints (e.g., CD-PRO/SS) will be imputed as 
part of the MMRM analysis framework, as described in Section 4.4.1.
For e-diary data excluding CD-PRO/SS, patients with insufficient daily diary entries (less 
than 4 out of the 7 days) for calculation of the weekly average will be flagged.  For these 
patients, the 7-day window will be extended up to 3 additional days to a maximum of a 
10-day window until there are 4 diary entries available.  For example, if diary entries are 
only available for 3 out of the 7 days prior to the visit, the 4 h entry will be used from 
either the 8th, 9th, or 10th day, depending on when the 4 h entry is first observed.  These 4 
entries will then be used to define clinical remission, and to calculate the 7-day total 
needed for the CDAI sub-component.  If 4 diary entries are not available within the 
extended 10-day window, patients will be set to non-responders in the clinical remission 
and CDAI endpoints respectively.  Patients will be flagged if their clinical remission is 
calculated using the extended 10 day window, and separate sensitivity analyses will be 
performed to assess robustness under alternative missing data handling methods (see
Sections 4.4.6 and 4.4.11).
All other data that are exploratory or descriptive in nature will handle missing data as 
detailed in Appendix 2
Missing data for endoscopy endpoints at Weeks 14 and 66 will be imputed using Multiple 
Imputation as described in Section 4.10.2.1. 
4.10.1
Sensitivity Analysis
Sensitivity and robustness to LOCF, using a wider 10 day window for e-diary data, and 
departures from missing data assumptions in MICE, will be investigated using non-
responder imputation (NRI) for the co-primary endpoints.


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In addition, to assess robustness of the approach for imputing missing values, multiple 
imputation will be performed for the clinical remission (see Section 4.10.2.2) and CDAI 
remission (see Section 4.10.2.3) endpoints as sensitivity analyses.
A tipping point analysis will be conducted to explore the impact of varying the 
assumptions about missing outcomes (MAR) on the treatments arms of interest e.g.,
etrolizumab 210 mg and placebo or etrolizumab/etrolizumab 105 mg and 
etrolizumab/placebo.  This will be performed as a sensitivity to the missing data handling 
methods for co-primary endpoints for induction and maintenance. The tipping point is 
defined as the difference in the number of missing data on clinical remission/endoscopic 
improvement between the treatment groups that result in a change in the primary 
outcome conclusions (Yan et al. 2009).  A two-dimensional plot will be produced for 
each primary comparison of the etrolizumab arm vs. the comparator to evaluate where 
the tipping point lies. The clinical plausibility of the combinations on the boundary will be
discussed in the CSR to evaluate robustness of study conclusions to missing data.
Within the tipping point analysis, the intercurrent events of withdrawal, rescue therapy 
and death will continue to follow the composite strategy and will be set to non-
responders. COVID-19 is an intercurrent event for the endoscopy co-primary endpoint 
only and yields non-observable data due to the pandemic impact making the site based 
assessments unfeasible. The patients with non-observable data due to COVID-19 
intercurrent event will also be included in the tipping point analysis to test the MAR 
assumption that was implied in the multiple imputation model used in the primary 
analysis method.
4.10.2
Multiple Imputation Strategy
The endpoints below will be imputed using a Fully Conditional Specification (FCS) 
logistic regression model. This is also known as multiple imputation by chained 
equations (MICE) and will follow the method described in White et. al (2011).  The model 
for imputation was developed based on Cohort 1 unblinded data for Induction and 
blinded data for all Cohorts in Maintenance. Development of the imputation model for 
each of the endpoints is described below and follows guidance by White et. al (2011) 
and van Buuren et. al (1999). Separate imputation models for each Induction and 
Maintenance phase were chosen. Data will be imputed after implementing the ICE 
strategy for events that relate to treatment withdrawals, rescue medications and death 
which will be handled by non-responder imputation under the composite strategy. 
COVID-19 related events for CDAI and Endoscopy endpoints and any other remaining 
missing data (i.e., true missing data), will be multiply imputed.
A candidate list of variables was put forward based on clinical knowledge and significant 
predictors for inclusion in the final imputation model were chosen using a stepwise 
model selection procedure using the corrected AIC method. The imputation model will 
also include treatment and all IxRS stratification factors as listed in Section 4.4.2 for both 
Induction and Maintenance as forced variables for inclusion in the analysis model. 


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Correlations were also investigated between the auxiliary variables and the endpoint of 
interest, where point-biserial correlation was investigated between the continuous 
variables and the binary endpoint of interest. If correlation exceeded |0.2|, these would 
be included in the final imputation model regardless of the results from the model 
selection procedure.  The selection of auxiliary variables was performed individually for 
each endpoint in Induction and Maintenance. However, for consistency, the union of 
significant auxiliary variables for each endpoint was chosen as a single final imputation 
model. 
The number of burn-in iterations of 100 and a seed of 983164 will be used with 15 
imputed datasets. A Wilson-Hilferty transformation is also applied to the CMH test 
statistic for normalization (Ratitch et al. 2013). Newcombe confidence intervals were 
obtained for the difference in proportions estimated from the CMH test. The standard 
errors associated with the Newcombe confidence intervals for the difference in 
proportions from the CMH test are also required in order to pool analyses using Rubin’s 
rules. However, this is not obtained as part of the CMH output in SAS. Therefore, these 
were calculated using the following:
)** + =
(,	-.+/0	 1	 2/ −,	-.+/0	 2+-	 2/)
4
Where 4 = 3.29 for 90% confidence intervals, or 4 = 3.92 for 95% confidence intervals 
(Higgins et al. 2021).
4.10.2.1
Imputation Model for Endoscopy Endpoints
Patients with partially available SES-CD scores are handled as part of the efficacy 
derivations, see Section 4.6.5.  Providing that an ICE has not occurred (as described in 
Section 4.4.3), patients where SES-CD scores that are not available from any reader will 
be treated as missing and assumed to be MAR. This will lead to missing response for 
endoscopic improvement and endoscopic remitters for the following endpoints:

Induction:
–
Endoscopic Improvement at Week 14
–
Endoscopic Remission at Week 14
–
SES-CD=0 at Week 14 

Maintenance:
–
Endoscopic Improvement at Week 66
–
Endoscopic Remission at Week 66
–
Endoscopic Improvement at Week 66 Among Patients Achieving Endoscopic 
Improvement at Week 14
–
SES-CD=0 at Week 66


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The SES-CD0 endpoint is highly difficult to achieve, with few patients available to 
provide a reliable imputation model. Patients with missing data will be considered as 
non-responders for this endpoint.
The final imputation model for the Induction endpoints included the following:

Treatment group (etrolizumab 105 mg, etrolizumab 210 mg, or Placebo)

Concomitant oral CS treatment at baseline (yes or no)

Prior anti-TNF exposure at baseline (yes or no)

Baseline CDAI330 (yes or no)

Sex

Age at Baseline

Albumin Level at Baseline

Average AP score at Baseline

Average AP score at Week 10

Average AP score at Week 14

Average SF score at Baseline

Average SF score at Week 10

Average SF score at Week 14

SES-CD Score at Baseline

Disease location
The final imputation model for the Maintenance endpoints included the following:

Treatment group (etrolizumab/etrolizumab or etrolizumab/Placebo)

Induction dose regimen (high or low etrolizumab)

Concomitant oral CS treatment at baseline (yes or no)

Prior anti-TNF exposure at baseline (yes or no)

Immunosuppressant use (yes or no)

Sex

CDAI score at Baseline

Disease Duration

SES-CD score at Baseline


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
SES-CD score at Week 14

Average AP score at Baseline

Average AP score at Week 32

Average SF score at Baseline

Average SF score at Week 14

Average SF score at Week 32

Average SF score at Week 56

Average SF score at Week 66

Albumin Level at Baseline

Albumin Level at Week 14

Albumin Level at Week 66

Baseline Age
The endoscopic improvement at Week 66 among patients achieving endoscopic 
improvement at Week 14 will only be conducted in the subset of patients with non-
missing data at Week 14.
4.10.2.2
Imputation Model for Clinical Remission
Patient symptom data was extensively collected during the study using daily diaries, this 
data provides a weekly assessment of the patient’s disease severity. The patient’s 
abdominal pain and stool frequency scores at key timepoints during the study were 
selected preferentially to predict the missing Week 14/66 timepoint. 
The variables to be included in the final multiple imputation model for clinical remission 
at Week 14 are:

Induction treatment (etrolizumab 105 mg, etrolizumab 210 mg or Placebo)

Prior aTNF experience (Yes or No)

Corticosteroid use at baseline (Yes or No)

Baseline CDAI score (330 or330)

Average AP and average SF at Baseline

Average AP and average SF at Week 6

Average AP and average SF at Week 13

Average AP and average SF at Week 14


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The variables to be included in the final multiple imputation model for clinical remission 
at Week 66 are:

Maintenance treatment (etrolizumab 105 mg or Placebo)

Induction treatment (etrolizumab 105 mg or etrolizumab 210 mg)

Prior aTNF experience (Yes or No)

Corticosteroid use at baseline (Yes or No)

Average AP and average SF at Week 32

Average AP and average SF at Week 56

Average AP and average SF at Week 65

Average AP and average SF at Week 66
4.10.2.3
Imputation Model for CDAI Remission
In addition to applying ICE strategies before imputation, any patients with partial CDAI 
scores available that sum to more than 150 will be imputed to non-remitters. Since the 
CDAI score is formed from 8 sub-scores, the CDAI sub-scores were included in the 
model preferentially over baseline disease characteristics and laboratory data (except 
haematocrit). Sub-scores that are ordinal will be treated as factors in the model to 
ensure only valid numeric values are imputed by the model (e.g., abdominal mass can 
only take values of 0, 20 or 50).
The variables to be included in the final multiple imputation model for CDAI remission at 
Week 14 are:

Induction treatment (etrolizumab 105 mg, etrolizumab 210 mg or Placebo)

Prior aTNF experience at baseline (Yes or No)

Corticosteroid use at baseline (Yes or No)

Baseline CDAI score (330 or330)

All 8 weighted CDAI subscores at Baseline

All 8 weighted CDAI subscores at Week 10

All 8 weighted CDAI subscores at Week 14
The variables to be included in the final imputation model for CDAI remission at Week 66 
are:

Maintenance treatment (etrolizumab 105 mg or Placebo)

Induction treatment (etrolizumab 105 mg or etrolizumab 210 mg)

Prior aTNF experience at baseline (Yes or No)

Corticosteroid use at baseline (Yes or No)

All 8 weighted CDAI subscores at Week 32

All 8 weighted CDAI subscores at Week 56


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
All 8 weighted CDAI subscores at Week 66


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5.
REFERENCES
Higgins JPT, Li  and Deeks JJ. Chapter 6: Choosing effect measures and computing 
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Etrolizumab—F. Hoffmann-La Roche Ltd
58/Statistical Analysis Plan GA29144
Appendix 2 Summary of Imputation Methods for Intercurrent 
Events (ICE) and Missing Data
INDUCTION PHASE
Endpoint
Intercurrent Event (Strategy)
Missing Data
Treatment 
Discontinuation
(Composite)
Rescue 
Medication
(Composite)
Death
(Composite)
COVID-19
(Hypothetical)
Primary Efficacy Endpoints
Clinical Remission 
at Week 14 
NRI
NRI
NRI
n/a
10 day 
window/NRI*
Endoscopic 
Improvement at 
Week 14 
NRI
NRI
NRI
MI
MI
Secondary Efficacy Endpoints
Clinical Remission 
at Week 6
NRI
NRI
NRI
n/a
10 day 
window/NRI*
Endoscopic 
Remission 
at Week 14
NRI
NRI
NRI
MI
MI
CD-PRO/SS 
Score 
at Week 14 
(Functional & 
Bowel Domain)
WOCF
WOCF
WOCF
MMRM
MMRM
CDAI Remission 
at Week 14
NRI
NRI
NRI
LOCF for non-
diary sub-
components; 
retain 
minimum 4/7 
day window 
for diary data 
LOCF for 
non-diary 
sub-
components; 
10 day 
window for 
diary 
components/
NRI* 


Etrolizumab—F. Hoffmann-La Roche Ltd
59/Statistical Analysis Plan GA29144
Appendix 2 Summary of Imputation Methods for Intercurrent 
Events (ICE) and Missing Data (cont.)
MAINTENANCE PHASE
Endpoint
Intercurrent Event (Strategy)
Missing Data
Treatment 
Discontinuation
(Composite)
Rescue 
Medication
(Composite
)
Death
(Compo
site)
COVID-
19
(Hypothe
tical)
Primary Efficacy Endpoints
Clinical Remission at Week 66 
NRI
NRI
NRI
n/a
10 day 
window/NRI*
Endoscopic Improvement at 
Week 66 
NRI
NRI
NRI
MI
MI
Secondary Efficacy Endpoints
Clinical Remission at Week 66 
Among Patients in Clinical 
Remission at Week 14
NRI
NRI
NRI
n/a
10 day 
window/NRI*
Endoscopic Improvement at 
Week 66 Among Patients 
Achieving Endoscopic 
Improvement at Week 14
NRI
NRI
NRI
MI
MI
Endoscopic Remission 
at Week 66
NRI
NRI
NRI
MI
MI
CDAI Remission 
at Week 66
NRI
NRI
NRI
LOCF for 
non-diary 
sub-
compone
nts; 
retain 
minimum 
4/7 day 
window 
for diary 
data
LOCF for 
non-diary 
sub-
components; 
10 day 
window for 
diary 
components/
NRI* 
CD-PRO/SS Score 
at Week 66 (Functional & 
Bowel Domain)
WOCF
WOCF
WOCF
MMRM
MMRM
Durable Clinical Remission 
WOCF
WOCF
WOCF
n/a
10 day 
window/NRI*
Corticosteroid-Free Clinical 
Remission for 24 Weeks at 
Week 66 Among Patients 
Receiving Corticosteroids at 
Baseline
NRI
NRI
NRI
n/a
10 day 
window/NRI*


Etrolizumab—F. Hoffmann-La Roche Ltd
60/Statistical Analysis Plan GA29144
Appendix 2 Summary of Imputation Methods for Intercurrent 
Events (ICE) and Missing Data (cont.)


Etrolizumab—F. Hoffmann-La Roche Ltd
61/Statistical Analysis Plan GA29144
Appendix 2 Summary of Imputation Methods for Intercurrent 
Events (ICE) and Missing Data (cont.)
CDAI Crohn’s Disease Activity Index; CD Crohn’s Disease; CD-PRO/SS Crohn’s 
Disease- Patient Reported Outcome/Signs and Symptoms (functional, bowel, 
 
domains); COVID-19 Coronavirus Disease-19; LOCF last observation carried forward; 
MI multiple imputation; MMRM mixed models for repeated measures; NRInon-responder 
imputation; SES-CD simplified endoscopic index for Crohn’s disease; WOCF worst-
observation-carried-forward.
* The 10 day extended window will first be applied, followed by non-responder imputation if 4 
days ediary data aren’t available within a maximum of 10 days.