Conditions: Ulcerative Colitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 195
Healthy volunteers: no

Brief summary:
This study is designed to evaluate the efficacy, safety, and pharmacokinetics of UTTR1147A compared with vedolizumab and with placebo in the treatment of participants with moderate to severe UC. This study will consist of two parts, Part A and Part B. Part A will test the induction of clinical remission and Part B will test the durability of clinical remission.

Detailed description:

Arms:
arm 1: Part A: UTTR1147A dose level 1 and Vedolizumab Placebo.

Part B: UTTR1147A maintenance dose and Vedolizumab Placebo. arm 2: Part A: UTTR1147A dose level 1 and Vedolizumab Placebo.

Part B: UTTR1147A Placebo and Vedolizumab Placebo. arm 3: Part A: UTTR1147A dose level 2 and Vedolizumab Placebo.

Part B: UTTR1147A maintenance dose and Vedolizumab Placebo. arm 4: Part A: UTTR1147A dose level 2 and Vedolizumab Placebo.

Part B: UTTR1147A Placebo and Vedolizumab Placebo. arm 5: Part A: UTTR1147A dose level 3 and Vedolizumab Placebo.

Part B: UTTR1147A maintenance dose and Vedolizumab Placebo. arm 6: Part A: UTTR1147A dose level 3 and Vedolizumab Placebo.

Part B: UTTR1147A Placebo and Vedolizumab Placebo. arm 7: Parts A and B: Vedolizumab and UTTR1147A Placebo. arm 8: Parts A and B: UTTR1147A Placebo and Vedolizumab Placebo.

Interventions: intervention 1: UTTR1147A intervention 2: UTTR1147A Placebo intervention 3: Vedolizumab intervention 4: Vedolizumab Placebo
Intervention descriptions: intervention 1: UTTR1147A will be administered intravenously (IV) at dose levels 1, 2, or 3 in Part A, and at the maintenance dose level in Part B, per the respective arm descriptions. intervention 2: The matching placebo to UTTR1147A (UTTR1147A Placebo) will be administered IV. intervention 3: Vedolizumab will be administered IV, as specified in the prescribing information. intervention 4: The matching placebo to vedolizumab (Vedolizumab Placebo) will be administered IV.

Protocol document:
Prot_SAP_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered.
Efmarodocokin Alfa—Genentech, Inc.
Protocol GA39925, Version 7
PROTOCOL
TITLE:
A PHASE II, RANDOMIZED, PARALLEL-GROUP, 
DOUBLE-BLIND, DOUBLE-DUMMY, PLACEBO-CONTROLLED, 
MULTICENTER STUDY TO EVALUATE THE EFFICACY, 
SAFETY, AND PHARMACOKINETICS OF UTTR1147A 
COMPARED WITH PLACEBO AND COMPARED WITH 
VEDOLIZUMAB IN PATIENTS WITH MODERATE TO SEVERE 
ULCERATIVE COLITIS
PROTOCOL NUMBER:
GA39925
VERSION NUMBER:
7
EUDRACT NUMBER:
2017-002350-36
IND NUMBER:
136180
NCT NUMBER:
NCT03558152
TEST PRODUCT:
Efmarodocokin alfa (UTTR1147A, RO7021610)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
Genentech, Inc.
DATE FINAL:
Version 1:  6 July 2017
 
Company Signatory
Approver's Name
Title
Date and Time (UTC)
26-Jul-2021 20:25:51


Efmarodocokin Alfa—Genentech, Inc.
2/Protocol GA39925, Version 7
DATES AMENDED:
Version 2:  16 November 2017
Version 3:  26 January 2018
Version 3 (VHP):  27 March 2018
Version 4:  30 March 2018
Version 4 (VHP):  18 July 2018
Version 5:  28 February 2020
Version 6:  8 April 2021
Version 7:  See electronic date stamp.


Efmarodocokin Alfa—Genentech, Inc.
3/Protocol GA39925, Version 7
PROTOCOL AMENDMENT, VERSION 7:
RATIONALE
Protocol GA39925 has been amended to align with the Investigator Brochure update 
(Version 8, April 2021) to include 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Efmarodocokin Alfa—Genentech, Inc.
4/Protocol GA39925, Version 7
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


Efmarodocokin Alfa—Genentech, Inc.
5/Protocol GA39925, Version 7
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 28
1.1
Background on ulcerative colitis ............................................ 28
1.2
Background on Efmarodocokin Alfa ...................................... 28
1.2.1
Summary of Nonclinical Studies............................................ 29
1.2.2
Summary of Clinical Studies.................................................. 29
1.3
Study Rationale and Benefit-Risk Assessment...................... 30
2.
OBJECTIVES AND ENDPOINTS ............................................................... 32
3.
STUDY DESIGN......................................................................................... 35
3.1
Description of the Study......................................................... 35
3.1.1
Overview of Study Design ..................................................... 35
3.1.2
Part A..................................................................................... 38
3.1.3
Part B..................................................................................... 39
3.1.4
Safety Follow-Up Period and Early Termination 
Visit........................................................................................ 40
3.1.5
Open-Label Extension Study GA40209................................. 41
3.1.6
Internal Monitoring Committee............................................... 41
3.2
End of Study and Length of Study......................................... 42
3.3
Rationale for Study Design.................................................... 42
3.3.1
Rationale for Efmarodocokin Alfa Dose and 
Schedule................................................................................ 42
3.3.2
Rationale for Patient Population ............................................ 43
3.3.3
Rationale for Placebo Control Group..................................... 44
3.3.4
Rationale for Active Comparator............................................ 45
3.3.5
Rationale for Pharmacokinetic Sample Collection................. 45
3.3.6
Rationale for Biomarker Assessments................................... 45
4.
MATERIALS AND METHODS .................................................................... 46
4.1
Patients.................................................................................. 46
4.1.1
Inclusion Criteria.................................................................... 46


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4.1.2
Exclusion Criteria................................................................... 49
4.2
Method of Treatment Assignment and Blinding..................... 52
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 54
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 54
4.3.1.1
Efmarodocokin Alfa and Efmarodocokin Alfa 
Placebo.................................................................................. 54
4.3.1.2
Vedolizumab and Vedolizumab Placebo ............................... 54
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 54
4.3.2.1
Efmarodocokin Alfa and Efmarodocokin Alfa 
Placebo.................................................................................. 54
4.3.2.2
Vedolizumab and Vedolizumab Placebo ............................... 55
4.3.3
Investigational Medicinal Product Accountability ................... 55
4.3.4
Continued Access to Efmarodocokin Alfa.............................. 55
4.4
Concomitant Therapy and additional restrictions................... 56
4.4.1
Concomitant Therapy for UC (Including Rescue 
Therapy) ................................................................................ 56
4.4.2
Other Concomitant Therapy .................................................. 61
4.4.2.1
Other Permitted Concomitant Therapy .................................. 61
4.4.2.2
Other Prohibited Concomitant Therapy ................................. 61
4.4.3
Additional Restrictions ........................................................... 62
4.5
Study Assessments ............................................................... 62
4.5.1
Informed Consent Forms and Screening Log........................ 62
4.5.2
Re-Testing for Laboratory Inclusion and 
Exclusion Criteria................................................................... 62
4.5.3
Re-Screening......................................................................... 62
4.5.4
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 63
4.5.5
Physical Examinations........................................................... 64
4.5.6
Vital Signs.............................................................................. 64
4.5.7
Clinical Outcome Assessments ............................................. 64
4.5.7.1
Mayo Clinic Score, Modified Mayo Clinic Score, 
and Partial Mayo Clinic Score................................................ 64
4.5.7.2
Patient-Reported Outcomes .................................................. 65


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7/Protocol GA39925, Version 7
4.5.7.3
Physician's Global Assessment............................................. 67
4.5.7.4
Colonoscopy or Flexible Sigmoidoscopy with 
Colonic Biopsies.................................................................... 67
4.5.7.5
Other Clinical Indices............................................................. 68
4.5.8
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 69
4.5.9
Chest X-Ray .......................................................................... 71
4.5.10
Electrocardiograms................................................................ 72
4.5.11
Samples for Whole Genome Sequencing.............................. 73
4.5.12
Samples for Research Biosample Repository ....................... 74
4.5.12.1
Overview of the Research Biosample Repository.................. 74
4.5.12.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 74
4.5.12.3
Sample Collection.................................................................. 75
4.5.12.4
Confidentiality........................................................................ 75
4.5.12.5
Consent to Participate in the Research 
Biosample Repository............................................................ 76
4.5.12.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 76
4.5.12.7
Monitoring and Oversight....................................................... 77
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 77
4.6.1
Study Treatment Discontinuation........................................... 77
4.6.2
Patient Discontinuation from Study........................................ 78
4.6.3
Study Discontinuation............................................................ 78
4.6.4
Site Discontinuation............................................................... 79
5.
ASSESSMENT OF SAFETY....................................................................... 79
5.1
Safety Plan ............................................................................ 79
5.1.1
Risks Associated with Efmarodocokin Alfa............................ 79
5.1.1.1
Dermatologic Reactions......................................................... 79
5.1.1.2
Infusion-Related Reactions.................................................... 80
5.1.1.3
Epithelial Tumor Promotion ................................................... 80
5.1.1.4
Neutralization of Endogenous IL-22 by ADAs........................ 81


Efmarodocokin Alfa—Genentech, Inc.
8/Protocol GA39925, Version 7
5.1.1.5
Worsening Of Clotting/Coagulation Dysfunction 
In High Risk Populations Due To Increased 
Fibrinogen.............................................................................. 81
5.1.2
Risks Associated with Vedolizumab ...................................... 83
5.1.3
Management of Patients Who Experience 
Specific Adverse Events........................................................ 83
5.1.3.1
Dose Modifications ................................................................ 83
5.1.3.2
Treatment Interruption ........................................................... 83
5.1.3.3
Management Guidelines........................................................ 83
5.2
Safety Parameters and Definitions ........................................ 89
5.2.1
Adverse Events ..................................................................... 89
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 90
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 91
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 91
5.3.1
Adverse Event Reporting Period ........................................... 91
5.3.2
Eliciting Adverse Event Information....................................... 92
5.3.3
Assessment of Severity of Adverse Events ........................... 92
5.3.4
Assessment of Causality of Adverse Events ......................... 93
5.3.5
Procedures for Recording Adverse Events............................ 94
5.3.5.1
Infusion-Related Reactions.................................................... 94
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 94
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 95
5.3.5.4
Persistent or Recurrent Adverse Events................................ 95
5.3.5.5
Abnormal Laboratory Values ................................................. 96
5.3.5.6
Abnormal Vital Sign Values ................................................... 96
5.3.5.7
Abnormal ECG Findings........................................................ 97
5.3.5.8
Abnormal Liver Function Tests.............................................. 97
5.3.5.9
Deaths ................................................................................... 98
5.3.5.10
Preexisting Medical Conditions.............................................. 98
5.3.5.11
Lack of Efficacy or Worsening of Ulcerative 
Colitis..................................................................................... 98


Efmarodocokin Alfa—Genentech, Inc.
9/Protocol GA39925, Version 7
5.3.5.12
Hospitalization or Prolonged Hospitalization.......................... 99
5.3.5.13
Patient-Reported Outcome Data ........................................... 99
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 99
5.4.1
Emergency Medical Contacts.............................................. 100
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 101
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 101
5.4.2.2
Events That Occur after Study Drug Initiation...................... 101
5.4.3
Reporting Requirements for Pregnancies............................ 101
5.4.3.1
Pregnancies in Female Patients.......................................... 101
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 102
5.4.3.3
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................. 102
5.4.4
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error.............................................. 103
5.5
Follow-Up of Patients after Adverse Events ........................ 104
5.5.1
Investigator Follow-Up......................................................... 104
5.5.2
Sponsor Follow-Up .............................................................. 104
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 105
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 105
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 106
6.1
Determination of Sample Size ............................................. 106
6.2
Summaries of Conduct of Study.......................................... 106
6.3
Summaries of Demographic and Baseline 
Characteristics..................................................................... 107
6.4
Efficacy Analyses ................................................................ 107
6.4.1
Primary Efficacy Endpoint.................................................... 107
6.4.2
Secondary Efficacy Endpoints............................................. 108
6.4.3
Exploratory Efficacy Endpoints............................................ 108
6.5
Safety Analyses................................................................... 109
6.6
Pharmacokinetic Analyses................................................... 109


Efmarodocokin Alfa—Genentech, Inc.
10/Protocol GA39925, Version 7
6.7
Immunogenicity Analyses.................................................... 110
6.8
Biomarker Analyses............................................................. 110
6.9
Interim Analyses .................................................................. 111
6.9.1
Planned Interim Analysis ..................................................... 111
6.9.2
Optional Interim Analyses.................................................... 111
7.
DATA COLLECTION AND MANAGEMENT ............................................. 111
7.1
Data Quality Assurance....................................................... 111
7.2
Electronic Case Report Forms............................................. 112
7.3
Electronic Patient- and Clinician-Reported 
Outcome Data ..................................................................... 112
7.4
Source Data Documentation................................................ 112
7.5
Use of Computerized Systems ............................................ 113
7.6
Retention of Records........................................................... 113
8.
ETHICAL CONSIDERATIONS.................................................................. 114
8.1
Compliance with Laws and Regulations .............................. 114
8.2
Informed Consent................................................................ 114
8.3
Institutional Review Board or Ethics Committee.................. 115
8.4
Confidentiality...................................................................... 116
8.5
Financial Disclosure ............................................................ 116
8.6
Patient Recruitment ............................................................. 116
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 117
9.1
Study Documentation .......................................................... 117
9.2
Protocol Deviations.............................................................. 117
9.3
Site Inspections ................................................................... 117
9.4
Administrative Structure....................................................... 118
9.5
Publication of Data and Protection of 
Trade Secrets...................................................................... 118
9.6
Protocol Amendments ......................................................... 119
10. REFERENCES ......................................................................................... 120


Efmarodocokin Alfa—Genentech, Inc.
11/Protocol GA39925, Version 7
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 32
Table 2
Treatment Regimens .................................................................. 37
Table 3
Permitted and Prohibited Concomitant Therapies for UC ........... 57
Table 4
Guidelines for Management of Patients Who Experience 
Specific Adverse Events ............................................................. 86
Table 5
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 93
Table 6
Causal Attribution Guidance ....................................................... 94
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 36
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................ 124
Appendix 2
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Blood Samples......................................................... 130
Appendix 3
Mayo Clinic Score..................................................................... 132
Appendix 4
Modified Mayo Clinic Score....................................................... 133
Appendix 5
Partial Mayo Clinic Score.......................................................... 134
Appendix 6
Signs and Symptoms of UC Daily Diary.................................... 135
Appendix 7
Ulcerative Colitis Patient-Reported Outcome Signs and 
Symptoms (UC-PRO/SS) Instrument........................................ 136
Appendix 8
Inflammatory Bowel Disease Questionnaire (IBDQ) ................. 144
Appendix 9
Anaphylaxis Precautions........................................................... 147


Efmarodocokin Alfa—Genentech, Inc.
12/Protocol GA39925, Version 7
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE II, RANDOMIZED, PARALLEL-GROUP, 
DOUBLE-BLIND, DOUBLE-DUMMY, 
PLACEBO-CONTROLLED, MULTICENTER STUDY 
TO EVALUATE THE EFFICACY, SAFETY, AND 
PHARMACOKINETICS OF UTTR1147A COMPARED 
WITH PLACEBO AND COMPARED WITH 
VEDOLIZUMAB IN PATIENTS WITH MODERATE 
TO SEVERE ULCERATIVE COLITIS
PROTOCOL NUMBER:
GA39925
VERSION NUMBER:
7
EUDRACT NUMBER:
2017-002350-36
IND NUMBER:
136180
NCT NUMBER:
NCT03558152
TEST PRODUCT:
Efmarodocokin alfa (UTTR1147A, RO7021610)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
Genentech, Inc.
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 of 
the signed form as instructed by the CRO.


Efmarodocokin Alfa—Genentech, Inc.
13/Protocol GA39925, Version 7
PROTOCOL SYNOPSIS
TITLE:
A PHASE II, RANDOMIZED, PARALLEL-GROUP, 
DOUBLE-BLIND, DOUBLE-DUMMY, PLACEBO-CONTROLLED,
MULTICENTER STUDY TO EVALUATE THE EFFICACY, SAFETY, 
AND PHARMACOKINETICS OF UTTR1147A COMPARED WITH 
PLACEBO AND COMPARED WITH VEDOLIZUMAB IN PATIENTS 
WITH MODERATE TO SEVERE ULCERATIVE COLITIS
PROTOCOL NUMBER:
GA39925
VERSION NUMBER:
7
EUDRACT NUMBER:
2017-002350-36
NCT NUMBER:
NCT03558152
IND NUMBER:
136180
TEST PRODUCT:
Efmarodocokin alfa (UTTR1147A, RO7021610)
PHASE:
II
INDICATION:
Ulcerative colitis
SPONSOR:
Genentech, Inc.
Objectives and Endpoints
This study will evaluate the safety, efficacy, and pharmacokinetics of efmarodocokin alfa
compared with placebo and compared with vedolizumab in patients with moderate to severe 
ulcerative colitis (UC).  Specific objectives and corresponding endpoints for the study are 
outlined below.  Endoscopic scores will be based on interpretation by a central reader.  
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint
– To evaluate the efficacy of 
efmarodocokin alfa compared with 
placebo and compared with 
vedolizumab 
Clinical remission at Week 8, with clinical remission 
defined as meeting both of the following criteria:
– Modified MCS a of 2
– Mayo rectal bleeding subscore of 0 and other 
Mayo subscores of 1
ADAanti-drug antibody; IBDQ Inflammatory Bowel Disease Questionnaire; MCSMayo Clinic 
Score; NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events; 
PDpharmacodynamic; PK pharmacokinetic; UC-PRO/SSUlcerative ColitisPatient-Reported 
Outcome Signs and Symptoms.
Note:  Endoscopic scores will be based on interpretation by a central reader.
a Modified MCS is the composite of three MCS assessments:  stool frequency, rectal bleeding, 
and centrally read endoscopy.


Efmarodocokin Alfa—Genentech, Inc.
14/Protocol GA39925, Version 7
Objectives and Corresponding Endpoints (cont.)
Secondary Efficacy Objective
Corresponding Endpoints
– To evaluate the efficacy of 
efmarodocokin alfa compared with
placebo and compared with 
vedolizumab
Sustained remission, defined as clinical remission at 
both Week 8 and Week 30
Clinical response at Weeks 8 and 30, with clinical 
response defined as achieving clinical remission or
meeting both of the following criteria: 
– A 3-point decrease from baseline in modified 
MCS 
– A 1-point decrease from baseline in Mayo rectal 
bleeding subscore or a Mayo rectal bleeding 
subscore of 0 or 1
Endoscopic healing at Weeks 8 and 30, with 
endoscopic healing defined as a Mayo endoscopic 
subscore of 1
Endoscopic remission at Weeks 8 and 30, with 
endoscopic remission defined as a Mayo endoscopic 
subscore of 0
Change from baseline in UC bowel movement signs 
and symptoms at Week 8 and at Week 30, as 
assessed by UC-PRO/SS score
Change from baseline in UC abdominal signs and 
symptoms at Week 8 and at Week 30, as assessed 
by UC-PRO/SS score
Change from baseline in patientreported 
health-related QOL at Week 8 and at Week 30, as 
assessed by IBDQ score
Exploratory Efficacy Objective
Corresponding Endpoints
– To evaluate the efficacy of 
efmarodocokin alfa compared with 
placebo and compared with 
vedolizumab
Mucosal healing, defined as endoscopic healing and 
histological remission 6 as per Robarts Histological 
Index, at Weeks 8 and 30
Change from baseline in UC Endoscopic Index of 
Severity at Week 8 and at Week 30
Histological healing, defined as Nancy score of 0 or 1 
as per Nancy Histological Index, at Weeks 8 and 30
Change from baseline in Geboes Score at Week 8 
and at Week 30
Change from baseline in Robarts Histological Index at 
Week 8 and at Week 30
ADAanti-drug antibody; IBDQ Inflammatory Bowel Disease Questionnaire; MCSMayo Clinic 
Score; NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events; 
PDpharmacodynamic; PK pharmacokinetic; UC-PRO/SSUlcerative ColitisPatient-Reported 
Outcome Signs and Symptoms.
Note:  Endoscopic scores will be based on interpretation by a central reader.
a Modified MCS is the composite of three MCS assessments:  stool frequency, rectal bleeding, 
and centrally read endoscopy.


Efmarodocokin Alfa—Genentech, Inc.
15/Protocol GA39925, Version 7
Objectives and Corresponding Endpoints (cont.)
Safety Objective
Corresponding Endpoints
To evaluate the safety of 
efmarodocokin alfa compared with
placebo and compared with 
vedolizumab 
Occurrence and severity of adverse events, with 
severity determined according to NCI CTCAE scale 
Change in targeted vital signs, physical findings, and 
clinical laboratory test results during and following 
study drug administration
Pharmacokinetic Objective
Corresponding Endpoint
To characterize the pharmacokinetics of 
efmarodocokin alfa in patients with UC
Serum concentration of efmarodocokin alfa at 
specified timepoints
Exploratory Pharmacokinetic 
Objectives
Corresponding Endpoints
To evaluate potential relationships 
between drug exposure and the efficacy 
and safety of study drug
Relationship between serum concentration or PK 
parameters for study drug and efficacy endpoints
Relationship between serum concentration or PK 
parameters for study drug and safety endpoints
To identify covariates that have 
significant impact on the exposure to 
efmarodocokin alfa
Relationship between identified covariates and serum 
concentration or PK parameters for efmarodocokin 
alfa
Immunogenicity Objective
Corresponding Endpoint
To evaluate the immune response to 
efmarodocokin alfa
Presence of ADAs during the study relative to the 
presence of ADAs at baseline
Exploratory Immunogenicity Objective
Corresponding Endpoint
To evaluate potential effects of ADAs
Relationship between ADA status and efficacy, safety, 
or PK endpoints
Exploratory Biomarker Objective
Corresponding Endpoint
To identify biomarkers that are 
predictive of response to efmarodocokin 
alfa (i.e., predictive biomarkers), are 
associated with progression to a more 
severe disease state (i.e., prognostic 
biomarkers), are associated with 
susceptibility to developing adverse 
events (i.e., safety biomarkers), can 
provide evidence of efmarodocokin alfa
activity (i.e., pharmacodynamic 
biomarkers), or can increase the 
knowledge and understanding of 
disease biology
Relationship between biomarkers in blood, stool, and 
colonic tissue, and efficacy, safety, PK, 
immunogenicity, or other biomarker endpoints
ADAanti-drug antibody; IBDQ Inflammatory Bowel Disease Questionnaire; MCSMayo Clinic 
Score; NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events; 
PDpharmacodynamic; PK pharmacokinetic; UC-PRO/SSUlcerative ColitisPatient-Reported 
Outcome Signs and Symptoms.
Note:  Endoscopic scores will be based on interpretation by a central reader.
a Modified MCS is the composite of three MCS assessments:  stool frequency, rectal bleeding, 
and centrally read endoscopy.


Efmarodocokin Alfa—Genentech, Inc.
16/Protocol GA39925, Version 7
Study Design
Description of Study
This is a Phase II, randomized, parallel-group, double-blind, double-dummy, placebo-controlled, 
multicenter study to evaluate the efficacy, safety, and pharmacokinetics of efmarodocokin alfa
compared with placebo and compared with vedolizumab in the treatment of moderate to severe 
UC.
This study will consist of a screening period of up to 4 weeks, a 22-week treatment period, and 
an 8-week safety follow-up period.  Part A (Weeks 08) will test the induction of clinical 
remission.  The durability of clinical response and remission will be evaluated during Part B 
(Weeks 922) through the end of the safety follow-up period (Week 30).  Upon approval of 
open-label extension (OLE) Study GA40209 by local Institutional Review Boards/Ethics 
Committees (IRBs/ECs) and relevant health authorities, patients enrolled in this study will have
the opportunity to participate in OLE Study GA40209, if eligible.
Overall, patients will be randomly assigned in a 1:1:1:1:1:1:2:1 ratio to one of eight treatment 
arms as outlined below.
Treatment Regimens
Arm
Part A (Weeks 08)
Part B (Weeks 922)
Active Drug
Placebo
Active Drug
Placebo
1A
Efmarodocokin alfa
30 g/kg IV
at Weeks 0, 4, 8
VDZ placebo IV
at Weeks 0, 2, 6
Efmarodocokin 
alfa 60 g/kg IV
at Weeks 14 
and 22
VDZ placebo IV
at Weeks 14 and 22
1B
Efmarodocokin alfa
30 g/kg IV
at Weeks 0, 4, 8
VDZ placebo IV
at Weeks 0, 2, 6

VDZ placebo IV 
Efmarodocokin alfa
placebo IV
at Weeks 14 and 22
2A 
Efmarodocokin alfa
60 g/kg IV
at Weeks 0, 4, 8
VDZ placebo IV
at Weeks 0, 2, 6
Efmarodocokin 
alfa 60 g/kg IV
at Weeks 14 
and 22
VDZ placebo IV
at Weeks 14 and 22
2B 
Efmarodocokin alfa
60 g/kg IV
at Weeks 0, 4, 8
VDZ placebo IV
at Weeks 0, 2, 6

VDZ placebo IV 
Efmarodocokin alfa
placebo IV
at Weeks 14 and 22
3A 
Efmarodocokin alfa
90 g/kg IV
at Weeks 0, 4, 8
VDZ placebo IV
at Weeks 0, 2, 6
Efmarodocokin 
alfa 60 g/kg IV
at Weeks 14 
and 22
VDZ placebo IV
at Weeks 14 and 22
3B 
Efmarodocokin alfa
90 g/kg IV
at Weeks 0, 4, 8
VDZ placebo IV
at Weeks 0, 2, 6

VDZ placebo IV 
Efmarodocokin alfa
placebo IV
at Weeks 14 and 22
4
VDZ 300 mg IV
at Weeks 0, 2, 6
Efmarodocokin alfa
placebo IV
at Weeks 0, 4, 8
VDZ
300 mg IV
at Weeks 14 
and 22
Efmarodocokin alfa
placebo IV
at Weeks 14 and 22
IVintravenous infusion; VDZ vedolizumab.


Efmarodocokin Alfa—Genentech, Inc.
17/Protocol GA39925, Version 7
Treatment Regimens (cont.)
Arm
Part A (Weeks 08)
Part B (Weeks 922)
Active Drug
Placebo
Active Drug
Placebo
5

VDZ placebo IV
at Weeks 0, 2, 6
Efmarodocokin alfa
placebo IV
at Weeks 0, 4, 8

VDZ placebo IV 
Efmarodocokin alfa
placebo IV
at Weeks 14 and 22
IVintravenous infusion; VDZ vedolizumab.
Patient disposition during the study will be based on whether patients receive rescue therapy or 
meet criteria for clinical remission, clinical response or disease flare, as defined below:

Rescue therapy, defined as initiation of any treatment for UC or an increase in the dose of 
oral 5-aminosalicylic acid (5-ASA) or oral corticosteroids compared with baseline 
(randomization)
Cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, and anti-integrin agents are 
not permitted as rescue therapy.

Clinical remission, defined as meeting both of the following criteria:
–
Modified MCS of 2
–
Mayo rectal bleeding subscore of 0 and other Mayo subscores of 1

Clinical response, defined as either achieving clinical remission or as meeting both of the 
following criteria:
–
A 3-point decrease from baseline in modified Mayo Clinic Score (mMCS), defined as 
the composite of three MCS assessments:  stool frequency, rectal bleeding, and 
centrally read endoscopy 
–
A 1-point decrease from baseline in rectal bleeding subscore or a rectal bleeding 
subscore of 0 or 1

Disease flare, defined as meeting one of the following sets of criteria during Part B:
–
An increase from Week 8 in partial MCS (pMCS), defined as a composite of three MCS 
assessments:  stool frequency, rectal bleeding, and Physician's Global Assessment, of 
3 points and an absolute pMCS of 5 and an endoscopy subscore of 2 
–
An absolute pMCS score of 7 and an endoscopy subscore of 2 
Part A
During Part A, patients will receive IV infusions of efmarodocokin alfa, efmarodocokin alfa
placebo, vedolizumab, or vedolizumab placebo.  At Week 0 only, two IV infusions will be 
administered.  At Weeks 2, 4, 6, and 8, patients will receive one IV infusion (see treatment 
regimens outlined above).
At Week 8 and prior to study drug administration, patients will undergo a flexible sigmoidoscopy 
with biopsy and a full MCS will be assessed.  The mMCS and pMCS will be derived from the 
MCS.
Patients who receive rescue therapy and patients with persistent or worsening disease for 
which rescue therapy is indicated, as determined by the investigator, should return to the clinic 
as soon as possible for a disease evaluation visit, which will include a flexible sigmoidoscopy 
and MCS evaluation.  The disease evaluation visit should occur no later than 1 week after 
initiation of rescue therapy.
Patients who receive rescue therapy will discontinue study drug and undergo all scheduled 
clinic assessments through Week 8, with the exception of the flexible sigmoidoscopy if already 
performed at a disease evaluation visit.  Upon completion of the Week 8 visit, these patients 
may enroll in OLE Study GA40209, if eligible.


Efmarodocokin Alfa—Genentech, Inc.
18/Protocol GA39925, Version 7
Patients who meet the criteria for clinical response at Week 8 (without use of rescue therapy) 
will continue into Part B.  Patients who do not meet the criteria for clinical response will 
discontinue study drug and may enroll in OLE Study GA40209, if eligible. Study drug should 
not be administered at Week 8 if determination is made at the visit that patient will enroll in OLE 
Study GA40209.  
Patients who are ineligible for or choose not to enroll in OLE Study GA40209 will enter the 
safety follow-up period.
Part B
During Part B, patients will receive IV infusions of efmarodocokin alfa and vedolizumab placebo 
(Arms 1A, 2A, and 3A), efmarodocokin alfa placebo and vedolizumab placebo (Arms 1B, 2B, 3B, 
and 5), or vedolizumab and efmarodocokin alfa placebo (Arm 4) at Weeks 14 and 22 as per the 
treatment regimens outlined above.
For patients on concomitant oral corticosteroids at baseline, the corticosteroid dose will be 
tapered until discontinuation, starting at Week 8.
For patients who cannot tolerate the corticosteroid taper without recurrence of UC symptoms or 
experience symptoms of corticosteroid withdrawal, the corticosteroid dose can be increased.  If 
the corticosteroid dose has not been increased above the baseline level, these patients should 
re-initiate corticosteroid dose tapering per the above regimen within 2 weeks.  Patients who are 
unable to tolerate a second taper should discontinue study drug and enroll in OLE Study 
GA40209, if eligible.  Treatment with corticosteroids above the baseline dose will be considered 
rescue therapy.
Patients who receive rescue therapy and patients with worsening disease for which rescue 
therapy is indicated, as determined by the investigator, should return to the clinic as soon as 
possible for a disease evaluation visit, which will include a flexible sigmoidoscopy and MCS 
evaluation.  The disease evaluation visit should occur no later than 1 week after initiation of 
rescue therapy.
Patients who receive rescue therapy or experience disease flare will discontinue study drug 
and may enroll in OLE Study GA40209, if eligible.  Study drug should not be administered 
at Weeks 14 or 22 if determination is made at the visit that patient will enroll in OLE 
Study GA40209.  Patients who are ineligible for or choose not to enroll in OLE Study GA40209 
will enter the safety follow-up period.
Patients who complete Part B (i.e., through Week 22) will enter the safety follow-up period.
Safety Follow-Up Period and Early Termination Visit
Patients who complete the treatment period (Parts A and B) and patients who discontinue study 
drug without entering OLE Study GA40209 will enter the safety follow-up period and undergo 
assessments at 4 and 8 weeks after their last dose of study drug.  Patients who discontinue 
study drug prematurely should return to the clinic for an early termination visit within 1 week of 
the event and will then enter the safety follow-up period.  Patients who are unwilling to complete 
the safety follow-up period should return to the clinic for an early termination visit as soon as 
possible and no later than 30 days after their final dose.
A flexible sigmoidoscopy and MCS evaluation will be performed at second visit of safety 
follow-up, approximately 8 weeks after the last dose of study drug, if patient has completed 
the treatment period (Parts A and B) and 8-week safety follow-up, i.e., second visit of safety 
follow-up corresponds to Week 30 for that patient.  
Patients who complete the treatment period (Parts A and B) and the safety follow-up period may 
enroll in OLE Study GA40209, if eligible.
Open-Label Extension Study GA40209
Upon approval of OLE Study GA40209 by local IRBs/ECs and relevant health authorities, 
patients who enter OLE Study GA40209 at Week 8 or during Part B (i.e., do not complete 
maintenance treatment will receive treatment with open-label efmarodocokin alfa during OLE
Study GA40209.
Patients who enter OLE Study GA40209 after completing the treatment period (Parts A and B) 
and the safety follow-up period will receive treatment with open-label efmarodocokin alfa, if 
protocol-defined criteria are met.


Efmarodocokin Alfa—Genentech, Inc.
19/Protocol GA39925, Version 7
Number of Patients
Approximately 270 patients will be enrolled across global investigational sites.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Ability to comply with requirements of the study, in the investigator's judgment

Age 1880 years, inclusive, at time of signing Informed Consent Form

Diagnosis of UC established and confirmed by clinical and endoscopic evidence at least 
3 months prior to randomization
The diagnosis of UC should be corroborated by histopathology and documented by a 
histopathology report. A histopathologic examination should be performed at screening 
if no prior report is readily available.

Confirmation of moderate to severe UC, defined as an mMCS of 49 with an endoscopic 
subscore of 2 as determined by the central reading procedure, a rectal bleeding subscore
of 1, and a stool frequency subscore of 1 during the screening period (i.e., prior to 
Day 1)

Evidence of UC a minimum of 20 cm from the anal verge as determined by baseline 
endoscopy (flexible sigmoidoscopy or colonoscopy) 

Colonoscopy within 1 year prior to randomization that confirms left-sided colitis 
(inflammation up to the splenic flexure), extensive colitis (inflammation beyond the splenic 
flexure but not involving the entire colon), or pancolitis (inflammation of the entire colon) and 
includes both of the following:
−
Removal of any adenomatous polyps 
−
Performance of multiple random mucosal biopsies to evaluate for dysplasia in all 
patients with left-sided colitis of 12 years' duration or extensive colitis or pancolitis of 
8 years' duration 

Inadequate response, loss of response, or intolerance to prior immunosuppressant 
treatment (i.e., AZA, 6-MP, MTX, or TNF inhibitors [maximum of two prior TNF inhibitors]) 
and/or corticosteroid treatment
Inadequate response, loss of response, or intolerance to prior AZA, 6-MP, or MTX 
treatment is defined as one or more of the following:
−
Persistent signs or symptoms of active disease despite treatment with at least one 
12-week regimen of AZA (2 mg/kg/day), 6-MP (1 mg/kg/day), and/or 
MTX (25 mg/week) within the previous 5 years
−
Persistent signs or symptoms of active disease despite a 6-TG level of 
230 pmol/8 108 RBCs (as measured by quantitative high-performance liquid 
chromatography or liquid chromatography/tandem mass spectrometry) during at least 
one 12-week regimen of AZA or 6-MP within the previous 5 years
−
History of intolerance to AZA, 6-MP, or MTX (including, but not limited to, 
nausea/vomiting, abdominal pain, pancreatitis, liver function test abnormalities, 
lymphopenia, TPMT genetic mutation, or infection) within the previous 5 years
Inadequate response, loss of response, or intolerance to prior TNF inhibitor treatment is 
defined as one or more of the following: 
−
Persistent signs or symptoms of active disease despite treatment with at least two
induction doses of infliximab (5 mg/kg), adalimumab (160 mg for first two doses and 
80 mg for subsequent doses, or 80 mg for first two doses and 40 mg for subsequent 
doses), or golimumab (200 mg for first two doses and 100 mg for subsequent doses)
−
Recurrence of signs or symptoms of active disease during maintenance after initial 
response to induction therapy with infliximab (5 mg/kg), adalimumab (40 mg), or 
golimumab (100 mg)


Efmarodocokin Alfa—Genentech, Inc.
20/Protocol GA39925, Version 7
−
Intolerance to TNF inhibitor (including, but not limited to, injection-site reaction, 
demyelination, congestive heart failure, or infection)
Inadequate response, loss of response, or intolerance to prior corticosteroid treatment is 
defined as one or more of the following: 
−
Persistent symptoms of active disease despite treatment with at least one 4-week 
induction regimen that included 30 mg/day of oral prednisone (or equivalent) for at 
least 2 weeks or 30 mg/day of IV prednisone (or equivalent) for at least 1 week within 
the previous 5 years (corticosteroid refractory)
−
Two failed attempts to taper corticosteroids below 10 mg/day of oral prednisone (or 
equivalent) (corticosteroid dependent)
−
History of intolerance to corticosteroids (including, but not limited to, 
Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, or infection) 
within the previous 5 years (corticosteroid intolerant)

For patients receiving ongoing UC therapy with oral 5-ASA, oral corticosteroids, or oral 
probiotics:  stable dose as outlined below.
−
Oral 5-ASA at a dose that has been stable for at least 4 weeks at the time of
randomization
−
Oral corticosteroid therapy at a dose of 20 mg/day of prednisone (or equivalent) that 
has been stable for at least 2 weeks at the time of randomization
Oral probiotic (e.g., Culturelle, or Saccharomyces boulardii) at a dose that has been 
stable for at least 2 weeks at the time of randomization

For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 1% per year 
during the treatment period and for 18 weeks after the last dose of study drug
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices
(recommendations related to contraception and pregnancy testing in clinical trials, 
CTFG Final version – 2014-09-15, Section 4.1).
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception.

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for 18 weeks after 
the last dose of study drug to avoid exposing the embryo.  Men must refrain from 
donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception.

Immunizations current according to local standards as described in the vedolizumab 
prescribing information and/or based on the investigator’s clinical judgment

Agreement to refrain from donating blood for 6 months after receiving the last dose of study 
drug


Efmarodocokin Alfa—Genentech, Inc.
21/Protocol GA39925, Version 7
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of psoriasis or psoriatic arthritis

History of any other inflammatory skin disorders requiring oral corticosteroids, 
immunosuppressants, or biological therapy within the previous year

History of cancer within the previous 5 years 

History of non-melanoma skin cancer, gastrointestinal (GI) cancer, or colon cancer, or 
known family history of GI cancer or colon cancer (defined as one first-degree relative or 
two second-degree relatives)

History of a cervical intraepithelial neoplasia of Grade 1, cervical smear indicating the 
presence of adenocarcinoma in situ, or high-grade squamous intraepithelial lesions (HSILs) 

Conditions other than UC (e.g., asthma) that could require treatment with 20 mg/day of 
prednisone (or equivalent) during the course of the study

Poorly controlled diabetes, defined as glycosylated hemoglobin (HbA1c) 8.0%

History of primary sclerosing cholangitis

Requirement for hospitalization during the study due to severity of UC

Hospitalized (other than for elective reasons) within 4 weeks prior to screening

Any acute or chronic condition that, in the opinion of the investigator, would limit the 
patient's ability to complete or participate in this clinical study

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
18 weeks after the last dose of study drug

Lack of peripheral venous access

Significant uncontrolled comorbidity, such as cardiac (e.g., moderate to severe heart failure 
[New York Heart Association Class III or IV]), pulmonary, renal, hepatic, endocrine, or GI
disorders (excluding UC)

History or presence of an abnormal ECG that is clinically significant in the investigator’s 
opinion, including complete left bundle branch block, second- or third-degree 
atrioventricular heart block, or evidence of prior myocardial infarction

Family history of sudden unexplained death or long QT syndrome

QT interval corrected through use of Fridericia’s formula 450 ms (men) or 470 ms 
(women) demonstrated by at least two ECGs

History of alcoholism or drug abuse as judged by the investigator within 1 year of screening

If stipulated by local or national laws:  employed by the site, the Sponsor, or Sponsor 
representatives or financially dependent on, or related to, an employee of the site, the 
Sponsor, or Sponsor representatives

If stipulated by local or national laws:  institutionalization or detention by way of official or 
judicial order 

Prior extensive colonic resection, subtotal or total colectomy, or proctocolectomy, or 
planned surgery for UC

Diagnosis of indeterminate colitis or granulomatous (Crohn's) colitis

Suspicion of ischemic colitis, radiation colitis, or microscopic colitis

Diagnosis of toxic megacolon within 12 months prior to screening 

Current fistula or history of fistula

Current pericolonic abscess 

History or current evidence of unresectable colonic mucosal dysplasia

History of high-grade colonic mucosal dysplasia

Stricture (stenosis) of the colon

Prior treatment with efmarodocokin alfa or participation in Study GA29469


Efmarodocokin Alfa—Genentech, Inc.
22/Protocol GA39925, Version 7

Prior treatment with vedolizumab, etrolizumab, natalizumab, efalizumab, or any other 
anti-integrin agents

Use of IV corticosteroids within 30 days prior to randomization with the exception of a single 
administration of IV corticosteroids

Treatment with corticosteroid enemas or suppositories or topical (rectal) 5-ASA 
preparations within 2 weeks prior to randomization

Treatment with AZA, 6-MP, or MTX within 2 weeks prior to randomization

Treatment with a TNF inhibitor within 8 weeks prior to randomization

Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil within 4 weeks prior to 
randomization

Prior treatment with rituximab

Use of agents that deplete B or T cells (e.g., alemtuzumab or visilizumab) within 12 months 
prior to randomization, with the exception of AZA and 6-MP

Chronic nonsteroidal anti-inflammatory drug (NSAID) use
Occasional use of NSAIDs or acetaminophen (e.g., for headache, arthritis, myalgias, or 
menstrual cramps) and aspirin up to 325 mg/day is permitted.

Use of anticoagulants, including, but not limited to, warfarin, heparin, enoxaparin, 
dabigatran, apixaban, rivaroxaban
Use of antiplatelet agents, such as aspirin up to 325 mg/day or clopidogrel, is permitted.

Apheresis (e.g., Adacolumnapheresis) within 2 weeks prior to randomization

Participation in an investigational study involving non-biologic therapy within 30 days or 
5 half-lives of the investigational product (whichever is greater) prior to randomization

Participation in an investigational study involving biologic therapy (including vaccines) within 
90 days or 5 half-lives of the investigational product (whichever is greater) prior to 
randomization

History of moderate or severe allergic, anaphylactic, or anaphylactoid reactions to chimeric, 
human, or humanized antibodies, fusion proteins, or murine proteins or hypersensitivity to 
efmarodocokin alfa (active drug substance) or any of the excipients (sucrose, methionine, 
sodium phosphate, or polysorbate 20)

Tube feeding, defined formula diets, or parenteral alimentation within 3 weeks prior to 
randomization

Congenital or acquired immune deficiency

Evidence of, or treatment for, Clostridium difficile (as assessed by C. difficile toxin testing) 
within 60 days prior to randomization or other intestinal pathogens (as assessed by stool 
culture and ova and parasite evaluation) within 30 days prior to randomization

History of invasive fungal infections such as Candida or Aspergillus (excluding thrush or 
other superficial fungal infections) within 6 months prior to randomization

History of severe herpes (simplex type 1, simplex type 2, or zoster) infection or reactivation
within 12 weeks prior to randomization, or frequent recurrence of herpes (more than two
times per year)

History of any other opportunistic infections within 12 weeks prior to randomization

Any major episode of infection requiring hospitalization or treatment with IV antibiotics
within 8 weeks prior to screening or oral antibiotics within 4 weeks prior to screening

History of organ transplant

Colonic biopsy positive for cytomegalovirus at screening, as determined by histologic 
examination or immunohistochemistry per local standards

Positive HIV antibody test at screening


Efmarodocokin Alfa—Genentech, Inc.
23/Protocol GA39925, Version 7

Positive hepatitis B surface antigen (HBsAg) test at screening
Patients with a negative HBsAg test and a positive total hepatitis B core antibody test at 
screening will not be excluded if they have a negative hepatitis B virus DNA test.

Positive hepatitis C virus (HCV) antibody test at screening, except in patients who meet 
either of the following sets of criteria:
−
Patient has undetectable HCV RNA levels for 6 months after completion of HCV 
anti-viral treatment and a negative HCV RNA test at screening
−
Patient has a history of HCV antibody positivity, a history of undetectable HCV RNA 
levels for 6 months, and a negative HCV RNA test at screening

Positive for tuberculosis during screening or within 3 months prior to screening, defined as a 
positive QuantiFERON-TB Gold test (QFT) or (if QFT is not available) a positive purified 
protein derivative (PPD) skin test according to Centers for Disease Control and Prevention 
guidelines, with the following exceptions:
−
Patients with a history of Bacillus Calmette-Guérin (BCG) vaccination who have a 
positive PPD skin test will not be excluded if they have a negative QFT at screening
−
Patients who have a positive or indeterminate QFT and patients with no history of 
BCG vaccination who have a positive PPD skin test will not be excluded if they meet all 
of the following criteria:
a)
No symptoms consistent with TB 
b)
Documented history of a completed course of adequate prophylaxis (completed 
treatment for latent TB) per local standard of care prior to screening
c)
No known exposure to a case of active TB after most recent prophylaxis
d)
No evidence of active TB on chest X-ray performed during screening or within 
3 months prior to screening

Glomerular filtration rate 60 mL/min as calculated through use of the Modification of Diet in 
Renal Disease (MDRD) study equation or creatinine clearance rate 60 mL/min as 
calculated by the Cockcroft-Gault formula

ALT, AST, or alkaline phosphatase 2.5 ULN, total bilirubin 1.5 ULN, or presence of 
abnormalities in synthetic function tests judged to be clinically significant by the investigator
Patients with known Gilbert syndrome who have unconjugated hyperbilirubinemia will 
not be excluded.

Platelet count 100 109/L (100,000/L)

Hemoglobin 90 g/L (9 g/dL)

ANC 1.5 109/L (1500/L)

Absolute lymphocyte count 0.5 109/L (500/L)
End of Study
The end of this study is defined as the date when the last patient completes his or her final 
study visit.  The end of the study is expected to occur approximately 30 weeks after the last 
patient initiates treatment.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 40 months.
Investigational Medicinal Products
The investigational medicinal products for this study are efmarodocokin alfa and vedolizumab 
(active comparator).


Efmarodocokin Alfa—Genentech, Inc.
24/Protocol GA39925, Version 7
Test Product (Investigational Drug)
Efmarodocokin alfa or efmarodocokin alfa placebo will be administered by IV infusion.
During Part A, patients will receive an infusion of efmarodocokin alfa or efmarodocokin alfa
placebo according to the following dosing regimen.

Arms 1A and 1B:  Efmarodocokin alfa 30 g/kg at Weeks 0, 4, and 8

Arms 2A and 2B:  Efmarodocokin alfa 60 g/kg at Weeks 0, 4, and 8

Arms 3A and 3B:  Efmarodocokin alfa 90 g/kg at Weeks 0, 4, and 8

Arm 4:  Efmarodocokin alfa placebo at Weeks 0, 4, and 8

Arm 5:  Efmarodocokin alfa placebo at Weeks 0, 4, and 8
During Part B, patients will receive an infusion of efmarodocokin alfa or efmarodocokin alfa
placebo according to the following dosing regimen.

Arms 1A, 2A, and 3A:  Efmarodocokin alfa 60 g/kg at Weeks 14 and 22

Arms 1B, 2B, and 3B, 4 and 5:  Efmarodocokin alfa placebo at Weeks 14 and 22
Comparator
Vedolizumab 300 mg or vedolizumab placebo will be administered by IV infusion.
During Parts A and B, patients in Arms 13 and Arm 5 will receive an infusion of vedolizumab 
placebo at Weeks 0, 2, 6, 14 and 22.
During Parts A and B, patients in Arm 4 will receive an infusion of 300 mg vedolizumab at 
Weeks 0, 2, 6, 14 and 22.
Statistical Methods
Primary Analysis
The primary efficacy endpoint is clinical remission at Week 8.  The primary analysis will be
conducted by first comparing the efmarodocokin alfa arms versus the placebo arm.  A 
comparison between the efmarodocokin alfa arms and the vedolizumab arm will be carried out 
secondarily.  The difference between pooled Arm 1, pooled Arm 2, and pooled Arm 3, versus 
Arm 4 and versus Arm 5 in the proportion of patients with clinical remission at Week 8 will be 
evaluated by the Mantel-Haenszel test statistic, stratified by prior treatment with TNF inhibitors 
(yes/no).  Additional stratification variables may be used if appropriate (e.g., if a large number of 
very small strata are not generated), such as concomitant treatment with corticosteroids (yes/no) 
or prior treatment with immunomodulators (AZA, 6-MP, or MTX) (yes/no).  An 80% two-sided 
confidence interval of the differences in the proportion of patients with clinical remission at 
Week 8 will be provided to aid in the interpretation of the study results. 
Determination of Sample Size
A target of approximately 270 patients will be enrolled and randomly assigned in a 
1:1:1:1:1:1:2:1 ratio to Arms 1A, 1B, 2A, 2B, 3A, 3B, 4, and 5.  The A and B arms for each 
efmarodocokin alfa dose will be pooled (i.e., 1A 1B; 2A 2B; 3A 3B) for analyses of endpoints 
at or before Week 8.  Thus, the primary efficacy analysis of clinical remission at Week 8 will 
compare data for pooled Arm 1 (1A 1B), pooled Arm 2 (2A 2B), and pooled Arm 3 (3A 3B), 
versus Arm 4 and versus Arm 5.  The sample size of 60 patients per pooled efmarodocokin alfa
arm provides approximately 80% power to detect an improvement of 16 percentage points over 
the vedolizumab arm (Arm 4; n 60) and approximately 80% power to detect an improvement of 
26 percentage points over the placebo arm (Arm 5; n 30) in the proportion of patients with 
clinical remission at Week 8, assuming a clinical remission rate of approximately 15%20% in a 
vedolizumab-treated population and approximately 5%10% in a placebo-treated population 
with both populations consisting of 25% TNF-naive patients and 75% TNF-IR patients and a 
two-sided type I error rate of 0.2. 
Interim Analyses
An interim analysis will be performed when approximately 50% of patients have completed 
Part A (through Week 8). The interim results will be evaluated on the basis of descriptive 
summaries of the primary and key secondary outcomes for Part A, including estimated rates, 
between-group differences in rates, 80% CIs, and exploratory p-values with no type I error 


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adjustments or formal stopping criteria. Results of the interim analysis may inform potential 
early stopping of enrollment if the benefit-risk profile for the efmarodocokin alfa arms is 
considerably unfavorable.  The interim analysis will be conducted by the Internal Monitoring 
Committee.  Recruitment of patients will continue during the period of the interim analysis.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
5-ASA
5-aminosalicylic acid
6-MP
6-mercaptopurine
ADA
anti-drug antibody, also known as anti-therapeutic 
antibody
AESI
adverse event of special interest
AIS
adenocarcinoma in situ
AZA
azathioprine
BCG
bacillus Calmette-Guérin
Cmax
maximum concentration
Cmin
minimum concentration
CIN
cervical intraepithelial neoplasia
CMV
cytomegalovirus
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
DE
disease evaluation (visit)
DMBT1
Deleted in Malignant Brain Tumors 1 (protein)
DSS
dextran sulfate sodium
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
FDA
Food and Drug Administration
GI
gastrointestinal
HBV
hepatitis B virus
HBsAg
hepatitis B surface antigen
HIPAA
Health Insurance Portability and Accountability Act
HSIL
high-grade squamous intraepithelial lesion
HV
healthy volunteer
IBD
inflammatory bowel disease
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Council for Harmonisation
IL-22
interleukin-22
IL-22R
interleukin-22 receptor
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IRB
Institutional Review Board
IV
intravenous


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Abbreviation
Definition
IxRS
interactive voice or web-based response system
MCS
Mayo Clinic Score
mMCS
modified Mayo Clinic Score
MMF
mycophenolate mofetil
MTD
maximum tolerated dose
MTX
methotrexate
NCI
National Cancer Institute
PD
pharmacodynamic
PGA
Physician's Global Assessment
PK
pharmacokinetic
pMCS
partial Mayo Clinic Score
PRO
patient-reported outcome
Q2W
every 2 weeks
Q4W
every 4 weeks
Q6W
every 6 weeks
QTcF
QT interval corrected using Fridericia’s formula
RBR
Research Biosample Repository
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SC
subcutaneous
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TNF
tumor necrosis factor
TNF-
tumor necrosis factor-alpha
TNF-IR
inadequate response to anti-tumor necrosis factor
UC
ulcerative colitis
UC-PRO/SS
Ulcerative Colitis Patient-Reported Outcome Signs and 
Symptoms
ULN
upper limit of normal
VHP
Voluntary Harmonisation Procedure


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1.
BACKGROUND
1.1
BACKGROUND ON ULCERATIVE COLITIS
Ulcerative colitis (UC) is a chronic inflammatory condition that affects the colon but has
the potential for extra-intestinal complications.  Although there are many risk factors 
associated with the development of UC, the disease fundamentally represents
dysregulation of the mucosal immune system in a genetically susceptible individual in 
response to commensal microbiota and other environmental triggers.  UC is 
characterized by mucosal ulceration, rectal bleeding, diarrhea, and abdominal pain and 
may be complicated by severe bloody diarrhea and toxic megacolon, requiring major 
and sometimes urgent surgery.  The overall incidence of UC ranges from 
6.3 to 24.3 cases per 100,000 persons per year, and prevalence ranges from 
4.9 to 505.0 cases per 100,000 persons, with the highest estimates in European and 
Northern American populations (Molodecky et al. 2012).  Although the incidence and 
prevalence vary between regions of the world, both have been increasing in some 
regions. This rise may be due in part to better detection and diagnosis as well as 
environmental factors such as improved hygiene and Western diet.  The disease can 
affect any age group, but occurrence peaks between the ages of 15 and 35 years.
Pharmacologic management of UC currently includes anti-inflammatory drugs 
(corticosteroids and aminosalicylates such as 5-aminosalicylic acid [5-ASA]), 
immunosuppressants (such as azathioprine [AZA], 6-mercaptopurine [6-MP], and 
methotrexate [MTX]), tumor necrosis factor (TNF) inhibitors, and anti-47 integrin 
agents (such as vedolizumab). Newer therapies aim to modify the disease by inducing 
mucosal healing, to decrease dependence on corticosteroids, and to reduce the 
probability of progression to surgery, without significantly compromising 
immune competence.
1.2
BACKGROUND ON EFMARODOCOKIN ALFA
Efmarodocokin alfa (also known as UTTR1147A) is a human interleukin-22 (IL-22) 
fusion protein in which the cytokine IL-22 is linked with the Fc portion of IgG4 to improve 
the cytokine’s pharmacokinetic (PK) characteristics.  The Fc portion of the fusion protein 
incorporates a mutation that minimizes the potential for Fc effector function.
IL-22 belongs to the IL-10 cytokine family (Ouyang et al. 2011) and binds specifically to 
the IL-22 receptor (IL-22R) heterodimer, which is expressed on a variety of epithelial 
tissues including the gastrointestinal (GI) tract epithelium, epidermal keratinocytes, liver 
hepatocytes, pancreatic acinar epithelium, and renal tubular epithelium (Gurney 2004).  
IL-22 modulates innate immunity in epithelial tissues (Wolk et al. 2004), including the 
GI tract mucosal epithelium, by upregulating antimicrobial peptides, increasing mucin 
production, and stimulating epithelial barrier repair (Sugimoto et al. 2008; 
Zheng et al. 2008).  In murine models of UC, IL-22 has demonstrated efficacy through 
these epithelial protective mechanisms (Sugimoto et al. 2008). Therefore, 


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efmarodocokin alfa is being developed as a therapeutic for inflammatory bowel diseases 
(IBDs) such as Crohn's disease and UC on the basis of IL-22’s demonstrated biology.
1.2.1
Summary of Nonclinical Studies
Extensive in vitro and in vivo nonclinical studies have been conducted to characterize 
the pharmacologic activity, safety, PK, and pharmacodynamic (PD) profiles of 
efmarodocokin alfa.  These studies define the pharmacologic activities and PK/PD 
relationships and provide a safety profile supporting IV dosing in humans.
In an in vivo model of dextran sulfate sodium (DSS)-induced mouse colitis, muIL-22 Fc, 
a mouse surrogate for efmarodocokin alfa with full-length mouse IL-22 and the Fc 
portion of mouse IgG2a, was efficacious in a dose-dependent manner.  At the lowest 
efficacious dose of 1.25 g (efficacy assessed by colon histologic score), the 
corresponding minimum serum concentration of muIL-22 Fc was approximately 
10 ng/mL.  These results are consistent with the conclusions reported by other 
investigators (Sugimoto et al. 2008; Pickert et al. 2009; Neufert et al. 2010).
REG3A was evaluated as a PD biomarker in cynomolgus monkeys (Studies 12-2623,
13-2601, and 15-0279).  Results from these studies demonstrated that elevations in 
REG3A correlate with efmarodocokin alfa drug levels. REG3A levels returned to 
baseline levels despite variability in individual responses by the end of these studies, 
with the exception of animals given 1,500 g/kg in Study 12-2623, where REG3A levels 
remained elevated throughout the duration of the study. Taken together, these in vivo 
biomarker data demonstrate that REG3A is a relevant biomarker for pharmacological 
activity of efmarodocokin alfa and suggest that IL-22R engagement was achieved.
Toxicology studies of up to 6 months duration have been conducted in rats, cynomolgus 
monkeys, and Yucatan minipigs. These studies have identified a transient acute phase
inflammatory response and epidermal hyperplasia with skin reddening as clinical safety 
risks. These risks are considered predictable, manageable, monitorable, and reversible 
in the clinic.
Refer to the Efmarodocokin Alfa Investigator's Brochure for details on nonclinical studies.
1.2.2
Summary of Clinical Studies
Results from Study GA29468, a Phase Ia, placebo-controlled, single-dose, 
dose-escalation study in healthy volunteers (HVs), showed that efmarodocokin alfa had 
acceptable tolerability at single IV doses of up to 90 g/kg and SC doses of up to 
60 g/kg.  Starting at 30 g/kg IV, dose-dependent reversible increases in the number 
and intensity of skin events (e.g., dry skin, patchy erythema, and subjective skin-related 
complaints such as skin discomfort) were reported (see Section 5.1.1.1 for additional 
details).  At the highest IV dose (120 g/kg), 3 of 4 HVs experienced protocol-defined 
dermatologic dose-limiting toxicities.


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Dose-dependent increases in serum levels of PD biomarkers SAA, REG3A, and 
Creactive protein (CRP), indicative of IL-22R engagement by efmarodocokin alfa, were 
observed following treatment with efmarodocokin alfa compared to placebo. Transient 
increases in CRP were consistent with data from nonclinical studies and importantly 
occurred in the absence of symptoms of inflammation (e.g., fever, leukocytosis, vital sign 
changes). 
All abnormal clinical laboratory results reported as treatment-emergent adverse events 
were assessed by the investigator as mild or moderate in intensity and not related to 
treatment with efmarodocokin alfa, except for mild to moderate dose-dependent 
elevations in CRP, as noted above. No clinically significant changes for individuals or 
dose-related trends by cohort were noted for laboratory tests (except for CRP and 
fibrinogen), vital signs measurements, 12-lead ECGs, or body weight measurements for 
this study.
Anti-drug antibodies (ADAs) occurred in 1 of 44 (2.3%) subjects.  This subject was in the 
low-dose (3 g/kg) SC treatment group.  A positive ADA result for this subject was first 
observed at Day 57 (study completion); ADAs were not detected at earlier timepoints.  
The safety and tolerability profile for this subject was similar to that for other subjects in 
the cohort.
In the Phase Ib, placebo-controlled, multiple-dose, dose-escalation study in HVs,
patients with UC, and patients with CD (Study GA29469), efmarodocokin alfa was 
adequately tolerated at IV doses up to 60 g/kg IV Q2W in HVs and patients in the 
only CD cohort evaluated, and up to 90 g/kg IV Q2W in patients with UC.  In HVs, a 
dose regimen of 90 g/kg Q2W was not tolerated, as two HVs experienced dermatologic 
dose-limiting adverse events at this dose (severe skin discomfort and severe dry skin)
that occurred after the second dose of blinded efmarodocokin alfa or placebo.  Topical 
emollients and topical corticosteroids provided minimal relief.  Skin effects were fully 
reversible. PK exposures were approximately dose proportional within HVs and within 
patients with UC. Patients with UC or CD had relatively low drug exposures as 
compared to HVs when dosed at the same level. Two participants had ADAs at baseline, 
and no participants were found to have treatment-emergent ADAs. The observed 
increases trending upwards with increasing efmarodocokin alfa dose levels returned to 
baseline levels for CRP and SAA, whereas REG3A levels returned to near baseline level 
by study completion suggestive of sustained pathway activation though considerable 
variability was observed in the different cohorts. 
Refer to the Efmarodocokin Alfa Investigator's Brochure for details on clinical studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
While effective therapeutic options, including anti-integrin agents and TNF inhibitors, are 
available to reduce the acute symptomatic flares in disease activity in patients with 
moderate to severe UC, no currently available therapy achieves sustained remission in 


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more than 10%30% of patients with chronic IBD (Hanauer et al. 2002; Sandborn et al. 
2005; Feagan et al. 2013).  Furthermore, anti-integrin agents and TNF inhibitors are 
associated with severe adverse events including hypersensitivity reactions and
increased risk of infections (including serious infections such as tuberculosis [TB]).  
Consequently, patients and physicians must carefully weigh the benefit-risk ratio both 
before starting and while managing long-term treatment with anti-integrin agents or 
TNF inhibitors.
Vedolizumab, an 47 integrin receptor antagonist, is the only biological therapy 
indicated for treating both patients who are TNF inhibitor naïve, as well as patients for 
whom treatment with TNF inhibitors, immunomodulators, and/or corticosteroids has 
failed.  However, vedolizumab has a slow onset of action (6 weeks) and reduced efficacy 
during induction for patients with inadequate response to anti-TNF therapy (TNF-IR).  At 
Week 6, the rate of response to vedolizumab and placebo were 39.0% and 20.6%, 
respectively, in TNF-IR patients (Feagen et al. 2017).
As described above, IL-22 stimulates mucin and anti-microbial peptide production in the 
intestine, which can modulate bacterial growth and protect the intestinal epithelium.  
Changes in bacterial flora have been associated with a variety of immunologically-
mediated diseases and, along with altered epithelial barrier function, are thought to be 
key drivers in the inflammatory process of IBD (Sugimoto et al. 2008; Zheng et al. 2008; 
Eidenschenk et al. 2014).  Efmarodocokin alfa, an IL-22 fusion protein, is a novel 
therapeutic agent being developed to promote mucosal healing and achieve sustained 
clinical remission while potentially allowing reduction or elimination of the 
immunosuppression associated with current therapies for UC.
The safety profile of efmarodocokin alfa, as demonstrated in the Phase I studies, 
supports further investigation to compare efmarodocokin alfa with placebo and with 
vedolizumab in the induction and maintenance of clinical remission for patients who 
have failed conventional therapy.
The present double-blind, double-dummy, comparator study employs a robust design
and utilizes an independent and centrally read endoscopy to confirm patient eligibility 
and endpoint determination.  Patients will receive an active therapy (vedolizumab or 
efmarodocokin alfa) or placebo during Part A (through Week 8).  Patients who respond 
to efmarodocokin alfa therapy through Week 8 of Part A will continue active treatment or 
switch to placebo during Part B (through Week 22), followed by an 8-week safety follow-
up period.  Patients who respond to vedolizumab or placebo through Week 8 of Part A 
will continue with vedolizumab or placebo, respectively, in Part B (through Week 22), 
followed by an 8-week safety follow-up period. Patients enrolled in this study will have 
the opportunity to participate in open-label extension (OLE) Study GA40209, if eligible 
(see Section 3.1.5).  See Section 3 for additional information regarding study design.


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As efmarodocokin alfa is an investigational medicinal product (IMP), the full safety profile 
will be further characterized as clinical development progresses.  A safety plan is 
outlined in Section 5.1.
Refer to the Efmarodocokin Alfa Investigator’s Brochure for details on nonclinical and 
clinical studies and additional safety information.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the safety, efficacy, and pharmacokinetics of efmarodocokin alfa 
compared with placebo and compared with vedolizumab in patients with moderate to 
severe UC.  Specific objectives and corresponding endpoints for the study are outlined 
below.  Endoscopic scores will be based on interpretation by a central reader.  
In this protocol, "study drug" refers to blinded drug (i.e., efmarodocokin alfa,
vedolizumab, or placebo).  
Table 1
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
efmarodocokin alfa compared with 
placebo and compared with 
vedolizumab 
Clinical remission at Week 8, with clinical remission 
defined as meeting both of the following criteria:
– Modified MCS a of 2
– Mayo rectal bleeding subscore of 0 and other 
Mayo subscores of 1
ADAanti-drug antibody; IBDQInflammatory Bowel Disease Questionnaire; MCSMayo Clinic 
Score; NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events; 
PDpharmacodynamic; PK pharmacokinetic; UC-PRO/SSUlcerative ColitisPatient-Reported 
Outcome Signs and Symptoms.
Note:  Endoscopic scores will be based on interpretation by a central reader.
a Modified MCS is the composite of three MCS assessments:  stool frequency, rectal bleeding, 
and centrally read endoscopy (see Appendix 3).


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Table 1
Objectives and Corresponding Endpoints (cont.)
Secondary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of 
efmarodocokin alfa compared with
placebo and compared with 
vedolizumab
Sustained remission, defined as clinical remission at 
both Week 8 and Week 30
Clinical response at Weeks 8 and 30, with clinical 
response defined as achieving clinical remission or
meeting both of the following criteria:
– A 3-point decrease from baseline in modified 
MCS
– A 1-point decrease from baseline in Mayo rectal 
bleeding subscore or a Mayo rectal bleeding 
subscore of 0 or 1
Endoscopic healing at Weeks 8 and 30, with 
endoscopic healing defined as a Mayo endoscopic 
subscore of 1
Endoscopic remission at Weeks 8 and 30, with 
endoscopic remission defined as a Mayo endoscopic 
subscore of 0
To evaluate the efficacy of 
efmarodocokin alfa compared with
placebo and compared with 
vedolizumab (cont.)
Change from baseline in UC bowel movement signs 
and symptoms at Week 8 and at Week 30, as 
assessed by UC-PRO/SS score
Change from baseline in UC abdominal signs and 
symptoms at Week 8 and at Week 30, as assessed 
by UC-PRO/SS score
Change from baseline in patientreported 
health-related QOL at Week 8 and at Week 30, as 
assessed by IBDQ score
Exploratory Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of 
efmarodocokin alfa compared with 
placebo and compared with 
vedolizumab
Mucosal healing, defined as endoscopic healing and 
histological remission 6 as per Robarts Histological 
Index, at Weeks 8 and 30
Change from baseline in UC Endoscopic Index of 
Severity at Week 8 and at Week 30
Histological healing, defined as Nancy score of 0 or 1 
as per Nancy Histological Index, at Weeks 8 and 30
Change from baseline in Geboes Score at Week 8
and at Week 30
Change from baseline in Robarts Histological Index at 
Week 8 and at Week 30
ADAanti-drug antibody; IBDQInflammatory Bowel Disease Questionnaire; MCSMayo Clinic 
Score; NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events; 
PDpharmacodynamic; PK pharmacokinetic; UC-PRO/SSUlcerative ColitisPatient-Reported 
Outcome Signs and Symptoms.
Note:  Endoscopic scores will be based on interpretation by a central reader.
a Modified MCS is the composite of three MCS assessments:  stool frequency, rectal bleeding, 
and centrally read endoscopy (see Appendix 3).


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Table 1
Objectives and Corresponding Endpoints (cont.)
Safety Objective
Corresponding Endpoints
To evaluate the safety of 
efmarodocokin alfa compared with
placebo and compared with 
vedolizumab 
Occurrence and severity of adverse events, with 
severity determined according to NCI CTCAE scale 
Change in targeted vital signs, physical findings, and 
clinical laboratory test results during and following 
study drug administration
Pharmacokinetic Objective
Corresponding Endpoint
To characterize the pharmacokinetics 
of efmarodocokin alfa in patients with 
UC
Serum concentration of efmarodocokin alfa at 
specified timepoints
Exploratory Pharmacokinetic 
Objectives
Corresponding Endpoints
To evaluate potential relationships 
between drug exposure and the 
efficacy and safety of study drug
Relationship between serum concentration or PK 
parameters for study drug and efficacy endpoints
Relationship between serum concentration or PK 
parameters for study drug and safety endpoints
To identify covariates that have 
significant impact on the exposure to 
efmarodocokin alfa
Relationship between identified covariates and 
serum concentration or PK parameters for 
efmarodocokin alfa
Immunogenicity Objective
Corresponding Endpoint
To evaluate the immune response to 
efmarodocokin alfa
Presence of ADAs during the study relative to the 
presence of ADAs at baseline
Exploratory Immunogenicity 
Objective
Corresponding Endpoint
To evaluate potential effects of ADAs
Relationship between ADA status and efficacy, 
safety, or PK endpoints
ADAanti-drug antibody; IBDQ Inflammatory Bowel Disease Questionnaire; MCSMayo Clinic 
Score; NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events; 
PDpharmacodynamic; PK pharmacokinetic; UC-PRO/SSUlcerative ColitisPatient-Reported 
Outcome Signs and Symptoms.
Note:  Endoscopic scores will be based on interpretation by a central reader.
a
Modified MCS is the composite of three MCS assessments:  stool frequency, rectal bleeding, 
and centrally read endoscopy (see Appendix 3).


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Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Biomarker Objective
Corresponding Endpoint
To identify biomarkers that are 
predictive of response to 
efmarodocokin alfa (i.e., predictive 
biomarkers), are associated with 
progression to a more severe disease 
state (i.e., prognostic biomarkers), are 
associated with susceptibility to 
developing adverse events (i.e., safety 
biomarkers), can provide evidence of 
efmarodocokin alfa activity (i.e., 
pharmacodynamic biomarkers), or can 
increase the knowledge and 
understanding of disease biology
Relationship between biomarkers in blood, stool, 
and colonic tissue, (listed in Section 4.5.8) and
efficacy, safety, PK, immunogenicity, or other 
biomarker endpoints
ADAanti-drug antibody; IBDQInflammatory Bowel Disease Questionnaire; MCSMayo Clinic 
Score; NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events; 
PDpharmacodynamic; PK pharmacokinetic; UC-PRO/SSUlcerative ColitisPatient-Reported 
Outcome Signs and Symptoms.
Note:  Endoscopic scores will be based on interpretation by a central reader.
a Modified MCS is the composite of three MCS assessments:  stool frequency, rectal bleeding, 
and centrally read endoscopy (see Appendix 3).
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design
This is a Phase II, randomized, parallel-group, double-blind, double-dummy, 
placebo-controlled, multicenter study to evaluate the efficacy, safety, and 
pharmacokinetics of efmarodocokin alfa compared with placebo and compared with 
vedolizumab in the treatment of moderate to severe UC.
This study will consist of a screening period of up to 4 weeks, a 22-week treatment 
period, and an 8-week safety follow-up period.  Part A (Weeks 08) will test the induction 
of clinical remission.  The durability of clinical response and remission will be evaluated 
during Part B (Weeks 922) through the end of the safety follow-up period (Week 30).  
Upon approval of OLE Study GA40209 by local Institutional Review Boards/Ethics 
Committees (IRBs/ECs) and relevant health authorities, patients enrolled in this study 
will have the opportunity to participate in OLE Study GA40209, if eligible 
(see Section 3.1.5).
Approximately 270 patients will be enrolled across global investigational sites. Overall,
patients will be randomly assigned in a 1:1:1:1:1:1:2:1 ratio to one of eight treatment 
arms (see Figure 1).  The treatment regimens for Part A and Part B are outlined for each 


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treatment arm in Table 2.  The first dose of study drug will be administered on Day 1 of 
Week 0.  A schedule of activities is provided in Appendix 1.
Figure 1
Study Schema
a Vedolizumab placebo will be administered at Weeks 0, 2, and 6.
b Vedolizumab placebo will be administered at Weeks 14 and 22.
c Efmarodocokin alfa placebo and vedolizumab placebo will be administered at Weeks 14 
and 22.
d Efmarodocokin alfa placebo will be administered at Weeks 0, 4, and 8.
e Efmarodocokin alfa placebo will be administered at Weeks 14 and 22.


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Table 2
Treatment Regimens
Arm
Part A (Weeks 08)
Part B (Weeks 922)
Active Drug
Placebo
Active Drug
Placebo
1A
Efmarodocokin alfa 30 g/kg IV
at Weeks 0, 4, 8
VDZ placebo IV
at Weeks 0, 2, 6
Efmarodocokin alfa 60 g/kg IV
at Weeks 14 and 22
VDZ placebo IV
at Weeks 14 and 22
1B
Efmarodocokin alfa 30 g/kg IV
at Weeks 0, 4, 8
VDZ placebo IV
at Weeks 0, 2, 6

VDZ placebo IV 
Efmarodocokin alfa placebo IV
at Weeks 14 and 22
2A
Efmarodocokin alfa 60 g/kg IV
at Weeks 0, 4, 8
VDZ placebo IV
at Weeks 0, 2, 6
Efmarodocokin alfa 60 g/kg IV
at Weeks 14 and 22
VDZ placebo IV
at Weeks 14 and 22
2B
Efmarodocokin alfa 60 g/kg IV
at Weeks 0, 4, 8
VDZ placebo IV
at Weeks 0, 2, 6

VDZ placebo IV 
Efmarodocokin alfa placebo IV
at Weeks 14 and 22
3A 
Efmarodocokin alfa 90 g/kg IV
at Weeks 0, 4, 8
VDZ placebo IV
at Weeks 0, 2, 6
Efmarodocokin alfa 60 g/kg IV
at Weeks 14 and 22
VDZ placebo IV
at Weeks 14 and 22
3B 
Efmarodocokin alfa 90 g/kg IV
at Weeks 0, 4, 8
VDZ placebo IV
at Weeks 0, 2, 6

VDZ placebo IV 
Efmarodocokin alfa placebo IV
at Weeks 14 and 22
4
VDZ 300 mg IV
at Weeks 0, 2, 6
Efmarodocokin alfa placebo IV
at Weeks 0, 4, 8
VDZ 300 mg IV
at Weeks 14 and 22
Efmarodocokin alfa placebo IV
at Weeks 14 and 22
5

VDZ placebo IV
at Weeks 0, 2, 6
Efmarodocokin alfa placebo IV
at Weeks 0, 4, 8

VDZ placebo IV 
Efmarodocokin alfa placebo IV
at Weeks 14 and 22
IVintravenous infusion; VDZ vedolizumab.


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Patient disposition during the study will be based on whether patients receive rescue 
therapy or meet criteria for clinical remission, clinical response or disease flare, as 
defined below:

Rescue therapy, defined as initiation of any treatment for UC or an increase in the 
dose of oral 5-ASA or oral corticosteroids compared with baseline (randomization)
Cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil (MMF), and 
anti-integrin agents are not permitted as rescue therapy (see Section 4.4.1
for details).

Clinical remission, defined as meeting both of the following criteria:
–
Modified MCS of 2
mMCS is a composite of three MCS assessments:  stool frequency, rectal 
bleeding, and centrally read endoscopy (see Appendix 3).
–
Mayo rectal bleeding subscore of 0 and other Mayo subscores of 1 

Clinical response, defined as achieving clinical remission or as meeting both of the 
following criteria:
–
A 3-point decrease from baseline in modified Mayo Clinic Score (mMCS) 
–
A 1-point decrease from baseline in rectal bleeding subscore or a 
rectal bleeding subscore of 0 or 1

Disease flare, defined as meeting one of the following sets of criteria during Part B:
–
A 3 increase from Week 8 in partial MCS (pMCS) and an absolute pMCS of 
5 and an endoscopy subscore of 2 
pMCS is a composite of three MCS assessments:  stool frequency, rectal 
bleeding, and Physician's Global Assessment (PGA) (see Appendix 4)
–
An absolute pMCS score of 7 and an endoscopy subscore of 2 
3.1.2
Part A
During Part A, patients will receive IV infusions of efmarodocokin alfa, efmarodocokin 
alfa placebo, vedolizumab, or vedolizumab placebo.  At Week 0 only, two IV infusions 
will be administered.  At Weeks 2, 4, 6, and 8, patients will receive one IV infusion 
(see treatment regimens outlined in Table 2).
Restrictions regarding treatment with concomitant therapy during Part A are outlined in 
Section 4.4.
At Week 8 and prior to study drug administration, patients will undergo a flexible 
sigmoidoscopy with biopsy and a full MCS will be assessed.  The mMCS and pMCS will 
be derived from the MCS (see Section 4.5.7.1).
Patients who receive rescue therapy (see Section 4.4.1) and patients with persistent or 
worsening disease for which rescue therapy is indicated, as determined by the 
investigator, should return to the clinic as soon as possible for a disease evaluation visit, 


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which will include a flexible sigmoidoscopy and MCS evaluation (see Appendix 1).  
The disease evaluation visit should occur no later than 1 week after initiation of 
rescue therapy.
Patients who receive rescue therapy will discontinue study drug and undergo all 
scheduled clinic assessments through Week 8, with the exception of the flexible 
sigmoidoscopy if already performed at a disease evaluation visit.  Upon completion of 
the Week 8 visit, these patients may enroll in OLE Study GA40209, if eligible.
Patients who meet the criteria for clinical response (see Section 3.1.1) at Week 8
(without use of rescue therapy) will continue into Part B.  Patients who do not meet the 
criteria for clinical response will discontinue study drug and may enroll in OLE Study 
GA40209, if eligible. Study drug should not be administered at Week 8 if determination 
is made at the visit that patient will enroll in OLE Study GA40209.  Details on Week 8 
visit are provided in Appendix 1.
Patients who are ineligible for or choose not to enroll in OLE Study GA40209 will enter 
the safety follow-up period (see Section 3.1.4).
3.1.3
Part B
During Part B, patients will receive IV infusions of efmarodocokin alfa and vedolizumab 
placebo (Arms 1A, 2A, and 3A), efmarodocokin alfa placebo and vedolizumab placebo 
(Arms 1B, 2B, 3B, and 5), or vedolizumab and efmarodocokin alfa placebo (Arm 4) at 
Weeks 14 and 22 as per the treatment regimens outlined in Table 2.
Restrictions regarding treatment with concomitant therapy during Part B are outlined in 
Section 4.4.
For patients on concomitant oral corticosteroids at baseline, the corticosteroid dose will 
be tapered until discontinuation, starting at Week 8.  The tapering schedule will be as 
follows:

For patients on 10 mg/day of oral prednisone (or equivalent), the dose should be 
reduced at a rate of 5 mg/week until a dose of 10 mg/day dose is reached.  
Thereafter, the dose should be reduced at a rate of 2.5 mg/week until 
discontinuation.

For patients on 10 mg/day of oral prednisone (or equivalent), the dose should be 
reduced at a rate of 2.5 mg/week until discontinuation.


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For patients who cannot tolerate the corticosteroid taper without recurrence of UC 
symptoms or experience symptoms of corticosteroid withdrawal, the corticosteroid dose 
can be increased.  If the corticosteroid dose has not been increased above the baseline 
level, these patients should re-initiate corticosteroid dose tapering per the above 
regimen within 2 weeks.  Patients who are unable to tolerate a second taper should
discontinue study drug and enroll in OLE Study GA40209, if eligible.  Treatment with 
corticosteroids above the baseline dose will be considered rescue therapy.
Patients who receive rescue therapy (see Section 4.4.1) and patients with worsening 
disease for which rescue therapy is indicated, as determined by the investigator, should 
return to the clinic as soon as possible for a disease evaluation visit, which will include a 
flexible sigmoidoscopy and MCS evaluation (see Appendix 1).  The disease evaluation 
visit should occur no later than 1 week after initiation of rescue therapy.
Patients who receive rescue therapy or experience disease flare (see Section 3.1.1) will 
discontinue study drug and may enroll in OLE Study GA40209, if eligible.  Study drug 
should not be administered at Weeks 14 or 22 if determination is made at the visit that 
patient will enroll in OLE Study GA40209. Patients who are ineligible for or choose not 
to enroll in OLE Study GA40209 will enter the safety follow-up period (see Section 3.1.4).
Patients who complete Part B (i.e., through Week 22) will enter the safety follow-up 
period (see Section 3.1.4).
3.1.4
Safety Follow-Up Period and Early Termination Visit
Patients who complete the treatment period (Parts A and B) and patients who 
discontinue study drug without entering OLE Study GA40209 will enter the safety 
follow-up period and undergo assessments at 4 and 8 weeks after their last dose of 
study drug.  Patients who discontinue study drug prematurely for the reasons listed in 
Section 4.6.1 should return to the clinic for an early termination visit within 1 week of the 
event and will then enter the safety follow-up period.  Patients who are unwilling to 
complete the safety follow-up period should return to the clinic for an early termination 
visit as soon as possible and no later than 30 days after their final dose (see Appendix 1
for additional details).
A flexible sigmoidoscopy and MCS evaluation will be performed at second visit of safety 
follow-up, approximately 8 weeks after the last dose of study drug, if patient 
has completed the treatment period (Parts A and B) and 8-week safety follow-up, 
i.e., second visit of safety follow-up corresponds to Week 30 for that patient.  
Patients who complete the treatment period (Parts A and B) and the safety follow-up 
period may enroll in OLE Study GA40209, if eligible.


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3.1.5
Open-Label Extension Study GA40209
Upon approval of OLE Study GA40209 by local IRBs/ECs and relevant health authorities, 
patients who enter OLE Study GA40209 at Week 8 or during Part B (i.e., do not 
complete maintenance treatment) as outlined in Sections 3.1.2 and 3.1.3 will receive 
treatment with open-label efmarodocokin alfa during OLE Study GA40209.
Patients who enter OLE Study GA40209 after completing the treatment period 
(Parts A and B) and the safety follow-up period will receive treatment with open-label 
efmarodocokin alfa, if protocol-defined criteria are met.
3.1.6
Internal Monitoring Committee
An Internal Monitoring Committee (IMC) will monitor data on safety, efficacy, and study 
conduct on an ongoing basis.  The IMC consists of Sponsor representatives from 
Clinical Science, Drug Safety, and Biostatistics, and may invite representatives from 
other functional areas (e.g., Clinical Pharmacology, Research) or external experts on an 
ad hoc basis when additional expertise is required. Sponsor representatives will not be 
involved in the conduct of the study or have any contact with study investigators or site 
staff.
The IMC will review cumulative unblinded data on a periodic basis as defined in the 
IMC charter.  In addition, ad hoc reviews may be requested by the IMC or the Sponsor at 
any time to address potential safety concerns.  The data will include, but will not be 
limited to, demographic data, adverse events data (including serious adverse events and 
adverse events of special interest), ECG data, and relevant laboratory data.  An interim 
efficacy analysis will be performed by the IMC (see Section 6.9).
After reviewing the data, the IMC may make recommendations such as the following:

The trial will continue as planned

The trial will continue with a reduction in dose level or frequency within a
treatment arm

The trial will continue with discontinuation of enrollment in a treatment arm, including 
placebo

The trial will stop for safety reasons 

Additional analyses will need to be performed

Enrollment will be held pending further safety evaluation
The IMC may also provide recommendations for amending the protocol after
consideration of all available data.  Final decisions will rest with the Sponsor's study 
team.


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Any outcomes of these reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of their respective IRBs/ECs.  Biannual 
summaries of the conclusions and recommendations of the IMC will be sent to the 
IRBs/ECs.
A detailed description of the procedures, data flow, and meeting schedule of the IMC will 
be provided in the IMC charter.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient completes his or her 
final study visit.  The end of the study is expected to occur approximately 30 weeks after 
the last patient initiates treatment.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 40 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Efmarodocokin Alfa Dose and Schedule
Three dose regimens, 30 g/kg Q4W, 60 g/kg Q4W, and 90 g/kg Q4W, have 
been selected for Part A of the study primarily on the basis of available safety data 
from the completed Phase Ia study (GA29468) in HVs and safety data from the
multiple-ascending dose Phase Ib study (GA29469) in HVs and patients with UC.  In 
the Phase Ia study, efmarodocokin alfa demonstrated an adequate safety and tolerability 
profile in HVs treated with single IV doses of up to 90 g/kg, the maximum tolerated 
dose (MTD) for that study per the protocol-specified criteria.  
Results of the Phase Ib study show that efmarodocokin alfa was adequately tolerated at 
IV doses up to 60 g/kg IV Q2W in HVs (MTD per protocol-specific criteria) and 
patients with CD, and up to 90 g/kg IV Q2W in patients with UC. 
Half-life of efmarodocokin alfa ranged from 15.7-17.7 days in HVs and 12.4 to 13.8 days 
in patients with UC based on Phase Ib data, so it is expected to have minimal drug 
accumulation with Q4W dosing. The observation was in line with data from studies with
anti-TNF and other biologic agents that patients with UC had lower systemic drug 
exposure than HVs at the same dose level (Hua et al. 2015), possibly due to increased 
drug clearance in patients with UC than HVs (Fausel et al. 2015; Rosen et al. 2015).  
The 90 g/kg Q4W dose regimen is the highest dose regimen tested within the tolerable 
exposure range to evaluate whether efmarodocokin alfa at this dose level is safe and 
efficacious in patients with UC. Given the minimal drug accumulation with Q4W dosing, 
as well as faster drug clearance observed in patients with UC, the Cmax with 90 g/kg 
Q4W in patients with UC at Week 8 is estimated to be similar to the Cmax seen in Phase 
Ia single IV dose of 90 g/kg in HVs. In addition, the predicted AUCtau,4wks would be well 


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covered by the exposure seen in Phase Ib adequately-tolerated 60 g/kg Q2W cohort in 
HVs. 
The 60 g/kg Q4W dose regimen has been adequately tolerated both in HVs and in 
patients with UC in the Phase Ib study.  Early signs of clinical activity were seen in 
Phase Ib so this dose regimen will be tested in larger cohort of patients with UC.
The 30 g/kg Q4W dose regimen will provide 3-fold exposure separation from the high 
dose cohort, and allows for a wider dose-ranging evaluation to define the therapeutic 
window for efmarodocokin alfa.  
The dose regimen for Part B has been selected to determine whether further dosing with 
efmarodocokin alfa is necessary to sustain clinical benefit.  Arms 1A, 2A, and 3A will 
receive 60 g/kg efmarodocokin alfa on Weeks 14 and 22. An 8-week dosing interval
corresponds to the maximum duration for sustained PD effects observed after a single 
dose of efmarodocokin alfa.  Arms 1B, 2B, and 3B will receive placebo during Part B as 
a short-term treatment control.  Data from efmarodocokin alfa-treated arms in Part B will 
be compared with data from placebo-treated Arms 1B, 2B, and 3B to evaluate the 
benefit-risk balance when continuing treatment with efmarodocokin alfa after clinical 
response is achieved during Part A.  
The safety follow-up period of 8 weeks is close to 5 times the efmarodocokin alfa half-life 
to allow complete drug washout and to provide sufficient safety monitoring.
3.3.2
Rationale for Patient Population
There is a high unmet medical need in the treatment of patients with moderate to severe 
UC.  These patients typically require use of immunosuppressive agents to achieve 
mucosal healing and clinical remission.  The current standard-of-care biologic therapies 
for this patient population are vedolizumab and TNF inhibitors.  However, the 
immunosuppressive nature of conventional and biologic therapies increases the overall 
risk of serious infections.  Furthermore, no currently available therapy achieves 
sustained remission in more than 10%30% of patients with chronic IBD (Hanauer et al.
2002; Sandborn et al. 2005; Feagan et al. 2013).  Vedolizumab is able to induce clinical 
remission in only about 10% of TNF-IR patients (Feagan et al. 2017).
Because of the limitations in the currently available therapies, a need exists for new 
treatments to achieve sustained corticosteroid-free remission and mucosal healing 
without increasing immune suppression.  Moreover, there is a need to develop therapies 
for patients for whom both conventional and biologic therapies have failed.  
Efmarodocokin alfa is being developed as a novel therapeutic agent to promote mucosal 
healing and achieve sustained clinical remission in patients with UC while potentially 
allowing reduction or elimination of immunosuppression.


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The eligibility criteria for this study define patients with moderate to severe UC who may 
benefit from the anticipated effects of efmarodocokin alfa.  All patients considered for 
participation will have a diagnosis of moderate to severe UC established and confirmed 
by clinical and endoscopic evidence at least 3 months prior to randomization. Patients 
must have demonstrated an inadequate response, loss of response, or intolerance to 
prior immunosuppressant treatment (i.e., AZA, 6-MP, MTX, or TNF inhibitors) and/or 
corticosteroid treatment (as defined in Section 4.1.1). Patients who have had prior 
exposure to vedolizumab and other anti-integrin agents will be excluded. Patients who 
may be at increased risk and those who require intervention other than the 
standard-of-care therapies as defined in this protocol are excluded.
3.3.3
Rationale for Placebo Control Group
In accordance with the International Council for Harmonisation (ICH) E10 guideline and 
the European Medicines Agency draft "Guideline on the development of new medicinal 
products for the treatment of Ulcerative Colitis" (EMA 2016), a placebo-treated control 
group will be used in this study to provide optimal evaluation of the efficacy and safety of 
efmarodocokin alfa.
The placebo group is utilized in UC trials to control for the variability in outcome 
measures associated with subjective assessments such as patient reported outcomes 
and disease factors such as spontaneous remission and the inherent variability in 
disease flares.  Furthermore, use of an active comparator alone in this study may 
underestimate the safety and efficacy profile of efmarodocokin alfa and would require a 
larger patient population to evaluate its benefit-risk profile.  
Use of a placebo control group (Arm 5) in Part A of the study will provide optimal 
evaluation of the efficacy and safety of efmarodocokin alfa, including the identification 
and evaluation of specific safety signals that may be unique to treatment with 
efmarodocokin alfa as compared with vedolizumab or compared with signals related to 
the underlying disease.  Patients in the placebo-treated arm who meet the criteria for 
clinical response (see Section 3.1.1) at Week 8 will continue treatment with placebo in 
Part B of the study to maintain study blind.
Use of placebo in Part B in efmarodocokin alfa Arms 1B, 2B, and 3B will allow for 
evaluation of the safety and efficacy of continued dosing after patients respond to 
efmarodocokin alfa.  Data from the Phase Ib study indicate that patients who received 
efmarodocokin alfa and achieved clinical remission maintained remission for up to 
3 months after discontinuation of study drug.  Therefore, use of placebo in Part B will
serve as a short-term treatment control and allow for evaluation of the benefit-risk profile 
of continuing treatment with efmarodocokin alfa and potentially minimize unnecessary 
exposure to efmarodocokin alfa after clinical response is achieved in Part A.  Any patient 
in Part B who cannot tolerate a second corticosteroid taper, receives rescue therapy 
(see Section 4.4.1), or experiences disease flare will have the opportunity to enter 
OLE Study GA40209, if eligible. 


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3.3.4
Rationale for Active Comparator
Vedolizumab, an 47 integrin receptor antagonist, is the only biological therapy 
indicated for treating both patients who are TNF inhibitor naive and patients for whom 
treatment with TNF inhibitors, immunomodulators, and/or corticosteroids has failed.
Because vedolizumab is a gut-selective antibody and works mechanistically on a 
different target than UTTR1174A, the adverse event profiles between the two drugs are 
different.  The adverse events documented for treatment with vedolizumab are well 
characterized.  The most common adverse events, affecting at least 5% of patients
receiving at least one dose of vedolizumab (Feagan et al. 2013), do not overlap with the 
most common adverse events observed for efmarodocokin alfa in the Phase Ia study 
(GA29468).  As a result, having vedolizumab as the active comparator will further 
contribute to the safety profile assessment of efmarodocokin alfa. 
As vedolizumab is one of the standard of care treatments for moderate to severe UC, it 
is an appropriate comparator when evaluating the efficacy of efmarodocokin alfa.
Moreover, because a high drop-out rate is expected in the placebo arm after Week 8, it 
is critical to have an active arm so control data are available for long-term assessment of 
the efficacy and safety of efmarodocokin alfa.
3.3.5
Rationale for Pharmacokinetic Sample Collection
The PK sampling schedule for this study is designed to capture data at specific 
timepoints to characterize several key PK parameters of efmarodocokin alfa, such as
Cmax at postdose and Cmin at predose.  Exploratory vedolizumab PK analyses may also 
be performed.
3.3.6
Rationale for Biomarker Assessments
Biomarkers will be assessed in serum, plasma, stool, and colonic tissue to demonstrate 
evidence of biologic activity of efmarodocokin alfa in patients with UC, to characterize
PK/PD relationships, and to support dose and dose regimen selection for future studies.
Plasma 4-hydroxycholesterol levels will be measured to assess the potential effect of 
efmarodocokin alfa on hepatic CYP3A activity.  The relationship between blood, stool, 
and colonic tissue biomarkers and safety, immunogenicity, and other biomarker 
endpoints may also be explored.  The assessment of PD biomarkers including, but not 
limited to, DMBT1 may be measured in colonic tissue biopsies to help understand 
concentrations of efmarodocokin alfa required to achieve a pharmacologic and 
therapeutic effect in diseased tissue. 
There is significant variability in response to current treatment and disease progression 
that likely reflects significant heterogeneity in UC pathobiology (Ananthakrishnan 2013; 
Loftus et al. 2014). Treatment with efmarodocokin alfa is predicted to benefit patients 
with UC by enhancing barrier function through direct effects on the intestinal epithelium, 
including increased mucus and antimicrobial peptide production, and direct effects on 


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epithelial proliferation and tight junctions.  Efmarodocokin alfa may also have an effect 
on the microbiome and may address the gut dysbiosis associated with IBD. Predictive 
biomarker samples collected prior to dosing will be assessed in an effort to identify those 
patients with an increased likelihood of responding to efmarodocokin alfa, thus 
potentially providing guidance for treatment decisions.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 270 patients with moderate to severe UC will be enrolled in this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Ability to comply with requirements of the study, in the investigator's judgment

Age 1880 years, inclusive, at time of signing Informed Consent Form

Diagnosis of UC established and confirmed by clinical and endoscopic evidence at 
least 3 months prior to randomization
The diagnosis of UC should be corroborated by histopathology and 
documented by a histopathology report. A histopathologic examination should
be performed at screening if no prior report is readily available.

Confirmation of moderate to severe UC, defined as an mMCS of 49 with an 
endoscopic subscore of 2 as determined by the central reading procedure 
described in Section 4.5.7, a rectal bleeding subscore of 1, and a stool frequency 
subscore of 1 during the screening period (i.e., prior to Day 1)

Evidence of UC a minimum of 20 cm from the anal verge as determined by baseline 
endoscopy (flexible sigmoidoscopy or colonoscopy) 

Colonoscopy within 1 year prior to randomization that confirms left-sided colitis 
(inflammation up to the splenic flexure), extensive colitis (inflammation beyond the 
splenic flexure but not involving the entire colon), or pancolitis (inflammation of the 
entire colon) and includes both of the following:
–
Removal of any adenomatous polyps 
–
Performance of multiple random mucosal biopsies to evaluate for dysplasia in
all patients with left-sided colitis of 12 years' duration or extensive colitis or 
pancolitis of 8 years' duration 

Inadequate response, loss of response, or intolerance to prior immunosuppressant 
treatment (i.e., AZA, 6-MP, MTX, or TNF inhibitors [maximum of two prior 
TNF inhibitors]) and/or corticosteroid treatment


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Inadequate response, loss of response, or intolerance to prior AZA, 6-MP, or MTX 
treatment is defined as one or more of the following: 
–
Persistent signs or symptoms of active disease despite treatment with at least 
one 12-week regimen of AZA (2 mg/kg/day), 6-MP (1 mg/kg/day), and/or 
MTX (25 mg/week) within the previous 5 years
–
Persistent signs or symptoms of active disease despite a 6-TG level of 
230 pmol/8108 RBCs (as measured by quantitative high-performance liquid 
chromatography or liquid chromatography/tandem mass spectrometry) during 
at least one 12-week regimen of AZA or 6-MP within the previous 5 years
–
History of intolerance to AZA, 6-MP, or MTX (including, but not limited to, 
nausea/vomiting, abdominal pain, pancreatitis, liver function test abnormalities, 
lymphopenia, TPMT genetic mutation, or infection) within the previous 5 years
Inadequate response, loss of response, or intolerance to prior TNF inhibitor
treatment is defined as one or more of the following: 
–
Persistent signs or symptoms of active disease despite treatment with at least 
two induction doses of infliximab (5 mg/kg), adalimumab (160 mg for first two 
doses and 80 mg for subsequent doses, or 80 mg for first two doses and 40 mg 
for subsequent doses), or golimumab (200 mg for first two doses and 100 mg
for subsequent doses)
–
Recurrence of signs or symptoms of active disease during maintenance after 
initial response to induction therapy with infliximab (5 mg/kg), adalimumab 
(40 mg), or golimumab (100 mg)
–
Intolerance to TNF inhibitor (including, but not limited to, injection-site reaction, 
demyelination, congestive heart failure, or infection)
Inadequate response, loss of response, or intolerance to prior corticosteroid 
treatment is defined as one or more of the following: 
–
Persistent symptoms of active disease despite treatment with at least one 
4-week induction regimen that included 30 mg/day of oral prednisone (or 
equivalent) for at least 2 weeks or 30 mg/day of IV prednisone (or equivalent)
for at least 1 week within the previous 5 years (corticosteroid refractory)
–
Two failed attempts to taper corticosteroids below 10 mg/day of oral 
prednisone (or equivalent) (corticosteroid dependent)
–
History of intolerance to corticosteroids (including, but not limited to,
Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, or
infection) within the previous 5 years (corticosteroid intolerant)


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
For patients receiving ongoing UC therapy with oral 5-ASA, oral corticosteroids, or 
oral probiotics:  stable dose as outlined below.
–
Oral 5-ASA at a dose that has been stable for at least 4 weeks at the time of
randomization
–
Oral corticosteroid therapy at a dose of20 mg/day of prednisone (or 
equivalent) that has been stable for at least 2 weeks at the time of 
randomization
–
Oral probiotic (e.g., Culturelle, or Saccharomyces boulardii) at a dose that has 
been stable for at least 2 weeks at the time of randomization

For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 
1% per year during the treatment period and for 18 weeks after the last dose of 
study drug
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices (recommendations related to contraception and pregnancy testing in 
clinical trials, CTFG Final version – 2014-09-15, Section 4.1).
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for 
18 weeks after the last dose of study drug to avoid exposing the embryo.  Men 
must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

Immunizations current according to local standards as described in the vedolizumab 
prescribing information and/or based on the investigator’s clinical judgment

Agreement to refrain from donating blood for 6 months after receiving the last dose 
of study drug


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4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of psoriasis or psoriatic arthritis

History of any other inflammatory skin disorders requiring oral corticosteroids, 
immunosuppressants, or biological therapy within the previous year

History of cancer within the previous 5 years

History of non-melanoma skin cancer, GI cancer, or colon cancer, or known family 
history of GI cancer or colon cancer (defined as one first-degree relative or two 
second-degree relatives)

History of a cervical intraepithelial neoplasia (CIN) of Grade 1, cervical smear 
indicating the presence of adenocarcinoma in situ (AIS), or high-grade squamous 
intraepithelial lesions (HSILs)

Conditions other than UC (e.g., asthma) that could require treatment with
20 mg/day of prednisone (or equivalent) during the course of the study

Poorly controlled diabetes, defined as glycosylated hemoglobin (HbA1c)8.0%

History of primary sclerosing cholangitis

Requirement for hospitalization during the study due to severity of UC

Hospitalized (other than for elective reasons) within 4 weeks prior to screening

Any acute or chronic condition that, in the opinion of the investigator, would limit the 
patient's ability to complete or participate in this clinical study

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 18 weeks after the last dose of study drug

Lack of peripheral venous access

Significant uncontrolled comorbidity, such as cardiac (e.g., moderate to severe heart 
failure [New York Heart Association Class III or IV]), pulmonary, renal, hepatic, 
endocrine, or GI disorders (excluding UC)

History or presence of an abnormal ECG that is clinically significant in the 
investigator’s opinion, including complete left bundle branch block, second- or 
third-degree atrioventricular heart block, or evidence of prior myocardial infarction

Family history of sudden unexplained death or long QT syndrome

QT interval corrected through use of Fridericia’s formula (QTcF) 450 ms (men) or
470 ms (women) demonstrated by at least two ECGs

History of alcoholism or drug abuse as judged by the investigator within 1 year of 
screening

If stipulated by local or national laws:  employed by the site, the Sponsor, or 
Sponsor representatives or financially dependent on, or related to, an employee of
the site, the Sponsor, or Sponsor representatives

If stipulated by local or national laws:  institutionalization or detention by way of 
official or judicial order 


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Exclusion Criteria Related to Inflammatory Bowel Disease

Prior extensive colonic resection, subtotal or total colectomy, or proctocolectomy, or 
planned surgery for UC

Diagnosis of indeterminate colitis or granulomatous (Crohn's) colitis

Suspicion of ischemic colitis, radiation colitis, or microscopic colitis

Diagnosis of toxic megacolon within 12 months prior to screening 

Current fistula or history of fistula

Current pericolonic abscess

History or current evidence of unresectable colonic mucosal dysplasia

History of high-grade colonic mucosal dysplasia

Stricture (stenosis) of the colon
Exclusion Criteria Related to Prior or Concomitant Therapy

Prior treatment with efmarodocokin alfa or participation in Study GA29469

Prior treatment with vedolizumab, etrolizumab, natalizumab, efalizumab, or any 
other anti-integrin agents

Use of IV corticosteroids within 30 days prior to randomization with the exception of 
a single administration of IV corticosteroids

Treatment with corticosteroid enemas or suppositories or topical (rectal) 5-ASA 
preparations within 2 weeks prior to randomization

Treatment with AZA, 6-MP, or MTX within 2 weeks prior to randomization

Treatment with a TNF inhibitor within 8 weeks prior to randomization

Use of cyclosporine, tacrolimus, sirolimus, or MMF within 4 weeks prior to 
randomization

Prior treatment with rituximab

Use of agents that deplete B or T cells (e.g., alemtuzumab or visilizumab) within 
12 months prior to randomization, with the exception of AZA and 6-MP

Chronic nonsteroidal anti-inflammatory drug (NSAID) use
Occasional use of NSAIDs or acetaminophen (e.g., for headache, arthritis, 
myalgias, or menstrual cramps) and aspirin up to 325 mg/day is permitted.

Use of anticoagulants, including, but not limited to, warfarin, heparin, enoxaparin, 
dabigatran, apixaban, rivaroxaban
Use of antiplatelet agents, such as aspirin up to 325 mg/day or clopidogrel, is
permitted.

Apheresis (e.g., Adacolumn® apheresis) within 2 weeks prior to randomization

Participation in an investigational study involving non-biologic therapy within 30 days 
or 5 half-lives of the investigational product (whichever is greater) prior to 
randomization


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
Participation in an investigational study involving biologic therapy (including 
vaccines) within 90 days or 5 half-lives of the investigational product (whichever is 
greater) prior to randomization

History of moderate or severe allergic, anaphylactic, or anaphylactoid reactions to 
chimeric, human, or humanized antibodies, fusion proteins, or murine proteins or 
hypersensitivity to efmarodocokin alfa (active drug substance) or any of the 
excipients (sucrose, methionine, sodium phosphate, or polysorbate 20)

Tube feeding, defined formula diets, or parenteral alimentation within 3 weeks prior 
to randomization
Exclusion Criteria Related to Infection Risk

Congenital or acquired immune deficiency

Evidence of, or treatment for, Clostridium difficile (as assessed by C. difficile toxin 
testing) within 60 days prior to randomization or other intestinal pathogens (as 
assessed by stool culture and ova and parasite evaluation) within 30 days prior to 
randomization

History of invasive fungal infections such as Candida or Aspergillus (excluding 
thrush or other superficial fungal infections) within 6 months prior to randomization

History of severe herpes (simplex type 1, simplex type 2, or zoster) infection or 
reactivation within 12 weeks prior to randomization, or frequent recurrence of herpes 
(more than two times per year)

History of any other opportunistic infections within 12 weeks prior to randomization

Any major episode of infection requiring hospitalization or treatment with 
IV antibiotics within 8 weeks prior to screening or oral antibiotics within 4 weeks 
prior to screening

History of organ transplant

Colonic biopsy positive for cytomegalovirus (CMV) at screening, as determined by 
histologic examination or immunohistochemistry per local standards
Exclusion Criteria Related to Screening Laboratory Values

Positive HIV antibody test at screening

Positive hepatitis B surface antigen (HBsAg) test at screening
Patients with a negative HBsAg test and a positive total hepatitis B core 
antibody (HBcAb) test at screening will not be excluded if they have a negative 
hepatitis B virus (HBV) DNA test.

Positive hepatitis C virus (HCV) antibody test at screening, except in patients who 
meet either of the following sets of criteria:
–
Patient has undetectable HCV RNA levels for 6 months after completion of 
HCV anti-viral treatment and a negative HCV RNA test at screening
–
Patient has a history of HCV antibody positivity, a history of undetectable 
HCV RNA levels for 6 months, and a negative HCV RNA test at screening


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
Positive for TB during screening or within 3 months prior to screening, defined as a 
positive QuantiFERON®-TB Gold test (QFT) or (if QFT is not available) a positive 
purified protein derivative (PPD) skin test according to Centers for Disease Control 
and Prevention guidelines, with the following exceptions:
–
Patients with a history of Bacillus Calmette-Guérin (BCG) vaccination who have 
a positive PPD skin test will not be excluded if they have a negative QFT at 
screening
–
Patients who have a positive or indeterminate QFT and patients with no history 
of BCG vaccination who have a positive PPD skin test will not be excluded if 
they meet all of the following criteria:
a)
No symptoms consistent with TB 
b)
Documented history of a completed course of adequate prophylaxis 
(completed treatment for latent TB) per local standard of care prior to 
screening
c)
No known exposure to a case of active TB after most recent prophylaxis
d)
No evidence of active TB on chest X-ray performed during screening or 
within 3 months prior to screening

Glomerular filtration rate 60 mL/min as calculated through use of the Modification 
of Diet in Renal Disease (MDRD) study equation or creatinine clearance rate 
60 mL/min as calculated by the Cockcroft-Gault formula

ALT, AST, or alkaline phosphatase 2.5ULN, total bilirubin 1.5ULN, or
presence of abnormalities in synthetic function tests judged to be clinically 
significant by the investigator
Patients with known Gilbert syndrome who have unconjugated 
hyperbilirubinemia will not be excluded.

Platelet count 100109/L (100,000/L)

Hemoglobin 90 g/L (9 g/dL)

ANC 1.5109/L (1500/L)

Absolute lymphocyte count 0.5109/L (500/L)
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Overall, patients will be assigned in a 1:1:1:1:1:1:2:1 ratio to one of eight treatment arms 
(see Figure 1).  Following completion of the screening period and after all patient 
eligibility requirements are confirmed, patients will be assigned a subject number and will 
be randomly assigned to a treatment arm through an interactive voice or web-based 
response system (IxRS).


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Patients will be randomized on the same day that treatment is to be initiated (Day 1).  
Randomization will be performed using a permuted blocks randomization method with 
stratification by prior treatment with TNF inhibitors (yes/no). 
Study site personnel (with the exception of the unblinded pharmacist) and patients will 
be blinded to treatment assignment during the study.  The Sponsor and its agents will 
also be blinded to treatment assignment, with the exception of individuals who require 
access to patient treatment assignments to fulfill their job roles during a clinical trial.
These roles include the unblinding group responsible, clinical supply chain managers, 
sample handling staff, operational assay group personnel, IxRS service provider, and 
IMC members.
While PK and ADA samples must be collected from all patients to maintain the blinding 
of treatment assignment, PK and ADA assay results for patients receiving placebo or
vedolizumab are generally not needed for the safe conduct or proper interpretation of 
this study.  Laboratories responsible for performing study drug PK and ADA assays will 
be unblinded to patients' treatment assignments to identify appropriate samples to be 
analyzed.  See Section 4.5.8 regarding serum sample analyses.
If unblinding is necessary for a medical emergency (e.g., in the case of a serious
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations.
If the investigator wishes to know the identity of the study drug for any reason other 
than a medical emergency, he or she should contact the Medical Monitor directly.  The 
investigator should document and provide an explanation for any non-emergency 
unblinding.  The investigator will be able to break the treatment code by contacting 
the IxRS.
If deemed necessary, the Medical Monitor may be unblinded to individual patient 
assignment after approval is obtained from the IMC Chair. 
As per health authority reporting requirements, the Sponsor's Drug Safety representative
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment.


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4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The IMPs for this study are efmarodocokin alfa and vedolizumab (active comparator).
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Efmarodocokin Alfa and Efmarodocokin Alfa Placebo
Efmarodocokin alfa and efmarodocokin alfa placebo will be supplied by the Sponsor as a 
sterile solution in single-use 2-mL vials.  Diluent will also be supplied by the Sponsor.  
For information on the formulation and handling of efmarodocokin alfa, see the 
pharmacy manual and the efmarodocokin alfa Investigator's Brochure.
4.3.1.2
Vedolizumab and Vedolizumab Placebo
Vedolizumab and vedolizumab placebo will be supplied by the investigative site or the 
Sponsor in selected countries as lyophilized powder in single-use vials or 0.9% sodium 
chloride (normal saline) bags, respectively. For information on the formulation and 
handling of vedolizumab, see the Summary of Product Characteristics for vedolizumab.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Table 2.  Study drug will be administered in 
a monitored setting where there is immediate access to trained personnel and adequate 
equipment and medicine to manage potentially serious reactions.
At clinic visits in which two infusions are administered (Weeks 0, 14, and 22), 
efmarodocokin alfa or efmarodocokin alfa placebo should be delivered first, followed by 
a monitoring period of approximately 30 minutes before administration of vedolizumab or 
vedolizumab placebo.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along 
with any associated adverse events, should be reported as described in Section 5.4.4.
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.3.
4.3.2.1
Efmarodocokin Alfa and Efmarodocokin Alfa Placebo
Efmarodocokin alfa or efmarodocokin alfa placebo will be administered by IV infusion, 
with the initiation infusion delivered over approximately 6010 minutes.  If the 60-minute 
infusion is tolerated without infusion-associated adverse events (e.g., fevers or chills), 
the second infusion may be delivered over 3010 minutes.  If the 30-minute infusion is 
tolerated, all subsequent infusions may be delivered over 155 minutes.
If a patient experiences an infusion-associated adverse event, refer to the pharmacy 
manual for management of infusion reactions.  All subsequent infusions should be 
delivered at the previously tolerated rate. 


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Patients should be monitored for at least 30 minutes after each infusion.
Weight-based infusions of efmarodocokin alfa, with a maximum dose given to be based 
on 100 kg total body weight, will be prepared per the instructions outlined in the 
pharmacy manual.
4.3.2.2
Vedolizumab and Vedolizumab Placebo
Vedolizumab 300 mg or vedolizumab placebo will be administered by IV infusion over 
30 minutes as specified in the prescribing information.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (efmarodocokin alfa and vedolizumab) will 
be provided by the Sponsor where required by local health authority regulations.  
Vedolizumab may be provided by the study site, if applicable.  The study site will 
acknowledge receipt of IMPs supplied by the Sponsor, using 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 (if supplied by the Sponsor) 
with the appropriate documentation.  The site’s method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form. The investigator or designee must confirm 
that appropriate temperature conditions have been maintained during transit, either by 
time monitoring (shipment arrival date and time) or temperature monitoring, for all 
IMP received and that any discrepancies have been reported and resolved before use of 
the IMP. The IMP must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions, with access limited to the investigator and authorized staff. 
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.
4.3.4
Continued Access to Efmarodocokin Alfa
Patients may be eligible to receive efmarodocokin alfa as part of an extension study 
offered by the Sponsor (Genentech, a member of the Roche Group), as described in 
Section 3.1.5.  The Roche Global Policy on Continued Access to Investigational 
Medicinal Product is available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf


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4.4
CONCOMITANT THERAPY AND ADDITIONAL RESTRICTIONS
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment in the period immediately prior to 
randomization (as specified in Sections 4.1.1 and 4.1.2) through the final study visit.  All 
such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF, along with the reason for their use.
At this time there is no evidence to suggest an interaction between efmarodocokin alfa 
and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. If a 
patient in the study elects to have a SARS-CoV-2 vaccine, it should not be given on 
the same day as study drug dosing, in order to distinguish any possible infusion-related 
reactions/injection-related reactions from each agent should one occur. The 
SARS-CoV-2 vaccine should be recorded on the Concomitant Medication eCRF. 
If there is any doubt as to whether a medication is permitted during the trial, the study 
site staff should contact the Medical Monitor.
4.4.1
Concomitant Therapy for UC (Including Rescue Therapy)
Permitted and prohibited concomitant therapies for UC, including rescue therapies, are 
outlined in Table 3.


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Table 3
Permitted and Prohibited Concomitant Therapies for UC
Therapy
Prior to and during Screening a
During Part A
During Part B and 
Safety Follow-Up
Rescue Therapy b
Anti-inflammatories
Topical (rectal) 5-ASA 
– May not have received topical
(rectal) 5-ASA within 2 weeks prior 
to randomization
– Initiation of topical (rectal) 5-ASA is not permitted
– Initiation of topical
(rectal) 5-ASA is 
considered rescue 
therapy
Oral 5-ASA 
– May be receiving oral 5-ASA if 
dose has been stable for at least 
4 weeks at the time of
randomization (baseline)
– Initiation of oral 5-ASA is not permitted
– Baseline level of oral 5-ASA must be maintained
during the study
– Initiation of oral 5-ASA 
or increase in dose of 
oral 5-ASA compared 
with baseline is 
considered rescue 
therapy
IV corticosteroids and rectal 
corticosteroids (i.e., enemas 
or suppositories)
– May not have received rectal
corticosteroid within 2 weeks prior 
to randomization
– May not have received IV 
corticosteroids within 30 days prior 
to randomization with the 
exception of a single 
administration of IV corticosteroids
– Initiation of IV or rectal corticosteroid is not 
permitted
– Initiation of IV or rectal
corticosteroid is 
considered rescue 
therapy
5-ASA5-aminosalicylic acid; 6-MP6-mercaptopurine; AZAazathioprine; IVintravenous; MMFmycophenolate mofetil; MTX methotrexate; 
TNFtumor necrosis factor.
a See inclusion and exclusion criteria in Sections 4.1.1 and Section 4.1.2 for additional details.
b See Sections 3.1.2 and Section 3.1.3 for information regarding rescue therapy as it applies to the disposition of patients. 


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Table 3
Permitted and Prohibited Concomitant Therapies for UC (cont.)
Therapy
Prior to and during Screening a
During Part A
During Part B and 
Safety Follow-Up
Rescue Therapy b
Anti-inflammatories (cont.)
Oral corticosteroids 
– May be receiving oral 
corticosteroid therapy 
(20 mg/day prednisone or 
equivalent) if dose has been 
stable for at least 2 weeks at the 
time of randomization (baseline
steroid level) c, d
– 20 mg/day prednisone or 
equivalent is exclusionary c, d
– Initiation of oral 
corticosteroids is 
not permitted
– Baseline level of 
oral corticosteroids 
must be 
maintained during 
the study
– Initiation of oral 
corticosteroids is not 
permitted
– For patients on oral 
corticosteroids at baseline, 
corticosteroid dose will be 
tapered until discontinuation,
starting at Week 8 
(see Section 3.1.3)
– For patients who cannot 
tolerate the corticosteroid 
taper without recurrence of 
UC symptoms or experience 
symptoms of corticosteroid 
withdrawal, the corticosteroid 
dose can be increased e
– Initiation of oral 
corticosteroids or 
increase in dose of oral 
corticosteroids 
compared with baseline 
is considered rescue 
therapy
5-ASA5-aminosalicylic acid; 6-MP6-mercaptopurine; AZAazathioprine; IVintravenous; MMFmycophenolate mofetil; MTX methotrexate; 
TNFtumor necrosis factor.
a See inclusion and exclusion criteria in Sections 4.1.1 and Section 4.1.2 for additional details.
b See Sections 3.1.2 and Section 3.1.3 for information regarding rescue therapy as it applies to the disposition of patients. 
c The equivalent dose of budesonide to prednisone has not been fully characterized; however, 9 mg/day budesonide has been shown to be as 
effective as 40 mg/day prednisolone (equivalent to 40 mg/day prednisone) in achieving remission in Crohn's disease (Rutgeerts et al. 1994; 
Campieri et al. 1997; Edsbäcker et al. 1999; Edsbäcker and Andersson 2004).
d There is limited/no data on beclometasone dipropionate equivalency in inflammatory bowel disease.  Beclometasone dipropionate should not be 
used for more than 4 weeks based on the Clipper Summary of Product Characteristics.
e If the corticosteroid dose has not been increased above the baseline level, these patients should re-initiate corticosteroid dose tapering per the 
regimen described in Section 3.1.3.  Patients who are unable to tolerate a second taper should discontinue study drug and enroll in OLE Study 
GA40209, if eligible.  Treatment with corticosteroids above the baseline dose will be considered rescue therapy.


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Table 3
Permitted and Prohibited Concomitant Therapies for UC (cont.)
Therapy
Prior to and during Screening a
During Part A
During Part B and 
Safety Follow-Up
Rescue Therapy b
Immunosuppressants
AZA, 6-MP, or MTX
– May not have received AZA, 
6-MP, or MTX within 2 weeks prior 
to randomization
– Initiation of AZA, 6-MP, or MTX is not permitted
– Initiation of AZA, 6-MP, 
or MTX is considered 
rescue therapy
TNF inhibitors:  adalimumab, 
certolizumab, golimumab, 
and infliximab  
– May not have received a TNF 
inhibitor within 8 weeks prior to 
randomization 
– Initiation of TNF inhibitors is not permitted
– Initiation of TNF 
inhibitors is considered 
rescue therapy 
Anti-integrin agents
Vedolizumab
– May not have received prior 
treatment with vedolizumab
– Patients in Arm 4 will receive blinded vedolizumab
as an investigational medicinal product and active 
comparator
– Vedolizumab is not 
permitted as rescue 
therapy
Natalizumab, etrolizumab, 
efalizumab, or other 
anti-integrin agents
– May not have received prior 
treatment with etrolizumab, 
natalizumab, efalizumab or other 
anti-integrin agents
– Initiation of anti-integrin agents (other than
vedolizumab for patients in Arm 4) is not permitted
– Anti-integrin agents are 
not permitted as rescue 
therapy
5-ASA5-aminosalicylic acid; 6-MP6-mercaptopurine; AZAazathioprine; IVintravenous; MMFmycophenolate mofetil; MTX methotrexate; 
TNFtumor necrosis factor.
a See inclusion and exclusion criteria in Sections 4.1.1 and Section 4.1.2 for additional details.
b See Sections 3.1.2 and Section 3.1.3 for information regarding rescue therapy as it applies to the disposition of patients. 


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Table 3
Permitted and Prohibited Concomitant Therapies for UC (cont.)
Therapy
Prior to and during Screening a
During Part A
During Part B and 
Safety Follow-Up
Rescue Therapy b
Other Therapies
Oral probiotics
– May be receiving oral probiotics 
(e.g., Culturelle, S. boulardii) if 
dose has been stable for at least 
2 weeks at the time of 
randomization
– Initiation of oral probiotics is not permitted
– Baseline usage of oral probiotics must remain 
stable during the study

Cyclosporine, tacrolimus, 
sirolimus, and MMF
– May not have received 
cyclosporine, tacrolimus, 
sirolimus, or MMF within 4 weeks 
prior to randomization
– Initiation of cyclosporine, tacrolimus, sirolimus, or 
MMF is not permitted
– Cyclosporine, 
tacrolimus, sirolimus, 
and MMF are not 
permitted as rescue 
therapy
Tofacitinib
– Prohibited within 30 days or 
5 half-lives of the drug 
(whichever is longer) prior to 
randomization
– Initiation of tofacitinib is not permitted
– Tofacitinib is not 
permitted as rescue 
therapy
Ustekinumab
– Prohibited within 90 days or 
5 half-lives of the drug 
(whichever is longer) prior to 
randomization
– Initiation of ustekinumab is not permitted
– Ustekinumab is not 
permitted as rescue 
therapy
5-ASA5-aminosalicylic acid; 6-MP6-mercaptopurine; AZAazathioprine; IVintravenous; MMFmycophenolate mofetil; MTX methotrexate; 
TNFtumor necrosis factor.
a See inclusion and exclusion criteria in Sections 4.1.1 and Section 4.1.2 for additional details.
b See Sections 3.1.2 and Section 3.1.3 for information regarding rescue therapy as it applies to the disposition of patients. 


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4.4.2
Other Concomitant Therapy
4.4.2.1
Other Permitted Concomitant Therapy
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, per local standard practice.  Patients will be permitted to use the 
following therapies during the study:

Oral contraceptives

Hormone-replacement therapy
Patients who experience infusion-associated symptoms may be treated symptomatically 
with acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor antagonists 
(e.g., famotidine, cimetidine), or equivalent medications per local standard practice.  
Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists).
Patients may continue on stable regimens of drugs they are receiving as treatment for
coexistent stable diseases (e.g., anti-hypertensives, cholesterol-lowering drugs, or 
bronchodilators).
Over-the-counter preparations deemed acceptable by the Sponsor and the investigator 
at the beginning of the study will be allowed during the study.  Initiation of 
over-the-counter medications during the study will need to be approved by the 
investigator and the Sponsor.
4.4.2.2
Other Prohibited Concomitant Therapy
Use of the following therapies is prohibited as specified below:

Use of rituximab is prohibited prior to and during the study

Use of agents that deplete B or T cells (e.g., alemtuzumab or visilizumab), with the 
exception of AZA and 6-MP (see Section 4.4.1), is prohibited within 12 months prior 
to randomization or during the study

Chronic use of NSAIDs is prohibited prior to and during the study
Occasional use of NSAIDs and acetaminophen (e.g., headache, arthritis, 
myalgias, or menstrual cramps) and aspirin up to 325 mg/day is permitted.

Use of anticoagulants (including, but not limited to, warfarin, heparin, enoxaparin, 
dabigatran, apixaban, rivaroxaban) is prohibited prior to and during the study
Use of antiplatelet agents, such as aspirin up to 325 mg/day or clopidogrel, is
permitted.

Apheresis (e.g., Adacolumnapheresis) is prohibited within 2 weeks prior to 
randomization and during the study

Use of a non-biologic investigational drug is prohibited within 30 days or 5 half-lives 
of the drug (whichever is longer) prior to randomization and during the study


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
Use of a biologic investigational drug is prohibited within 90 days or 5 half-lives of 
the drug (whichever is longer) prior to randomization and during the study
4.4.3
Additional Restrictions
At study visits where fasting lipids are measured, no food or fluids other than water will 
be allowed for approximately 8 hours prior to the visit and until after study laboratory 
samples are obtained.  On study-drug dosing days, no food will be allowed from at 
least 2 hours before dosing until 30 minutes after the last infusion, when a light meal will 
be allowed.
To avoid potential contamination of blood supply with the investigational product, 
patients will be restricted from donating blood for 6 months after receiving the last dose 
of efmarodocokin alfa or vedolizumab.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities must be performed and documented for each patient.  
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Re-Testing for Laboratory Inclusion and Exclusion Criteria
Two re-tests are permitted in order for potential participants to meet the laboratory 
inclusion and exclusion criteria (see Sections 4.1.1 and 4.1.2). If a patient does not 
meet laboratory criteria for a third time, he or she will be considered a screen failure. 
Laboratory testing that is repeated because of administrative or technical issues
(e.g., breakage of a sample vial during transit to the central laboratory or degradation of 
a sample during transportation) is not considered to be re-screening. 
4.5.3
Re-Screening
If a patient does not meet all eligibility criteria within the screening window, 
one re-screening is permitted.  Each patient must be re-consented before 
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The screening endoscopy and colonic biopsies do not need to be repeated during 
re-screening provided that all of the following criteria are met:

All endoscopy-related inclusion criteria have been met, with corresponding e-diary 
data for MCS calculation (see Section 4.5.7.2).

The initial endoscopy has been performed within 28 days prior to the day of 
randomization for second screening.

Colon biopsies as specified by the protocol have been obtained.
If a negative TB screening test result has been documented within 3 months prior to
screening or re-screening, no repeat test is required.
Patients who are classified as being screen failures due to the presence of C. difficile or 
CMV infection may be re-screened with randomization occurring (if eligible) at least 
60 days after successful treatment. For patients who screen fail due to CMV infection, 
laboratory analysis of CMV from colon biopsy samples is required during re-screening 
evaluation to rule out CMV infection. 
4.5.4
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking 
history, and use of alcohol and drugs of abuse, will be recorded at baseline.  In addition, 
all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 24 weeks
prior to randomization will be recorded.  At the time of each follow-up physical 
examination, an interval medical history should be obtained and any changes in 
medications and allergies should be recorded.
A UC-specific history including complications and surgeries related to UC, and a detailed
history of UC medications used by the patient within 1 year prior to the screening visit
will be recorded.  In addition, a detailed history of biologics used by the patient within
5 years prior to the screening visit (e.g., name and duration of previous biologic 
therapies and reason for discontinuation) will be recorded.  
The extent and duration of the patient’s disease, as recorded in the patient's medical 
record, will be captured in the eCRF.  The extent of disease should be identified as one 
of the following:

Left-sided colitis (inflammation up to the splenic flexure)

Extensive colitis (inflammation beyond the splenic flexure but not involving the 
entire colon)

Pancolitis (inflammation of the entire colon)
Demographic data will include age, sex, and self-reported race/ethnicity.


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4.5.5
Physical Examinations
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, GI, genitourinary, and 
neurologic systems.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF.
Limited, symptom-directed physical examinations, including an abdominal examination,
should be performed at specified post-baseline visits and as clinically indicated.  
Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF.
4.5.6
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure, and temperature while the patient is in a seated position after at 
least 10 minutes of rest.
4.5.7
Clinical Outcome Assessments
Clinical outcome will be assessed through the MCS (see Section 4.5.7.1), which 
incorporates stool frequency and rectal bleeding as reported by the patient
(see Section 4.5.7.2), the PGA as reported by the clinician (see Section 4.5.7.3), and 
endoscopic evaluations by a central reader (see Section 4.5.7.4).  Clinical outcome will 
also be assessed through the Inflammatory Bowel Disease Questionnaire (IBDQ)
(see Section 4.5.7.2), and the Ulcerative Colitis Patient-Reported Outcome Signs and 
Symptoms (UC-PRO/SS) (see Section 4.5.7.2), as well as the Ulcerative Colitis 
Endoscopic Index of Severity (UCEIS), the Robarts Histopathological Index, the Nancy 
Histological Index, and the Geboes Score (see Section 4.5.7.5).
4.5.7.1
Mayo Clinic Score, Modified Mayo Clinic Score, and Partial 
Mayo Clinic Score
The MCS is a composite of four assessments, each having a scoring range of 03:  
stool frequency, rectal bleeding, centrally read endoscopy, and PGA.  The MCS has a 
range of 012, with higher scores indicating more severe disease (see Appendix 2).
The mMCS is a composite of three assessments from the MCS, each having a scoring 
range of 03: stool frequency, rectal bleeding, and centrally read endoscopy.  The 
mMCS has a range of 09, with higher scores indicating more severe disease
(see Appendix 3).
The pMCS is a composite of three assessments from the MCS, each having a scoring 
range of 03:  stool frequency, rectal bleeding, and PGA.  The pMCS has a range of 
09, with higher scores indicating more severe disease (see Appendix 4).


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mMCS with centrally read endoscopy assessment during screening (i.e., a score of 2, 
if Robarts’ assessment confirms that a patient is eligible) will be used as efficacy 
baseline and for inclusion. mMCS using locally read endoscopy assessment will be 
utilized to assess clinical response at Week 8 and for determination of eligibility in the 
OLE study or continuation into Part B.
Patients are to report their stool frequency and rectal bleeding on a daily basis, as 
described in Section 4.5.7.2.
4.5.7.2
Patient-Reported Outcomes
Patient-reported outcome (PRO) data will be collected through use of an electronic 
device (e-diary).  The e-diary and/or instructions for completing the questionnaires 
electronically will be provided by site staff.  Data captured between clinic visits should be 
reviewed with the patient at each clinic visit.  The data will be transmitted to a centralized 
database maintained by the electronic device vendor.  The data will be available for 
access by appropriate study personnel.
In cases of device malfunction or failure, data may be captured via paper questionnaires.
The PRO questionnaires, translated into the local language as appropriate, will be 
completed in their entirety at specified timepoints during the study. To ensure 
instrument validity and compliance with health authority requirements, questionnaires 
will be self-administered before the patient receives any information on disease status, 
before non-PRO assessments are performed, and before administration of study 
treatment, unless otherwise specified. Study site staff will ensure that questionnaires 
are provided to the patients for completion per the schedule of assessments 
(see Appendix 1) and will confirm completion or document any reasons for 
non-completion before the visit concludes.


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Stool Frequency and Rectal Bleeding
Stool frequency and rectal bleeding are components of the MCS, mMCS, and pMCS 
(see Section 4.5.7.1).
At screening, the investigator will document the patient’s normal number of stools, 
defined as the number of stools passed when a patient is in remission (i.e., not in flare).
Patients are to record stool frequency and rectal bleeding in the e-diary daily throughout 
the study, beginning with the first screening visit (see Appendix 6).  If available, stool 
frequency and rectal bleeding scores from the three most recent e-diary entries prior to 
bowel preparation for screening endoscopy and the screening endoscopy will be used 
as efficacy baseline and for inclusion. The three most recent e-diary entries prior to 
Day 1 randomization will also be used for inclusion. The screening endoscopy should 
not be performed without adequate symptoms. Adequate symptoms are defined as
meeting both of the following criteria:

Stool frequency1 in at least 2 out of 3 days or stool frequency 2 in at least 1 out 
of 3 days.

Rectal bleeding1 in at least 2 out of 3 days or rectal bleeding 2 in at least 1 out 
of 3 days.
In rare cases where there are 3 days of e-diary data available prior to bowel 
preparation for screening endoscopy, the minimum number of e-diary entries from day 2 
until day 4 post endoscopy may be used in addition to pre-endoscopy entries to obtain 
3 total days of entries for baseline and inclusion.

If 3 days of e-diary data are available prior to screening endoscopy, that data will be 
used. The patient should have adequate symptoms before endoscopy is performed 
or it will be considered a protocol deviation.

If 2 days of e-diary data are available prior to screening endoscopy, that data and 
the first available e-diary entry 2 days after the endoscopy will be used. The patient 
should have adequate symptoms (i.e., stool frequency and rectal bleeding scores of 
1 on both days) before endoscopy is performed or it will be considered a protocol 
deviation.

If 1 day of e-diary data is available prior to screening endoscopy, that data and the 
first two available e-diary entries 2 days after the endoscopy will be used. The 
patient should have adequate symptoms (i.e., stool frequency and rectal bleeding 
scores of 2) before endoscopy is performed or it will be considered a protocol 
deviation.

If 0 days of e-diary data are available prior to screening endoscopy, data from the 
first three available e-diary entries 2 days after the endoscopy will be used.
Because the endoscopy and associated bowel preparation can interfere with the 
assessment of PROs, e-diary entries on days of bowel preparation, endoscopy, and the 


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day after endoscopy will not be used to calculate any stool frequency or rectal bleeding 
scores.  
Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms
Patients are to complete the UC-PRO/SS on the 9 consecutive days preceding each 
clinic visit in which the UC-PRO/SS is assessed.
The UC-PRO/SS will be used to assess patient-reported UC signs and symptoms.  The 
9-item questionnaire contains two domains:  bowel movement signs and symptoms and 
abdominal symptoms.  The UC-PRO/SS assesses the presence of UC symptoms and in 
some cases the severity or frequency of the symptoms.  The UC-PRO/SS measure has 
a recall specification of 24 hours.  A copy of the UCPRO/SS measure is provided in 
Appendix 7.
Inflammatory Bowel Disease Questionnaire 
The IBDQ should be administered at the investigational site prior to the completion of 
other nonPRO assessments and before the patient receives any disease status 
information or study drug.
The IBDQ will be used to assess patients’ health-related quality of life (QOL) 
(Guyatt et al. 1989; Irvine 1999).  The 32-item questionnaire contains four domains: 
bowel symptoms (10 items), systemic symptoms (5 items), emotional function (12 items), 
and social function (5 items).  The items are scored on a 7-point Likert scale with a 
higher score indicating better health-related QOL.  The IBDQ has a recall specification of 
2 weeks.  A copy of the IBDQ is provided in Appendix 8.
4.5.7.3
Physician's Global Assessment
PGA data will be collected through use of an electronic device or paper form.  The PGA 
is a component of the MCS and pMCS (see Section 4.5.7.1).  The PGA should reflect
the clinician's assessment of the patient's current overall status, taking into account stool 
frequency and rectal bleeding scores, clinician endoscopy findings, patient-reported 
symptoms, clinician observations, physical examination findings, and other pertinent 
findings.  The clinician who completes the PGA should not be the same clinician who 
assesses adverse events.
4.5.7.4
Colonoscopy or Flexible Sigmoidoscopy with Colonic Biopsies
All patients will undergo a flexible sigmoidoscopy with collection of colonic biopsies at 
baseline/screening, at Weeks 8 and 30, and at the disease evaluation/early termination 
visit.  Patients without documentation of colon cancer surveillance within 1 year prior to 
randomization will have a screening colonoscopy in lieu of a flexible sigmoidoscopy.  
Every effort should be made to schedule on-treatment endoscopies on the same day as 
the protocol-specified study visit. Stool frequency and rectal bleeding scores from the 
three most recent e-diary entries and the screening endoscopy will be used as efficacy 


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baseline and for inclusion. The screening endoscopy should not be performed without 
adequate symptoms (see Section 4.5.7.2).
Bowel preparation prior to the colonoscopy and flexible sigmoidoscopy procedures
should be done per local practice.  Medications used for bowel preparation should be 
reported on the Concomitant Medications eCRF.  Scheduled stool samples should be 
taken prior to bowel preparation.
For each patient, a video recording will be performed during the colonoscopy (if colon 
cancer surveillance performed during screening) or flexible sigmoidoscopy procedure 
through use of a medical DVD recorder in the high-quality mode per the endoscopy 
manual.  Video recordings should be taken of the entire endoscopic procedure, starting 
from insertion into the bowel.  Biopsies should be performed upon withdrawal of the 
endoscope from the bowel. The endoscopist should ensure that the video recording of 
the procedure will allow for adequate assessment of disease activity, taking into 
consideration the possibility of minor bleeding associated with biopsies. Technical 
instructions for video recording and biopsy collection will be provided in the laboratory 
manual.
The clinician who performs the endoscopy will take into account endoscopy findings
when completing the PGA (see Section 4.5.7.3).
All video recordings will be submitted to a central reading facility to be centrally reviewed
for mucosal lesions and endoscopic severity by an independent gastroenterologist 
experienced in UC who is blinded to the patient’s clinical activity, study visit, and 
treatment allocation.  Endoscopic videos will be assessed to determine if patients meet 
the endoscopic inclusion criterion as well as to objectively document subsequent 
disease activity.  For efficacy assessment of primary, secondary, and exploratory 
endpoints, Mayo endoscopic subscore and UCEIS will be calculated on the basis of 
centrally read patient videos.  Locally read endoscopic videos will be used to inform 
investigator-determined clinical or treatment decisions.
4.5.7.5
Other Clinical Indices
The UCEIS is a scoring system used to predict the overall assessment of endoscopic 
severity based on three descriptors: vascular pattern, bleeding, and erosions and ulcers. 
The descriptors are scored on a Likert scale with a higher score indicating more 
endoscopic severity (Travis et al. 2012).
The Robarts Histopathological Index is used to evaluate histological disease activity in 
UC based on four components: chronic inflammatory infiltrate, lamina propria 
neutrophils, neutrophils in epithelium, and erosion or ulceration.  The components are 
scored on a 03 Likert scale with a higher score indicating more severe disease activity 
(Mosli et al. 2017).


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The Nancy Histological Index is used to evaluate histological disease activity in UC
based on three histological components:  ulceration, acute inflammatory infiltrate, and 
chronic inflammatory infiltrate.  The components are scored on a 05 Likert scale with a 
higher score indicating more severe disease activity (Marchal-Bressenot et al. 2017).
The Geboes Score is used to evaluate histological disease severity in UC based on a 
six-grade classification system: 0-structural change only; 1-chronic inflammation; 
2-lamina propria neutrophils; 3-neutrophils in epithelium; 4-crypt destruction; 5-erosions 
or ulcers.  A higher grade indicates more severe disease activity (Geboes et al. 2000).
4.5.8
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis.  Samples may be analyzed at a central laboratory if local analysis is not 
available.

Urinalysis: specific gravity, pH, blood, quantitative protein, ketones, glucose, 
bilirubin, nitrite, leukocyte esterase, color, and appearance
If urinalysis is abnormal, the same urine sample will be sent to the laboratory for 
microscopic analysis (sediment, WBCs, RBCs, casts, crystals, epithelial cells, 
and bacteria), culture, and sensitivity.

Urine pregnancy test
All women of childbearing potential will have a urine pregnancy test performed 
monthly during the study.  Urine pregnancy tests will be performed at specified 
subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by 
a serum pregnancy test.

Stool sample analysis: culture and sensitivity, ova and parasites, and 
C. difficile toxin

Analysis of colonic tissue sample obtained by biopsy performed during screening 
endoscopic procedure (flexible sigmoidoscopy or colonoscopy):
–
CMV, as determined by histologic examination or immunohistochemistry per 
local standards
–
Patients without a prior histopathology report:  histopathologic examination

Patients with no documentation of colonic cancer surveillance within 1 year prior to 
randomization:  analysis of multiple random mucosal tissue samples obtained during 
screening colonoscopy to evaluate for dysplasia
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis:

Patients with a history of drug abuse:  urine drug screening

Serum pregnancy test
All women of childbearing potential will have a serum pregnancy test at 
screening.


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
HIV serology

HBV serology:  HBsAg, total HBcAb
If a patient has a negative HBsAg test and a positive HBcAb test, an 
HBV DNA test will be performed.

HCV serology:  HCV antibody test
If a patient has a positive HCV antibody test, an HCV RNA test will be 
performed.

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells)

Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, 
creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, 
alkaline phosphatase, ALT, AST, uric acid, LDH

Lipase and CRP
Site and Sponsor personnel, with the exception of the IMC, will be blinded to 
CRP test results.

Coagulation:  INR, aPTT, PT, fibrinogen
Site and Sponsor personnel, with the exception of the IMC, will be blinded to 
fibrinogen test results.

Lipids (fasting):  cholesterol, LDL cholesterol, HDL cholesterol, triglycerides
No food or fluids other than water will be allowed for approximately 8 hours 
prior to the visit and until after sample collection.

TB test: QFT or, if QFT is unavailable, PPD skin test
Test may be performed locally.

Patients with known diabetes:  HbA1c
The following samples will be sent to the Sponsor or a designee for analysis:

Serum samples for PK analysis
Serum ADA may be measured using PK samples if ADA samples have not 
been collected at the same timepoint. 

Serum samples for immunogenicity (ADA) analysis
Serum drug concentrations may be measured in ADA samples if PK samples 
have not been collected at the same timepoint.
Baseline ADA samples will be analyzed for all patients.
Post-baseline ADA samples will be analyzed for all patients receiving 
efmarodocokin alfa.


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
Serum samples for exploratory research on biomarkers that may include, but will not 
be limited to, IL-22, IL-22BP, REG3A, and sMAdCAM
Site and Sponsor personnel, with the exception of the IMC, will be blinded to 
REG3A test results.

Plasma samples for exploratory research on biomarkers that may include, but will 
not be limited to, propionate, 4-hydroxycholesterol, and cholesterol

Stool samples for exploratory research on biomarkers that may include, but will not 
be limited to, bacterial DNA and calprotectin

Colonic tissue samples obtained by biopsy performed during screening and 
subsequent endoscopic procedures (flexible sigmoidoscopy or colonoscopy) for 
exploratory research on tissue histology and on biomarkers that may involve 
extraction of DNA or RNA and bacterial DNA and may include, but will not be limited 
to, analysis of IL-22RA2, IL-22RA1, and DMBT1
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.12), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Serum samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization and PK and immunogenicity assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed.

Serum, plasma, stool, and colonic tissue samples collected for biomarker research 
will be destroyed no later than 15 years after the final Clinical Study Report has 
been completed.  However, the storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health 
authority requirements)
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
4.5.9
Chest X-Ray
A chest X-ray will be performed during screening or within 3 months prior to screening to 
rule out TB for patients who have a positive or indeterminate QFT and patients with no


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history of BCG vaccination who have a positive PPD skin test (see Section 4.1.2 for 
details on requirements for TB testing).
4.5.10
Electrocardiograms
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1), and may be obtained at unscheduled timepoints 
as indicated.
All ECG recordings must be performed using an electrocardiograph machine 
equipped with computer-based interval measurements. Lead placement should be as 
consistent as possible.  ECG recordings must be performed after the patient has been 
resting in a supine position for at least 10 minutes.  All ECGs are to be obtained prior 
to other procedures scheduled at that same time (e.g., vital sign measurements, 
blood draws) and should not be obtained within 3 hours after any meal, if possible.  
Circumstances that may induce changes in heart rate, including environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG 
resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  The following will be transmitted to a central ECG vendor:  heart 
rate, RR interval, QRS interval, PR duration, uncorrected QT interval, and QTcF based 
on the machine readings of the individual ECG tracings.  Clinically significant
waveform changes or other ECG abnormalities must be documented as an adverse 
event on the Adverse Event eCRF.  An ECG finding must be reported as an adverse 
event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all ECG findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated ECG finding should be 
classified as an adverse event. If a clinically significant finding is a sign of a disease or 
syndrome, only the diagnosis should be recorded on the Adverse Event eCRF. 
If considered appropriate by the Sponsor, ECGs may be analyzed retrospectively at a
central laboratory.
If at a particular postdose timepoint the mean QTcF is 500 ms and/or 60 ms 
longer than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 


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successive ECGs.  The Medical Monitor should be notified.  Standard-of-care treatment 
may be instituted per the discretion of the investigator.  If a PK sample is not scheduled 
for that timepoint, an unscheduled PK sample should be obtained.  A decision on study 
drug discontinuation should be made.  The investigator should also evaluate the patient 
for potential concurrent risk factors (e.g., electrolyte abnormalities, co-medications 
known to prolong the QT interval, severe bradycardia).
4.5.11
Samples for Whole Genome Sequencing
At participating sites, blood samples will be collected for DNA extraction to enable whole 
genome sequencing (WGS) to identify germline mutations and/or somatic mutations that 
are predictive of response to study drug, are associated with progression to a more 
severe disease state, are associated with acquired resistance to study drug, are 
associated with susceptibility to developing adverse events, or can increase the
knowledge and understanding of disease biology.  The blood samples may be sent to 
one or more laboratories for analysis.
Collection and submission of WGS samples is contingent upon the review and approval 
of the exploratory research 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 WGS sampling, this section of the protocol (Section 4.5.11) 
will not be applicable at that site.
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches.  Data will be analyzed in the context of this study but will also be explored 
in aggregate with data from other studies.  The availability of a larger dataset will assist 
in identification of important pathways, guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
Blood samples collected for WGS are to be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
Patient medical information associated with WGS 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.
Given the complexity and exploratory nature of the WGS analyses, data derived from 
these analyses will generally not be provided to study investigators or patients unless 


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required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
4.5.12
Samples for Research Biosample Repository
4.5.12.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used 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, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or 
disease progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.12.2
Approval by the Institutional Review Board or 
Ethics Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's IRB/EC and, if applicable, an appropriate regulatory body.  
If a site has not been granted approval for RBR sampling, this section of the protocol 
(Section 4.5.12) will not be applicable at that site.


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4.5.12.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to efmarodocokin alfa or 
diseases:

Leftover serum, plasma, stool, and colonic biopsy tissue samples and any 
derivatives thereof (e.g., DNA, RNA, proteins, peptides), including leftover tissue 
samples from medically indicated procedures (e.g., esophagogastroduodenoscopy, 
colonoscopy) performed at the investigator's discretion during the course of the 
study
The above samples may be sent to one or more laboratories for analysis of germline or
somatic mutations via whole genome sequencing (WGS), whole exome sequencing 
(WES), next-generation sequencing (NGS), or other genomic analysis methods.
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome,
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches.  Data will be analyzed in the 
context of this study but will also be explored in aggregate with data from other studies.  
The availability of a larger dataset will assist in identification of important pathways, 
guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.12.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR 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.
Given the complexity and exploratory nature of the analyses of RBR specimens, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.


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Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.12.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.5.12.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
consent at any time for any reason. After withdrawal of consent, any remaining 
samples will be destroyed or will no longer be linked to the patient. However, if RBR 
specimens have been tested prior to withdrawal of consent, results from those tests will 
remain as part of the overall research data.  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 through use of the appropriate RBR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RBR Research 
Sample Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent 
to the testing of his or her RBR sample after closure of the site, the investigator must 
inform the Sponsor by emailing the study number and patient number to the following 
email address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from Study GA39925 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from Study GA39925.


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4.5.12.7
Monitoring and Oversight
RBR 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.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  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 RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study drug if they experience any of the following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues to receive study drug

Investigator or Sponsor determines it is in the best interest of the patient

Pregnancy

Drug-related anaphylaxis or other severe (Grade 3 or 4) drug-related 
hypersensitivity reaction

Unresectable colonic mucosal dysplasia

High-grade colonic mucosal dysplasia or colon cancer

Requirement for rescue therapy outside defined limits of the protocol 
(see Section 4.4.1)

Malignancy or cervical Pap test with CIN of Grade 1,AIS, or HSILs

De novo or reactivated serious viral infection, such as hepatitis B virus, hepatitis C 
virus, HIV, disseminated varicella zoster virus, or disseminated herpes simplex virus, 
should discontinue study medication.  For other serious or severe infections, see 
Section 5.1.3.3 and Table 4

Severe liver injury as defined by Hy’s Law (see Section 5.3.5.7)

Grade 4 thromboembolism or deep vein thrombosis
The primary reason for study drug discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study drug prematurely will not be replaced.  
Patients who discontinue study drug prematurely for the reasons listed above will be 
asked to return to the clinic for an early termination visit within 1 week of the event and 
will undergo assessments at 4 and 8 weeks after their last dose of study drug
(safety follow-up period; see Section 3.1.4 and Appendix 1 for additional details).  


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Patients who receive rescue therapy or do not meet the criteria for clinical response 
during Part A will discontinue study drug but may be eligible to receive treatment in 
OLE Study GA40209 (see Section 3.1.2).
Patients who receive rescue therapy, experience disease flare (see Section 3.1.1), or 
cannot tolerate corticosteroid tapering during Part B will discontinue study drug but may 
be eligible to receive treatment in OLE Study GA40209 (see Section 3.1.3).
Patients who experience disease flare or receive rescue therapy and discontinue study 
drug should return to the clinic for a disease evaluation visit no later than 1 week after 
initiation of rescue therapy (see Appendix 1 for additional details).
Patients who discontinue study drug without entering OLE Study GA40209 will undergo 
assessments at 4 and 8 weeks after their last dose of study drug (safety follow-up 
period).  Patients who are unwilling to complete the safety follow-up period should return 
to the clinic for an early termination visit as soon as possible and no later than 30 days 
after the final dose (see Appendix 1 for additional details).
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Patient non-compliance, specifically defined as missing scheduled visits or 
non-adherence with concomitant medications for UC
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.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study or stop enrollment at any time.  
Reasons for terminating the study or stopping enrollment may include, but are not 
limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  


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4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the ICH E6 guideline for Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Efmarodocokin alfa is not approved, and clinical development is ongoing.  The safety 
plan for patients in this study is based on clinical experience with efmarodocokin alfa in 
completed and ongoing studies.  The anticipated important safety risks for 
efmarodocokin alfa are outlined below.  Please refer to the Efmarodocokin Alfa
Investigator's Brochure for a complete summary of safety information.
Vedolizumab is an approved biologic therapy for patients with moderate to severe UC.  
The important safety risks for vedolizumab are available in the vedolizumab prescribing 
information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for clinically 
significant adverse events.  Patients will undergo safety monitoring during the study, 
including assessment of the nature, frequency, and severity of adverse events.  
In addition, guidelines for managing adverse events, including criteria for treatment 
interruption or discontinuation, are provided below.
5.1.1
Risks Associated with Efmarodocokin Alfa
The general risks associated with biologic agents and the potential or hypothetical risks 
of efmarodocokin alfa are based on available clinical and nonclinical data.  Risks are 
summarized below and are described in detail in the Efmarodocokin Alfa Investigator's 
Brochure.
5.1.1.1
Dermatologic Reactions
Results from Study GA29468, a Phase Ia single-dose study in HVs, showed that IV 
efmarodocokin alfa induced reversible skin changes, including dry lips and skin, patchy 
erythema, scaling skin (primarily on the face and upper body), and skin discomfort.  
At doses of up to 90 g/kg, the MTD for HVs in Study GA29468, most dermatologic
manifestations were mild (Grade 1) and sometimes moderate (Grade 2).  These 
cutaneous adverse events were manageable with topical emollients that provided 


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symptomatic relief when needed and were fully reversible (i.e., resolving within 
approximately 2 weeks of onset).
In the Phase Ib multiple-dose study (GA29469) in HVs and patients with UC, skin 
changes similar in nature and duration to those occurring in Study GA29468 have been 
observed at tolerated dose levels. Dermatologic manifestations at tolerated dose levels 
(e.g., dry, erythematous, scaling skin and skin discomfort) have been reversible and 
managed with topical emollients.  In two HVs, a dose level of 90 g/kg Q2W induced 
protocol-defined dermatologic dose-limiting adverse events that occurred after the 
second dose of blinded efmarodocokin alfa or placebo. The dermatologic manifestations 
included severe (Grade 3) skin discomfort and severe (Grade 3) dry skin; topical 
emollients and topical corticosteroids provided minimal relief. The adverse events were 
fully reversible.  For additional details, refer to the Efmarodocokin Alfa Investigator’s 
Brochure.
Patients with a history of psoriasis and other inflammatory skin disorders requiring oral 
corticosteroids, immunosuppressants, or biologic therapy within the past year will be 
excluded from the study.
Guidelines for management of patients who develop dermatologic reactions are provided 
in Section 5.1.3.3.
5.1.1.2
Infusion-Related Reactions
With the introduction of a foreign biological molecule such as efmarodocokin alfa, there 
is a potential risk of infusion-related reactions.  Infusion-related reactions may include 
both acute allergic/hypersensitivity (e.g., anaphylactic) reactions and acute 
pseudoallergic/hypersensitivity-like (e.g., anaphylactoid) reactions. Anaphylactic and 
anaphylactoid reactions are the more severe forms of allergic and pseudoallergic 
reactions, respectively. However, in the Phase Ia single-dose study and the Phase Ib 
multiple-dose study, no anaphylactic or anaphylactoid reactions were observed. 
Patients with a history of moderate or severe allergic, anaphylactic, or anaphylactoid 
reactions to chimeric, human, or humanized antibodies, fusion proteins, or murine 
proteins or hypersensitivity to efmarodocokin alfa or any of the excipients (sucrose, 
methionine, sodium phosphate, or polysorbate 20) are not eligible for this study.  
Anaphylaxis and hypersensitivity reactions will be closely monitored.
Guidelines for management of patients who develop infusion-related reactions are 
provided in Section 5.1.3.3.
5.1.1.3
Epithelial Tumor Promotion
IL-22 has been reported to promote epithelial tumor progression, including squamous 
cell and basal cell carcinoma (Nardinocchi et. al. 2015) and colorectal cancer 
(Kryczek et. al. 2014; Kirchberger et al. 2013).  There has been no evidence of epithelial 


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tumor promotion in the Phase Ia study, the Phase Ib study, or nonclinical studies to date.  
Nevertheless, given the a priori elevated risk of malignancy in this patient population,
and the potential for epithelial tumor promotion with IL-22 in tumor cells that may 
express the IL22 receptor (refer to the Efmarodocokin Alfa Investigator’s Brochure), the 
trial includes selection criteria and additional safety monitoring to minimize any 
hypothetical risk.
Patients with a history of cancer within the past 5 years are to be excluded from the 
study.  In addition, patients with a history of non-melanoma skin cancer or GI and/or 
colon cancer, or a known family history of GI and/or colon cancer (defined as one 
first-degree relative or two second-degree relatives) will be excluded.  Patients must 
have documentation of colon cancer surveillance within 1 year prior to randomization. 
Patients who have evidence of unresectable colonic mucosal dysplasia or high-grade 
colonic mucosal dysplasia will be excluded from the study.  Furthermore, patients are 
excluded who have a history of CIN of Grade 1, cervical smear indicating the presence 
of AIS, or HSIL. 
Guidelines for management of patients who develop epithelial tumor promotion are 
provided in Section 5.1.3.3.
5.1.1.4
Neutralization of Endogenous IL-22 by ADAs
Though not seen in nonclinical and human studies to date, there is a possibility that 
efmarodocokin alfa may induce ADAs that neutralize endogenous IL-22 and thus be 
associated with an increased risk for opportunistic infections (including bacterial and 
fungal infections).  ADAs may also reduce the therapeutic effect of efmarodocokin alfa.  
In addition, because IL-22 is involved in stimulating epithelial barrier repair, ADAs that
neutralize endogenous IL-22 could impair epithelial barrier repair in the GI epithelium.  
These potential effects could be long-lasting if neutralizing ADAs are persistent.  
Any patient who is found to test positive for ADAs to efmarodocokin alfa, including ADAs 
that may neutralize endogenous IL22, should be followed, when possible, every 
2 months for up to 6 months after the last dose of study drug, or until ADA titers are 
below the assay-cut point level, whichever occurs first.
Guidelines for management of patients who develop infections are provided in 
Section 5.1.3.3.
5.1.1.5
Worsening Of Clotting/Coagulation Dysfunction In High 
Risk Populations Due To Increased Fibrinogen
Fibrinogen increases along with CRP are consistent with acute phase protein response, 
and are considered on-target effects of IL-22 signaling. A meta-analysis of clinical 
studies reported associations between plasma fibrinogen levels and the risks of coronary 
heart disease, stroke, other vascular mortality, and nonvascular mortality.  However,
whether the high fibrinogen levels are causal or are an effect of inflammation is not 


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established (FSC 2005). In mice, infusion of fibrinogen was shown to induce a state of 
hyperfibrinogenemia, which was then associated with an increased risk of coagulation 
dysfunction and thrombosis (Machlus et al. 2011) but the translatability to humans 
remains uncertain (Ariens 2011; Klovaite et al. 2011).
Dose dependent increases in fibrinogen have been observed following efmarodocokin alfa 
treatment in the nonclinical studies with cynomolgus monkeys and in the Phase I 
studies (GA29468 and GA29469) which included HVs, patients with UC, and patients 
with CD.  These increases in fibrinogen were considered on-target effects of IL-22 
signaling, with peak mean cohort values within 2-fold of baseline.  The fibrinogen 
increases were not accompanied by changes in other clotting parameters measured 
(prothrombin time, activated partial thromboplastin time, and internal normalized 
ratio), or by clinical signs or adverse events of clotting/coagulation abnormalities.  As 
of the data cutoff of 05 February 2021 in the ongoing blinded Phase II Study GA39925, 
there has been 1 serious adverse event of deep venous thrombosis in 1 patient (out of 
161 patients enrolled) that was considered unrelated to the study drug/placebo by the 
investigator.  In a preliminary data analysis from the Phase II Study GA42969 in 
patients with severe COVID-19 pneumonia, the number of thrombotic or embolic 
adverse events were comparable between efmarodocokin alfa, comparator, and placebo 
arms.
Relative to the healthy population, a higher incidence of coagulation dysfunction and 
thromboembolic phenomena is reported in patients with IBD (Danese et al. 2007; 
Grainge et al. 2010). It is unclear but possible that a fibrinogen increase observed with 
efmarodocokin alfa treatment may contribute to worsening the risk of 
clotting/coagulation dysfunction in high-risk populations. To minimize the risk of 
clotting/coagulation dysfunction, investigators are advised to closely monitor patients 
for signs and symptoms suggestive of thromboembolism or deep vein thrombosis. If any 
Grade 2 or 3 thromboembolism or deep vein thrombosis occur, efmarodocokin alfa 
should be withheld until the event resolves to Grade 1 or lower. Efmarodocokin alfa 
should be permanently discontinued in any patient who develops a Grade 4 
thromboembolism or deep vein thrombosis. Grade 2 or higher thromboembolism or deep 
vein thrombosis should be reported to the Sponsor in an expedited manner as an adverse 
event of special interest (see Section 5.2.3).  Based on current data and literature, it is 
not believed that excluding patients with other risk factors such as use of oral 
contraceptives is justified. The association between fibrinogen and coagulation/clotting 
dysfunction is correlative, and it is important to assess if these risk factors, which are 
common in the general population, pose an enhanced risk in a controlled clinical trial 
setting.
Guidelines for management of patients who develop Grade ≥2 thromboembolism or deep 
vein thrombosis are provided in Section 5.1.3.3.


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5.1.2
Risks Associated with Vedolizumab
Investigators should be aware of the risks associated with vedolizumab and guidelines 
for managing those risks (see vedolizumab prescribing information).
5.1.3
Management of Patients Who Experience Specific Adverse 
Events
Guidelines for the monitoring and management of patients who experience specific
adverse events are provided in Table 4.
5.1.3.1
Dose Modifications
The dose of efmarodocokin alfa or vedolizumab should not be modified when managing 
individual patients who experience adverse events.
5.1.3.2
Treatment Interruption
Study treatment may be temporarily suspended in patients who experience a 
treatment-emergent adverse event considered to be related to study drug.  If the event 
resolves to Grade 2 or better, treatment will resume at the next scheduled dose.  If more 
than one scheduled dose will be missed because of an on-going adverse event, the 
patient should be permanently discontinued from treatment, unless resumption of 
treatment is determined following investigator discussion with the Medical Monitor.  
Study treatment may be suspended for reasons other than a treatment-emergent 
adverse event (e.g., surgical procedures) after discussion with the Medical Monitor.  The 
investigator and the Medical Monitor will determine the acceptable length of treatment 
interruption.
5.1.3.3
Management Guidelines
Dermatologic Reactions 
Investigators should remain vigilant for dermatologic signs or symptoms at scheduled 
study visits. Symptomatic relief of dermatologic manifestations can include topical 
emollients for mild to moderate skin effects and topical corticosteroids and/or oral 
antihistamines for more severe skin effects.  Inability to achieve symptomatic relief may 
require local dermatologic assessment for further evaluation, including recommended 
biopsy and management.
Guidelines for the management of patients who develop dermatologic reactions are 
provided in Table 4.
Infusion-Related Reactions 
All infusions will be administered in the clinic to enable monitoring for possible 
infusion-related reactions.  Patients must be monitored for approximately 30 minutes 
after each study drug infusion. Medicinal products for the treatment of severe reactions 
(e.g., epinephrine, antihistamines, and glucocorticoids) must be available for immediate 
use in the clinic. Resuscitation equipment should also be available. 


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Infusion-related reactions may include both acute allergic/hypersensitivity
(e.g., anaphylactic) reactions and acute pseudoallergic/hypersensitivity-like
(e.g., anaphylactoid) reactions. These may have similar clinical manifestations, but they 
have different mechanisms (e.g., only allergic reactions are IgE mediated) and risks of 
re-challenge. Differentiating allergic reactions from pseudoallergic reactions is important 
because it may impact the understanding of the risk profile of the drug. In instances 
where the reaction occurs with the first infusion of the study drug without any suspicion 
of prior sensitization, it is less likely to be an allergic reaction. When a new reaction is 
seen with the second or subsequent infusions, or if there is an atypical presentation 
(e.g., rapid onset within 15 minutes or increase in severity when compared with previous 
reactions), there is a higher likelihood that the reaction is allergic. Investigators should 
report infusion-related reactions using the most appropriate term, based on their medical 
judgment. The investigator should also discuss with the Medical Monitor the possibility 
of obtaining additional supportive data, if available, to inform the diagnosis of allergic 
versus pseudoallergic reaction (e.g., serum histamine, serial tryptase measurements).
Patients should be instructed to recognize the symptoms of a severe allergic 
(e.g., anaphylactic) or pseudoallergic (e.g., anaphylactoid) reaction and to contact a 
healthcare provider 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 these 
instructions.
Guidelines for the management of patients who develop infusion-related reactions are 
provided in Table 4.
Epithelial Tumors
Investigators should remain vigilant for signs or symptoms of cancer in scheduled study 
visits.  Any signs or symptoms that could be suggestive of malignancy should be 
promptly and aggressively evaluated and reported to the Sponsor.  If a patient develops
malignancy or high-grade colonic dysplasia during the study, study drug must be 
discontinued permanently. In cases of newly diagnosed malignancy or epithelial high 
grade dysplasia, unstained slides and/or representative tissue blocks may be requested 
by the Sponsor for further evaluation and characterization.
Guidelines for the management of patients who develop epithelial tumors are provided 
in Table 4.
Serious Infections
To assess for the potential development of an immune response, including neutralizing 
ADAs against endogenous IL-22, antibody samples will be obtained at baseline, at 
regular intervals during treatment, and during the safety follow-up period
(see Appendix 1) and stored appropriately for further evaluation as needed.
Guidelines for the management of patients who develop infections are provided 


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in Table 4.
Hepatic Events
If treatment-emergent ALT or AST elevations are observed, ALT, AST, alkaline 
phosphatase, and total bilirubin tests (i.e. liver function tests [LFT]) should be repeated 
within 4872 hours to confirm the abnormality and to determine whether transaminases 
are increasing or decreasing.
For re-testing done locally or at a central laboratory facility, normal laboratory ranges 
should be recorded, results should be made available to trial investigators immediately, 
and the data should be included in the eCRF.
If treatment-emergent ALT or AST elevations are confirmed, other laboratory tests 
should be performed to rule out acute viral hepatitis (i.e., hepatitis A, B, C, D, or E), 
autoimmune hepatitis (i.e., antinuclear antibody, anti-smooth muscle antibody, 
anti-mitochondrial antibody, or antiLKM-1 antibody), or functional hepatic impairment 
(i.e., INR or fractionated bilirubin).  Further LFT monitoring to ensure patient safety 
should be performed on the basis of clinical judgement and local practice.  Imaging tests 
and hepatology consultation should be considered.  In addition, a more detailed history 
of the event should be obtained, including symptoms, prior or current diseases, 
concomitant drug use (including nonprescription medications and herbal and dietary 
supplements), alcohol use, recreational drug use, and special diets.
Guidelines for the management of patients who develop treatment-emergent ALT or 
AST elevations are provided in Table 4.  For patients with suspected or confirmed 
severe liver injury as defined by Hy’s Law, refer to Section 5.3.5.7.
Thromboembolism or Deep Vein Thrombosis
Investigators should remain vigilant for signs and symptoms suggestive of 
thromboembolism or deep vein thrombosis in scheduled study visits. Any signs or 
symptoms that could be suggestive of thromboembolism or deep vein thrombosis should 
be promptly and aggressively evaluated and reported in an expedited manner to the 
Sponsor (see Section 5.2.3). Guidelines for the management of patients who develop 
Grade ≥2 thromboembolism or deep vein thrombosis are provided in Table 4.


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Table 4
Guidelines for Management of Patients Who Experience Specific 
Adverse Events
Event
Action to Be Taken
Dermatologic adverse event
Grade 1 or 2
Continue study drug.
Treat with topical emollients.
Grade 3 
Withhold study drug.
Treat with topical emollients and with topical corticosteroids 
and/or oral antihistamines.
If no symptomatic relief, refer patient to dermatologist for 
further assessment and treatment.
If treatment with oral immunosuppressants is required, 
discontinue study drug.
If event resolves to Grade 2 or better with topical treatment,
resume study drug at the next scheduled dose.  If more than 
one scheduled dose will be missed because of an on-going 
adverse event, permanently discontinue study drug.
Grade 4
Permanently discontinue study drug.
Refer patient to dermatologist for assessment and treatment.
Infusion-related reactions 
Grade 1 or 2
Reduce infusion rate to50% of original infusion rate.
Interrupt infusion if symptoms persist.
Provide supportive treatment if indicated.
If infusion was interrupted, resume infusion at 50% of original 
infusion rate upon symptom resolution.
If infusion reaction reoccurs, discuss with Medical Monitor
before premedicating with acetaminophen or 
diphenhydramine at subsequent infusions.
Grade 3 and 4 
Stop infusion immediately and administer supportive 
treatment as per local or institutional standard operating 
procedures (see Appendix 9 for guidance on anaphylaxis).
Permanently discontinue study drug.
Discuss with the Medical Monitor the possibility of obtaining 
additional supportive data, if available, to inform the 
diagnosis of allergic versus pseudoallergic reaction (e.g., 
serum histamine, serial tryptase measurements).
ADAanti-drug antibody; AESIadverse event of special interest; IRRinfusion-related reaction; 
LFTliver function test; PKpharmacokinetic; ULNupper limit of normal.


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Table 4
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Infection
Grade 1 or 2
Continue study drug.
Grade 3
Withhold study drug.
Collect PK and ADA sample if not collected at study visit, 
and treat according to local standards.
If the infection is clearly not study-drug related (i.e., there is a 
clear alternative explanation for the infection), the infection 
and symptoms are fully resolved at least 1 week prior to the 
next scheduled dose, and any treatment for the infection has 
been completed at least 1 week prior to the next scheduled 
dose, consult the Medical Monitor to determine if study drug 
can be resumed.  If these conditions are not met or the 
Medical Monitor indicates that study drug should not be 
resumed, permanently discontinue study drug.
Grade 4
Permanently discontinue study drug.
Collect PK and ADA sample if not collected at study visit, 
and treat according to local standards.
Suspected or confirmed COVID-19 infection
Grades 13
Withhold study drug
If the infection and symptoms are fully resolved at least 
1 week prior to the next scheduled dose, and any treatment 
for the infection has been completed at least 1 week prior to 
the next scheduled dose, consult the Medical Monitor to 
determine if study drug can be resumed. If these conditions 
are not met or the Medical Monitor indicates that study drug 
should not be resumed, permanently discontinue study drug.
Grade 4
Permanently discontinue study drug.
Epithelial tumor
New malignancy, unresectable 
colonic mucosal dysplasia, or any 
high-grade colonic mucosal 
dysplasia
Permanently discontinue study drug.
New cervical intraepithelial 
neoplasia of Grade 1, cervical 
smear indicating the presence of 
adenocarcinoma in situ, or 
high-grade squamous 
intraepithelial lesion
Permanently discontinue study drug.
ADAanti-drug antibody; AESIadverse event of special interest; IRRinfusion-related reaction; 
LFTliver function test; PKpharmacokinetic; ULNupper limit of normal.


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Table 4
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Hepatic event
ALT or AST 3ULN
to 5 ULN 
Continue study drug. 
Repeat LFTs within 48-72 hours. 
If LFT results confirmed, test for alternative cause(s) as 
described in Section 5.1.3.3.
ALT or AST 5ULN
to 8 ULN
Withhold study drug.
Repeat LFTs within 48-72 hours. 
If LFTs confirmed, test for alternative cause(s) as described 
in Section 5.1.3.3.
Monitor LFTs weekly until AST and ALT 5ULN.  
If event resolves to AST or ALT 5x ULN within 2 weeks 
after event onset, resume study drug.  If not, monitor as 
described in the next category.
Any one of the following:

ALT or AST elevation
8ULN

ALT or AST 5ULN for 
more than 2 weeks

ALT or AST 3ULN
and total bilirubin 2 ULN 
or INR 1.5

ALT or AST 3ULN with 
the appearance of fatigue, 
nausea, vomiting, right 
upper quadrant pain or 
tenderness, fever, rash, 
and/or eosinophilia (> 5%), 
or jaundice
Withhold study drug.
Repeat LFTs within 48-72 hours. 
If LFTs confirmed, test for alternative cause(s) as described 
in Section 5.1.3.3. 
Monitor LFTs two to three times per week until decreasing or 
stabilized, then monitor LFTs weekly until AST and ALT are
5ULN and total bilirubin is 2 ULN.
Discontinuation of study drug should be considered.  
However, if event resolves to AST and ALT 5ULN with 
total bilirubin 2 ULN, study drug may be resumed after 
consultation with the Medical Monitor.  If a decision is made 
to permanently discontinue study drug, offer medical 
management per local standard of care and follow for safety.
Thromboembolism or deep vein 
thrombosis
Grade 1
Continue study drug and monitor closely for worsening of 
symptoms.
Grade 2 or 3
Treat as per local standard of care. Withhold study drug 
until the event resolves to a Grade 1 or lower
Report event to Sponsor in an expedited manner as an AESI 
(Section 5.2.3)
Grade 4 
Permanently discontinue study drug
Notify Medical Monitor and offer medical management per 
local standard of care, and follow for safety.
Report event to Sponsor in an expedited manner as an AESI 
(Section 5.2.3) 
ADAanti-drug antibody; AESIadverse event of special interest; IRRinfusion-related reaction; 
LFTliver function test; PKpharmacokinetic; ULNupper limit of normal.


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Table 4
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Efmarodocokin alfa- and vedolizumab-related adverse events not described above
Grade 1 or 2
Continue study drug.
Grade 3
Withhold study drug.
If event resolves to Grade 2 or better, resume study drug at 
the next scheduled dose.  If more than one scheduled dose 
will be missed because of an on-going adverse event, 
permanently discontinue study drug.
Grade 4
Permanently discontinue study drug, offer medical 
management per local standard of care, and follow for 
safety.
ADAanti-drug antibody; AESIadverse event of special interest; IRRinfusion-related reaction; 
LFTliver function test; PKpharmacokinetic; ULNupper limit of normal.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH E6 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 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.10
and 5.3.5.11 for more information)

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:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.12)

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)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to study drug

Is a 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]; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).


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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 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

New or worsening neurologic signs and symptoms that are consistent with a 
diagnosis of PML

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7)

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.

Any adverse event leading to discontinuation of study drug

Suspected or confirmed COVID-19 infection

Grade ≥2 thromboembolism or deep vein thrombosis
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.  The 
clinician who assesses adverse events should not be the same clinician who assesses
UC efficacy outcomes (e.g., PROs and endoscopic evaluation).
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.


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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 biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 8 weeks after the 
last dose of study drug.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints. Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity. Table 5 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 5
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.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration
(see also Table 5):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of 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 
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Table 6
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria 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).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse 
Event eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis
(e.g., "infusion-related reaction" or "anaphylactic reaction") on the Adverse Event eCRF.  
If possible, avoid ambiguous terms such as "systemic reaction."  Associated signs and 
symptoms should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a 
patient experiences both a local and systemic reaction to the same dose of study drug, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs 
and symptoms also recorded separately on the dedicated Infusion-Related 
Reaction eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
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 


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based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
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 GI 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.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious" 
to "serious," providing the date that the event became serious, and completing all data 
fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.


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5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5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 whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.


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If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal ECG Findings
Not every ECG abnormality qualifies as an adverse event. An ECG finding must be 
reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment
It is the investigator’s responsibility to review all ECG findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated ECG abnormality should 
be classified as an adverse event.
If a clinically significant ECG abnormality is a sign of a disease or syndrome (e.g., high 
blood pressure), only the diagnosis should be recorded on the Adverse Event eCRF.
Observations of the same clinically significant ECG abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (See Section 5.3.5.4 for details 
on recording persistent adverse events). 
5.3.5.8
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
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 an adverse event of special interest 
(see Section 5.4.2).


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5.3.5.9
Deaths
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of UC.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed to progression of UC, "ulcerative colitis progression" should be 
recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.10
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. Medical conditions (serious or non-serious) that occur after screening 
but before study drug administration and are not due to a protocol-mandated intervention 
should not be recorded as adverse events but should be recorded on the General 
Medical History and Baseline Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.11
Lack of Efficacy or Worsening of Ulcerative Colitis
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on the MCS, which includes endoscopic disease evaluation.  
In rare cases, the determination of clinical progression will be based on symptomatic 
deterioration.  However, every effort should be made to document progression through 
use of objective criteria.  If there is any uncertainty as to whether an event is due to 
disease progression, it should be reported as an adverse event.


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5.3.5.12
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient 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.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Planned hospitalization required by the protocol (e.g., for study drug administration,
insertion of access device for study drug administration, or procedure required by 
the study)

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 experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed through use of PRO data.  Sites are not expected to 
review the PRO data for adverse events.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)


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
Accidental overdoses or medication errors (see Section 5.4.4 for details on reporting 
requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Pharmaceutical Product Development (PPD) Medical Monitor contact information:
Telephone Number
(24-Hour Safety Hotline)
Fax Number
North America
+1 888 483 7729
+1 888 529 3580
North America (Alternate)
+1 800 201 8725
+1 888 488 9697
EMEA/Asia Pacific
+44 1223 374 240
+44 1223 374 102
Alternate Medical Monitor contact information for all sites:
Medical Monitor:
, M.D., Ph.D
Telephone Nos.:
Mobile:
Office:  


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5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), by faxing the form using the fax number provided below:
Region
Fax Number
North America
+1 888 529 3580
EMEA/Asia Pacific
+44 1223 374 102
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 8 weeks after the last dose of study drug.  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 Safety 
Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), by faxing the form using the fax number 
provided in Section 5.4.2.1.  Once the EDC system is available, all information will need 
to be entered and submitted via the EDC system.  
Instructions for reporting serious adverse events that occur 8 weeks after the last dose 
of study drug are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during the 
study or within 18 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), by 
faxing the form using the fax number provided in Section 5.4.2.1.  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 


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effects on the fetus.  Monitoring of the patient should continue until conclusion of the 
pregnancy.  Any serious adverse events associated with the pregnancy (e.g., an event in 
the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF.  In 
addition, the investigator will submit a paper Clinical Trial Pregnancy Reporting Form 
when updated information on the course and outcome of the pregnancy becomes 
available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
18 weeks after the last dose of study drug.  The investigator should report the 
pregnancy on the paper Clinical Trial Pregnancy Reporting Form and submit the form to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), by faxing the form using the fax number provided in Section 5.4.2.1.  
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 with additional information on the pregnant partner and the 
course and outcome of the pregnancy as it becomes available.  An investigator who is 
contacted by the male patient or his pregnant partner may provide information on the 
risks of the pregnancy and the possible effects on the fetus, to support an informed
decision in cooperation with the treating physician and/or obstetrician.
5.4.3.3
Congenital Anomalies/Birth Defects and Abortions
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2).  
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).  
If a therapeutic or elective abortion was performed because of an underlying maternal 
or embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.


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All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.4
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  All special situations associated with efmarodocokin alfa, regardless of whether 
they result in an adverse event, should be recorded on the Adverse Event eCRF and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event).  Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.


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For efmarodocokin alfa and vedolizumab, each adverse event associated with a special 
situation should be recorded separately on the Adverse Event eCRF.  If the associated 
adverse event fulfills seriousness criteria or qualifies as an adverse event of special 
interest, the event should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.4.2).  For efmarodocokin alfa, 
adverse events associated with special situations should be recorded as described 
below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source 
data verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.


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5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
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 (defined as 
8 weeks after the last dose of study drug), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, by faxing the paper Clinical Trial 
Serious Adverse Event/Adverse Event of Special Interest Reporting Form using the 
email/fax numbers provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through the use of the reference safety 
information in the documents listed below: 
Drug
Document
Efmarodocokin alfa
Efmarodocokin Alfa Investigator's Brochure
Vedolizumab
Summary of Product Characteristics
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.
Currently there are no expected serious adverse drug reactions for efmarodocokin alfa
described in the Efmarodocokin Alfa Investigator’s Brochure.  Thus, any treatment-
emergent serious adverse event deemed related to efmarodocokin alfa will be reported 
as a suspected unexpected serious adverse reaction (SUSAR).  Reporting of individual 
SUSARs to investigators, IRBs, ECs, and applicable health authorities will be done in 
accordance with applicable legislation.
For the purpose of SUSAR reporting, the version of the Efmarodocokin Alfa
Investigator’s Brochure valid at the time of SUSAR occurs will apply. SUSARs will be 


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kept blinded unless required for medical safety reasons and/or country regulatory 
reasons.  Unblinding to study personnel and Genentech study team members will be 
documented.
Six-month SUSAR reports related to efmarodocokin alfa will be provided as per local 
regulatory requirements.  If a significant safety issue arises altering the benefit-risk 
profile of efmarodocokin alfa, the investigators, IRBs, ECs, and applicable health 
authorities will be informed prior to the next update of the Efmarodocokin Alfa
Investigator’s Brochure, in accordance with applicable legislation.
Certain adverse events are anticipated to occur in the study population at some 
frequency independent of study drug exposure and will be excluded from expedited 
reporting.  These anticipated events include, but are not limited to, those associated with 
the progression of UC.
The IMC will monitor the incidence of events associated with progression of UC during 
the study.  An aggregate report of any clinically relevant imbalances that do not favor the 
test product will be submitted to health authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
6.1
DETERMINATION OF SAMPLE SIZE
A target of approximately 270 patients will be enrolled and randomly assigned in a 
1:1:1:1:1:1:2:1 ratio to Arms 1A, 1B, 2A, 2B, 3A, 3B, 4, and 5.  The A and B arms for 
each efmarodocokin alfa dose will be pooled (i.e., 1A1B; 2A2B; 3A3B) for analyses 
of endpoints at or before Week 8.  Thus, the primary efficacy analysis of clinical 
remission at Week 8 will compare data for pooled Arm 1 (1A1B), pooled Arm 2 
(2A2B), and pooled Arm 3 (3A3B), versus Arm 4 and versus Arm 5.  The sample 
size of 60 patients per pooled efmarodocokin alfa arm provides approximately 
80% power to detect an improvement of 16 percentage points over the vedolizumab arm 
(Arm 4; n60) and approximately 80% power to detect an improvement of 26 
percentage points over the placebo arm (Arm 5; n30) in the proportion of patients with 
clinical remission at Week 8, assuming a clinical remission rate of approximately 
15%20% in a vedolizumab-treated population and approximately 5%10% in a 
placebo-treated population with both populations consisting of 25% TNF-naive patients 
and 75% TNF-IR patients (derived from data presented by Feagan et al. 2013) and a 
two-sided type I error rate of 0.2.
6.2
SUMMARIES OF CONDUCT OF STUDY
The numbers of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study withdrawal will be listed and summarized.  
Enrollment and major protocol deviations will be listed and evaluated for their potential 
effects on the interpretation of study results.


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6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, and self-reported 
race/ethnicity) will be summarized through use of means, standard deviations, medians, 
and ranges for continuous variables and proportions for categorical variables, as 
appropriate.  Summaries will be presented overall and by treatment arm.
6.4
EFFICACY ANALYSES
The efficacy analysis population will consist of all randomized patients who received at 
least one dose of study drug and have at least one postbaseline efficacy measurement, 
with patients grouped according to their treatment assigned at randomization.  Unless 
otherwise noted, analyses of efficacy endpoints will be stratified by the stratification 
factor used at randomization (i.e., prior treatment with TNF inhibitors [yes/no]). 
Patients who are non-evaluable for a response- or remission-type efficacy endpoint at a 
specific timepoint (e.g., due to missing data or early discontinuation from study) will be 
considered non-responders for that endpoint. 
Because the study is hypothesis-generating in nature, no adjustment for multiplicity will 
be performed.  Hypothesis testing will be carried out in an exploratory fashion, at a 
two-sided 0.20 significance level. Sensitivity analyses, through use of last observation 
carried forward, baseline observation carried forward, or worst observation carried 
forward may be performed.  A separate Data Analysis Plan will contain more details on 
the statistical analyses.
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is clinical remission at Week 8 (see definition of clinical 
remission in Section 2, Table 1).  The primary analysis will be conducted by first 
comparing the efmarodocokin alfa arms versus the placebo arm. A comparison between 
the efmarodocokin alfa arms and the vedolizumab arm will be carried out secondarily.
The difference between pooled Arm 1, pooled Arm 2, and pooled Arm 3, versus Arm 4
and versus Arm 5 in the proportion of patients with clinical remission at Week 8 will be 
evaluated by the Mantel-Haenszel test statistic, stratified by prior treatment with TNF 
inhibitors (yes/no). Additional stratification variables may be used if appropriate (e.g., if 
a large number of very small strata are not generated), such as concomitant treatment 
with corticosteroids (yes/no) or prior treatment with immunomodulators (AZA, 6-MP, or 
MTX) (yes/no). An 80% two-sided confidence interval of the differences in the 
proportion of patients with clinical remission at Week 8 will be provided to aid in the 
interpretation of the study results.


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6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are defined in Section 2, Table 1.  The secondary 
efficacy endpoints will be summarized by descriptive statistics based on the following 
calculations:

Proportion of patients with sustained remission (clinical remission at both Week 8 
and Week 30)

Proportion of patients with clinical response at Week 8 and Week 30 (separate 
proportion calculated for each timepoint)

Proportion of patients with endoscopic healing at Week 8 and Week 30 (separate 
proportion calculated for each timepoint)

Proportion of patients with endoscopic remission at Week 8 and Week 30 (separate 
proportion calculated for each timepoint)

Average change from baseline in UC bowel movement signs and symptoms at 
Week 8 and at Week 30, as assessed by UC-PRO/SS score (separate average 
calculated for each timepoint)

Average change from baseline in UC abdominal symptoms at Week 8 and at 
Week 30, as assessed by UC-PRO/SS score (separate average calculated for 
each timepoint)

Average change from baseline in patient-reported health-related QOL at Week 8
and at Week 30, as assessed by the IBDQ score (separate average calculated for 
each timepoint)
Data will be summarized for pooled Arms 1, 2, and 3, for Arm 4, and for Arm 5 if the 
endpoint is at or before Week 8. Data will be summarized separately for all arms if the 
endpoint is after Week 8.
6.4.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are defined in Section 2, Table 1.  The exploratory 
efficacy endpoints will be summarized by descriptive statistics based on the following 
calculations:

Proportion of patients with mucosal healing at Week 8 and Week 30 (separate 
proportion calculated for each timepoint)

Average change from baseline in UC endoscopic index severity at Week 8 and at 
Week 30 (separate average calculated for each timepoint)

Proportion of patients with histological healing, defined as Nancy score of 0 or 1 as 
per Nancy Histological Index, at Week 8 and Week 30 (separate proportion 
calculated for each timepoint)

Average change from baseline in Geboes Score at Week 8 and at Week 30 
(separate average calculated for each timepoint).

Average change from baseline in Robarts Histological Index at Week 8 and at 
Week 30 (separate average calculated for each timepoint)


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Data will be summarized for pooled Arms 1, 2, and 3, for Arm 4, and for Arm 5 if the 
endpoint is at or before Week 8.  Data will be summarized separately for all arms if the 
endpoint is after Week 8.
6.5
SAFETY ANALYSES
The safety analysis population will consist of all randomized patients who received at 
least one dose of study drug, with patients grouped according to treatment received.
Safety will be assessed by recording adverse events and conducting clinical laboratory 
evaluations.  
Separate summaries of adverse events will be provided for the screening period, the 
8-week induction treatment period (Part A), and the 22-week maintenance period
(Part B).  Adverse events will be summarized by treatment arm.  
Clinical laboratory data will also be summarized by treatment arm through use of 
appropriate descriptive statistics.
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities thesaurus terms, and adverse event severity will be graded according to 
NCI CTCAE v4.0.
6.6
PHARMACOKINETIC ANALYSES
The efmarodocokin alfa PK analysis population will consist of patients who received at 
least one dose of efmarodocokin alfa and have at least one postdose blood draw to 
determine serum concentration of efmarodocokin alfa.
The following PK parameters will be measured and reported:

Maximum serum concentration after the first dose (Cmax,wk0) during Part A

Maximum serum concentration after the last dose (Cmax,wk8) during Part A

Predose concentration at Weeks 4, and 8 (Cwk4, Cwk8) during Part A

Trough (predose) concentration at Weeks 14 and 22(Cwk14, Cwk22) during Part B

Serum concentration at Week 26 (Cwk26) during safety follow-up
Individual and mean serum efmarodocokin alfa concentration-versus-time data will be 
tabulated and plotted by arm.  The PK parameters will be tabulated and summarized 
(mean, standard deviation, coefficient of variation, median, and range). Additional PK 
analyses will be conducted as appropriate. 
Exploratory vedolizumab PK analyses may also be performed.


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6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients with at least one
postdose ADA assessment.  Patients will be grouped according to treatment received or, 
if no treatment is received prior to study discontinuation, according to treatment assigned.
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (postbaseline incidence) 
will be summarized by treatment arm.  When determining postbaseline incidence, 
patients are considered to be ADA positive if they are ADA negative or have missing 
data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more postbaseline samples is at least 0.60 titer unit greater than the titer of the 
baseline sample (treatment-enhanced ADA response).  Patients are considered to be 
ADA negative if they are ADA negative or have missing data at baseline and all 
postbaseline samples are negative, or if they are ADA positive at baseline but do not 
have any postbaseline samples with a titer that is at least 0.60 titer unit greater than the 
titer of the baseline sample (treatment unaffected).
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported via descriptive statistics.
6.8
BIOMARKER ANALYSES
The PD biomarker analyses will include all patients with one pre-treatment and at least 
one post-treatment biomarker assessment, with patients grouped according to the 
treatment actually received.  PD biomarker analyses will include examination of changes 
from baseline (pre-treatment) in biomarkers over time.  PD biomarkers will be assessed 
as an absolute increase over time, and/or as a percent change relative to original 
baseline for each patient.  In addition, efforts will be made to perform PK/PD analyses 
based on PD and PK exposure data.  Results will be summarized through use of
summary statistics and or other graphs as required. Descriptive statistics will be listed 
by dose, treatment arm, and response status.  Additional PD analyses will be conducted 
as appropriate.
Non-PD (e.g., predictive and prognostic) biomarker analyses will include all patients with 
one pre-treatment biomarker assessment, with patients grouped according to the 
treatment actually received, provided there are sufficient data in each biomarker arm to 
facilitate a meaningful analysis.  Baseline values will be used to evaluate predictive 
biomarkers in the context of activity (clinical and/or pharmacological), drug levels, safety, 
and/or immunogenicity endpoints.  Results will be summarized descriptively.


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6.9
INTERIM ANALYSES
6.9.1
Planned Interim Analysis
An interim analysis will be performed when approximately 50% of patients have 
completed Part A (through Week 8). The interim results will be evaluated on the basis of
descriptive summaries of the primary and key secondary outcomes for Part A, including 
estimated rates, between-group differences in rates, 80% CIs, and exploratory p-values 
with no type I error adjustments or formal stopping criteria.  
Results of the interim analysis may inform potential early stopping of enrollment if the 
benefit-risk profile for the efmarodocokin alfa arms is considerably unfavorable. The 
interim analysis will be conducted by the IMC (see Section 3.1.6).  Recruitment of 
patients will continue during the period of the interim analysis.  
6.9.2
Optional Interim Analyses
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct additional interim efficacy analyses.  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.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and all other 
electronic data, including endoscopy and ECG data, will be sent directly to the Sponsor, 
using the Sponsor’s standard procedures to handle and process the electronic transfer 
of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
PRO and clinician-reported outcome (ClinRO) data will be collected through the use of 
an electronic device provided by a vendor (see Section 7.3 for details).


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7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual 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 that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
ELECTRONIC PATIENT- AND CLINICIAN-REPORTED 
OUTCOME DATA
An electronic device will be used to capture PRO and, at applicable sites, ClinRO data.  
The device is designed for entry of data in a way that is attributable, secure, and 
accurate, in compliance with U.S. Food and Drug Administration (FDA) regulations for 
electronic records (21 CFR Part 11).  The data will be transmitted to a centralized 
database maintained by the electronic device vendor.
The electronic data will be available for view access only, via a secure web server.  Only 
identified and trained users may view the data, and their actions will 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.
Once the study is complete, the 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 data in a machine-readable format on a 
compact disc.
In cases of device malfunction or failure, data may be captured via paper questionnaires.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
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evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
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 on 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 and review, 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, electronic or paper PRO and ClinRO data (if applicable), 
Informed Consent Forms, laboratory test results, and medication inventory records, must 
be retained by the Principal Investigator for 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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Genentech will retain study data for 25 years after the final Clinical Study Report has 
been completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and the General Data Protection Regulation (GDPR).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing 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.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.    A 
separate, specific signature will be required to document a patient's agreement to 
participate in optional procedures.  Patients who decline to participate will not provide a 
separate signature.
After discussion of the study with the investigator, patients must be given ample time to 
review what has been discussed and have their questions answered prior to signing 
Consent Forms. Patients must be told that they are free to refuse to participate and 
may withdraw their consent at any time for any reason without penalty or loss of benefits 
to which they are otherwise entitled.  The Consent Forms must be signed and dated by 
the patient 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.


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The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient.  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 (HIPAA) of 1996.  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. 


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8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of 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 (see definition of end of 
study in Section 3.2).
8.6
PATIENT RECRUITMENT
Recruitment procedures will follow the ICH E6 guideline for Good Clinical Practice and 
are customized in accordance with local requirements and regulations.  Recruitment
strategies for this study may include, but are not necessarily limited to, recruitment from 
the investigator's local practice or referrals from other physicians. All patient recruitment 
materials must be reviewed and approved by the IRB/EC prior to study use 
(see Section 8.3).


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117/Protocol GA39925, Version 7
To ensure that patients are adequately informed and free from coercion, patient 
recruitment procedures must adhere to the following guidelines:

After discussion of the study with the investigator, patients must be given ample 
time to review what has been discussed and have their questions answered prior to 
signing Consent Forms (see Section 8.2)

Patients must be told that they are free to refuse to participate and may withdraw 
their consent at any time for any reason without penalty or loss of benefits to which 
they are otherwise entitled (see Section 8.2)

Patients must be provided with IRB/EC-approved study educational material and a 
copy of each signed Consent Form (see Section 8.2)

Patients with the potential of exposure to any coercion will be excluded from the 
study (see Section 4.1.2)
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 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.


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118/Protocol GA39925, Version 7
9.4
ADMINISTRATIVE STRUCTURE
This study is sponsored by Genentech.  A contract research organization will be 
contracted to manage the study and perform monitoring activities.  Centralized facilities 
(vendors) will perform endoscopy reading and interpretation; however, the investigator or 
a designee will also read the endoscopy as part of the MCS and mMCS evaluation.  In 
addition, a central vendor will collect ECG data.
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests), as specified in Section 4.5.  Accredited local 
laboratories will be used for routine monitoring; local laboratory ranges will be collected.  
A selected group of assessments will be performed on site or by a local laboratory and 
urine pregnancy tests will be conducted by the patient at home if appropriate.
The eCRF data will be recorded via a Sponsor-designated EDC system.  An IxRS will be 
used for study treatment inventory management and to randomly assign patients to 
study treatment.
An IMC will be employed to monitor and evaluate patient safety throughout the study.
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, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request. For more information, refer to the Roche Global Policy on Sharing of Clinical
Trials Data at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 


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119/Protocol GA39925, Version 7
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1
Schedule of Activities
Assessment or 
Procedure
Screening
28 to 1 a
Study Week (3 days)
DE/ET 
Visit e
UV
Visit f
Part A
Part B
Safety 
Follow-Up
0 b
(D 1)
1
(D 8)
2
(D 15)
4
(D 29)
6
(D 43)
8
(D 57)
11 c
(D 78)
14
(D 99)
18 c
(D 127)
22
(D 155)
4 wks d
26
(D 183)
8 wks d
30
(D 211)
Informed consent
x
Review eligibility 
criteria
x
x
Demographic data
x
Medical history and 
baseline conditions
x
Concomitant 
medications
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events g
x
x
x
x
x
x
x
x
x
x
x
x
x
IBDQ
x
x
x
x
x
x
UC-PRO/SS h
x
x
x
x
x
Vital signs i
x
x
x
x
x
x
x
x
x
x
x
x
x
Height
x
Weight
x
x
x
x
x
x
x
x
Physical
examination j
x
x
x
x
x
ECG k
x
x
x
x
Hematology l and 
chemistry m
x
x
x
x
x
x
x
x
x


Appendix 1
Schedule of Activities (cont.)
Efmarodocokin Alfa—Genentech, Inc.
125/Protocol GA39925, Version 7
Assessment or 
Procedure
Screening
28 to 1 a
Study Week (3 days)
DE/ET 
Visit e
UV
Visit f
Part A
Part B
Safety 
Follow-Up
0 b
(D 1)
1
(D 8)
2
(D 15)
4
(D 29)
6
(D 43)
8
(D 57)
11 c
(D 78)
14
(D 99)
18 c
(D 127)
22
(D 155)
4 wks d
26
(D 183)
8 wks d
30
(D 211)
Lipase, coagulation, n
and lipids (fasting) o
x n
x o
x o
x o
x n
CRP p
x
x
x
x
x
x
x
x
x
x
HbA1c
q
x
x
x
Pregnancy test r
x
x
x
x
x
x
x
x
x
x
x
Urinalysis s
x
x
x
x
x
Urine drug screening t
x
Viral serology
x u
TB testing (may 
include chest X-ray) v
x
PK w and/or ADA w, x
(serum)
See Appendix 2.
Biomarkers (plasma 
and/or serum) p
See Appendix 2.
WGS (blood) y
x
Stool sample z
x
x
x
x y
x
x
x
x
Endoscopy aa with 
biopsy bb 
x y
x cc
x dd
x


Appendix 1
Schedule of Activities (cont.)
Efmarodocokin Alfa—Genentech, Inc.
126/Protocol GA39925, Version 7
Assessment or 
Procedure
Screening
28 to 1 a
Study Week (3 days)
DE/ET 
Visit e
UV
Visit f
Part A
Part B
Safety 
Follow-Up
0 b
(D 1)
1
(D 8)
2
(D 15)
4
(D 29)
6
(D 43)
8
(D 57)
11 c
(D 78)
14
(D 99)
18 c
(D 127)
22
(D 155)
4 wks d
26
(D 183)
8 wks d
30
(D 211)
Stool frequency and 
rectal bleeding
x ee
MCS (pMCS plus 
endoscopy) ff
x
x
x dd
x
pMCS gg
x
x
x
x
x
x
x
x
x dd
Efmarodocokin alfa or 
efmarodocokin alfa
placebo administration
x
x
x hh
x hh
x hh
Vedolizumab or 
vedolizumab placebo 
administration
x
x
x
x
x
ADAanti-drug antibody; CMVcytomegalovirus; CRP C-reactive protein; Dday; DEdisease evaluation; eCRFelectronic Case Report Form; 
ETearly termination; HBVhepatitis B virus; HbA1cglycosylated hemoglobin; HCVhepatitis C virus; HIVhuman immunodeficiency virus; 
IBDQInflammatory Bowel Disease Questionnaire; IMC Internal Monitoring Committee; MCSMayo Clinic Score; OLEopen-label extension; 
PDpharmacodynamic; PGAPhysician’s Global Assessment; PKpharmacokinetic; pMCSpartialMayo Clinic Score; PPDpurified protein derivative; 
QFTQuantiFERON®-TB Gold test; TBtuberculosis; UCulcerative colitis; UC-PRO/SSUlcerative Colitis Patient-Reported Outcomes Signs and 
Symptoms; UVunscheduled visit; WGSwhole genome sequencing; Wksweeks.
Note: All assessments should be performed prior to study drug administration, unless otherwise stated.
a Informed consent must be documented before any study-specific screening procedure is performed.  Screening window begins after the first procedure 
is performed. Screening may be extended to accommodate an unanticipated delay in CMV results. Local safety laboratory results (i.e., chemistry, 
hematology, urinalysis, urine pregnancy [for women of childbearing potential only]) would have to be reconfirmed prior to randomization.
b Day 1 of Week 0.


Appendix 1
Schedule of Activities (cont.)
Efmarodocokin Alfa—Genentech, Inc.
127/Protocol GA39925, Version 7
c Weeks 11 and 18 visits (1 week) for women of childbearing potential only.
d Patients who complete the treatment period (Parts A and B) and patients who discontinue study drug without entering OLE Study GA40209 will undergo 
assessments at 4 and 8 weeks after their last dose of study drug.
e A disease evaluation visit is required if a patient receives rescue therapy or experiences persistent or worsening disease for which rescue therapy is 
indicated, as determined by the investigator.  A disease evaluation visit should occur no later than 1 week after initiation of rescue therapy.  All indicated 
assessments are required for a disease evaluation visit, with the exception of the UC-PRO/SS, which is not required if it has not been completed for 9 
consecutive days prior to visit.  Patients who discontinue study drug prematurely for the reasons listed in Section 4.6.1 should return to the clinic for an 
early termination visit within 1 week of the event and will then enter the safety follow-up period.  Patients who are unwilling to complete the safety follow-
up period should return to the clinic for an early termination visit no later than 30 days after their final dose.  All indicated assessments should be 
completed for an early termination visit.
f
An unscheduled visit represents a visit that is not specified by the protocol but is determined to be necessary by the investigator or Sponsor (e.g., for 
evaluation of an adverse event).  The indicated assessments are required for an unscheduled visit. Other assessments are optional for an unscheduled 
visit, per investigator discretion.  
g After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention 
should be reported.  After initiation of study drug, all adverse events will be reported until 8 weeks after the last dose of study drug.  After this period, the 
Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior study drug treatment 
(see Section 5.6).  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.
h Patients are to complete the UC-PRO/SS on the 9 consecutive days preceding the clinic visit.
i
Vital signs include measurements of respiratory rate, pulse rate, systolic blood pressure, diastolic blood pressure, and temperature.  Patient should be in 
a seated position after at least 10 minutes of rest prior to measuring vital signs. 
j
A complete physical examination is required at screening and includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF.  A limited, symptom-driven physical examination, including an abdominal examination, is 
required at all other indicated timepoints.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
k Patient must be resting in a supine position for at least 10 minutes prior to ECG assessment. The Day 1 ECG can be taken anytime from Day 28 to 
Day 1 prior to study drug administration.
l
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, and other cells).


Appendix 1
Schedule of Activities (cont.)
Efmarodocokin Alfa—Genentech, Inc.
128/Protocol GA39925, Version 7
m Serum chemistry includes sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total 
and direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, and LDH.
n Coagulation includes INR, aPTT, PT, and fibrinogen.  Site and Sponsor personnel, with the exception of the IMC, will be blinded to fibrinogen test 
results.
o Lipid panel includes cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides.  Patients must be fasting (no food or fluids other than water will be 
allowed for approximately 8 hours prior to the visit and until after sample collection).
p Site and Sponsor personnel, with the exception of the IMC, will be blinded to CRP and exploratory biomarker REG3A test results.
q Test for HbA1c will be performed only for patients with known diabetes.
r
All women of childbearing potential will have a serum pregnancy test at screening.  Urine pregnancy tests will be performed monthly and at specified 
subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
s Urinalysis includes specific gravity, pH, blood, qualitative protein, ketones, glucose, bilirubin, nitrite, leukocyte esterase, color, and appearance.  If 
urinalysis is abnormal, the same urine sample will be sent to the laboratory for microscopic analysis (sediment, WBCs, RBCs, casts, crystals, epithelial 
cells, and bacteria), culture, and sensitivity.
t
Patients with a history of drug abuse will undergo urine drug screening.
u At screening, patients will be tested for HIV, HBsAg, total HBcAb, and HCV antibody.  If a patient has a negative HBsAg test and a positive total HBcAb 
test at screening, an HBV DNA test must be performed.  If a patient has a positive HCV antibody test at screening, an HCV RNA test must be performed.
v Patients must have a negative TB test during screening or within 3 months prior to screening.  TB testing will consist of the QFT, if available, or the PPD 
test.  A chest X-ray will be performed to rule out TB for patients with a positive or indeterminant QFT and patients with no history of BCG vaccination who 
have a positive PPD skin test (see Section 4.1.2 for details on TB testing).
w PK and ADA samples should be collected in patients with signs and symptoms of serious opportunistic infections, if not already scheduled to be 
collected at that timepoint. See Appendix 2 for additional details.
x ADA samples may be used to assess PK if needed.  ADA samples should be collected in patients with signs and symptoms of infusion-related reactions, 
if not scheduled to be collected at that timepoint.  See Appendix 2 for additional details.
y Collect blood sample for WGS after all other predose samples are taken.  Not applicable for a site that has not been granted approval for WGS.
z Stool samples scheduled for Weeks 8 and 30 should be obtained prior to bowel preparation for sigmoidoscopy. Samples will be analyzed for culture and 
sensitivity, ova and parasites, and C. difficile at screening.  Samples collected at screening and subsequent timepoints will be used for exploratory 
biomarker research.


Appendix 1
Schedule of Activities (cont.)
Efmarodocokin Alfa—Genentech, Inc.
129/Protocol GA39925, Version 7
aa All patients will undergo a flexible sigmoidoscopy at screening, with the exception of patients without documentation of colon cancer surveillance within 1 
year prior to randomization.  Such patients will undergo a colonoscopy in lieu of a flexible sigmoidoscopy at screening. Stool frequency and rectal 
bleeding scores from the three most recent e-diary entries and the screening endoscopy will be used as efficacy baseline and for inclusion. The
screening endoscopy should not be performed without adequate symptoms (see Section 4.5.7.2). A flexible sigmoidoscopy will be performed for all 
other scheduled endoscopies.  Video recordings should be taken of the entire endoscopic procedure (colonoscopy or flexible sigmoidoscopy), starting 
from with insertion into the bowel.  Biopsies should be performed upon withdrawal of the endoscope from the bowel.  Technical instructions for video 
recording and biopsy collection will be provided in the laboratory manual.
bb Tissue collected at screening will be analyzed for CMV, as determined by histologic examination or immunohistochemistry per local standards, and will 
undergo histopathologic examination for patients without a prior histopathology report.  Tissue collected at screening and subsequent timepoints will be 
used for exploratory biomarker research.  For patients who undergo a screening colonoscopy, multiple random mucosal tissue samples will be evaluated 
for dysplasia.
cc Not performed for patients who have undergone a flexible sigmoidoscopy as part of a disease evaluation visit.
dd Full MCS (i.e., pMCS plus endoscopy) to be performed only if patient has completed Parts A and B and 8-week safety follow-up, otherwise, pMCS 
should be performed.
ee At screening, the investigator will document the patient’s normal number of stools, defined as the number of stools passed when a patient is in remission 
(i.e., not in flare).  Patients are to record stool frequency and rectal bleeding (MCS and pMCS components) in the e-diary daily throughout the study, 
beginning with the first screening visit.  However, e-diary entries on days of bowel preparation and endoscopy will not be used to calculate stool 
frequency scores, and rectal bleeding scores will be derived from e-diary entries prior to endoscopy. Stool frequency and rectal bleeding scores from the 
three most recent e-diary entries and the screening endoscopy will be used as efficacy baseline and for inclusion (see Section 4.5.7.2).
ff MCS is a composite of four assessments, each having a scoring range of 03:  stool frequency, rectal bleeding, endoscopy, and PGA.
gg pMCS is a composite of three assessments from the MCS, each having a scoring range of 03:  stool frequency, rectal bleeding, and PGA.
hh Study drug should not be administered if determination is made at visit that patient will enroll in OLE Study GA40209.


Efmarodocokin Alfa—Genentech, Inc.
130/Protocol GA39925, Version 7
Appendix 2
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Blood Samples
Visit
(3 days)
Timepoint
Sample Type
Screening
(Day 28 to Day –1)
NA
Biomarker (serum) including sample for 
diagnostic biomarkers a
Biomarker (plasma)
Week 0
(Day 1)
Prior to the first infusion
PK (serum)
Biomarker (serum) including sample for 
diagnostic biomarkers a
Biomarker (plasma) including sample for 
4-hydroxycholesterol and cholesterol a
ADA (serum)
30 minutes (5 minutes) 
after the end of the first 
infusion
PK (serum)
Week 1
(Day 8)
NA
PK (serum)
Biomarker (serum)
Biomarker (plasma) for 
4-hydroxycholesterol and cholesterol 
only a
Week 2
(Day 15)
Prior to the first infusion
PK (serum)
Biomarker (serum)
ADA (serum)
Week 4
(Day 29)
Prior to the first infusion
PK (serum)
Biomarker (serum)
Biomarker (plasma)
ADA (serum)
Week 8
(Day 57)
Prior to the first infusion
PK (serum)
Biomarker (serum)
Biomarker (plasma) including sample for 
4-hydroxycholesterol and cholesterol a
ADA (serum)
30 minutes (5 minutes) 
after the end of the 
efmarodocokin alfa
infusion
PK (serum)
Week 14
(Day 99)
Prior to the first infusion
PK (serum)
Biomarker (serum)
Biomarker (plasma) including sample for 
4-hydroxycholesterol and cholesterol a
ADA (serum) 


Appendix 2
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Blood Samples (cont.)
Efmarodocokin Alfa—Genentech, Inc.
131/Protocol GA39925, Version 7
Visit
(3 days)
Timepoint
Sample Type
Week 22
(Day 155)
Prior to the first infusion
PK (serum)
Biomarker (serum)
Biomarker (plasma) including sample for 
4-hydroxycholesterol and cholesterol a
ADA (serum)
30 minutes (5 minutes) 
after the end of the 
efmarodocokin alfa
infusion
PK (serum)
Week 26
Safety follow-up
4 weeks
(Day 183)
NA
PK (serum) 
Biomarker (plasma) including sample for 
4-hydroxycholesterol and cholesterol a
Week 30
Safety follow-up
8 weeks
(Day 211)
NA
Biomarker (serum)
Biomarker (plasma) including sample for 
4-hydroxycholesterol and cholesterol a
ADA (serum)
Unscheduled b or 
DE/ET Visit
NA
PK (serum)
Biomarker (serum)
Biomarker (plasma)
ADA (serum)
ADAanti-drug antibody; DEdisease evaluation; ETearly termination; NAnot applicable; 
PKpharmacokinetic.
Notes:  Samples may be used for exploratory research (see Section 4.5.8).  ADA samples may 
be used to assess PK if needed.  Serum ADA may be measured in PK samples if ADA samples 
have not been collected at the same timepoint. PK and ADA samples should be collected in 
patients with signs and symptoms of serious opportunistic infections, if not already scheduled to 
be collected at that timepoint.  ADA samples should be collected in patients with signs and 
symptoms of infusion-related reactions, if not scheduled to be collected at that timepoint.  Site 
and Sponsor personnel, with the exception of the IMC, will be blinded to exploratory biomarker 
REG3A test results
a See laboratory manual for specific sample handling procedures
b For unscheduled visits, PK, ADA, or biomarker samples may be collected per investigator 
discretion.


Efmarodocokin Alfa—Genentech, Inc.
132/Protocol GA39925, Version 7
Appendix 3
Mayo Clinic Score
Please respond to the following questions after reviewing the patient’s Signs and 
Symptoms of UC Daily Diary at each visit as per the schedule of activities.
1. Stool frequency 
0 = Normal
1 = 1-2 stools/day more than normal
2 = 3-4 stools/day more than normal
3 = >4 stools/day more than normal
2. Rectal bleeding
0 = None
1 = Visible blood with stool less than half the time
2 = Visible blood with stool half of the time or more
3 = Passing blood alone
3. Mucosal appearance at endoscopy
0 = Normal or inactive disease
1 = Mild disease (erythema, decreased vascular pattern)
2 = Moderate disease (marked erythema, absent vascular pattern, friability, 
erosions)
3 = Severe disease (spontaneous bleeding, ulceration)
4. Physician's Global Assessment
0 = Normal
1 = Mild
2 = Moderate
3 = Severe


Efmarodocokin Alfa—Genentech, Inc.
133/Protocol GA39925, Version 7
Appendix 4
Modified Mayo Clinic Score
Please respond to the following questions after reviewing the patient’s Signs and 
Symptoms of UC Daily Diary at each visit as per the schedule of activities.
1. Stool frequency 
0 = Normal
1 = 1-2 stools/day more than normal
2 = 3-4 stools/day more than normal
3 = >4 stools/day more than normal
2. Rectal bleeding
0 = None
1 = Visible blood with stool less than half the time
2 = Visible blood with stool half of the time or more
3 = Passing blood alone
3. Mucosal appearance at endoscopy
0 = Normal or inactive disease
1 = Mild disease (erythema, decreased vascular pattern)
2 = Moderate disease (marked erythema, absent vascular pattern, friability, 
erosions)
3 = Severe disease (spontaneous bleeding, ulceration)


Efmarodocokin Alfa—Genentech, Inc.
134/Protocol GA39925, Version 7
Appendix 5
Partial Mayo Clinic Score
Please respond to the following questions after reviewing the patient’s Signs and 
Symptoms of UC Daily Diary at each visit as per the schedule of activities.
1. Stool frequency
0 = Normal
1 = 1-2 stools/day more than normal
2 = 3-4 stools/day more than normal
3 = >4 stools/day more than normal
2. Rectal bleeding
0 = None
1 = Visible blood with stool less than half the time
2 = Visible blood with stool half of the time or more
3 = Passing blood alone
3. Physician's Global Assessment
0 = Normal
1 = Mild
2 = Moderate
3 = Severe


Efmarodocokin Alfa—Genentech, Inc.
135/Protocol GA39925, Version 7
Appendix 6
Signs and Symptoms of UC Daily Diary
Please respond to the following questions before you go to bed each evening.  
1. How many stools/bowel movements did you have today, compared to your
normal number?
0 = Normal
1 = 1-2 stools/day more than normal
2 = 3-4 stools/day more than normal
3 = >4 stools/day more than normal
2. How much rectal bleeding did you experience today?
0 = None
1 = Visible blood with stool less than half the time
2 = Visible blood with stool half of the time or more
3 = Passing blood alone


Efmarodocokin Alfa—Genentech, Inc.
136/Protocol GA39925, Version 7
Appendix 7
Ulcerative Colitis Patient-Reported Outcome Signs and 
Symptoms (UC-PRO/SS) Instrument
















Efmarodocokin Alfa—Genentech, Inc.
144/Protocol GA39925, Version 7
Appendix 8
Inflammatory Bowel Disease Questionnaire (IBDQ)






Efmarodocokin Alfa—Genentech, Inc.
147/Protocol GA39925, Version 7
Appendix 9
Anaphylaxis Precautions
These guidelines are intended as a reference and should not supersede pertinent local
or institutional standard operating procedures.
REQUIRED EQUIPMENT AND MEDICATION

Oxygen

Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance
with standard practice

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study drug infusion, the 
following procedures should be performed:
1.
Stop the study drug infusion.
2.
Maintain an adequate airway.
3.
Administer antihistamines, epinephrine, or other medications as required by patient
status and directed by the physician in charge.
4.
Continue to observe the patient and document observations.